What Every Physician Should Know About Malpractice Insurance Medical InBrief by Stuart M. Caplen, MD Depending on the employment arrangement, a malpractice insurance policy may be owned by the physician, or if the physician is an employee, the employer may be paying for the coverage. There are also hospitals that either partially or fully self-insure their employed physicians.[1] There are two main types of policies a physician can be covered by, claims-made and occurrence. A physician should be aware of the type of policy they have, and the ramifications if they change insurance carriers, jobs, locations, or retire. Claims-Made Malpractice Insurance Claims-made insurance provides malpractice coverage only for incidents that both occurred, and were reported while insured with an insurance carrier. Both the incident and the filing of the claim must happen while the policy is in effect. If a physician changes insurance carriers, leaves the state or retires, thereby terminating a claims-made policy, the insured physician is not covered for any suits filed later unless tail coverage is purchased. Tail coverage protects the physician for malpractice suits filed after the insurance was terminated for incidents that occurred during the time the physician was insured. If it is not purchased, the physician could be held personally liable for any judgements. An employed physician should inquire as to whether an employer who pays for a claims-made policy for the physician will pay for the tail coverage when employment ends. This can be expensive as tail coverage can cost from 200% to 300% of a year’s premium. This may be a significant financial issue for a physician who wants to move to a new position that results in a change of malpractice insurance carrier, or move to a different state.[1] Another option rather than buying tail coverage is buying prior acts coverage, also known as nose coverage. Nose coverage may be offered by the new insurance carrier the physician is switching to. This will cover the physician for any litigation filed after termination of the previous insurance company’s claims-made policy. Purchasing nose coverage is typically less expensive than buying tail coverage.[2] Occurrence Malpractice Insurance The other type of malpractice policy is an occurrence insurance policy which provides lifetime coverage for incidents that occurred while the policy was in effect, regardless of when the claim is filed. An occurrence policy typically has a more expensive yearly premium than a claims-made policy, but no tail coverage is required when terminating the insurance.[2] Statute of Limitations The statute of limitations to file a malpractice suit varies by state, but is typically two to three years from when the injury is discovered in adults. If a surgeon leaves a surgical sponge in a patient the statute of limitations would typically start when the error was discovered, not when the surgery was actually done.[3] In minors, the statute of limitations may be much longer than for adults, and is different from state to state. In some states the statute of limitations deadline only first starts after the minor’s 18th birthday, making exposure to pediatric malpractice suits potentially as long as two decades.[4,5] Consent-To-Settle Clause [1] A consent-to-settle clause may be part of a malpractice policy, which specifies that a claim can't be settled without the written consent of the insured physician. This may be an important aspect of the policy as the physician’s and insurance company’s interests might not always be aligned. There may also be times where a hospital’s interests and the physician’s interests may not be the same when both are being sued. Some insurance carriers may prefer to settle a malpractice suit that may not have much merit because the cost of defending it may exceed the amount of a negotiated settlement. The insurance company also may feel that the jury will be sympathetic to the patient based on the clinical outcome, and not wish to risk higher damages at a trial. However, any settlement must be reported to the National Practitioner Data Bank, which potentially can adversely affect a physician’s insurance status, ability to participate in a managed-care group, and application for hospital privileges. The consent-to-settle clause is beneficial to have in a policy, but physicians should be aware of the so-called hammer clause that may be contained in some policies accompanying a consent-to-settle clause. The hammer clause goes into effect if the physician refuses the insurer's settlement recommendation, and chooses instead to go to trial. If the trial results in a monetary award higher than the settlement recommendation, the physician must pay the amount over the settlement recommendation price. For example, If the insurer wanted to settle a claim for $250,000, and at trial damages are assessed at $600,000, the insurance company will only pay $250,000, and the physician who insisted on the trial must pay the difference of $350,000 to the plaintiff. Policy Limits [1] Most typical physician malpractice insurance policies offer coverage of $1 million/$3 million, but higher coverage amounts are also available. In a $1 million/$3 million policy, one million dollars is the maximum amount the insurance company will pay per each claim during the policy period, which is typically one year. Three million dollars is the maximum amount the company will pay for all claims during the same policy period. A physician can be held personally responsible for any payment of monetary damages in excess of the insurance policy limits. Statistics about Malpractice and Malpractice Insurance Malpractice premiums for physicians may vary with place of practice and specialty. The litigiousness of the area, state malpractice regulations, the history of local juries and judges regarding high priced verdicts, a community trend to favor plaintiffs or defendants, and the individual liability risk of the doctor’s medical specialty may all contribute to differences in malpractice premiums. In 2020, according to an American Medical Association (AMA) research paper, an internist would pay $8,274 in Los Angeles, $15,900 in New Jersey, $33,852 in Long Island, and $51,345 in Miami for a $1million/$3 million malpractice coverage policy. General surgeons would pay $41,775 in Los Angeles, $60,810 in New Jersey, $154,056 in Long Island, and $205,380 in Miami, for the same $1million/$3million coverage.[6] As can be seen, paying for tail coverage would be very expensive for a claims-made policy, especially for general surgeons from Florida. Malpractice insurance is much less expensive in Los Angles than other areas in the AMA database. Part of this may be due to California’s malpractice laws. In California, there is a maximum cap of $250,000 for non-economic damages in any successful medical malpractice suit. This includes pain and suffering, physical impairments, or a loss of the enjoyment of life or companionship.[7] Likelihood of a Physician Getting Sued for Malpractice [8] There is AMA data from 2016 that approximately 34% of all physicians have been sued for malpractice. In the over 55 years of age group, 49.2 % have been sued once and 28% sued two or more times. In doctors 55 years of age or older, grouped by specialty, 76.7% of OB/Gyns, 75.7% of general surgeons, 72.2% of emergency physicians, 67.4% of surgical subspecialists, 53.5% of radiologists, 51.4 % of family practitioners and anesthesiologists, 45.6 % of internists, 43.1% of internal medicine subspecialists, 27.9% of pediatricians and 23% of psychiatrists have been involved in malpractice litigation at least once during their career. 50.1% of general surgeons and 44.1% of OB/GYNs have been sued two or more times,. Those specialties had the two highest percentages of multiple malpractice suits in that AMA data. Malpractice Litigation Outcomes [9] In an AMA research paper reviewing data from 2006 to 2015, it was found that 68.2% of all medical professional liability claims were either withdrawn, dropped, or dismissed. 23.3% of claims were settled. 1.2% were settled by alternative dispute resolution (arbitration or previous contractual agreement). 7% of claims went to trial, of which 87.1% were won by defendant physicians, and 12.9% won by plaintiffs. The average payment was $341,015 for settlements, $1,121,815 for plaintiff verdicts and $256,596 for alternative dispute resolution. The average expense for the insurance company for defending withdrawn, dropped or dismissed claims was $30,475. The average expense to the insurance company of going to trial (not including judgments paid to the plaintiff) ranged from $191,341 to $262,141. From a financial point of view, it may be more advantageous for an insurance company to settle a claim rather than pay for the expenses of a trial. Conclusion Every physician should be aware of which type of malpractice liability insurance they have, and what options are available to them if they do get sued. While a consent-to- settle clause is beneficial to have, physicians should also determine if their policy also has a hammer clause which makes it more difficult to go against an insurance company’s decision to settle a claim. Malpractice premiums vary widely in different geographic areas, as well as by specialty. When looking to change jobs or move to another state, the expense of tail or nose coverage may need to be considered. Physicians whose employers are the payors of their claims-made malpractice policy or self-insure, should be cognizant if the employer will cover claims that are filed after they leave employment. FibonacciMD.app includes our Library, CME, Compendium, and Annotate. #InBrief Medical In Brief Author’s Note: There are hospitals and medical centers that have a formalized error communication and resolution process which can reduce the litigation and settlement costs of medical errors. If you wish to learn more about this process it is discussed at the link below in the FibonacciMD blog article, The Medical Apology, Is It a Good Idea? References [1] Malpractice Insurance: What You Need to Know. J Oncol Pract . 2007;3(5):274-277. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793838/ [2] Rekieta R. Is your tail covered? Why physicians must consider tail coverage when switching practices. Practicelink. January 11, 2021. Retrieved from: https://magazine.practicelink.com/title=Is-your-tail-covered-Why-physicians-must-consider-tail-coverage-when-switching-practices/category=Physician%20Employment%20contracts/publishedin=Spring%202018 [3] State-by-State Medical Malpractice Laws and Deadline Requirements. NOLO, 2022. Retrieved from: https://www.nolo.com/legal-encyclopedia/state-state-medical-malpractice-statute-limitations [4] WHAT IS THE STATUTE OF LIMITATIONS ON PEDIATRIC MALPRACTICE IN NEW JERSEY? Nagel Rice LLP. 2022. Retrieved from: https://nagelrice.com/medical-malpractice/statute-limitations-pediatric-malpractice-new-jersey/ [5] New York Medical Malpractice Laws & Statute of Limitations. NOLO 2022. Retrieved from: https://www.alllaw.com/articles/nolo/medical-malpractice/laws-new-york.html [6] Guardado JR. New Data Show the Highest Prevalence of Medical Liability Premium Increases in 15 Years. AMA Policy research perspectives. 2021. Retrieved from: https://www.ama-assn.org/system/files/2021-03/prp-mlm-premiums-2020.pdf [7] California Medical Malpractice Law. HG.org. 2022. https://www.hg.org/california-medical-malpractice.asp [8] Guardado JR. Medical Liability Claim Frequency Among U.S. Physicians. AMA Policy research perspectives. 2017. Retrieved from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwjTyYH0xb71AhV7rHIEHeDXCHQQFnoECBIQAQ&url=https%3A%2F%2Fwww.ama-assn.org%2Fmedia%2F21976%2Fdownload&usg=AOvVaw0VaKPZ1AF-PnUeFIiJXeV2 [9] Guardado JR. Medical Professional Liability Insurance Indemnity Payments, Expenses and Claim Disposition, 2006-2015. AMA Policy research perspectives. 2018. Retrieved from: https://www.ama-assn.org/sites/ama-assn.org/files/corp/media-browser/public/government/advocacy/policy-research-perspective-liability-insurance-claim.pdf

Bright blue popsicles and cherry-red drinks may look fun, but are synthetic food dyes safe? Explore the history, the risks, and recent regulations. Culinary Medicine by Lori A Smolin, PhD   and Mary B Grosvenor, MS, RD Bright blue popsicles, cherry-red fruit punch, and rainbow-colored cereal – color enhances the appeal of food almost as much as taste and smell. We are so used to these colorful foods that we often do not think about the fact that most of these bright colors come from synthetic dyes. More than 10% of all US food products contain at least one synthetic dye, but this may be changing. [1]  In January of 2025 the Food and Drug Administration (FDA) announced that FD&C Red No. 3 will no longer allowed in food.[2] In March, West Virginia passed legislation banning seven food dyes (including Red No. 3) from food and a California law will ban these from schools beginning in 2028.[3,4] Will these laws make our food supply safer, or just less attractive? History and Regulation of Food Dyes We have dyed our food for centuries. The Egyptians used dyes as early as 1500 BC . Ancient Romans and Greeks also colored their food to enhance its visual appeal.[5] The first dyes were made from natural plant products and minerals, for example paprika, turmeric, saffron, iron, and copper.[6] In 1856 the first synthetic dye, called mauve or aniline purple, was discovered accidently by a chemist trying to make quinine from coal.[6,7] Today most synthetic dyes are petroleum-based products, produced at a fraction of the cost of making natural dyes.[8] At the turn of the 20th concern that food dyes were introducing potentially poisonous metals such as lead, arsenic, and mercury into food, and were being used to disguise defective foods, led to federal investigation into the use of dyes.[ 6] In 1906, the Food and Drugs Act prohibited poisonous dyes and the use of any dye to conceal damaged or inferior foods. Today the FDA enforces food coloring regulations; they specify which dyes are allowed, the amounts that can be used, and the foods to which they can be added.[6] Each batch of synthetic food dye must be certified to ensure it meets purity and composition specifications before it can be used.  These “certified color additives” must be listed on product labels, for example FD&C (Food, Drugs & Cosmetics) Red No. 3 .[6] Dyes made from natural sources do not need to be certified but must still be approved for use. On food labels natural dyes can be listed specifically by name, for example beet powder, or more generally as “color,” or “color added.” Safety Concerns Claims have been made that synthetic food dyes cause serious health problems. Since the 1970s there have been concerns that they exacerbate Attention Deficit/Hyperactivity Disorder (ADHD). The current consensus is that these dyes may increase ADHD symptoms, with some children being more sensitive than others.[9,10]   Some dyes can also cause food intolerances or allergic reactions  - most often mild - but anaphylaxis has been reported.[11] Cancer is another concern. FD&C Red No. 3 or erythrosine, has been under review for its association with cancer since the 1980s when studies in rats showed that consumption of large amounts of this dye promoted the development of thyroid cancer.[12] In the 1990s, Red No. 3 was banned in cosmetics but it continued to be allowed in foods including candy, cake icings, and maraschino cherries.[13,14]  Although there is no evidence that the dye causes cancer in humans, the connection between it and cancer in animals led to its ban by the FDA.  Food manufacturers have until 2027 to reformulate their products to remove this additive.[ 2]  With the exception of Red No. 3, there is currently no conclusive evidence that synthetic food dyes cause cancer in animals or humans. However, there has been little research on this topic in the last few decades. Bottom Line Although there is little evidence that most synthetic food dyes are a health risk, there is also no reason they need to be in the food supply other than to make foods more attractive. They do not preserve food, prevent food poisoning, or make food more nutritious. Foods that include these dyes are generally highly processed foods that should be limited in our diet. By avoiding these dyes, you will most likely also reduce your consumption of ultra-processed foods. Our natural food supply is vibrant (see photo), and a variety of natural pigments are already used to color our food. For example, extracts from beets and radishes provide a red violet color. Turmeric and saffron are spices that provide a yellow color, and blueberries and grape skins are natural blue dyes. If synthetic dyes are eliminated from the food supply we may miss out on some vivid fun food colors, but we will not be doomed to totally pale cereals and treats. References [1] Newman, J, Mollica, A, Fernandez, R. How Prevalent are Dyes in Foods? We Crunched the Numbers. The Wall Street Journal., March 23, 2025. https://www.wsj.com/business/artificial-food-dyes-database-fcf34296 . [2] Center for Food Safety and Applied Nutrition. FD&C Red No. 3. FDA. Published online December 14, 2023. https://www.fda.gov/industry/color-additives/fdc-red-no-3 [3] West Virginia Office of the Governor. Governor Patrick Morrisey Signs Food Dye Legislation into Law. March 24, 2025. https://governor.wv.gov/article/governor-patrick-morrisey-signs-food-dye-legislation-law . Accessed April 12, 2025. [4] Moniuszko, S. CBS News. What Artificial Food Dye Bans Mean for Your Health and Your Fridge. March 26, 2025. https://www.cbsnews.com/news/food-dye-ban-red-health/ . Accessed April 12, 2025. [5] Fit for The Soul. The History of Food Dyes: How Colors Came to Your Plate. Published October 31, 2024. https://fitforthesoul.com/what-is-the-history-of-food-dyes/ ‌ [6] Center for Food Safety and Applied Nutrition. Color Additives in Foods. FDA. Published online July 6, 2023. https://www.fda.gov/food/color-additives-information-consumers/color-additives-foods ‌ [7] Mercal A. The Surprising History of Color Additives in Food - ID Times. id-times.com . Published December 24, 2024. https://id-times.com/cooking/the-surprising-history-of-color-additives-in-food/ ‌ [8] Rohrig B. Eating with Your Eyes: The Chemistry of Food Colorings - American Chemical Society. American Chemical Society. Published October 2015. https://www.acs.org/education/chemmatters/past-issues/2015-2016/october-2015/food-colorings.html ‌ [9] Miller, M.D., Steinmaus, C., Golub, M.S. et al. Potential impacts of synthetic food dyes on activity and attention in children: a review of the human and animal evidence. Environ Health 21, 45 (2022). https://doi.org/10.1186/s12940-022-00849-9 [10] Arnold LE, Lofthouse N, Hurt E. Artificial Food Colors and Attention-Deficit/Hyperactivity Symptoms: Conclusions to Dye for. Neurotherapeutics. 2012;9(3):599-609. doi: https://doi.org/10.1007/s13311-012-0133-x [11] Feketea G, Tsabouri S. Common food colorants and allergic reactions in children: Myth or reality? Food Chemistry. 2017;230:578-588. doi: https://doi.org/10.1016/j.foodchem.2017.03.043 [12] Hiasa Y, Ohshima M, Kitahori Y, et al. The Promoting Effects of Food Dyes, Erythrosine (Red 3) and Rose Bengal B (Red 105), on Thyroid Tumors in Partially Thyroidectomized N-Bis(2-hydroxypropyl)- nitrosamine-treated Rats. Japanese Journal of Cancer Research. 1988;79(3):314-319. doi: https://doi.org/10.1111/j.1349-7006.1988.tb01593.x [13] Hopkins A. What is food dye? | Environmental Working Group. www.ewg.org . Published March 27, 2024. https://www.ewg.org/news-insights/news/2024/03/what-food-dye [14] Center for Science in the Public Interest. Artificial colorings (synthetic food dyes). Center for Science in the Public Interest. Published November 4, 2022. https://www.cspinet.org/article/artificial-colorings-synthetic-food-dyes

There are two FDA-approved uses for tranexamic acid - to treat the symptoms of heavy menstrual bleeding (menorrhagia) and for short-term use in patients with hemophilia following tooth extraction. This article will also discuss the many other non-FDA approved, off-label uses of this drug. ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 by Stuart M. Caplen, MD Tranexamic acid (TXA) is a useful antifibrinolytic drug synthetic which is a chemical derivative of lysine. It works by blocking lysine binding sites on plasminogen molecules, inhibiting the conversion of plasminogen to plasmin. This prevents the breakdown of fibrin and stabilizes the fibrin meshwork produced in secondary hemostasis, reducing bleeding. Tranexamic acid is available both in intravenous and oral formulations. Intravenous TXA has a reported half-life of two hours. Renal clearance is the major mechanism of excretion. TXA may reduce serum D-dimer levels but does not affect results of other coagulopathy tests. Heparin does not affect the activity of TXA, which may make it useful in heparinized patients.[1] Uses of Tranexamic Acid The only two FDA-approved uses for tranexamic acid are to treat the symptoms of heavy menstrual bleeding (menorrhagia) and in patients with hemophilia, for short-term use following tooth extraction. All other uses are considered off-label. (All doses referenced are for adult patients except for post-tonsillectomy bleeding.) Post-partum Hemorrhage In the WOMAN trial, a randomized controlled trial (RCT) of over 20,000 subjects, the risk of death from bleeding in women with post-partum hemorrhage was significantly reduced with TXA when administered within 3 hours after delivery.[2] A Cochrane Database review concluded that “TXA when administered intravenously reduces mortality due to bleeding in women with primary post-partum hemorrhage, irrespective of mode of birth, and without increasing the risk of thromboembolic events.”[3] Typical post-partum hemorrhage TXA dose: 1 g of tranexamic acid intravenously as soon as possible after giving birth at a rate of 1ml/min followed by a second dose if bleeding continues after 30 minutes or restarts again within 24 hours after the first dose.[1] Abnormal Uterine Bleeding In one study of women with menorrhagia there was a significant decrease in menstrual blood loss with use of TXA versus no treatment or placebo.[4] In another study of subjects with heavy menstrual bleeding, TXA use resulted in a significant drop in blood loss.[5] A systematic review of the topic concluded that TXA was effective and safe for patients presenting with heavy menstrual bleeding and resulted in a decrease in menstrual blood loss of 34% to 54%. For intrauterine device-induced menorrhagia, short term TXA use reduced blood loss by up to 70% compared to placebo. [6] Typical menorrhagia TXA dose: 1300 mg orally 3 times daily for up to 5 days during menses.[1] Caesarian Delivery A number of studies have found decreased blood loss with the use of TXA compared to placebo during caesarian section surgery.[7,8,9,10] Typical caesarian delivery TXA dose: 1 g IV before surgery.[7,9] Trauma TXA has been tested extensively in trauma with acute blood loss. The CRASH-2 trial of over 20,000 trauma patients compared TXA with placebo and found a significant decrease in the mortality rate with TXA (4.9% died in the TXA group vs 5.7% in the placebo group). The results were time-dependent with TXA treatment between zero- and three-hours reducing mortality from traumatic injury, but treatment after three hours from injury actually increased mortality.[1,11] The CRASH-3 study included over 12,000 trauma patients with traumatic brain injury (TBI) and no other source of extracranial bleeding, who were assigned to receive either placebo or TXA within three hours of injury. They found a substantial reduction in head injury-related deaths with TXA in patients with mild and moderate head injuries but no reduction in those with severe head injury. The risk of vascular occlusive event, stroke, and seizures was similar in both groups. The Glasgow coma scale (GCS) was used to define severity of injury, with mild to moderate TBI being a GCS of 9 to15 and severe TBI being a GCS of 3 to 8. Pupillary reactivity was also used to help assess severity.[11] Another study of polytrauma patients with associated severe brain injury compared TXA to no treatment found no difference in mortality, which was a similar finding to the CRASH-3 study.[12] Typical trauma TXA dose: 1 g intravenously as a loading dose within three hours of injury, with administration of an additional 1 g for continued bleeding.[1] Vascular Complications One of the concerns with use of TXA is it will increase the incidence of deep vein thrombosis or pulmonary embolism. In the very large CRASH -2 and CRASH-3 studies, no increase in these events from the use of TXA was found.[10,11] Cardiac Surgery TXA was trialed and used during cardiac surgery to try to reduce the amount of bleeding. In a number of studies patients treated with TXA were found to have a lower risk of bleeding than placebo, without a higher risk of death or thrombotic complications.[1] However, TXA was associated with a higher risk of postoperative seizures.[1,13] A meta-analysis concluded that seizures were found to be more likely with prolonged or open chamber cardiac procedures, and using lower doses of TXA could reduce bleeding episodes with less chance of seizures.[14] However, the optimal dose needed to reduce bleeding without increasing the risk of seizures, is still not established and requires further study.[15] Typical TXA dose for cardiac surgery: Optimal dose is not established. A preoperative IV dose of 20 mg/kg or alternatively 10mg/kg followed by 1mg/kg/hour continuous IV infusion has been suggested to decrease both bleeding complications and the chance of seizures.[14,15] Non-traumatic Brain Hemorrhage A systematic review and meta-analysis of the use of TXA in non-traumatic brain hemorrhage found use of TXA reduced mortality 22% overall over placebo or standard treatment. The difference between the two groups was only significant for subarachnoid hemorrhage (SAH) and not intracerebral hemorrhage (ICH), suggesting it might be effective in SAH but not in ICH.[16] In contrast, the ULTRA study (Ultra-early tranexamic acid after subarachnoid hemorrhage) found TXA treatment did not improve SAH clinical outcomes at six months and had no effect on mortality.[17] A Cochrane database review found that antifibrinolytic treatment did not improve clinical outcomes in patients after SAH, although it did reduce the risk of rebleeding by 35%. The authors concluded that based on the current data, treatment with antifibrinolytic drugs cannot be recommended for use in subarachnoid hemorrhage from an aneurysmal origin.[19] Another meta-analysis found that use of TXA significantly reduced the amount of hematoma expansion (HE) in ICH but had no effect on 90-day mortality.[18] A third meta-analysis had a similar result, that use of TXA reduced HE but had no effect on mortality, outcomes, need for neurosurgery, rebleeding, or the duration of the hospital stay.[20] The FDA prescribing information for IV TXA specifically states that it is contraindicated in patients with subarachnoid hemorrhage due to anecdotal experience indicating that cerebral edema and cerebral infarction may be caused by the drug in such patients.[21] Hip and Knee Surgery A meta-analysis of the use of TXA in hip fracture surgery found blood loss and transfusion requirements were reduced by 46% without increasing thromboembolic events.[22,23] Another meta-analysis found a decrease in total blood loss with the use of TXA in hip fracture surgery. However, the authors felt that more robust data was needed from high-quality RCTs.[24] A systematic review and meta-analysis on the use of TXA in knee and hip arthroplasties found oral, topical, intraarticular, or combinations of them all worked to reduce transfusion requirements but the combination of IV and topical was the most effective. In patients with a higher risk of thrombosis, topical TXA alone was suggested. Topical treatment refers to TXA that was applied topically to the exposed joint surface before closure of joint capsule. There was no increase in deep vein thrombosis (DVT) rates in the TXA treated groups compared to placebo or routine care.[25] Typical TXA dose in orthopedic surgery: 10 mg/kg IV loading dose prior to skin incision, followed by a maintenance infusion of 1 mg/kg/hour.[1] Spinal Surgery There is some data that TXA can reduce blood loss in spinal surgery. A meta-analysis found it did reduce blood loss and the need for transfusion without increasing DVT risk, but larger RCTs were recommended to confirm the findings were needed. [10,26-28] Typical TXA dose in spinal surgery: 10 mg/kg IV loading dose prior to skin incision, followed by a maintenance infusion of 1 mg/kg/hour.[1] Prostate surgery A metanalysis and systematic review found that TXA administration reduced bleeding from transurethral resection of the prostate (TURP) surgery but had no effect on the level of hemoglobin post-procedure or the need for blood transfusion.[28] Another meta-analysis found that TXA did reduce blood loss both for TURPs and prostatectomies over control groups and reduced the need for blood transfusion in the prostatectomy group.[30] Typical dose of TXA in prostate surgery: Different dosing regimens used in various studies. Dental Surgery Anticoagulated patients A meta-analysis and systemic review found that TXA, as compared to placebo, reduced the risk of bleeding when used before dental procedures in anticoagulated patients.[31] Some studies have found that use of oral mouthwashes with 5% TXA in anticoagulated patients for dental surgery reduced the amount of bleeding significantly.[1,32] Guidelines from the British Committee for Standards in Haematology are 5% tranexamic acid mouthwashes used four times a day for two days for anticoagulated patients undergoing dental surgery.[32] Hemophilia Patients In one study of hemophilia patients, oral TXA compared to placebo significantly reduced blood loss and transfusion requirements after tooth extraction.[33] Another study found that administering 1 gram of TXA orally starting 2 hours before dental extraction and then three times a day for 5 days resulted in a significant decrease in bleeding compared to placebo.[34] Other guidelines recommend 1 gram of oral TXA three times a day to be started the day before the procedure and continued for a total of 7 days.[35] There are also suggested IV TXA guidelines for hemophilia patients (in addition to factor replacement therapy) before dental surgery. One manufacturer recommendation is TXA 10 mg/kg IV immediately prior to the surgery and then TXA 10 mg/kg IV 3 to 4 times daily for 2-8 days.[21] If there is continued bleeding in the extraction site, one suggested therapy in hemophilia patients, is to have the patient use a 10% TXA solution for 1 minute as a mouthwash. In hemophilia patients getting tooth extractions it is recommended that a premade splint cover the empty tooth socket. The splint is removed during this treatment and replaced right after. This may be repeated every 2-3 hours if needed.[35] Traumatic Hyphema A Cochrane review found that TXA did not affect final vision outcome but did appear to reduce the risk of secondary bleeding in traumatic hyphema.[36] Hemoptysis A meta-analysis and systemic review found that use of TXA in hemoptysis reduced short-term mortality rate and led to shorter bleeding time, lower bleeding volume, shorter length of hospital stay, and less need for intervention compared with the control.[37] Several small studies have tried endobronchial topical TXA for hemoptysis.[1] In one trial endobronchial TXA was found equivalent to epinephrine.[38] In another study, endobronchial TXA was found to be efficacious in about 40% of the patients with medical causes of hemoptysis and 100% of the patients with iatrogenic endobronchial bleeding after bronchoscopy, typically after a biopsy procedure.[39] A study comparing nebulized inhaled TXA to saline for hemoptysis found a higher resolution of hemoptysis within 5 days of admission, lower hospital length of stay and fewer patients required invasive procedures with the inhaled TXA versus placebo.[40] One systemic review and meta-analysis concluded that IV or nebulized TXA led to a shorter bleeding time, lower bleeding volume, shorter length of hospital stay, and less requirements for intervention compared with the control group. There was a significant decrease in the short-term mortality rate overall using all the trials (including observational studies), but this was not found to be a significant finding when only RCTs were used for the analysis.[41] A second systemic review and meta-analysis concluded that TXA for hemoptysis reduced bleeding volume, further need for interventions, and length of hospital stay, however, the findings were of low statistical power because of limited sample sizes.[42] Dose of TXA in hemoptysis: In one study 500mg/5ml was nebulized three times a day in adults.[39] Epistaxis A trial comparing topical TXA to nasal packing, in anterior nasal epistaxis, found the TXA group had more subjects stop bleeding in ten minutes, a faster discharge time from the ED and higher patient satisfaction than with the use of nasal packing.[43] Another trial by the same group comparing topical TXA to nasal packing in patients on antiplatelet medication found faster bleeding cessation, less rebleeding at one-week, shorter emergency department length of stay, and higher patient satisfaction compared with nasal packing.[44] However, another more recent larger trial of 496 epistaxis patients found no difference between topical TXA and placebo.[45] Although early studies looked promising for topical TXA to treat epistaxis, a larger study found no difference between TXA use and placebo, which brings into question topical TXA’s efficacy for this condition. Post-tonsillectomy Hemorrhage A retrospective study of the use of three doses of nebulized TXA in pediatric patients for the treatment of post-tonsillectomy hemorrhage found TXA compared to routine care decreased the need for an operation to restore hemostasis by 44%.[46] TXA dose: In the above study for patients between 2 and 18 years of age, 250 mg (0.25 mL) was used for those weighing less than 25 kg and 500 mg (0.5 mL) for those over 25 kg in three sequential nebulized doses delivered back-to-back. The actual dose administered was modified if needed so as not to exceed the maximum systemic dose based on age and weight of the patient. Intravenous TXA solution 1000mg/10 mL was used in the nebulizations in that study.[46] Patients with Hematologic Malignancies A limited number of studies have been performed with mixed results trialing TXA in patients with hematologic malignancies.[1] A small trial of 12 patients with acute promyelocytic leukemia found decreased red cell and platelet transfusions were needed for the TXA group compared to the placebo group during chemotherapy.[47] Another trial of three patients with amegakaryocytic thrombocytopenia receiving prophylactic TXA, each acting as their own control, found no difference in bleeding episodes or need for platelet transfusions by the use of TXA.[48] In another small study of acute myeloid leukemia patients, TXA was found to reduce platelet transfusions.[49] Von Willebrand’s disease Although evidence from RCTs is lacking, TXA is used clinically by some clinicians to try to control mucocutaneous bleeding in Von Willebrand’s disease.[1,50] Hereditary Angioedema TXA has been found to be useful for prophylaxis of hereditary angioedema with normal C1 inhibitor levels. TXA inhibits conversion of plasminogen to plasmin, a step in kallikrein activation and bradykinin formation.[1,51] TXA’s usefulness as a treatment for hereditary angioedema is less important than in the past due to the development of newer and more efficacious medications. A systematic review of the literature on the use of TXA for hereditary angioedema concluded that there was limited positive evidence for the use of TXA as an acute treatment but that it was inferior to other treatments such icatibant or pdC1INH (subcutaneous plasma‐derived human C1‐Inhibitor concentrate).[52] The evidence for the use of TXA in long-term prophylaxis for hereditary angioedema was mixed with some trials showing TXA reduced attack frequency or severity and others finding that TXA was ineffective in some patients and was less effective than C1-INH (C1 esterase inhibitor).[52] For short-term prophylaxis, TXA may be more effective than no treatment and there may be limited effectiveness of TXA in short term prophylaxis prior to dental procedures and minor surgery.[52] Angioedema from Angiotensin-converting enzyme (ACE) inhibitors. There are some case reports of TXA being used successfully for ACE inhibitor-related angioedema.[53,54,55] Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia or Osler-Weber-Rendu disease is a multisystem disorder of abnormal angiogenesis and is the second most common hereditary bleeding disorder in the world. Most patients with this disorder will develop recurrent epistaxis. Anti-angiogenics, which prevents the growth of new blood vessels, are currently used to reverse underlying vascular defects to prevent bleeding. However, some studies have found TXA to be useful for reducing epistaxis episodes.[1,56,57] Melasma Melasma is an acquired condition, seen more commonly in women, where hyperpigmentation of the skin occurs due to ultraviolet radiation sun exposure. Though not a common treatment, TXA injected into the lesions, or administered either topically or orally have been studied as treatments. A meta-analysis and systematic review found that TXA reduced the size of melasma lesions, both alone or in combination with other therapies.[1,58] Conclusions TXA is FDA-approved as a treatment for heavy menstrual bleeding and short-term prevention of bleeding in patients with hemophilia after dental extraction. Other uses are considered off-label.[10] TXA has a wide range of indications including trauma, post-partum hemorrhage, excessive uterine bleeding, dental and tonsillar surgery, hemoptysis, angioedema, orthopedic surgery, melasma and possibly epistaxis. Some of the trials were large, such as the CRASH trauma trials, while evidence for TXA use in other conditions is not as robust, coming from case reports or smaller studies. In some diseases, such as hereditary angioedema, TXA’s usefulness as a treatment is less important than in the past due to the development of newer medications. In all of the larger studies there was no increased incidence of thrombotic complications with TXA use. Seizures from TXA in cardiac surgery have resulted in the use of lower doses for that indication. Clinicians should be familiar with the indications for TXA as some of their patients may be taking it prophylactically or may be candidates for its use clinically. Author’s note: Many treatments using tranexamic acid are considered off-label. Before administering tranexamic acid, clinicians are advised to review doses with existing institutional protocols, other reference sources, or their hospital pharmacist to ensure dosage, method of administration and timing are correct. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References [1] Cai J et al. The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients. Eur J Haematol. 2020 Feb;104(2):79-87. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023891/#R3 [2] WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017 May 27;389. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446563/ [3] Shakur H et al. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2018 Feb 20;2(2). Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491317/ [4] Callender ST, Warner GT, Cope E. Treatment of menorrhagia with tranexamic acid. A double-blind trial. Br Med J. 1970 Oct 24;4(5729):214-6. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819762/pdf/brmedj02159-0046.pdf [5] Lukes AS, Moore KA, Muse KN, et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010;116(4):865–875. https://pubmed.ncbi.nlm.nih.gov/20859150/ [6] Naoulou B, Tsai MC. Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: A systematic review. Acta Obstetricia et Gynecologica Scandinavica, 91: 529-537. 2012. Retrieved from: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/j.1600-0412.2012.01361.x [7] Gungorduk K et al. Efficacy of intravenous tranexamic acid in reducing blood loss after elective cesarean section: a prospective, randomized, double-blind, placebo-controlled study. Am J Perinatol. 2011 Mar;28(3):233-40. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/20979013/ [8] Lakshmi SD, Abraham R. Role of Prophylactic Tranexamic Acid in Reducing Blood Loss during Elective Caesarean Section: A Randomized Controlled Study. J Clin Diagn Res. 2016;10(12):QC17-QC21. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296516/ [9] Sentilhes L et al. Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery. N Engl J Med 2021; 384:1623-1634. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2028788 [10] Chauncey JM, Wieters JS. Tranexamic Acid. [Updated 2022 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK532909/ [11] Roberts I et al, The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013 Mar;17(10):1-79. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780956/ [12] The CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext [12] van Wessem KJP, Jochems D, Leenen LPH. The effect of prehospital tranexamic acid on outcome in polytrauma patients with associated severe brain injury. Eur J Trauma Emerg Surg. 2022 Jun;48(3):1589-1599. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590807/ [13] Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017;376(2): 136–148. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1606424?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov [14] Zufferey PJ et al. Exposure–Response Relationship of Tranexamic Acid in Cardiac Surgery: A Model-based Meta-analysis. Anesthesiology 2021; 134:165–178. Retrieved from: https://pubs.asahq.org/anesthesiology/article/134/2/165/114744/Exposure-Response-Relationship-of-Tranexamic-Acid [15] Faraoni D, Levy JH. Optimal Tranexamic Acid Dosing Regimen in Cardiac Surgery: What Are the Missing Pieces? Anesthesiology 2021; 134:143–146. Retrieved from: https://pubs.asahq.org/anesthesiology/article/134/2/143/114753/Optimal-Tranexamic-Acid-Dosing-Regimen-in-Cardiac [16] Bouillon-Minois, JB., Croizier, C., Baker, J.S. et al. Tranexamic acid in non-traumatic intracranial bleeding: a systematic review and meta-analysis. Sci Rep 11, 15275 (2021). Retrieved from: https://www.nature.com/articles/s41598-021-94727-y#citeas [17] Post R et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. The Lancet. Volume 397, ISSUE 10269, P112-118, January 09, 2021. Retrieved from: https://www.thelancet.com/article/S0140-6736(20)32518-6/fulltext [18] Guo Y, Guo XM, Li RL, et al. Tranexamic Acid for Acute Spontaneous Intracerebral Hemorrhage: A Meta-Analysis of Randomized Controlled Trials. Front Neurol. 2021;12:761185. Published 2021 Dec 20. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720763/ [19] Baharoglu MI et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Library. 30 August 2013. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407182/ [20] Xu Jiao X et al. Early Tranexamic Acid in Intracerebral Hemorrhage: A Meta-Analysis of Randomized Controlled Trials. Front. Neurol., 06 December 2021. Retrieved from: https://www.frontiersin.org/articles/10.3389/fneur.2021.721125/full [21]CYKLOKAPRON® (tranexamic acid) injection. Prescribing information. Pfizer. 3/2021. Retrieved from: https://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=556 [22] Colomina MJ et al. Clinical use of tranexamic acid: evidences and controversies. Brazilian Journal of Anesthesiology. Retrieved from: https://bjan-sba.org/article/10.1016/j.bjane.2021.08.022/pdf/rba-0-AheadOfPrint-617ae53ba953954c5c5f4404.pdf [23]Farrow, L. S., Smith, T. O., Ashcroft, G. P., and Myint, P. K. (2016) A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol, 82: 1458– 1470. [24] Xiao C, Zhang S, Long N, Yu W, Jiang Y. Is intravenous tranexamic acid effective and safe during hip fracture surgery? An updated meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2019 Jul;139(7):893-902. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/30637503/ [25] Xu S, Chen JY, Zheng Q, et al. The safest and most efficacious route of tranexamic acid administration in total joint arthroplasty: A systematic review and network meta-analysis. Thromb Res. 2019;176:61-66. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/30776688/ [26] Yoo JS, Ahn J, Karmarkar SS, Lamoutte EH, Singh K. The use of tranexamic acid in spine surgery. Ann Transl Med. 2019 Sep;7(Suppl 5):S172. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778277/ [27] Choi HY, Hyun SJ, Kim KJ, Jahng TA, Kim HJ. Effectiveness and Safety of Tranexamic Acid in Spinal Deformity Surgery. J Korean Neurosurg Soc. 2017;60(1):75-81. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223760/ [28] Li ZJ, Fu X, Xing D, Zhang HF, Zang JC, Ma XL. Is tranexamic acid effective and safe in spinal surgery? A meta-analysis of randomized controlled trials. Eur Spine J. 2013;22(9):1950-1957. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777050/ [29] Mina SH, Garcia-Perdomo HA. Effectiveness of tranexamic acid for decreasing bleeding in prostate surgery: a systematic review and meta-analysis. Cent European J Urol. 2018;71(1):72-77. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926641/ [30] Marcelo A. Longo MA et al. Systematic review and meta-analyses of tranexamic acid use for bleeding reduction in prostate surgery. Journal of Clinical Anesthesia. Volume 48, 2018, Pages 32-38. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0952818018302150?via%3Dihub [31] Johana Alejandra Moreno JA et al. Effectiveness of local hemostatic to prevent bleeding in dental patients on anticoagulation: A systematic review and network meta-analysis. Journal of Cranio-Maxillofacial Surgery. Volume 49, Issue 7, Pages 570-583. 2021. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S1010518221001232?via%3Dihub [32] Perry, D., Noakes, T. & Helliwell, P. Guidelines for the management of patients on oral anticoagulants requiring dental surgery. Br Dent J 203, 389–393 (2007). Retrieved from: https://www.nature.com/articles/bdj.2007.892 [33] Forbes CD, Barr RD, Reid G, et al. Tranexamic acid in control of haemorrhage after dental extraction in haemophilia and Christmas disease. Br Med J. 1972;2(5809):311–313. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1788188/pdf/brmedj02202-0017.pdf [34] Forbes CD, Barr RD, Reid G, et al. Tranexamic acid in control of haemorrhage after dental extraction in haemophilia and Christmas disease. Br Med J. 1972;2(5809):311-313. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1788188/ [35] Brewer A. Dental Management of Patients with Inhibitors to Factor VIII or Factor IX. Treatment of Hemophilia monograph no 45. Montreal: World Federation of Hemophilia, 2008. Retrieved from: https://www.novomedlink.com/content/dam/medical/rarebleedingdisorders/resources/documents/guidelines-and-recommendations/WFH%20Dental%20Management.pdf [36] Gharaibeh A, Savage HI, Scherer RW, Goldberg MF, Lindsley K. Medical interventions for traumatic hyphema. Cochrane Database Syst Rev. 2013;12(12):CD005431. Published 2013 Dec 3. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268787/ [37] Chen LF, Wang TC, Lin TY, et al. Does tranexamic acid reduce risk of mortality on patients with hemoptysis?: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021;100(20):e25898. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137080/ [38] Fekri MS et al. Comparing Adrenaline with Tranexamic Acid to Control Acute Endobronchial Bleeding: A Randomized Controlled Trial. Iran J Med Sci. 2017;42(2):129-135. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366360/ [39] Márquez-Martín E, Vergara DG, Martín-Juan J, Flacón AR, Lopez-Campos JL, Rodríguez-Panadero F. Endobronchial administration of tranexamic Acid for controlling pulmonary bleeding: a pilot study. J Bronchology Interv Pulmonol. 2010 Apr;17(2):122-5. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/23168726/ [40] Wand O et l. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial. Chest. 2018 Dec;154(6):1379-1384. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/30321510/ [41] Chen, LF et al. Does tranexamic acid reduce risk of mortality on patients with hemoptysis?: A protocol for systematic review and meta-analysis. Medicine: May 21, 2021 - Volume 100 - Issue 20. Retrieved from: https://journals.lww.com/md-journal/Fulltext/2021/05210/Does_tranexamic_acid_reduce_risk_of_mortality_on.37.aspx [42] Tsai YS, Hsu LW, Wu MS, Chen KH, Kang YN. Effects of Tranexamic Acid on Hemoptysis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig. 2020;40(9):789-797. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/32661913/ [43] Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013 Sep;31(9):1389-92. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/23911102/ [44] Zahed R, Mousavi Jazayeri MH, Naderi A, Naderpour Z, Saeedi M. Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial. Acad Emerg Med. 2018 Mar;25(3):261-266. https://pubmed.ncbi.nlm.nih.gov/29125679/ [45] Reuben A et al The Use of Tranexamic Acid to Reduce the Need for Nasal Packing in Epistaxis (NoPAC): Randomized Controlled Trial. Ann Emerg Med. 2021 Jun;77(6):631-640. doi: 10.1016/j.annemergmed.2020.12.013. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/33612282/ [46] Erwin DZ, Heichel PD, Wright LM BS, Goldstein NA, McEvoy TP, Earley MA, Meyer AD. Post-tonsillectomy hemorrhage control with nebulized tranexamic acid: A retrospective cohort study. Int J Pediatr Otorhinolaryngol. 2021 Aug;147:110802. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/34146910/ [47] Avvisati G, Büller HR, Cate JT, Mandelli F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet. 1989;2(8655):122–124. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)90181-5/fulltext [48] Fricke W, Alling D, Kimball J, Griffith P, Klein H. Lack of efficacy of tranexamic acid in thrombocytopenic bleeding. Transfusion. 1991;31(4):345–348.Retrieved from: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1537-2995.1991.31491213301.x?sid=nlm%3Apubmed [49] Shpilberg O et al. A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia. Leuk Lymphoma. 1995 Sep;19(1-2):141-4. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/8574160/ [50] Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Engl J Med. 2016;375(21):2067–2080. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMra1601561 [51] Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. March 19, 2020. 382:1136-1148. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMra1808012 https://www.sciencedirect.com/science/article/abs/pii/S0735675720309232?via%3Dihub [52] Horiuchi, T, Hide, M, Yamashita, K, Ohsawa, I. The use of tranexamic acid for on-demand and prophylactic treatment of hereditary angioedema—A systematic review. J Cutan Immunol Allergy. 2018; 1: 126– 138. Retrieved from: https://onlinelibrary.wiley.com/doi/full/10.1002/cia2.12029 [53] Wang K et al. Tranexamic acid for ACE inhibitor induced angioedema. The American Journal of Emergency Medicine Volume 43, May 2021, Pages 292.e5-292.e7. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/33164754/ [54] Awsare S, Chirikian D, Rogers J: Administration of Tranexamic Acid as Treatment for Angiotensin Converting Enzyme Inhibitor-Induced Angioedema: A Case Report. Case Rep Acute Med 2021:71-75. Retrieved from: https://www.karger.com/Article/FullText/517621# [55] Judge R, Kolaski S, Qadeer F (2021) Use of Tranexamic Acid Prevents Intubation in ACE Inhibitor-Induced Angioedema. Int J Crit Care Emerg Med 7:127. Retrieved from: https://clinmedjournals.org/articles/ijccem/international-journal-of-critical-care-and-emergency-medicine-ijccem-7-127.php?jid=ijccem [56] Geisthoff UW, Seyfert UT, Kübler M, et al. Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-controlled cross-over phase IIIB study. Thromb Res. 2014;134(3):565–571. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/25005464/ [57] Zaffar N, Ravichakaravarthy T, Faughnan ME, Shehata N. The use of anti-fibrinolytic agents in patients with HHT: a retrospective survey. Ann Hematol. 2015 Jan;94(1):145-52. Epub 2014 Jul 27. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/25064693/ [58] Kim HJ et al. Efficacy and Safety of Tranexamic Acid in Melasma: A Meta-analysis and Systematic Review. Acta Derm Venereol. 2017 Jul 6;97(7):776-781. Retrieved from: https://www.medicaljournals.se/acta/content_files/files/pdf/97/7/4948.pdf Disclaimer IMIT takes pride in its work, and the information published on the IMIT Platform is believed to be accurate and reliable. The IMIT Platform is provided strictly for informational purposes, and IMIT recommends that any medical, diagnostic or treatment decisions be based on a practitioner’s knowledge, experience and multiple informational sources. The information contained on the IMIT Platform should be considered another source of information toward your decision making and should carry no additional weight relative to other information sources on similar subject matter. The information contained on the IMIT Platform is not intended to be a definitive source on any particular subject matter. For nonproviders, IMIT recommends that any medical, diagnostic, or other advice be obtained from a medical professional. Read full disclaimer.

Lyme disease, Ehrlichiosis, Anaplasmosis and Babesiosis Infectious Disease and Emergency Medicine ✅ Earn Free CME Credit for Reading This Article Eligible for 1 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 [1] (L to R) Larva, Nymph, adult male and female Ixodes scapularis ticks (AKA blacklegged or deer ticks) on a dime by Stuart M. Caplen, MD This article explores the diagnosis and treatment of four tick borne illnesses: Lyme disease, ehrlichiosis, anaplasmosis and babesiosis. Diagnosis can be challenging, as the tick bite may not have been noticed, clinical symptoms may be non-specific, and laboratory confirmation of infection can be problematic, especially early in the course of these diseases. At times clinicians may need to treat on clinical suspicion alone. Lyme Disease Although there are only about 30,000 cases of Lyme disease reported to the CDC per year, the CDC estimates the actual total is about 476,000 cases per year in the United States.[2] As can be seen on the map below, most cases of Lyme disease occur in the Mid-Atlantic states, New England and the Midwest, although there is significant distribution around the country. The geographic distribution of the three other tickborne infections under discussion can also be seen below. Tick Life Cycle and Infection Transmission Lyme disease is a tick transmitted disease, with protean manifestations, usually caused by the spirochete, Borrelia burgdorferi, although it can rarely be caused by Borrelia mayonii. Ticks go through four life stages: egg, six-legged larva, eight-legged nymph, and adult. After hatching from the eggs, ticks must eat blood to survive. Ticks can take up to 3 years to complete their full life cycle, although the Ixodes scapularis tick, also known as the blacklegged or deer tick, that typically spreads Lyme disease has a 2-year life cycle. Most nymph infections occur in the spring and summer, with adult tick caused infections typically occurring during the cooler months. Nymph ticks are much harder to detect, as they are typically less than 2 mm in size, and may be more likely to feed unnoticed, as opposed to an adult tick.[4] For Lyme disease to occur, the tick needs to be attached for a significant time, typically 36-48 hours before an infection can be transmitted.[5] The more engorged the tick the higher the likelihood of an infection being transmitted. Most tick bites do not result in Lyme disease infections. In some studies, only 2% to 3% of people bitten by ticks in endemic areas actually contract Lyme disease.[6,7] Ixodes scapularis life and feeding cycle[4] Ticks can detect an animal’s breath and sense body odors, heat, moisture, and vibrations. Ticks can’t fly or jump, but many tick species wait in a position known as “questing” on well walked paths. When questing, ticks hold onto leaves and grass by their third and fourth pair of legs and keep their first pair of legs outstretched. When a host brushes by the tick, it climbs aboard, and either attaches quickly or goes looking for places where the skin is thinner. Ticks transmit pathogens that cause disease through the process of feeding. When the tick finds a feeding spot, it grasps the skin and cuts into the surface. The tick then inserts its feeding tube, which may have barbs to help keep the tick in place. Many species also secrete a substance that keeps them firmly attached to the host during the meal. Tick saliva contains an anesthetic like substance, to prevent the host from feeling the attached tick. A tick will then suck the host’s blood slowly for several days. If the host animal has a bloodborne infection, the tick can ingest the pathogens and become infective. If the tick’s saliva contains a pathogen, it may enter the host animal during feeding causing an infection. After feeding, most ticks will drop off the host and move on to the next life stage.[4] [4] How to Remove a Tick Never crush a tick with your fingers. Use fine-tipped tweezers to grasp the tick as close to the skin’s surface as possible. Pull upward with steady, even pressure. Don’t twist or jerk the tick, as this can cause the mouth-parts to break off and remain in the skin. If this happens, remove the mouth-parts with tweezers if they are easily removable. If a significant debridement is necessary, most sources recommend leaving the mouth parts in place. After removing the tick, thoroughly clean the bite area with rubbing alcohol or soap and water. Dispose of a live tick by putting it in alcohol, placing it in a sealed bag or container, wrapping it tightly in tape, or flushing it down the toilet. Methods for tick removal that have been tried, but are not recommended include; applying a hot match or nail to the tick, covering the tick with petroleum jelly, nail polish, alcohol or gasoline, using injected or topical lidocaine, or passing a suture needle through the tick.[8,9] Tick Removal Technique[8] Should You Send the Removed Tick for Laboratory Testing? It may be helpful diagnostically to identify which tick a patient has been bitten by, either with identification by the clinician, or sending the tick to a laboratory for identification.[10,11] Testing if a tick is carrying B. burgdorferi is not recommended, for the following reasons: Positive results showing that the tick contains a disease-causing organism do not necessarily mean that it caused an infection. Negative results can lead to false assurance, as the patient may have unknowingly been bitten by another infected tick as well. Clinical symptoms will typically occur prior to the test results returning. Laboratories that conduct tick testing are not required to have the same standards of quality control used by clinical diagnostic laboratories, potentially leading to misdiagnosis.[10] Lyme Disease Testing Testing for Lyme disease is both complicated, and potentially inaccurate. Currently a 2-tier antibody assay method is the recommended testing method. This has a sensitivity of only 30%–40% during the typical 30-day window period of early infection, while the antibody response is developing. The 2-tier method does have a 70%–100% sensitivity for disseminated disease. Specificity of 2-tier testing is >95% during all stages of Lyme disease.[12] In 2-tier Lyme disease antibody testing, a screening test is done either using an enzyme immunoassay or immunofluorescence assay. If the screening test is negative another diagnosis should be considered, or the test may have been done during the 30-day antibody window period, before enough antibody has been produced to be detected, and repeat testing may be needed later on. If the screening test is positive or equivocal, immunoglobulin G(IgG) and or immunoglobulin M(IgM) western blot tests are confirmative. If symptoms are less than 30 days both IgG and IgM western blot tests are recommended, with IgM being the acute phase antibody first produced, and IgG the later phase and longer lasting antibody. Theoretically, if symptoms have been present for over 30 days only the IgG western blot is needed, but most labs routinely test for both.[14] The western blot is an immunoassay that allows visualization of Borrelia antibodies in specific bands. The IgM western blot is considered positive if two of three antibody bands measured are positive. An IgG western blot is positive if five of the ten antibody bands measured are positive. It is important to avoid interpreting fewer bands as evidence of infection because some of the antibodies tested for are cross-reactive with non-Borrelial antigens. Therefore, presence of one IgM band or less than five IgG bands does not indicate an overall positive result. Overinterpreting a small number of antibody bands leads to reduced specificity and potential misdiagnosis.[10,12] Polymerase chain reaction(PCR) testing can provide highly specific evidence of B. burgdorferi nucleic acid in synovial fluid, skin biopsy tissue, blood, and cerebral spinal fluid(CSF). However, its clinical utility is limited by low sensitivity, particularly for blood and CSF samples. Studies of PCR on blood have found that its high specificity is outweighed by its lack of clinical sensitivity and potential for contamination, and as a result, PCR testing of blood or CSF for Lyme disease is not recommended . [12] For CSF infections, obtaining simultaneous samples of CSF and serum for determination of anti-Borrelia antibodies allows for calculation of the CSF:serum antibody index. This test can differentiate between intrathecal synthesis versus passive diffusion of specific anti-Borrelia antibodies into the CSF.[10,13] Because B.burgdorferi is a slow-growing organism and current culturing methods are labor-intensive and have poor sensitivity, culture is generally not recommended. Routine hospital blood cultures will not grow B.burgdorferi.[10] It is not recommended to perform Lyme disease testing in asymptomatic patients after a tick bite, as an infection may be too early to detect, and even if delayed testing is done 4-6 weeks later there is insufficient evidence that patients with asymptomatic seropositivity should receive antibiotic therapy.[10] Symptoms of Early Lyme Disease[15] Possible symptoms of early Lyme disease include fever, chills, headache, fatigue, muscle and joint aches, and swollen lymph nodes. A small bump or redness at the site of a tick bite that occurs immediately and resembles a mosquito bite is common. This generally goes away in 1-2 days and is not a sign of Lyme disease. The erythema migrans rash occurs in approximately 70 to 80 percent of infected persons. It begins at the site of a tick bite after an average delay of 7 days but onset can range from 3 to 30 days. It typically has a bullseye appearance, but may present with central sparing or complete central involvement.[15A] Possible Signs and Symptoms of Disseminated Lyme Disease[15] Musculoskeletal/Rheumatological Intermittent pain in tendons, muscles, joints, and bones Arthritis with severe joint pain and swelling, particularly the knees and other large joints. Baker’s cyst Neurologic Bell’s palsy or other cranial neuropathies Headache, meningitis, or rarely encephalitis Motor and sensory radiculoneuropathy, mononeuritis multiplex Problems with short-term memory and cognitive problems Cardiac Lyme carditis- leading to heart block, myocarditis, or pericarditis Dermatologic Multiple erythema migrans lesions Multiple truncal erythema migrans lesions [17] Acrodermatitis chronica atrophicans A rash that can potentially be seen in chronic Lyme disease, especially on the dorsal surfaces of the hands, feet, knees, and elbows. Initially the rash is erythematous, followed by discoloration, inflammation and potentially skin atrophy. Acrodermatitis chronica atrophicans of the hand [18] Borrelial lymphocytoma Borrelial lymphocytoma is an uncommon manifestation of early disseminated Lyme disease reported only in Europe, possibly due to infection by other Borrelia strains more common there. It is a bluish-red nodular swelling that typically occurs on the ear lobe in children, or on the breast in adults. Borrelial lymphocytoma of the earlobe [19] Recommended Treatment for Lyme Disease Antibiotic Prophylaxis Prophylactic antibiotic therapy is recommended for adults and children within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal or low risk. One meta-analysis concluded that there was a 2.2% chance of getting Lyme disease in untreated patients, compared to 0.2% infection rate in the antibiotic prophylaxis group.[21] A prospective study of prophylactic antibiotics after tick bites found a 3.2% infection rate in the placebo group and a 0.4% infection rate in the antibiotic prophylaxis group.[22] A tick bite is considered to be high-risk only if it meets these three criteria: The tick bite was from an identified Ixodes vector species. The tick bite occurred in a highly endemic area The tick was attached for ≥36 hours. The duration of tick attachment is an important predictor of subsequent Lyme disease. Unfed or flat recently attached ticks do not pose a significant risk for Lyme disease. The likelihood of transmission increases with the duration of attachment and the majority of transmission occurs after 36–48 hours of attachment.[10] Nymphal Blacklegged Tick After Feeding [22] For high-risk tick bites in all age groups, a single dose of oral doxycycline within 72 hours of tick removal is recommended. Doxycycline is given as a single oral dose, 200 mg for adults and 4.4 mg/kg (up to a maximum dose of 200 mg) for children. There is no study of the efficacy of doxycycline in children under 12 years of age and the parents should understand that monitoring for symptoms and signs is important. Doxycycline is contraindicated in pregnancy, and the recommendation for tick bites during pregnancy most commonly is watchful waiting and treating if Lyme disease occurs, rather than using prophylaxis. Amoxicillin in a 10-day course might work for prophylaxis in the pregnant patient, but is not recommended because the frequency of adverse reactions is higher than the Lyme disease cases it prevents.[23] The latest Lyme disease prophylaxis during pregnancy recommendation of 3 different professional societies, which includes the Infectious Diseases Society of America is this: “Because of uncertainty about the safety of doxycycline in pregnancy, we advise pregnant women to have an informed discussion with their physicians about the risks, benefits, and uncertainties of antibiotic treatment versus observation.”[10] Please note that while amoxicillin and cefuroxime are not recommended currently for prophylaxis, due to a lack of data, they can be used for treatment of early Lyme disease. Recommended Treatment of Erythema Migrans Rash/Early Lyme Disease Doxycycline, amoxicillin, or cefuroxime are recommended as treatment for erythema migrans rash/early Lyme disease. The dosage and duration are listed in the table below. NOTE: For people intolerant of amoxicillin, doxycycline, and cefuroxime, the macrolides azithromycin, clarithromycin, or erythromycin may be used, although they have a lower efficacy. People treated with macrolides should be closely monitored to ensure that symptoms resolve. [24] Additional considerations for treating erythema migrans rash/early Lyme disease include: In the pregnant patient or woman who wants to continue breast feeding, amoxicillin would be the first drug of choice. In infants and children, amoxicillin or cefuroxime can be used to avoid the use of doxycycline.[10] If azithromycin is used, the indicated duration is 5–10 days, with a 7-day course being the most common one prescribed most commonly [10]. In patients with acrodermatitis chronica atrophicans, oral antibiotic therapy for 21–28 days is recommended.[12] In patients with borrelial lymphocytoma, oral antibiotic therapy for 14 days is recommended.[10] Coinfection should be investigated in patients who have a persistent fever while on antibiotic treatment for Lyme disease. If fever persists despite treatment with doxycycline, Babesia microti infection is an important consideration.[10] For more information on the CDC recommended antibiotic regimes for Lyme carditis/heart block, arthritis or neurologic Lyme disease, some of which may require intravenous antibiotics as initial therapy, go to this link; https://www.cdc.gov/lyme/treatment/index.html . For more information on the specific treatment of Lyme disease complications, such as heart block, go to this link; https://www.idsociety.org/practice-guideline/lyme-disease/ . Post-Treatment Lyme Disease Although most cases of Lyme disease can be cured with a 10-day to 4-week course of oral antibiotics, patients can sometimes have symptoms of pain, fatigue, or difficulty thinking that lasts for more than 6 months after they finish treatment, called Post-Treatment Lyme Disease Syndrome (PTLDS). It has been hypothesized that the syndrome is caused by an autoantibody response. There is no proven treatment for PTLDS, and studies have found that prolonged antibiotic treatment works no better than patients who received placebo. Patients with PTLDS usually get better over time, but it can take many months to feel completely well.[10,25] Ehrlichiosis Ehrlichiosis is caused by three bacteria, Ehrlichia chaffeensis, Ehrlichia ewingii, or Ehrlichia muris eauclairensis. The majority of reported cases are due to infection with E. chaffeensis. E. chaffeensis and E. ewingii are carried by the lone star tick, Amblyomma americanum, found primarily in the south-central and eastern United States. E. muris eauclairensis is carried by the blacklegged tick, Ixodes scapularis, but despite this tick’s wide distribution has only been reported in Wisconsin and Minnesota.[26] In 2018, there were 1,799 cases of E. chaffeensis reported to the CDC. The other Ehrlichia infections are much rarer, with only 218 cases of E . ewingii ehrlichiosis reported to CDC from 2008–2018, and about 115 cases of ehrlichiosis caused by E. muris eauclairensis reported since its discovery in 2009.[27] Morula inside a monocyte [15] Ehrlichia are small, gram-negative bacteria, round or ellipsoidal in shape. They preferentially invade monocytes, macrophages, and neutrophils. In all of these cell types they occupy cytoplasmic vacuoles, usually in bacterial microcolonies known as morulae.[28] Early Signs and Symptoms of Ehrlichiosis[29] Signs and symptoms of ehrlichiosis typically begin within 5 to 14 days after the bite of an infected tick. Early signs and symptoms are usually mild or moderate and may include: Fever, chills Severe headache Muscle aches Nausea, vomiting, diarrhea, loss of appetite Gastrointestinal symptoms are less common in patients with E. ewingii ehrlichiosis than with the other two species. Confusion Rash A rash develops in up to 60% of children, and less than 30% of adults, and typically begins about 5 days after symptom onset. The rash usually spares the face, but in some cases may spread to the palms of hands and soles of feet. The rash associated with E. chaffeensis infection may range from maculopapular to petechial in nature and is usually non-pruritic. Rash is infrequent in cases of E. muris eauclairensis. Late Symptoms of Ehrlichiosis[29] If treatment is delayed and the ehrlichiosis infection is allowed to continue, the disease may become severe. Severe illness may involve: Meningitis, meningoencephalitis, and other central nervous system involvement (20% of patients) Acute respiratory distress syndrome Toxic shock-like or septic shock-like syndromes Renal failure Hepatic failure Coagulopathies E.chaffeensis generally is the more serious illness, as neither E. ewingii nor E. muris eauclairensis infections have been associated with fatalities. The case fatality rate of E. chaffeensis is about 1%. Laboratory Findings in Ehrlichiosis[28] General laboratory findings in ehrlichiosis can include absolute leukopenia, thrombocytopenia, and moderately elevated hepatic transaminases. Anemia is reported in about half of patients, but generally occurs later in the course of the illness. Testing for Ehrlichiosis[29] Microscopic examination of a blood smear may reveal morulae, which are microcolonies of Ehrlichiae in the cytoplasm of white blood cells. E. chaffeensis most commonly infects monocytes while E. ewingii more commonly infects granulocytes. No specific target cell has been identified for E. muris eauclairensis. A concentrated buffy-coat smear can improve the yield of morulae evaluation compared with a standard blood smear. When positive, the diagnosis can be made relatively easily, but unfortunately blood smear examination is relatively insensitive for detecting the disease. If a bone marrow biopsy is performed as part of the investigation of cytopenias, immunostaining the bone marrow biopsy specimen to look for morulae, may help diagnose ehrlichiosis. Organ biopsies, if done for other purposes may also show evidence of morulae. Immunohistochemical stain demonstrating Ehrlichia chaffeensis morulae (red) within monocytes in the kidney [15] The indirect immunofluorescence antibody (IFA) assay for IgG, is the test most widely performed to diagnose ehrlichiosis. IgG IFA assays should be performed on paired acute and convalescent serum samples collected 2–4 weeks apart with a fourfold increase or decrease in the titers needed to be interpreted as positive. Antibody titers are frequently negative in the first week of illness. Ehrlichiosis cannot be confirmed using a single acute set of antibody results. IgM IFA assays are also offered by reference laboratories but are not necessarily indicators of acute infection, and appear to be less specific than IgG antibodies. It is therefore not recommended to use IgM antibody titers alone for diagnosis. Polymerase chain reaction (PCR) amplification can be performed from whole blood specimens. PCR is most sensitive in the first week of illness and decreases in sensitivity following the administration of appropriate antibiotics (within 48 hours). Although a positive PCR result is helpful, a negative result does not rule out the diagnosis, and treatment should not be withheld due to a negative result if ehrlichiosis is clinically suspected. PCR may also be used to amplify DNA in solid tissue and bone marrow specimens. Culture of Ehrlichia species is only available at specialized laboratories, and routine hospital blood cultures cannot detect the organism. Treatment of Ehrlichiosis [30] As opposed to Lyme disease, post-tick bite antibiotic prophylaxis is currently not recommended to prevent ehrlichiosis. Doxycycline is the treatment of choice for ehrlichiosis if the diagnosis is suspected, for patients of all ages, including children <8 years. Doxycycline is most effective at preventing severe complications from developing if started within the first week of illness. The recommended dosage for is doxycycline for adults is 100 mg every 12 hours, and for children under 45 kg (100 lbs.) the dose is 2.2 mg/kg body weight given twice a day. Dental staining in children has been a concern with doxycycline, but a study of 58 children under eight years of age with Rocky Mountain spotted fever, found no evidence of dental staining from doxycycline treatment.[31] Patients with suspected ehrlichiosis should be treated with doxycycline for at least 3 days after the fever subsides, and there is evidence of clinical improvement, typically in 5-7 days. In cases of life-threatening allergies to doxycycline, severe doxycycline intolerance, and in some pregnant patients for whom the clinical course of ehrlichiosis appears mild, physicians might consider alternate antibiotics. Rifampin appears effective against E. chaffeensis in a laboratory setting, but has not been evaluated as an alternative therapy in a clinical setting. Caution is advised when exploring treatments other than doxycycline, as other tickborne co-infections like Lyme disease or Rocky Mountain spotted fever may go intreated. An infectious disease consult is recommended when treating the pregnant patient. Anaplasmosis Anaplasmosis, also known as human granulocytic anaplasmosis, is a tickborne disease caused by the bacterium Anaplasma phagocytophilum. Blacklegged ticks, Ixodes scapularis, in the eastern United States, and western blacklegged ticks, Ixodes pacificus, on the West Coast are the main causes of infection. Coinfections with other tickborne illness such as Lyme disease have been reported. Infections have occasionally been reported through blood transfusion and organ donation.[32] Peak transmission is during June to November. Two peaks of increased case reporting usually occur, with the first peak during June–July and a smaller peak during October-November. There are about 4,000 to 5,700 cases reported per year to the CDC.[33] Signs and Symptoms of Early Illness of Anaplasmosis[34] Signs and symptoms typically begin within 5-14 days after the bite of an infected tick, and are non-specific. They may include: Fever, chills, rigors Severe headache Malaise Myalgia Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia) in about 20% of cases A non-specific rash occurs in less than 10% of patients with anaplasmosis. As rash is a rare finding in anaplasmosis, if a rash is present, consider a coinfection with Lyme disease, or another tickborne disease. Rarely: Nervous system involvement (e.g., meningoencephalitis, focal paralysis) Late Illness Symptoms of Anaplasmosis[34] If treatment is delayed severe illness can occur but is rare. Symptoms may include: Renal or respiratory failure Peripheral neuropathies Disseminated intravascular coagulation (DIC)-like coagulopathies Rhabdomyolysis Hemorrhage The clinical course of anaplasmosis varies from person to person, and may depend on patient age, co-morbid conditions, immune status and time of treatment. Laboratory Findings in Anaplasmosis[34] Laboratory findings can include mild anemia, thrombocytopenia, leukopenia and mild to moderate elevations in hepatic transaminases. However, normal laboratory findings do not rule out possible infection. Testing for Anaplasmosis[35] Laboratory testing for anaplasmosis is similar to ehrlichiosis. Indirect immunofluorescence antibody (IFA) assay for IgG using Anaplasma phagocytophilum antigen, is the standard diagnostic test for anaplasmosis. IgG IFA assays should be performed on paired acute and convalescent serum samples collected 2–4 weeks apart to demonstrate evidence of a fourfold rise. Antibody titers are frequently negative in the first week of illness. Anaplasmosis cannot be confirmed using a single acute antibody test. Between 5–10% of healthy people in some areas might have elevated antibody titers due to past exposure to A. phagocytophilum or similar organisms, which is why comparison of paired, serologic assays provides the best evidence of recent infection. Some reference laboratories offer IgM IFA assays which are not necessarily indicators of acute infection, and might be less specific than IgG antibodies. Therefore, IgM antibody titers alone should not be used for laboratory diagnosis. Polymerase chain reaction (PCR) amplification can be performed on DNA extracted from whole blood specimens. PCR is most sensitive in the first week of illness, and decreases in sensitivity following the administration of appropriate antibiotics. Unfortunately, a negative result does not rule out the diagnosis. PCR can also be used to amplify DNA in solid tissue and bone marrow specimens for testing. During the first week of illness a peripheral blood smear might reveal morulae (microcolonies of anaplasmae) in the cytoplasm of granulocytes and is highly suggestive of a diagnosis. However, blood smear examination is relatively insensitive, and should not be relied upon solely to diagnose anaplasmosis. The observance of morulae in a particular cell type cannot reliably differentiate between Anaplasma and Ehrlichia species. If a bone marrow biopsy is performed as part of the investigation of cytopenias, immunostaining of the bone marrow biopsy specimen looking for morulae can diagnose anaplasmosis. They may also be seen in organ biopsies taken for other purposes. Anaplasma phagocytophilum morela in granulocyte on blood smear [15] Immunohistochemical stain demonstrating A. phagocytophilum morulae (red) in the spleen [35] Culture of A. phagocytophilum is only available at specialized laboratories, and routine hospital blood cultures cannot detect the organism Treatment of Anaplasmosis[36] Post-tick bite antibiotic prophylaxis is not currently recommended to prevent anaplasmosis. Doxycycline is recommended as the first-line treatment for anaplasmosis in adults and children of all ages. The dosage in adults is 100 mg every 12 hours, in children under 45 kg (100 lbs.)the dose is 2.2 mg/kg body weight given twice a day. Patients with suspected anaplasmosis should be treated with doxycycline for 10–14 days to provide appropriate length of therapy for possible concurrent Lyme disease infection. Lack of a clinical response to doxycycline suggests that the patient’s condition might not be due to anaplasmosis, or might be a due to a coinfection. Resistance to doxycycline or relapses in anaplasmosis symptoms after the completion of the recommended course have not been documented. In cases of life-threatening allergies to doxycycline, severe doxycycline intolerance, and in some pregnant patients for whom the clinical course of anaplasmosis appears mild, rifampin might be considered. Rifampin has been used successfully in several pregnant women with anaplasmosis, and small numbers of children <8 years for a 7–10-day course. However, rifampin is not effective in treating Rocky mountain spotted fever, a disease that might be confused with anaplasmosis, nor is it an effective treatment for a potential Lyme disease coinfection. An infectious disease consult is recommended when treating the pregnant patient. Babesiosis Babesiosis is typically caused by a microscopic parasite Babesia microti that infects red blood cells. There are other species of Babesia that can cause infection, but B. microti is the most common. It is transmitted by bites from infected Ixodes scapularis ticks (also called blacklegged ticks or deer ticks), but occasionally can be transmitted by blood transfusion, or congenitally from mother to infant.[37] It is typically seen in the Northeast and upper Midwest. In 2018, 2,161 cases of babesiosis were reported to the CDC.[38] Babesia Life Cycle Babesia Life and Feeding Cycle [39] The Babesia microti life cycle involves two hosts, most commonly the white-footed mouse, Peromyscus leucopus, and a tick in the genus Ixodes. During a blood meal, a Babesia-infected tick introduces sporozoites into the mouse host. Sporozoites enter erythrocytes and undergo asexual reproduction (budding). In the mouse’s blood, some of the spores differentiate into male and female gametes. These gametes can be ingested by another tick, unite and form more sporozoites. The Babesia-infected tick then can introduce the sporozoites into a human host during a blood meal. The sporozoites enter erythrocytes and undergo asexual replication, (budding) which then is responsible for the clinical manifestations of the disease.[39] Symptoms of Babesiosis[40] Many people who are infected with Babesia microti feel fine, and do not have any symptoms. Others develop nonspecific flu-like symptoms, such as fever, chills, sweats, headache, body aches, loss of appetite, nausea, or fatigue. As Babesia parasites infect and destroy red blood cells, hemolytic anemia leading to jaundice may occur. Some patients may have splenomegaly, or hepatomegaly. Coinfection should be investigated in patients who have a persistent fever while on antibiotic treatment for Lyme disease. If fever persists despite treatment with doxycycline, B. microti infection is an important consideration. Laboratory Findings in Babesiosis[41] For acutely ill patients, the findings on routine laboratory testing frequently include hemolytic anemia and thrombocytopenia. Additional findings may include proteinuria, hemoglobinuria, elevated levels of liver enzymes, blood urea nitrogen, and creatinine. Testing for Babesiosis[42] Diagnosis can be made by microscopic examination of thick and thin blood smears which are Giemsa stained. Repeated smears may be needed sometimes to detect parasites. Babesia microti in Giemsa-stained blood smears [42] Antibody testing may be useful in asymptomatic patients who are donating blood, or if the diagnosis is uncertain after a blood smear is checked. The indirect fluorescent antibody test (IFA) using B. microti parasites as antigen detects antibodies in 88-96% of patients with B. microti infection . The extent of cross-reactivity between Babesia species is variable. A negative result with B. microti antigen for a patient exposed on the West Coast of the US may be a false-negative, and the patient should be specifically be tested for antibodies to Babesia duncani. PCR testing can be used to confirm the diagnosis after a positive blood smear to identify the species and also differentiate it from malarial species, such as Plasmodium falciparum, which can look similar microscopically. Treatment of Babesiosis [43] Most asymptomatic persons do not require treatment. Treatment decisions should be individualized, especially for patients who are at risk for severe disease such as asplenic or immunosuppressed individuals. For ill patients, babesiosis usually is treated for at least 7-10 days with a combination of two medications — typically either: Atovaquone PLUS azithromycin; OR Clindamycin PLUS quinine (this combination is the standard of care for severely ill patients). Recommended CDC adult dosages are listed in the table below. Atovaquone is pregnancy category C and the risk to the fetus is unknown. Because there is data about the safe administration of quinine plus clindamycin during pregnancy, this drug combination is generally recommended for treatment of symptomatic babesiosis during pregnancy. An infectious disease consult is recommended when treating a pregnant patient. Conclusion Given that diagnostic testing for these tickborne diseases is not 100% sensitive, and symptoms initially may be non-specific, a clinician in an endemic area should keep tickborne infections in mind when considering diagnoses in an ill patient without a clear cause. Unexplained fever, anemia, thrombocytopenia, leukopenia, new onset heart block, myocarditis, pericarditis, cranial nerve palsies, or arthritis can be seen as potential clues to a tickborne infection. A specific history of tick bites may be helpful, although the patient might not even know they have been bitten. Antibiotic prophylaxis for Lyme disease, when appropriate, will help reduce the incidence of symptomatic disease. While this article is just about four tickborne infections, keep in mind that ticks can transmit many different infections including: Borrelia miyamotoi disease, Colorado tick fever, Heartland and Bourbon virus diseases, Pacific Coast tick fever, Powassan virus disease, Rocky Mountain spotted fever, Rickettsia parkeri rickettsiosis, Rickettsialpox, Tickborne relapsing fever, and Tularemia.[44,45] Author’s Note: Dosages and recommended medications are based on current recommendations, and are correct to the best of my knowledge. However, treatment recommendations may change, and clinicians are advised to review the most current dosages, medications and contraindications prior to treating any patient. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References: [1]Lyme Disease, CDC, last reviewed: February 24, 2021. Retrieved from: https://www.cdc.gov/lyme/index.html [2]Lyme Disease, Data and Surveillance, CDC, last reviewed January 14, 2021. Retrieved from: https://www.cdc.gov/lyme/datasurveillance/index.html [3]Tickborne Diseases of the United States, CDC, last reviewed September 22, 2020. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/overview.html [4]How ticks spread disease, CDC, last reviewed: September 21, 2020. Retrieved from: https://www.cdc.gov/ticks/life_cycle_and_hosts.html [5]Lyme Disease Transmission. CDC, last reviewed January 29, 2020. Retrieved from: https://www.cdc.gov/lyme/transmission/index.html#:~:text=Ticks%20can%20attach%20to%20any,disease%20bacterium%20can%20be%20transmitted [6]Hofhuis, A et al., Predicting the risk of Lyme borreliosis after a tick bite, using a structural equation model. PloS one vol. 12,7 e0181807. 24 Jul. 2017. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524385/ [7]Nadelman RB et al. Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease after an Ixodes scapularis Tick Bite, N Engl J Med 2001; 345:79-84, July 12, 2001. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejm200107123450201 [8]Tick removal and testing, CDC, last reviewed April 22, 2019. Retrieved from: https://www.cdc.gov/lyme/removal/index.html [9]Gammons M, Salam G, Tick Removal, Am Fam Physician. 2002 Aug 15;66(4):643-646. Retrieved from: https://www.aafp.org/afp/2002/0815/p643.html#afp20020815p643-b7 [10]Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease, Clinical Infectious Diseases, November 30, 2020. Retrieved from: https://www.idsociety.org/practice-guideline/lyme-disease/ [11]Tick removal and testing, CDC, last reviewed: April 22, 2019. Retrieved from: https://www.cdc.gov/lyme/removal/index.html [12]Moore, Andrew et al. “Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States.” Emerging infectious diseases vol. 22,7 (2016): 1169–1177. Retrieved from https://wwwnc.cdc.gov/eid/article/22/7/15-1694_article [13]Theel, Elitza S et al., “Limitations and Confusing Aspects of Diagnostic Testing for Neurologic Lyme Disease in the United States.” Journal of clinical microbiology vol. 57,1 e01406-18. 2 Jan. 2019. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322465/ [14]Two-tiered Testing Decision Tree, CDC, last updated: November 15, 2011. Retrieved from: https://www.cdc.gov/lyme/healthcare/clinician_twotier.html [15]Tickborne Diseases of the United States, CDC, 5th edition 2018. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf [15A]Signs and Symptoms of Untreated Lyme Disease, CDC, last reviewed: January 15, 2021. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/index.html [16] Photo credits: Alison Young, Taryn Holman, Yevgeniy Balagula/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [17]Photo Credit: Bernard Cohen/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [18]Moniuszko-Malinowska A, Czupryna P, Dunaj J, et al. Acrodermatitis chronica atrophicans: various faces of the late form of Lyme borreliosis. Postepy Dermatol Alergol. 2018;35(5):490-494. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232541/ [19]Photo credit, Glatz M et al., Clinical Spectrum of Skin Manifestations of Lyme Borreliosis in 204 Children in Austria, Advances in Dermatology and Venereology, Vol 95, Issue 5, Nov 4, 2014. Retrieved from: https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2000 [20]Warshafsky S et al., Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy, Volume 65, Issue 6, June 2010, Pages 1137–1144. Retrieved from: https://academic.oup.com/jac/article-pdf/65/6/1137/2086677/dkq097.pdf [21]Nadelman R et al., Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease after an Ixodes scapularis Tick Bite, N Engl J Med 2001; 345:79-84. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJM200107123450201 [22]Photo Credit- Ticks Image Gallery, CDC, last reviewed: December 18, 2020. Retrieved from: https://www.cdc.gov/ticks/gallery/index.html [23]Smith G et al., Management of Tick Bites and Lyme Disease During Pregnancy, J Obstet Gynaecol Can 2012;34(11):1087–1091. Retrieved from: https://www.jogc.com/article/S1701-2163(16)35439-1/pdf [24] Treatment for erythema migrans, CDC, last reviewed: November 3, 2020. Retrieved from: https://www.cdc.gov/lyme/treatment/index.html [25]Post-Treatment Lyme Disease Syndrome, CDC, last reviewed: November 8, 2019. Retrieved from: https://www.cdc.gov/lyme/postlds/index.html [26]Ehrlichiosis Transmission, CDC, last reviewed: January 17, 2019. Retrieved from: https://www.cdc.gov/ehrlichiosis/transmission/index.html [27] Ehrlichiosis Epidemiology and Statistics, CDC, last reviewed: March 26, 2020. Retrieved from: https://www.cdc.gov/ehrlichiosis/stats/index.html [28]Ehrlichiosis Clinical and Laboratory Diagnosis, CDC, last reviewed: January 17, 2019. Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/diagnosis.html [29]Ehrlichiosis Signs and Symptoms, CDC, last reviewed: January 17, 2019. Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/diagnosis.html [30]Ehrlichiosis Treatment, CDC, last reviewed: January 17, 2019.Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/treatment.html [31]Todd S et al., No Visible Dental Staining in Children Treated with Doxycycline for Suspected Rocky Mountain Spotted Fever, J Pediatrics 2015;166:1246-51. Retrieved from: http://www.jpeds.com/article/S0022-3476(15)00135-3/pdf?ext=.pdf [32]Anaplasmosis Transmission, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/transmission/index.html [33]AnaplasmosisEpidemiology and Statistics, CDC, last reviewed: March 26, 2020. Retrieved from: https://www.cdc.gov/anaplasmosis/stats/index.html [34]Anaplasmosis Signs and Symptoms, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/symptoms/index.html [35]Anaplasmosis Clinical and Laboratory Diagnosis, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/healthcare-providers/clinical-lab-diagnosis.html [36]Anaplasmosis Treatment, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/healthcare-providers/treatment.html [37]Parasites- Babesiosis, General Information, CDC, last reviewed: April 11, 2018. Retrieved from:https://www.cdc.gov/parasites/babesiosis/gen_info/index.html [38]Swanson M, Gray EB, Surveillance for Babesiosis — United States, 2018, Annual Summary, CDC, Data current as of: April 22, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/resources/babesiosis_surveillance_summary_2018.pdf [39]Babesiosis, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [40]Parasites – Babesiosis Resources for Health Professionals, CDC, last reviewed: October 30, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html [41]Babesiosis, Laboratory diagnosis, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [42]Photo credit- Babesiosis Image Gallery, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [43]Parasites – Babesiosis, Resources for Health Professionals- Treatment, CDC, last reviewed: October 30, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html#tx [44]Diseases Transmitted by Ticks, CDC, last reviewed: April 2, 2020. Retrieved from: https://www.cdc.gov/ticks/diseases/index.html [45]Other Spotted Fever Group Rickettsioses, CDC, last reviewed: January 18, 2019. Retrieved from: https://www.cdc.gov/otherspottedfever/ Originally published 4/29/2021

Should the practicing clinician recommend cardiac ablation for atrial fibrillation? Continuing Medical Education Overview: Normal atrial contraction also known as the atrial kick can increase left ventricular filling and cardiac output by 20 to 30%. This is lacking in atrial fibrillation and can negatively impact exercise tolerance and quality of life. Should the practicing clinician recommend cardiac ablation for atrial fibrillation? ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 by Stuart M. Caplen, MD Normally, electrical signals from sinoatrial node cardiac pacemaker cells cause the heart to contract in an efficient manner pushing blood from the atria into the ventricles and then out to the lungs and the rest of the body. In atrial fibrillation (AF) the electrical signals become rapid, irregular and disorganized overriding the normal pacemaker cells, and the heart pumps less efficiently. In the United States it is projected that 12.1 million people will have AF by 2030.[1] More than 454,000 people are hospitalized each year with AF as the primary diagnosis, and this is a contributing factor to an estimated 158,000 deaths a year. The estimated mortality rate of new AF varies in the literature. In one large study of over 185,000 Medicare, patients with an AF diagnosis there was a 48.8% 5-year risk of mortality, a 13.7% risk for heart failure and a 7.1 % risk of stroke.[2,3] Other sources note that the presence of AF is associated with a 1.5 to 2-fold increase in death and heart failure (HF) and 5-fold increase in the rates of stroke and systemic thromboembolism.[3] Normal atrial contraction also known as the atrial kick can increase left ventricular filling and cardiac output by 20 to 30%. This is lacking in AF and can negatively impact exercise tolerance and quality of life.[3] Ablation Therapy Ablation therapy for AF is considered a standard of care and may be used regardless of previous medication history. It can be performed by radiofrequency, cryoenergy, or laser to destroy the abnormal tissue that precipitates AF. Myocardial muscle fibers from the left atrium extend like sleeves around all the pulmonary veins (PV). It is known that areas near the pulmonary veins may frequently contain triggers for paroxysmal AF due to the presence of large numbers of autonomic nerves that reside there. Conducting fibers in that area also have shorter refractory times than those in the left atrium. For those reasons, the most common ablation technique is to create an electrical isolation of the pulmonary veins (PV) with circumferential lesions around the PV. In addition, a “roof line” connecting the mitral valve to the ablations around the left PV may be added. An encircling lesion of the superior vena cava (SVC) may also be performed if focal firing from the SVC can be demonstrated. Individual AF triggers are found in about 10-33% of patients during electrophysiologic mapping and may be also targets for ablation.[6] Some cardiologists will also try to ablate any areas of fibrotic scar tissue found there which can also serve as AF triggers.[6] Rapid electrical reconduction from the PV after an initial attempt at ablation can be as high as 33% in 30 minutes and 50% in 60 minutes after the procedure. An observational waiting period of at least 20 to 30 minutes during the procedure is recommended to see if any acute reconduction does occur and if additional targeted ablation might be needed.[4] Intraprocedural adenosine infusion may also be used to help differentiate a permanently blocked conduction path from one that is dormant and could become active, however studies on efficacy have been mixed.[6,7,8,9,10] Isoproterenol infusion is the most commonly used agent to provoke and locate non-PV triggers to be ablated and is sometimes also used with adenosine.[6] Electrical pacing techniques may also be used intra-procedure to try to ensure that the PV are electrically isolated from the left atrium.[6] Open cardiac ablation may be performed at times by surgeons on patients receiving concomitant cardiac valve replacements or coronary artery bypass grafts. Complications of Ablation Listed complications of ablation include: death (<0.1% to 0.4%), stroke or TIA (0% to 2%), asymptomatic cerebral emboli (2% to 15%), pericarditis (0% to 50%), cardiac tamponade (0.2% to 5%). Other potential complications include: air embolism, atrial esophageal fistula, esophageal perforation, coronary artery stenosis/occlusion, gastric hypomotility from vagus nerve injury, permanent phrenic nerve paralysis, pulmonary vein stenosis, stiff left atrial syndrome (dyspnea, heart failure, pulmonary hypertension and atrial dysfunction, typically from atrial scarring if due to ablation)[11], mitral valve entrapment of the catheter, as well as other vascular complications.[6] Atrial Fibrillation Recurrence After Ablation Due to the fairly frequent reoccurrence rate, reablation is a commonly needed procedure. Early recurrence within the first 3 months after ablation is observed in 50% or more of patients and may be due to tissue inflammation from the procedure. A “blanking period” of 3 months is recommended after the procedure, during which reintervention should be avoided, because up to half of the patients with early recurrence remain AF- free during long-term follow-up. Patients who experience multiple early recurrences are more likely at one-year to be back in AF and may be candidates for early reablation.[6] Late recurrence, from 3 to 12 months post-procedure occurs in approximately 25%–40% of cases. The mechanism for late-term recurrence is predominantly linked to the recovery of electrical conduction between the PVs and the left atrium.[4] Scar tissue from a previous ablation procedure affecting electrical conduction may also lead to AF recurrence.[6] In one study only 26.4% of subjects who had ablations were still in sinus rhythm after 4.8 years.[12] Another trial found after 1, 2, and 5 years, 40%, 37%, and 29% of subjects respectively were arrhythmia-free post-ablation.[13] Obesity, obstructive sleep apnea, and uncontrolled HTN, have been found to put patients at risk for recurrent AF after ablation, although use of CPAP and controlling HTN reverses that higher risk.[6] Ablation Versus Drug Therapy In the literature, ablation trials had a 59%–89% success rate in terminating paroxysmal AF after 12 months compared to drug therapy’s reported success rate of 5%–23%. Trials which included patients with persistent AF or combined paroxysmal and persistent AF, reported success rates with ablation ranging from 59%–80% at 6 or 12 months, compared to success rates with drug therapy only ranging from 9%–58%.[6] There have been mixed results in trials with respect to ablation for AF and its effect on mortality, although some other quality of life measures favor ablation. A study of 411 patients with persistent or frequent AF and heart failure compared ablation to drug therapy. The primary outcome was a composite of all-cause mortality and heart failure events, with at least 2 years follow-up. There was no significant difference in the primary outcome between the ablation and drug therapy groups. Secondary endpoints favored ablation. Left ventricular ejection fraction, 6-minute walk distance and the AF Effect on QualiTy-of-Life questionnaire scores were statistically higher in the ablation group. However, the trial was prematurely terminated at 19 months after an interim review revealed a lack of benefit in mortality or heart failure symptom improvement with ablation compared to drug therapy.[14] A larger prospective trial with more than 2,000 subjects, The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial found that catheter ablation, compared with drug therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. Catheter ablation was associated with a lower AF recurrence rate than drug therapy (50% vs 69% at 3 years). One secondary endpoint, mortality or CV hospitalization revealed a significant 17% lower event rate for the catheter ablation group.[15] Another study of 203 heart failure patients with AF and an implanted pacemaker or defibrillator, compared ablation to amiodarone therapy. At two years, 70% of patients in the ablation group were AF-free vs only 34% in the amiodarone group. The ablation group also had significantly less hospitalizations and mortalities.[16] A large study of over 37,000 patients followed for at least 3 years found that AF subjects who had ablations had lower rates of death, dementia, and stroke than those who did not have ablations.[17] A meta-analysis comparing ablation to drug therapy for AF found that catheter ablation is associated with a 32.3% rate of recurrent atrial arrhythmias (AF, atrial flutter, or atrial tachycardia) compared to a higher 53% in the medication group. The number needed to treat (NNT) with ablation to prevent 1 arrhythmia was estimated to be 5 patients. Hospitalizations were 5.6% in the ablation group compared to 18.7% in the drug therapy group.[18] Other trials have found that ablation for AF significantly improved patients’ quality of life. In one of the trials AF patients had significantly reduced cardioversions, emergency department visits and hospitalizations compared to the pre-ablation period.[19,20] In competitive athletes, it is suggested that ablation may be a first line therapy to avoid the adverse effects of medication on performance.[6] Summary: There are mixed results for improvement of mortality from ablation versus drug therapy and the true impact is unknown.[6] There are some preliminary studies that have shown a decrease in strokes and dementia in patients who have received ablation.[6,20] It is clear from the literature that ablation prevents recurrent AF more effectively than drug therapy, and a primary benefit from AF ablation is an improvement in quality of life, with a decrease in fatigue and an improvement in exercise tolerance.[6] Time From Atrial Fibrillation Diagnosis to Ablation A study of the relationship between time of AF diagnosis to the performance of an ablation procedure found that the time frame affected efficacy. Four time periods from diagnosis to ablation were studied, ≤1, 1.1–3.0, 3.1–6.5, and >6.5 years, and any atrial arrhythmia recurrence (not just AF) rates at two years were 33.6%, 52.6%, 57.1%, and 54.6% respectively.[21] A meta-analysis and systematic review found that when AF diagnosis to ablation time was less than one year there were 27% less recurrences than if the time frame for ablation was greater than one year.[22] Anticoagulation After Ablation Patients in AF are typically anticoagulated to prevent blood clots form forming in the left atrium which can dislodge and potentially cause a stroke. One advantage of ablation used to terminate AF is the possibility of eliminating the need for anticoagulation, and the potential adverse events associated with that therapy. Patients are at increased risk for thromboembolism during the ablation procedure and also up to several months after. A consensus recommendation is that post-ablation anticoagulation should be continued for at least 2 months. After that, the need for anticoagulation should be based on the patient's stroke risk profile rather than the success or failure of the ablation procedure. If anticoagulation is discontinued after ablation termination of AF, continuous or frequent ECG monitoring to screen for AF recurrence is recommended.[4] Conclusion Ablation therapy for AF is a recognized treatment option. Traditionally, medication was recommended as the first therapy for AF and only if that failed was ablation recommended. However, some studies have found that the sooner the procedure is done, the higher the likelihood of success and earlier first-line ablation is sometimes recommended. Ablation procedures do carry some risk of adverse events. Some studies are inconclusive whether ablation significantly reduces mortality over drug therapy, but compared to medical treatment ablation can reduce symptomatic atrial arrythmias, hospitalizations and improve exercise tolerance and quality of life. There are also some preliminary data that ablation may reduce stroke and dementia risk. Some of the varying results in trials may be due to the different ablation techniques or the primary and secondary endpoints employed in those studies. In some patients, returning to sinus rhythm can eliminate the need for anticoagulation, but the need for anticoagulation should be based on the patient's stroke risk profile and not solely on a positive result of ablation therapy. Due to recovery of electrical pathways, recurrence of AF may necessitate repeat ablation procedures. While short term results are good, according to some studies, less than 30% of patients who received ablation are still in sinus rhythm after 5 years. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References [1] Atrial Fibrillation. CDC. Last Reviewed: October 14, 2022. Retrieved from: https://www.cdc.gov/heartdisease/atrial_fibrillation.htm [2] Piccini JP et al. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke, European Heart Journal, Volume 35, Issue 4, 21 January 2014, Pages 250–256. Retrieved from: https://academic.oup.com/eurheartj/article/35/4/250/466888 [3] Mujović N et al. Catheter Ablation of Atrial Fibrillation: An Overview for Clinicians. Adv Ther. 2017;34(8):1897-1917. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565661/ [4]Atrial fibrillation. CDC. Last Reviewed: October 14, 2022. Retrieved from: https://www.cdc.gov/heartdisease/atrial_fibrillation.htm [5] van der Hooft CS, Heeringa J, Brusselle GG, et al. Corticosteroids and the Risk of Atrial Fibrillation. Arch Intern Med. 2006;166(9):1016–1020. Retrieved from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/410283 [6] Calkins H et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm, Vol 14, No 10, October 2017. Retrieved from: https://www.heartrhythmjournal.com/article/S1547- 5271(17)30590-8/fulltext#tbl4 [7] Kobori A et al. the UNDER-ATP Trial Investigators, Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial, European Heart Journal, Volume 36, Issue 46, 7 December 2015, Pages 3276–3287. Retrieved from: https://academic.oup.com/eurheartj/article/36/46/3276/2398363#84932991 [8] Macle L et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet. 2015; 386: 672-679. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60026-5/fulltext [9] Papageorgiou N et al. Adenosine-guided pulmonary vein isolation versus conventional pulmonary vein isolation in patients undergoing atrial fibrillation ablation: An updated meta-analysis. Volume 227, P151-160, January 15, 2017. Internation Journal of Cardiology. Retrieved from: https://www.internationaljournalofcardiology.com/article/S0167-5273(16)33612- 9/fulltext [10] Chen YH et al. Role of adenosine-guided pulmonary vein isolation in patients undergoing catheter ablation for atrial fibrillation: a meta-analysis. Europace. 2017;19(4):552-559. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/28431050/ [11] Gibson DN, Di Biase L, Mohanty P, et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors [published correction appears in Heart Rhythm. 2011 Nov;8(11):1828]. Heart Rhythm. 2011;8(9):1364-1371. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/21354332/ [12] Ouyang F et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation. 2010; 122: 2368-2377. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.110.946806 [13] Weerasooriya R et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol. 2011; 57: 160-166. https://www.jacc.org/doi/full/10.1016/j.jacc.2010.05.061 [14] Ratika Parkash R, MD Randomized Ablation-Based Rhythm-Control Versus Rate- Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT- AF trial. Circulation. June 7, 2022. Vol 145, Issue 23. Retrieved from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057095 [15] Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1261– 1274. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/2728676 Di [16] Biase L et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation. 2016; 133: 1637-1644. Retrieved from: https://www.ahajournals.org/doi/10.1161/circulationaha.115.019406 [17] Bunch TJ et al. Patients Treated with Catheter Ablation for Atrial Fibrillation Have Long-Term Rates of Death, Stroke, and Dementia Similar to Patients Without Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 22: 839-845. https://doi.org/10.1111/j.1540-8167.2011.02035.x [18] Turagam MK, Musikantow D, Whang W, et al. Assessment of Catheter Ablation or Antiarrhythmic Drugs for First-line Therapy of Atrial Fibrillation: A Meta-analysis of Randomized Clinical Trials. JAMA Cardiol. 2021;6(6):697–705. Retrieved from: https://jamanetwork.com/journals/jamacardiology/article-abstract/2779384 [19]Wilber DJ, Pappone C, Neuzil P, et al; ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303(4):333-340. Retrieved from: https://jamanetwork.com/journals/jama/article- abstract/185277 [20]Andrade JG, Macle L, Verma A, et al; CIRCA-DOSE Study Investigators. Quality of life and health care utilization in the CIRCA-DOSE Study. JACC Clin Electrophysiol. 2020;6(8):935-944. Retrieved from: https://www.jacc.org/doi/abs/10.1016/j.jacep.2020.04.017 [21] Hussein AA, Saliba WI, Barakat A, et al. Radiofrequency ablation of persistent atrial fibrillation: diagnosis-to-ablation time, markers of pathways of atrial remodeling, and outcomes. Circ Arrhythm Electrophysiol. 2016;9(1):e003669. Retrieved from: https://www.ahajournals.org/doi/full/10.1161/CIRCEP.115.003669 [22] Chew DS, Black-Maier E, Loring Z, et al. Diagnosis-to-ablation time and recurrence of atrial fibrillation following catheter ablation: a systematic review and meta-analysis of observational studies. Circ Arrhythm Electrophysiol. 2020;13(4):e008128. Retrieved from: https://www.ahajournals.org/doi/full/10.1161/CIRCEP.119.008128

✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 by Simone Weinmann, MS, CGC, Anna Xue, MS, CGC , Dani Temares MS, CGC , and Nancy Mills, MD Introduction Cancer is one of the leading causes of death worldwide. Nearly 40% of the population will be diagnosed with cancer in their lifetime.1 Breast, lung, and prostate cancers are the most common types. The average woman has a 12-13% chance of developing breast cancer; in other words, 1 out of every 8 women will develop breast cancer in her lifetime.[2] Cancer is inherently a disease of abnormalities of genetic origin; the accumulation of genetic mutations causes cancer by affecting important cellular mechanisms involved in cell proliferation and apoptosis, leading to uncontrolled cell growth.3 Mutations may arise from endogenous errors in replication or exogenous agents such as radiation and chemical carcinogens. The activation of oncogenes, which typically stimulate cell proliferation, and the inactivation of tumor suppressor genes, which typically inhibit cell proliferation, both disturb cellular homeostasis and can lead to malignancy.[4] Cancer can be sporadic or have a hereditary component. Only about five to ten percent of cancers are hereditary.[5] If cancer is inherently a disease of genetic abnormalities, it may seem paradoxical that only a small percentage of cancers occur on the basis of genetic inheritance. The ”two-hit” hypothesis, tumorigenesis. Sporadic vs hereditary. The “two-hit” hypothesis postulates that tumorigenesis requires two “hits”, or mutations, as humans have two copies, or alleles of most genes. The NIH defines tumorigenesis as the pathologic process that involves the transformation of normal cells to a neoplastic state resulting in polyclonal or monoclonal neoplastic cell proliferation. In sporadic cases of cancer, both of these mutational events are randomly acquired on the somatic level in the tumor over the course of someone’s lifetime. In hereditary cases of cancer, there is an inherited germline mutation already in place (from birth), so cells only need one more “hit” to trigger tumorigenesis.[6] These inherited mutations increase one’s risk of cancer compared to the general population, as only one additional mutation is necessary to allow the process of tumorigenesis to occur. Germline pathogenic mutations are considered to be disease causing and are associated with an inherited cancer predisposition. These mutations are typically inherited in an autosomal dominant manner, so each child has a 50% chance of inheriting the cancer predisposition mutation from a parent. Therefore, if one person is found to have a germline mutation, their siblings, their children, and their parents each have a 50% chance of having the same genetic mutation. The caveat here is that these mutations are not fully penetrant, meaning not everyone with an inherited mutation will develop cancer in their lifetime. This is thought to be due to the second hit (mutation) that needs to be acquired for cancer to develop. Sometimes this second hit never occurs, or it occurs in an organ type where the specific genetic defect does not substantially contribute to tumorigenesis. The exact science behind why specific genetic mutations increase certain cancer types is not fully understood at this time. Given this reduced penetrance, cancers and cancer risk can often give the appearance of “skipping a generation” as not everyone in each generation who carries the mutation will be affected with cancer. Family History Family history can be an underutilized tool when evaluating for hereditary cancer. An in- depth family history is indeed the backbone of a genetic counseling session and allows for proper risk assessment when evaluating for hereditary cancer syndromes. A hereditary cancer syndrome describes the range of cancers an individual may be at risk for if they are found to have a germline mutation. A strong family history of cancer can be indicative of a familial germline mutation. Certain “red flags” in the family history that increase suspicion for a genetic predisposition to cancer include the following: Young age of cancer diagnosis (<50 years old) Multiple family members with the same type of cancer Individuals with multiple primary cancers or for paired organs bilateral cancers (such as breast) Rare cancers (such as male breast cancer, ovarian cancer, pancreatic cancer, or medullary thyroid cancer) Rare tumors (paragangliomas and pheochromocytomas) When evaluating a family history, certain patterns can be indicative of specific hereditary cancer syndromes. Breast and ovarian cancers tend to group together, and are often associated with the hereditary breast and ovarian cancer syndrome (HBOC). Hereditary Cancer Syndromes While the most common cause of hereditary breast and ovarian cancer syndrome are mutations in BRCA1 or BRCA2 genes, approximately 20 additional genes can be associated with increased risk for these cancer types. Many of the earliest studies of hereditary breast cancer risk focused on individuals of Ashkenazi Jewish ancestry. It is now known that individuals of Ashkenazi Jewish ancestry may harbor founder mutations in the BRCA genes, which are mutations that occurred in the original ancestors of this specific ethnicity. As such, individuals of Ashkenazi Jewish ancestry have a much higher chance of having mutations in the BRCA genes - 1/40 compared to the general population risk of 1/400. For someone with HBOC, their risk of developing breast cancer can be as high as 60-80%, and the risk of developing ovarian cancer 40-60%. Other cancer risks can also be associated with this syndrome, such as prostate cancer, pancreatic cancer, and melanoma. Another common hereditary cancer syndrome is marked by a family history of colon and uterine/endometrial cancer. Lynch Syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC) can increase the lifetime risk for colon cancer to 60%, endometrial cancer to 60% and increase risk for a variety of other cancers such as ovarian, renal pelvis, bladder, gastric, pancreatic and even brain cancer. Five genes ( MLH1, MSH2, MSH6, PMS2, EPCAM ) can harbor a germline mutation which causes Lynch Syndrome, and each gene confers a different set of risks for these cancer types. Additionally, more rare cancer types can be strongly associated with hereditary cancer syndromes. Specifically, cancer diagnoses of diffuse gastric cancer, paragangliomas, pheochromocytomas, hemangiomas, medullary or follicular thyroid cancer, renal cell carcinoma in young people, and adrenocortical carcinomas are all cancers that could be a sign of a hereditary cancer syndrome. Both HBOC and Lynch Syndrome are caused by an inherited mutation in one out of two copies of these genes. If parents each carry a mutation in the same gene, and the child inherits both non-working copies of this gene (25% chance), the child will have an increased risk of pediatric cancer. For this reason, individuals who have tested positive for mutations in genes related to HBOC or Lynch Syndrome and are considering family planning should have their partner tested regardless of their partner’s family history. Genetic Testing Recognizing specific signs and patterns in a family history should prompt providers to refer patients to genetic counselors. Genetic counselors spend time taking an extended medical and family history in order to provide an accurate risk assessment. Not all family history confers the same level of risk, and specific genetic testing options will be based on the family history, and whether the patient meets the National Comprehensive Cancer Network’s (NCCN) guidelines for genetic testing. During the session the genetic counselor will explain the process of genetic testing, including details of what information is examined, possible results, and implications of those results for the patient and the family. The process of genetic testing varies depending on the clinical laboratory, but standard testing for hereditary cancer syndromes takes 3-4 weeks, with many patients who meet NCCN criteria having an out-of-pocket cost of $100 or less. Genetic testing for hereditary cancer predisposition syndromes often occurs in the format of panel testing, where multiple genes associated with cancer risk are analyzed at once. Panel testing can be cancer specific such as a breast and gynecological cancers panel or a panel only including genes associated with paragangliomas and/or pheochromocytomas. Larger, multi-cancer panels are also available and these are ordered the most often, but it is the patient’s choice. For example, if the only reason someone meets genetic testing criteria is due to a first degree relative (sibling, parent, child) having pancreatic cancer and they are only concerned about the pancreatic cancer in their family, a pancreatic cancer panel can be ordered for them. Currently, if someone tests positive for a pancreatic cancer gene, they may be eligible for pancreatic cancer screening at an academic medical center starting at age 50. The current screening consists of contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS) for such high- risk individuals. Screening methodologies are usually alternated each year, but there is no current standardization. Typically, genetic counseling is only provided to individuals 18 years of age and older. Mutations in the majority of these genes increases the risk for adult-onset cancers, and as such testing is usually deferred until the age of 18 to allow the patient to make an autonomous decision about testing. In rare cases, germline mutations increase risk for childhood onset cancers, and in this scenario, testing is facilitated by a specialized pediatric team. The goal of genetic testing is to identify mutations in an individual or family in order to implement recommended screening measures. NCCN provides screening and surveillance guidelines for individuals who are at high risk of developing cancer due to a genetic predisposition. These recommendations have data that suggests that they reduce morbidity and mortality associated with an inherited cancer predisposition syndrome. As research around early cancer detection progresses rapidly, these guidelines and recommendations are continuously updated. As such, it is recommended that NCCN guidelines be assessed via their website for the most up to date recommendations. Screening for Cancer Screening recommendations are based on the cancer type and the level of risk that a mutation in a specific gene confers, and so not everyone with a diagnosis of HBOC will have the same screening guidelines. An example of how a hereditary cancer syndrome can impact screening is with the BRCA genes. In the general population, it is recommended that women begin annual mammograms at age 40 to address breast cancer risk. For BRCA female mutation carriers, breast cancer screening should begin at age 25 with annual breast MRIs with intravenous contrast. Beginning at age 30, BRCA mutation carriers will be advised to begin annual mammograms in addition to their annual breast MRI. Prophylactic surgical options, such as risk reducing bilateral mastectomy, are also discussed with BRCA female mutation carriers as an alternative to increased screening. Preventive endocrine therapy can also be considered. Female BRCA mutation carriers are also at increased risk for ovarian cancer. Unlike breast cancer screening, there is no proven effective screening method for ovarian cancer. Transvaginal ultrasounds and CA-125 blood tests can be offered, but they have no proven efficacy in detecting ovarian cancer at early stages. Therefore, for women who test positive for a germline BRCA mutation, the recommendation is removal of the ovaries between the ages of 35 and age 40. NCCN currently states that it is reasonable to delay this risk-reducing salpingo-oophorectomy surgery in BRCA2 carriers until ages 40-45 unless someone in the family was diagnosed with ovarian cancer at an earlier age. Both men and women BRCA carriers are at increased risk for pancreatic cancer as well as melanoma. Screening for BRCA carriers for pancreatic cancer is dependent on family history, and melanoma screening is the same as the recommended annual full body skin exam for the general population. Male BRCA carriers are at increased risk for prostate cancer and are recommended to begin prostate cancer screening via annual PSA at age 40. Male breast cancer screening recommendations vary, but minimum recommendations consist of an annual clinical breast exam for male BRCA carriers beginning at age 35. Screening and surveillance recommendations can change even if someone has a negative genetic testing result. Additional contributing factors, such as family history, personal history and risk models are all evaluated when the genetic counselor discloses results and provides a final risk assessment for the patient. For example, any individual with a first degree relative with breast cancer is considered to have double the lifetime risk to develop breast cancer. This is due to assumed shared environmental factors, lifestyle factors, and additional genetic factors that we are not able to test for given current technology and understanding. As such, many patients who test negative on genetic testing will still meet a threshold for increased cancer screening and will be referred to additional providers to discuss specific recommendations. Genetic Testing in the Affected Patient When offering genetic testing to individuals, it is always most informative to test the person in the family who has been affected with the most relevant cancer at the youngest age. If a family history consists of three female breast cancers - one at age 86, one at age 65, and one at age 38, the individual with the breast cancer at age 38 is most likely to have a genetically driven breast cancer, and therefore is most likely to test positive. If testing is offered to the 86-year-old and she is negative, it still does not inform us about the other individuals in the family, and perhaps there could be a genetic mutation responsible for the younger ages of cancer diagnosis. Genetic Information Non-Discrimination Act If an unaffected individual is being offered testing, it is important to review the specifics of the law protecting them against genetic discrimination. The Genetic Information Non- Discrimination Act (GINA) was passed in 2008 as a part of the Affordable Care Act. GINA restricts employers and other entities covered by Title II from requesting, requiring or purchasing genetic information, and strictly limits the disclosure of genetic information. This law prevents health insurers and employers from discriminating against someone based on his or her genetic information. However, the law does not include protection from discrimination by life, disability, and long-term care insurance companies. Direct-to-Consumer Genetic Testing Finally, it is important to note that not all genetic testing is created equal. While direct-to- consumer genetic testing is steadily increasing access to genetic testing for a variety of individuals, it is not considered a clinical level test. Direct-to-consumer genetic testing often assays only a small fraction of possible mutations, and so a negative test result is not considered a comprehensive, or clinical level negative result. A patient should never have their screenings determined by or be discharged from high-risk cancer screening based on a negative direct-to-consumer test result. Individuals with negative direct-to- consumer genetic testing with a strong family history of cancer should be referred to genetic counseling for a full risk assessment and additional clinical level testing that is considered comprehensive. Conclusion Genetics and Cancer - does family history matter? The answer is a resounding yes. While family history is not the only factor in considering an individual’s risk for cancer, it is often a major aspect of the many pieces genetic counselors and other genetic professionals use to assess an individual's cancer risk. If the family history of a patient seems unusual, that patient may benefit from a referral to a genetic counselor or genetics provider for a full risk assessment. That initial assessment may start a chain reaction and reduce the chances that patients and their family members will be diagnosed in the future with a late-stage cancer. Editor’s note: Male and female in this article refer to sex assigned at birth. Specific recommendations and stipulations for cancer screening may exist for individuals who do not identify as cis gender. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References 1 https://www.cancer.gov/about-cancer/understanding/statistics . Accessed June 19, 2023. 2 Giaquinto AN, Sung H, Miller, KD, et al. Breast Cancer Statistics, 2022. CA: A Cancer Journal for Clinicians. 2022; 72(6). doi:10.3322/caac.21754 3 Kontomanolis EN, Koutras A, Syllaios A, et al. Basic Principles of molecular biology of cancer cell – Molecular cancer indicators. JBUON. 2021; 26(5): 1723-1734. https://www.jbuon.com/archive/26-5-1723.pdf Accessed June 19 , 2023 4 Bertram JS. The molecular biology of cancer. Mol Aspects Med. 2000;21(6):167-223. doi:10.1016/s0098-2997(00)00007-8 5 National Cancer Institute. The Genetics of Cancer. https://www.cancer.gov/about- cancer/causes- prevention/genetics#:~:text=Inherited%20genetic%20mutations%20play%20a,individual s%20to%20developing%20certain%20cancers . Accessed June 19, 2023. 6 Knudson Jr AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proceedings of the National Academy of Sciences. 1971;68(4):820-823. doi: 10.1073/pnas.68.4.820.

The “Simple” Urinary Tract Infection? A few controversies - do we treat the asymptomatic bacteriuria, can we rely on urine dipsticks, which colony count on a culture plate actually signifies an infection, how long do we treat, and which antibiotic? ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 by Stuart M Caplen, MD and Arno Housman, MD Diagnosing and treating the “simple” uncomplicated urinary tract infection (UTI), also called simple cystitis, has become a complex issue. Controversies include whether to treat asymptomatic bacteriuria, the sensitivity of urine dipsticks, which colony count on a culture plate actually signifies an infection, the length of antibiotic therapy, and the choice of antibiotic given the emergence of resistant strains of bacteria. This article will look at those issues and report on the latest science on adult UTIs. Pyelonephritis, infections in children and complicated infections will not be discussed. Incidence UTIs are common with an estimated 40% of women reporting having had one episode in the past. It is the most common source of gram-negative bacteremia.[1] Symptoms Typically, a patient with a non-complicated UTI, will not have any evidence of fever, back pain or other systemic involvement. Symptoms of a UTI may include urinary frequency, dysuria, gross or microscopic hematuria, suprapubic pain, urinary urgency and urge incontinence (which may be denied by patients but is manifested by the need to wear absorbent pads.*) Other Infections That May Mimic UTI Symptoms Urethritis, vulvovaginitis. prostatitis, and Candida balanitis can all cause dysuria which may be misdiagnosed as a UTI. Dysuria or urinary frequency symptoms which are not improving despite therapy should be a clue for the clinician to look for an alternate etiology. History, physical exam and specific testing for other causes such as Chlamydia , gonorrhea, and occult Trichomonas in men may be needed to make the correct diagnosis.[2] What Defines a Urinary Tract Infection? In the past, 100,000 colony-forming units per milliliter (CFU per ml) in a urine culture was considered the gold standard for diagnosing a UTI. However, some research has suggested that lower levels of CFU per ml in certain situations actually also indicate an infection. In a young woman with symptoms of cystitis, a bacterial count of more than 100 CFU per mL may be sufficient for diagnosis.[1,3,4] In young men, a urine culture with a bacterial count of over 1,000 CFU per mL of urine may be considered positive. Some laboratories do not report counts of less than 10,000 CFU per mL of urine and as a result, low-coliform-count infections may not be diagnosed.[1] Thus, what has been considered a negative test for UTI based on 100,000 CFU per mL, may still indicate an infection depending on the clinical setting and method used to collect the urine sample. There is some evidence that for young non-pregnant women with a UTI, a urine culture may not need to be sent initially. The European Association of Urology guideline for uncomplicated infections in non-pregnant women is that a urine culture is recommended in patients with atypical symptoms, as well as those who fail to respond to appropriate antimicrobial therapy.[5] Patients with risk factors or symptoms of complicated UTIs, pregnant women, women with UTI symptoms and a vaginal discharge, and male patients with symptoms should all have cultures sent.[6] Clean Catch Urine Specimens The use of the clean-catch midstream technique to collect urine samples is considered the standard to try to prevent contamination of the sample from skin and urogenital organisms. Although intuitively it seems that the clean-catch midstream technique with cleaning of the urogenital region should be a better technique, a number of studies have found that there was no significant difference in the rate of contamination in women using a clean-catch midstream technique versus just voiding into a collection cup.[7,8,9] A systematic review found that no specific collection technique affected diagnostic accuracy in non-pregnant women, but did note the evidence was limited.[10] (It is also possible that some female patients, even with careful instruction, may not provide a true clean catch urine specimen. For this reason, when obtaining a truly non-contaminated specimen is required, a straight catheterized specimen might be considered.*) However, there are studies that demonstrated that midstream urine collection in men is more accurate than first void urine and recommended that technique when collecting urine samples.[11,12] Asymptomatic Bacteriuria Asymptomatic bacteriuria (ASB) is defined as the presence of one or more species of bacteria in a urine culture at a CFU growth level considered to be an infection with the patient having no signs or symptoms of a UTI. Subtle signs of a UTI without dysuria such as urinary urgency, incontinence or urinary frequency (defined as voiding more than 5X/day) should be ruled out before diagnosing ASB.* The presence or absence of pyuria, or white blood cells in the urine is not used in defining ASB. In women with no symptoms who have ASB, it is recommended that two specimens be obtained within two weeks, as 10% to 60% of women may not have persistent bacteriuria found on a repeat specimen. For men, a single positive urine specimen is considered adequate for ASB diagnosis. The incidence of ASB varies with the population studied. In premenopausal women the incidence is 1%-5%, post-menopausal women 2.8%–8.6%, and women over 70 years of age 10.8%–16%. In men over 70 years of age, the incidence is 3.6%–19%. In elderly residents living in a long-term care facility the incidence is 15%-50%. Patients with a long-term indwelling bladder catheter have an ASB incidence of close to 100%.[13] Elderly female patients in long term care facilities may develop urinary incontinence which should be addressed to try to reduce ASB and UTI incidence in that population.* A number of studies have not found any benefit of antimicrobial therapy in ASB, with the exception of pregnant women and for endoscopic urologic procedures. In pregnancy, treatment of ASB has been found to reduce the incidence of pyelonephritis, premature labor, and low birth weight. For endoscopic urologic procedures, a short course of one to two doses of antibiotics starting 30 to 60 minutes before the procedure is recommended to reduce the incidence of post-operative sepsis. In urologic surgery where the mucosal barrier will be broken, standard practice is to administer prophylactic antibiotics regardless of whether there is ASB or not.[14] The Infectious Diseases Society of America guidelines recommend against routine screening for ASB in almost all circumstances except pregnancy and pre-operatively. For all other groups, ASB has not been linked to an increase in the incidence of renal failure or pyelonephritis. Treating ASB increases the risks of adverse side effects from the use of antibiotics as well as possibly increasing antibiotic resistance. Trying to maintain a sterile, bacteria free urine for extended periods of time in patients with ASB may not prove possible in some patients.[13] Patients with indwelling bladder catheters frequently have multiple organisms in their urine, some of which are present at lower CFU counts. Organisms present in lower CFU counts may represent contamination of the urine specimen from biofilm organisms along the device rather than true bacteriuria and for those patients 100,000 CFU/mL appears to be an appropriate level to define bacteriuria in an asymptomatic patient with an indwelling catheter.[13] Long-term indwelling urinary catheters should be avoided whenever possible by use of clean intermittent urinary catheterization to try to reduce the incidence of UTIs.* Lower CFU counts from urine specimens collected by a one-time in and out catheterization or following insertion of a new indwelling catheter suggests bacteriuria, but the clinical significance of lower quantitative counts in asymptomatic patients without UTI symptoms is not clear.[13] There are no specific recommendations by the Infectious Diseases Society of America to screen for ASB prior to removal of bladder catheter in an asymptomatic patient as a way of possibly reducing post-catheter removal infections.[13] Urine Dipsticks As urine cultures can take two days or more to produce results, urine dipsticks that can test for blood, leukocyte esterase (LE) and nitrites as signs of a UTI are used to assist in more rapid diagnosis. How accurate are they? Neutrophils produce leukocyte esterase proteins. Nitrites are an indirect measure of nitrate-reducing bacteria, but to have good sensitivity, the urine must contain sufficient dietary nitrates which have been retained in the bladder for more than 4 hours. Nitrate-reducing bacteria include Enterobacteriaceae. However, Candida , Streptococci , and Enterococci do not reduce nitrates and will not test positive on a urine dipstick.[15] In one study, the sensitivity** for UTI for a positive nitrite test compared to urine culture was 23.3%. LE had a UTI sensitivity of 48.5% and finding blood in the urine had a UTI sensitivity of 63.9%. When all three were combined; if nitrite and/or LE and/or blood was positive, the UTI sensitivity was 74%. False positive LE results may be seen in conditions when the urine is not a clean catch specimen and contaminated with bacteria or Trichomonas . A false negative LE test may be due to proteinuria, vitamin C in the urine, or technical error.[15] A meta-analysis of urine dipstick trials found that testing positive for one or both nitrites and LE had a sensitivity of 68 to 88% for UTI, compared to urine culture. The specificity*** was 70% to 87%. Requiring both nitrite and LE to be positive to diagnose a UTI had a sensitivity of 17% to 72% with a specificity of 77% to 100%. The authors concluded that both tests being negative may be useful in ruling out a UTI, although it is not 100% accurate. A positive result may need to be confirmed by culture.[16] Interestingly, one meta-analysis found that clinical examination by itself did not aid in the diagnosis of uncomplicated UTI in women, but did find the urine dipstick helpful.[17] ** (Sensitivity-The percentage of people who have a UTI and test positive.) *** (Specificity -The percentage of people who do not have a UTI and test negative.) Antibiotic Resistance A 2019 Saudi Arabian study found that more than 92 percent of bacteria that cause UTIs are resistant to at least one common antibiotic, and almost 80 percent are resistant to at least two.[18] In a U.S. study of ambulatory patients with positive urine cultures there was a 55.8% resistance to beta-lactams, 22.4% resistance to trimethoprim/sulfamethoxazole, 21.6% resistant to nitrofurantoin, and 21.6% resistance to fluoroquinolones. In addition, 8.6% of the positive cultures were extended-spectrum beta-lactamase–producing. Multidrug resistance for two or more antibiotics was 17.7% and 6.4% for three or more antibiotics.[19] The rise of extended spectrum beta-lactamase organism UTIs, the most common being Escherichia coli and Klebsiella pneumoniae , may complicate what appears to be a simple UTI due to the multiple drug resistances of those organisms. Antibiotic Recommendations The 2010 Practice guidelines for the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases are being updated and have not yet been released. The European Association of Urology guidelines are from 2023. The recommendations for treating uncomplicated UTIs are similar in the two guidelines.[5,20] In women, antibiotics recommended as first line treatment include nitrofurantoin 100 mg twice a day for 5 days, fosfomycin 3 grams once, pivmecillinam 400 mg three times a day for 3–5 days (not currently approved for use in the U.S.). Cephalosporins such as cefadroxil, 500 mg twice a day for 3 days are an alternative choice. If local resistance is less than 20%, Trimethoprim-Sulfamethoxazole, 160/800 mg twice a day for 3 days can be considered, except during the first trimester of pregnancy. In the European Association of Urology guidelines, Trimethoprim-Sulfamethoxazole 160/800 mg twice a day for 7 days depending on local sensitivities can be a first line choice for men, with fluoroquinolones as a second choice. Cystitis in men may also involve the prostate gland which may require more prolonged treatment, and by definition is considered a complicated infection which may require urologic evaluation. [5,20] Extended spectrum beta-lactamase organism urinary infections may require intravenous antibiotics, but depending on sensitivities, oral fosfomycin, nitrofurantoin, trimethoprim-sulfamethoxazole and fluroquinolones may be effective.[21] The fluoroquinolones can be effective for treating UTIs, but due to adverse side effects such as tendinopathy and tendon rupture, peripheral neuropathy and aortic aneurysm,[22] should not be used routinely for uncomplicated UTIs. Fosfomycin is only one dose but may not be as effective as other short course regimens. Beta lactams such as amoxicillin-clavulanate, cefdinir, cefaclor, and cefpodoxime-proxetil can be used but may not be as effective as other first line drugs. Amoxicillin or ampicillin should not be used for UTI treatment as world-wide bacterial resistance is high.[5,20] Conclusion Treating the “simple” uncomplicated UTI is actually a complex issue. A clinician needs to take into account varying definitions of what a positive urine culture is depending upon the clinical scenario, decide if a patient has asymptomatic bacteriuria that does not require treatment, understand the advantages and limitations of a urine dipstick, know the antibiotic sensitivities in one’s community to try to prescribe the best antibiotic in an era of increasing bacterial resistance, and be on the lookout for UTI mimics such as vaginitis, or contaminated urine samples. While clean-catch midstream urine sample collection is still used as the standard, in a number of studies it has not been found to be superior at reducing specimen contamination in women more than a simple voided specimen. There is evidence that a midstream urine in men is better at reducing contamination than a first void specimen. * Clinical observation/suggestion by Dr. Housman 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Download PDF [1] Orenstein R, Wong ES. Urinary tract infections in adults. Am Fam Physician. 1999;59(5):1225-1237. Retrieved from: https://www.aafp.org/pubs/afp/issues/1999/0301/p1225.html [2] Behzadi P, Behzadi E, Pawlak-Adamska EA. Urinary tract infections (UTIs) or genital tract infections (GTIs)? It's the diagnostics that count. GMS Hyg Infect Control. 2019;14:Doc14. Published 2019 Feb 18. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449866/ [3] Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med. 1982;307:463-8. Retrieved from: https://www.nejm.org/doi/10.1056/NEJM198208193070802?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [4] Komaroff AL. Urinalysis and urine culture in women with dysuria. Ann Intern Med. 1986;104:212-8. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/3511813/ [5]Bokat G et al. EAU Guidelines on Urological Infections. European Association of Urology 2023. Limited Update March 2023. Retrieved from: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Urological-infections-2023.pdf [6]Tan CW, Chlebicki MP. Urinary tract infections in adults. Singapore Med J. 2016;57(9):485-490. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027397/ [7]Lifshitz E, Kramer L. Outpatient Urine Culture: Does Collection Technique Matter? Arch Intern Med. 2000;160(16):2537–2540. Retrieved from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/485431 [8]Pradoni et al. Assessment of urine collection technique for microbial culture. Am J Infect Control 1996;24:2 19-21. Retrieved from: https://www.ajicjournal.org/article/S0196-6553(96)90018-8/pdf [9]Leisure MK et al. Does a Clean-Catch Urine Sample Reduce Bacterial Contamination? Correspondence. N Engl J Med 328:289-290. January 28, 1993. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJM199301283280420 [10] Holm A, Aabenhus R. Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review. BMC Fam Pract 17, 72 (2016). Retrieved from: https://bmcprimcare.biomedcentral.com/articles/10.1186/s12875-016-0465-4 [11]LaRocca MT et al. Effectiveness of Preanalytic Practices on Contamination and Diagnostic Accuracy of Urine Cultures: a Laboratory Medicine Best Practices Systematic Review and Meta-analysis. Clinical Microbiology Reviews. Vol. 29, No. 1. January 2016. Retrieved from: https://journals.asm.org/doi/epub/10.1128/cmr.00030-15 [12] Lipsky BA et al. Is the clean-catch midstream void procedure necessary for obtaining urine culture specimens from men? The American Journal of Medicine. Volume 76, ISSUE 2, P257-262, February 1984. Retrieved from: https://www.amjmed.com/article/0002-9343(84)90782-4/pdf [13] Nicolle LE et al. Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America. JF Clinical Infectious Diseases. Volume 68, Issue 10, 15 May 2019, Pages e83–e110. 2019. Retrieved from: https://academic.oup.com/cid/article/68/10/e83/5407612?login=false [14] Lightner DJ et al. Best Practice Statement on Urologic Procedures and Antimicrobial Prophylaxis. The Journal of Urology. Volume 203, Issue 2, pages 351-356. February 2020. Retrieved from: https://www.auajournals.org/doi/epdf/10.1097/JU.0000000000000509 [15] Mambatta AK et al. Reliability of dipstick assay in predicting urinary tract infection. J Family Med Prim Care. 2015;4(2):265-268. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408713/ [16] Devillé, W.L., Yzermans, J.C., van Duijn, N.P. et al. The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy. BMC Urol 4 , 4 (2004). Retrieved from: https://bmcurol.biomedcentral.com/articles/10.1186/1471-2490-4-4 [17] Medina-Bombardó, D., Jover-Palmer, A. Does clinical examination aid in the diagnosis of urinary tract infections in women? A systematic review and meta-analysis. BMC Fam Pract 12 , 111 (2011). Retrieved from: https://bmcprimcare.biomedcentral.com/articles/10.1186/1471-2296-12-111 [18] Ahmed SS et al. Uropathogens and their antimicrobial resistance patterns: Relationship with urinary tract infections. Int J Health Sci (Qassim). 2019;13(2):48-55. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436442/ [19] Aronin SI et al. Regional Differences in Antibiotic-resistant Enterobacterales Urine Isolates in the United States: 2018-2020, International Journal of Infectious Diseases, Volume 119, Pages 142-145. 2022. Retrieved from: https://www.sciencedirect.com/science/article/pii/S1201971222001904#tb1fn2 [20] Gupta K et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, Clinical Infectious Diseases, Volume 52, Issue 5, 1 March 2011, Pages e103–e120. Retrieved from: https://academic.oup.com/cid/article/52/5/e103/388285?login=false [21] Tamma PD et al. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2022;75(2):187-212. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890506/ [22] Baggio D, Ananda-Rajah MR. Fluoroquinolone antibiotics and adverse events. Aust Prescr. 2021;44(5):161-164. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542490/

This CME is a two-part series on transaminitis, elevated liver enzymes, and the fatty liver with actionable knowledge to improve outcomes in patients with liver health concerns. Part 1: Transaminitis: What Does It Mean and What Should Be Done When It Occurs?  explores a common challenge in primary care, providing practical insights into identifying and managing elevated liver enzymes. Part 2:  NAFLD vs. NASH: Is Your Patient at Risk?  delves into the distinctions between nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), helping clinicians assess risks and tailor patient care effectively. ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Transaminitis CME - Part 1 Transaminitis, What does it mean and what should be done when it occurs? A Common Conundrum in Primary Care by Eleni Florakis and Jeffrey R. Abergel, M.D . Transaminitis Introduction / Signs and Symptoms The term transaminitis, refers to an elevation in serum transaminases. These transaminases include alanine transaminase (ALT) and aspartate transaminase (AST). ALT is also known as SGPT (serum glutamic pyruvic transaminase), and AST as SGOT (serum glutamic-oxaloacetic transaminase). An elevation in these enzymes may indicate hepatocellular injury. ALT is a more specific marker of hepatocellular cell injury since it is found almost exclusively in liver tissue, whereas AST is also present in cardiac muscle, skeletal muscle, kidney, and brain. Both are released into the bloodstream during liver injury. Transaminitis is a common occurrence in the primary care setting and can be discovered incidentally or as part of a workup for a symptomatic patient. Some symptoms that can be associated with transaminitis include fatigue, pruritis, jaundice, abdominal pain or swelling, nausea, vomiting, and edema of the legs/ankles. Asymptomatic transaminitis is also quite common. It has been estimated that approximately 1% to 9% of asymptomatic people have elevated liver enzyme levels at any given time. Thus, it is important to recognize when testing should be done for these patients and what to look for. Causes Nonalcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis (NASH) are among the most common causes of transaminitis. It can affect up to 30 percent of the population. Other causes include alcoholic liver disease, drug-induced liver injury (DILI), viral hepatitis (Hepatitis B and C), autoimmune hepatitis, hemochromatosis, Wilson’s Disease, alpha 1 antitrypsin deficiency, and infiltrative diseases. Below is a list of common medications associated with elevated liver transaminase levels. Selected Medications Associated with Elevated Liver Transaminase Levels (list not complete) Ace Inhibitors (lisinopril (Prinivil, Zestril), captopril, enalapril) Two possible causes, both rare- cholestasis or acute hepatitis2 Acetaminophen Allopurinol (Zyloprim) Amiodarone Anabolic steroids Anti-depressant medications3 Isoniazid (INH) Kava kava4 Ketoconazole Methotrexate Phenytoin (Dilantin)- mild transaminase elevation usually transient but if significant elevation persists discontinuation is warranted5 Nonsteroidal anti-inflammatory drugs (NSAIDs) Rifampin Statins Tamoxifen6 Tetracyclines Valproic acid (Depakene) Diagnosis The first step in evaluating a patient with abnormal liver enzymes is a thorough history and physical examination. Many causes of liver injury, such as alcoholic liver disease and DILI, can be identified by gathering a detailed history. Risk factors for other causes of liver injury that can be ascertained through a careful history include intravenous drug use, travel to areas endemic for viral hepatitis, weight gain, history of other autoimmune conditions, family history of liver disease, and occupational/recreational exposure to hepatotoxins. Physical examination is crucial for identifying the etiology of transaminitis. Exam findings that may indicate cirrhosis include spider nevi, palmar erythema, gynecomastia, and caput medusae (enlarged superficial epigastric veins). Spider Nevi The presence of Virchow’s node (enlarged left supraclavicular node), Sister Mary Joseph’s nodule (periumbilical nodule), or an abdominal mass may suggest malignancy. The degree of aminotransferase elevation and ratio of AST to ALT can also provide clues. There are just a few conditions that can lead to very high aminotransferase levels, in the range of thousands of units/liter. In this scenario, the clinician should focus on acute viral hepatitis, toxins (most commonly acetaminophen), autoimmune hepatitis, liver ischemia and rarely, acute bile duct obstruction. If a patient’s AST to ALT ratio is 2:1 or greater, when both values are elevated, alcoholic liver disease should be considered, especially if the gamma-glutamyl transferase levels are elevated. Initial testing for transaminitis should include Hepatitis A, B and C serologies, as well as serum ferritin and percent iron saturation(also known as percent transferrin saturation), to assess for hemochromatosis. If the above tests are unrevealing and liver enzyme elevation persists, a right upper quadrant ultrasound should be ordered to rule out dilated bile ducts or masses. Anti-nuclear Antibody(ANA), anti-smooth muscle antibody, anti-mitochondrial M2 antibody, anti-liver kidney microsomal antibody and quantitative immunoglobulins should be checked to rule out autoimmune diseases of the liver. Wilson’s Disease and alpha 1 antitrypsin deficiency, two rare disorders, can be identified by checking ceruloplasmin and alpha-1 antitrypsin enzyme level (respectively). The patient’s medication list should be carefully reviewed using LiverTox produced by the National Institute of Diabetes and Digestive and Kidney Diseases or the FDA Liver Toxicity Knowledge Base . If all of the above tests are unrevealing, the most likely diagnosis is nonalcoholic fatty liver disease. To make this diagnosis, there are two options. NASH Fibrosure is a panel of tests whose results are calculated to identify the degree of steatohepatitis and fibrosis. (For more information about this test use this hyperlink https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/604200 ). A more invasive option is a liver biopsy which has the added benefits of being more accurate than the NASH Fibrosure and can identify other pathologies that were not identified in the bloodwork. Liver elastography is an imaging study that can estimate the fibrotic content of the liver, though it is primarily available at large academic centers. Management If an underlying liver disease, such as Hepatitis C, NASH, autoimmune hepatitis or cirrhosis are discovered, referral to a hepatologist or gastroenterologist is a reasonable course of action. If LFTs remain mildly elevated for 6 months, referral is warranted as well. If DILI is suspected, nonessential medications that have the potential to cause elevations in transaminases should be held and alternatives to essential medications should be considered. If alcoholic liver disease or DILI is suspected, transaminase levels should be reassessed after 6-8 weeks of abstinence. Editor’s note: What do you do about a new elevation in transaminases after initiation of a statin? In our opinion, if less than 2 times normal, address the risk factors (alcohol, etc,), check hepatitis C Ab and other lab tests as described above, and continue the statin and monitor LFT's first after 3 months, then in 6 months and then yearly. Another approach is to stop the statin to see if LFTs improve. And if they do, consider restarting the statin and recheck every 6 months to make sure they are not continuing to rise. Transaminitis CME - Part 2 NAFLD vs NASH: Is Your Patient At Risk? Nonalcoholic fatty liver disease (NAFLD) vs Nonalcoholic steatohepatitis (NASH) by Madeleine Beckman and David Kauvar, MD Nonalcoholic steatohepatitis (NASH), a form of liver disease, is associated with obesity, high blood pressure, type-2 diabetes, high cholesterol and triglyceride levels, use of certain medications, and genetics. In addition, it commonly is seen among patients with metabolic syndrome and insulin resistance. NASH is most prevalent during middle age, but it has been seen in pediatric populations. Primary complications of the disease include fibrosis, cirrhosis, and liver cancer. Nonalcoholic fatty liver disease (NAFLD), a condition caused by fat accumulation in the liver, may progress to NASH, which includes further fat accumulation and progressive inflammation. Increased inflammation can lead to scarring of the liver and/or cirrhosis. Approximately 20% of people with NAFLD develop NASH, and some 12% of NASH patients develop cirrhosis. Signs and symptoms associated with NAFLD include enlarged liver, obesity, elevated serum liver transaminase levels, and insulin resistance. Evidence of liver fibrosis can be identified by utilizing the NASH Fibrosure blood test, magnetic resonance elastography or vibration-controlled transient elastography. Consider one of these assessments if the patient is at higher risk for developing steatohepatitis (e.g., those with poorly controlled diabetes). Fatty Liver Biopsy Pathologic evaluation by biopsy is the most accurate way to truly distinguish NAFLD from NASH; however, the need for a biopsy should be decided by either a hepatologist or an experienced gastroenterologist. The primary physician should try to exclude other causes of elevated liver transaminases, such as alcohol consumption, viral hepatitis , autoimmune disease, or hemochromatosis. Fatty Liver The association between genetic variations and NAFLD and NASH is being widely studied. Results of one study by Speliotes et al. at the Massachusetts General Hospital showed that certain inherited variations in lipid metabolism precede and possibly lead to the development of liver disease. Variation of the PNPLA3 gene correlates with an increased risk of severe histologic features of NAFLD without having a strong effect on metabolic syndrome component traits. The PNPLA3 gene produces adiponutrin, a protein that seems to help regulate the production of adipocytes, lipogenesis, and lipolysis in hepatocytes and adipocytes. PNPLA3 appears to be part of a family of enzymes that affect lipid metabolism. Altered lipid metabolism, particularly within the liver, can affect fat accumulation, subsequent development of NAFLD, and possibly NASH. Genetic analyses may allow researchers to chart the causal pathways that lead to disease complications of NAFLD and other metabolic risk factors to potentially target them for therapeutic intervention. Results from a recent Temple University study by Gerhard et al. showed that increased expression of the AEBP1 gene correlates with the severity of liver fibrosis in patients with NASH. Having the AEBP1 gene appears to correlate with the onset and severity of fibrosis in NASH patients, suggesting that AEBP1 may represent a specific therapeutic target to prevent development of NASH fibrosis. DIAGNOSIS NAFLD is usually asymptomatic. However, some patients report feeling tired or experience discomfort in the right upper quadrant of the abdomen if they have progressed to NASH or cirrhosis. NASH can be diagnosed using bloodwork (NASH Fibrosure) or imaging (Elastography) ; however, needle biopsy is considered to be the diagnostic “gold” standard. MANAGEMENT A serious concern with respect to diagnosis and treatment of NASH is the growing obesity rate. In 10 years, there may be more than a 50% annual increase in NASH patients needing a liver transplant. The basic and most effective strategy for treating NASH is for patients to improve their overall health by changing their lifestyles. Steps include: Lowering high blood pressure Eating a low-fat diet Restricting alcohol Lowering triglyceride and cholesterol levels Losing weight Getting more exercise In patients with type II Diabetes Mellitus, pioglitazone (Actos), should be considered as it has been shown to reduce fibrosis, steatosis, and inflammation. Vitamin-E supplementation may also be useful in noncirrhotic patients with biopsy confirmed steatohepatitis. Recently, use of obeticholic acid (Ocaliva), an agonist of the farnesoid X receptor that was approved by the US Food and Drug Administration to treat primary biliary cholangitis, was shown to significantly improve regression of fibrosis in NASH patients. The Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment (REGENERATE) was conducted by the National Institutes of Health and is now in phase-III testing with 931 patients. Results have shown a 28% rate of fibrosis regression, and a significant number of study patients showed normalization of liver enzyme levels. Conclusion NASH, whether driven by genetics, body composition, dietary indiscretion, use of toxic medications, or possible viral infections, still remains a mostly elusive condition in cause, prognosis, and management. More complete information on its etiology, diagnosis, and treatment ultimately will lead to a healthier population and a lesser demand for liver transplantation. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References for Transaminitis 1 Devarbhavi H. An Update on Drug-induced Liver Injury. J Clin Exp Hepatol. 2012 Sep; 2(3): 247–259. Published online 2012 Sep 21. doi: 10.1016/j.jceh.2012.05.002 2 Lisinopril. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases ; 2012-. Last Update: February 11, 2018 3 Voican C, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014 Apr;171(4):404-15. doi: 10.1176/appi.ajp.2013.13050709. 4 Fu P, Xia Q, Guo L, Yu H and Chan P. Toxicity of Kava Kava. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008 Jan-Mar; 26(1): 89–112. doi: 10.1080/10590500801907407 5 Phenytoin. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases ; 2012-. 6 Tamoxifen. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases ; 2012-. Last Update: August 20, 2020. ArAGon G, Younossi ZM. When and how to evaluate mildly elevated liver enzymes in apparently healthy patients. Cleve Clin J Med. 2010 Mar 1;77(3):195-204. Alatalo PI, Koivisto HM, Hietala JP, Puukka KS, Bloigu R, Niemelä OJ. Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. The American journal of clinical nutrition. 2008 Oct 1;88(4):1097-103. Alempijevic T, Zec S, Milosavljevic T. Drug-induced liver injury: Do we know everything?. World J Hepatol. 2017;9(10):491-502. doi:10.4254/wjh.v9.i10.491 Coates P. Liver function tests. Australian Family Physician. March 2011;40(3):113-115. Forlani G, Di Bonito P, Mannucci E, Capaldo B, Genovese S, Orrasch M, Scaldaferri L, Di Bartolo P, Melandri P, Dei Cas A, Zavaroni I. Prevalence of elevated liver enzymes in Type 2 diabetes mellitus and its association with the metabolic syndrome. Journal of endocrinological investigation. 2008 Feb;31(2):146-52. Fox A, Sanderlin JB, McNamee S, Bajaj JS, Carne W, Cifu DX. Elevated liver enzymes following polytraumatic injury. Journal of Rehabilitation Research & Development. 2014 Jun 1;51(6). Friedman L. Approach to the patient with abnormal liver biochemical and function tests. UpToDate Web site. Updated Jun 10, 2020. Accessed February 18, 2021. Jeon CY, Roberts CK, Crespi CM, Zhang ZF. Elevated liver enzymes in individuals with undiagnosed diabetes in the US. Journal of Diabetes and its Complications. 2013 Jul 1;27(4):333-9. Krier M, Ahmed A. The Asymptomatic Outpatient with Abnormal Liver Function Tests. Clinics in Liver Disease. 2009;13(2):167-177. https://doi.org/10.1016/j.cld.2009.02.001. Lee, Tae Hoon, W. Ray Kim, and John J. Poterucha. Evaluation of elevated liver enzymes. Clinics in Liver Disease. 2012; 16(2):183-198. Madan, Kaushal, et al. Role of polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach. Journal of gastroenterology and hepatology. 2004;19(11): 1291-1299. Mahady SE, Wong G, Turner RM, Mitchell P, Macaskill P, Craig JC, George J. Elevated Liver Enzymes and Mortality in Older Individuals. Journal of clinical gastroenterology. 2017 May 1;51(5):439-45. Mainous AG, Diaz VA, King DE, Everett CJ, Player MS. The relationship of hepatitis antibodies and elevated liver enzymes with impaired fasting glucose and undiagnosed diabetes. The Journal of the American Board of Family Medicine. 2008 Nov 1;21(6):497-503. Malakouti M, Kataria A, Ali SK, Schenker S. Elevated Liver Enzymes in Asymptomatic Patients - What Should I Do?. J Clin Transl Hepatol. 2017;5(4):394-403. doi:10.14218/JCTH.2017.00027 Oh R, Hustead TR, Ali SM, et al. Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. Am Fam Physician. 2017 Dec 1;96(11):709-715. Papatheodoridis GV, Goulis J, Christodoulou D, Manolakopoulos S, Raptopoulou M, Andrioti E, Alexandropoulos N, Savvidou S, Papachristou A, Zervou E, Seferiadis K. High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity. European journal of gastroenterology & hepatology. 2007 Apr 1;19(4):281-7. Rahmani J, Miri A, Namjoo I, Zamaninour N, Maljaei MB, Zhou K, Cerneviciute R, Mousavi SM, Varkaneh HK, Salehisahlabadi A, Zhang Y. Elevated liver enzymes and cardiovascular mortality: a systematic review and dose–response meta-analysis of more than one million participants. European journal of gastroenterology & hepatology. 2019 May 1;31(5):555-62. Senadhi V. A paradigm shift in the outpatient approach to liver function tests. Southern Medical Journal.2011 Jul;104(7):521-525. DOI: 10.1097/smj.0b013e31821e8ff5. Singh, Wg Cdr Vishal, and Wg Cdr Prateek Kinra. Mild Transaminitis in asymptomatic aircrew-a clinical dilemma. Ind J Aerospace Med 52 (2008): 2. St. George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Effect of a lifestyle intervention in patients with abnormal liver enzymes and metabolic risk factors. Journal of gastroenterology and hepatology. 2009 Mar;24(3):399-407. Tapper EB, Saini SD, Sengupta N. Extensive testing or focused testing of patients with elevated liver enzymes. Journal of hepatology. 2017 Feb 1;66(2):313-9. References for NAFLD vs NASH Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge . J Clin Epidemiol. 1993;46:1331–1336. Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012; 35:66-75. Bril F, Kalavalapalli S, Clark VC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16:558-566.e2. Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate Web site . Updated June 24, 2019. Accessed August 15, 2019. Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1330. Gerhard GS, Hanson A, Wilhelmsen D, et al. AEBP1 expression increases with severity of fibrosis in NASH and is regulated by glucose, palmitate, and miR-372-3p. PLoS One . 2019;14:e0219764. Harrison SA. Correlation between insulin resistance and hepatitis C viral load. Hepatology. 2006;43:1168. Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of D-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology. 1997;113:1069–1073. Kirkendoll SM. NASH may overtake hepatitis C as top liver transplant cause. M Health Lab Web site . October 31, 2017. Accessed August 15, 2019. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165–169. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55:429-436. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:412–423. Nonalcoholic fatty liver disease. Barnes-Jewish St. Peters Hospital Web site . Accessed August 15, 2019. Patel A, Harrison SA. Hepatitis C virus infection and nonalcoholic steatohepatitis. Gastroenterol Hepatol (N.Y.) 2012;8:305-312. Patal B, Sanyal AJ. Drug-induced steatohepatitis. Clin Liver Dis. 2013;17:533-vii. Pessayre D, Fromenty B, Berson A, et al. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev. 2012;44:34–87 Rivera C. Risk factors and mechanisms of non-alcoholic steatohepatitis. Pathophysiology. 2008;15:109-114. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362:1675-1685. Shteyer E, Villenchik R, Mahamid M, Mator N, Safadi R. Low serum lysosomal acid lipase activity correlates with advanced liver disease. Int J Mol Sci . 2016;17:312. Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2017;23:1-12. Speliotes EK , Butler JL , Palmer CD , et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010;52:904-912. Younossi Z, Lavine JE, Charlton M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases . Hepatology. 2018;67:328–357. Zoler ML. Obeticholic acid reversed NASH liver fibrosis in phase 3 trial. MDEdge Web site. April 12, 2019. Accessed August 15, 2019. Initially published 8/1/2021

What is Lipoprotein (a), why is it important, and how are elevations of it treated? Apolipoproteins are proteins that bind to lipids to form lipoproteins. Lipoprotein (a) is a lipoprotein that contains apolipoprotein B100 (apoB) which is bound to apolipoprotein(a) (apo(a)). The apoB part of Lp(a) is thought to be atherogenic because of its similarity to LDL. ApoB has an LDL-like lipid core and is proatherogenic. Although there are much fewer circulating plasma Lp(a) particles than LDL particles, Lp(a) may be selectively retained in the arterial wall through binding of apo(a) to extracellular matrix proteins. There are a number of different subtypes of apo(a) to which proinflammatory and proatherogenic phospholipids can bind.[1] Lp(a) carries endogenous oxidized phospholipids which stimulate the immune system and can trigger sterile inflammation and calcification. Apo(a) also interacts with fibrin/fibrinogen and endothelial cells through its lysine-binding site and is found in human atheromas and calcified aortic valves.[1] Lipoprotein (a) (Lp(a)) elevation is an independent risk factor for cardiovascular disease. This article will discuss what Lp(a) is, why it is problematic and how to treat abnormally elevated levels. Cardiology ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 By Stuart M Caplen MD Lipoprotein (a) (Lp(a)) elevation is an independent risk factor for cardiovascular disease. This article will discuss what Lp(a) is, why it is problematic and how to treat abnormally elevated levels. Lp(a) was discovered in 1963 by Kare Berg who found it in the low-density lipoprotein (LDL) fraction of serum. He discovered the connection between abnormal elevations of Lp(a) and the presence of coronary artery disease.[1] Lp(a) is a lipoprotein that contains apolipoprotein B100 (apoB) which is bound to apolipoprotein(a) (apo(a)). ApoB has an LDL-like lipid core and is proatherogenic. There are a number of different subtypes of apo(a) to which proinflammatory and proatherogenic phospholipids can bind.[1] Apolipoproteins are proteins that bind to lipids to form lipoproteins Genetic Variation 70% to over 90% of Lp(a) production is genetically determined, although environmental factors and medical conditions may also play a role.[1] Abnormally high Lp(a) levels can differ depending on ethnicity and the type of assay used, making standardization of normal ranges difficult. Blacks of African descent and South Asians have been found to have generally higher median Lp(a) levels than Whites or East Asians.[1] Lp(a) blood levels are dependent on 2 LPA gene alleles. Other gene loci are involved to a much lesser extent in regulating Lp(a) levels. The LPA gene is thought to have evolved from the gene for plasminogen. There can be more than a 1000-fold range of Lp(a) concentrations between individuals, from less than 0.1 mg/dL (milligrams per deciliter) to more than 300 mg/dL. Lp(a) blood levels are not greatly influenced very much by age, gender, fasting state, diet, or physical activity.[2] Lipoprotein (a) Structure [3] Lp(a) has an LDL-like core. Apo(a) binds to apoB-100 via a single disulfide bond (A) at a location near the LDL receptor binding site (B). Apo(a) has kringle structures KIV and KV. There are 10 variants of apo(a) KIV of which type 2 is present in multiple copies. Apo(a) binds to proinflammatory and proatherogenic oxidized phospholipids (C). Apo(a) also has a protease domain (D) that lacks proteolytic activity. Lp(a) is produced in the liver. Lp(a) concentrations are dependent on the number of kringle IV (KIV) repeats in an individual’s apo(a), which is controlled by the LPA gene. A kringle is named after a Scandinavian pretzel-like pastry they resemble. It is a protein folded in on itself in a loop that becomes part of a larger molecule. There are ten different genetic variants of Kringle IV but one, KIV type 2, can be repeated from 2 to 40 times in apo(a). The number of KVI type 2 repeats are thought to be responsible for most of the genetic variation seen. Individuals having smaller apo(a) molecules with less than 22 KVI type 2 repeats have, on average, markedly higher Lp(a) concentrations than individuals having larger apo(a) isoforms with more than 22 KIV type 2 repeats. There is also a kringle V (KV) that can be found in Lp(a), but it only appears once and does not repeat like the KIV type 2.[2] Adverse Effects The apoB part of Lp(a) is thought to be atherogenic because of its similarity to LDL. Although there are much fewer circulating plasma Lp(a) particles than LDL particles, Lp(a) may be selectively retained in the arterial wall through binding of apo(a) to extracellular matrix proteins. Lp(a) also carries endogenous oxidized phospholipids which stimulate the immune system and can trigger sterile inflammation and calcification. Apo(a) interacts with fibrin/fibrinogen and endothelial cells through its lysine-binding site and is found in human atheromas and calcified aortic valves.[1] Cardiovascular Events One study found that each doubling of the Lp(a) level is associated with 22% greater risk of myocardial infarction.[4] A meta-analysis found that high Lp(a) levels are an independent risk factor for cardiovascular disease with an odds ratio of 2.57.[5] Another large study found that the development of heart failure increased with increasing levels of Lp(a).[6] While there appears to be a linear relationship between Lp(a) levels and cardiovascular outcomes, an Lp(a) level of 30–50 mg/dL is frequently used as the cut-off for concern about cardiovascular disease (CVD).[5] The European Atherosclerosis Society Consensus Panel guideline states that the desired Lp(a) level for the prevention of CVD is less than 50 mg/dL.[7] A large Scandinavian study postulated that based on their findings, to reduce major adverse cardiovascular events in a population of patients with existing CVD by 20%, Lp(a) levels would need to be reduced a median of 50 mg/dL (105 nmol/L (nanomoles per liter)) for five years in that population.[8] Aortic Valve Calcification Patients with elevated Lp(a) levels have more rapid aortic valve calcification progression on serial computed tomography scans, and worse clinical outcomes.[1] One study found accelerated progression of aortic stenosis in individuals in the top third of measured Lp(a) levels.[1,9] It was also found that in patients with diagnosed aortic stenosis, elevated Lp(a) levels and elevated numbers of oxidized phospholipids attached to the Lp(a) molecules were associated with more rapid aortic stenosis progression and need for aortic valve replacement.[9] Another study identified a single mutation of the LPA gene to be associated with the presence of aortic-valve calcification with an odds ratio of 2.05.[10] The same study found evidence that suggested lifelong elevations in Lp(a) levels lead to a markedly increased prevalence of aortic-valve calcification in adulthood.[10] A meta-analysis looking at calcific aortic valve disease (CAVD) found an association between Lp(a) levels ≥50 mg/dL and CAVD, but there was insufficient evidence to link Lp(a) levels between 30 mg/dL and 50 mg/dL similarly to CAVD. The authors suggested that the magnitude of the Lp(a) concentration might have a dose-response relationship with CAVD.[11] Stroke Lp(a) elevation is thought to possibly be a stroke risk but at a lower level of risk than for cardiac disease, but the data is conflicting. One large study found subjects whose Lp(a) levels were an average of 28 mg/dL lower than a comparison group with higher Lp(a) levels, had 13% less stroke events.[1,12] However, a meta-analysis found evidence that Lp(a) elevation caused CVD but found no evidence of a relationship to stroke.[13] Thrombosis Because of Lp(a)s similarity to plasminogen, and the fact that apo(a) inhibits plasmin-mediated fibrinolysis in vitro, the question of whether elevated Lp(a) levels can lead to thrombotic events has been investigated. Although some data from trials suggest a positive association of Lp(a) level and risk of venous thromboembolism,[14-16] the literature is mixed. Another study found no effect of Lp(a) on venous thromboembolism[17]. Meta-analyses have been both positive and negative for a correlation between Lp(a) levels and venous thrombosis.[18-20] Diabetes Mellitus An inverse association of very low Lp(a) levels and type 2 diabetes mellitus has been discovered with very low levels of Lp(a) associated with a higher risk of developing diabetes. Lp(a) levels of less than 4 mg/dL were associated with approximately a 20% to 50% higher relative risk of diabetes development, with Lp(a) levels of less than 1 mg/dL having the highest risk.[21] This was confirmed by a number of other studies.[22,23] One of them also found that prediabetes, insulin resistance, and hyperinsulinemia were all increased in subjects with very low levels of Lp(a).[22] Testing The National Lipid Association recommends that testing for Lp(a) levels be considered when there is a significant family history of premature ASCVD (arteriosclerotic cardiovascular disease) in first-degree relatives, personal history of premature ASCVD, or severe primary hyperlipidemia. The American College of Cardiology and American Heart Association screening guidelines mention Lp(a) testing as an optional risk enhancer measurement. [24] The European Society of Cardiology has a general recommendation to screen Lp(a) levels at least once in a person’s lifetime.[25.26] One of the difficulties in standardizing testing for Lp(a) is that there a number of different assays. The gold standard is considered to be the ELISA test (enzyme-linked immunosorbent assay). The ELISA test measures the true number of Lp(a) particles and is reported in nanomoles per liter (nmol/L). Other immunoassay tests may overestimate or underestimate true Lp(a)levels due to calibration in milligrams/deciliter (mg/dL). Mg/dL is a weight-based measure, that does not fully take into account the variability in size of the apo(a) segment due to the differing numbers of attached kringle units. However, recent improvements in immunoassay testing have been able to increase the precision of mg/dL testing methods.[1] A significant portion of the medical literature on Lp(a) has been reported in mg/dL units but there have been recommendations that nmol/L per liter, be selected as the standard in the future.[1] One suggested method of converting Lp(a) nmol/L units to mg/dL units is to divide the nmol/L result by 2.15.[27] Ethnicity Abnormally high Lp(a) levels can differ depending on ethnicity, making standardization of normal ranges difficult. Blacks of African descent and South Asians have been found to have generally higher median Lp(a) levels than Whites or East Asians.[1] In another study of subjects with familial hypercholesterolemia, mean Lp(a) levels were 30-33% higher in Druze, Christian-Arabs, and Jewish-Ashkenazi groups than the control group who were family members without hypercholesterolemia. Lp(a) levels were increased over control levels by 110% in the Jewish-Sephardic subject group in that trial.[28] What to do with this information when treating patients is unclear as the literature is sometimes conflicting and more definitive research is needed. Blacks have median Lp(a) levels two to three times higher than Whites, and there are conflicting study findings that elevated Lp(a) levels in Blacks both cause and don’t cause harm.[29-32] Part of this may be that Blacks predominantly carry the larger apo(a) isoform which is less atherogenic. However, one study found 26% of African-Americans carried the more atherogenic smaller apo(a) isoform. Not controlling for different apo(a) isoforms within an ethnic group may explain some of the conflicting findings of different studies.[33] Treatment There are data to support that lowering the Lp(a) can reduce adverse cardiovascular events.[1] Results from studies of dietary intervention show only very modest effects on reducing Lp(a) levels. [1,3] A clinical goal, especially when adverse events occur even after aggressively lowering the LDL cholesterol and apoB levels is to secondarily attempt to lower the Lp(a) level if elevated.[1] Lipoprotein Apheresis The most effective intervention for Lp(a) lowering is lipoprotein apheresis. Blood is withdrawn from one intravenous line by a blood pump and the plasma is then separated out and filtered to remove LDL and Lp(a). Both the treated plasma and the rest of the blood components are returned to the patient’s circulation by a second intravenous line. It is typically performed every 2 weeks as Lp(a) levels return to previous levels after that time period. The Food and Drug Administration approval for Lp(a) lowering using lipoprotein apheresis is for a Lp(a) level greater than 60 mg/dL and LDL greater than 100 mg/dL with either documented coronary artery disease or documented peripheral artery disease.[34] During a 3- to 4-hour apheresis session, the Lp(a) level typically is lowered by about 50% to 85%. There is also a reduction in oxidized phospholipids, as well as lowering LDL concentrations by 60% to 85%. There is clinical data suggesting that Lp(a) lowering with lipoprotein apheresis may reduce the risk of cardiovascular events.[1] In one study, patients with Lp(a) above the 95th percentile who continued to have major adverse coronary events (MACE) despite being on maximally tolerated lipid-lowering therapy, were started on lipoprotein apheresis. In the study group Lp(a) levels were lowered 73% and the MACE rate decreased 86% compared to a pre-apheresis phase of the study used as the control.[2,35] Another similar trial demonstrated that lipoprotein apheresis effectively lowered the incidence of MACE by 78%.[36] In a different study, subjects with an Lp(a) over 50 mg/dL who were treated with apheresis plus statin for 18 months had significantly more regression of coronary atherosclerosis lesions when compared to a statin only group.[2,37] Statins Standard hyperlipidemia treatments such as statins have minimal Lp(a)-lowering efficacy, and some statins may increase Lp(a) levels.[1] One meta-analysis found that statins significantly increased baseline plasma Lp(a) levels 8.5% to 19.6%.[38] The mechanism is not well understood but the authors postulated that statin-induced increased production of apo(a) may lead to increased plasma levels of Lp(a). Another possible mechanism may depend on statin mediated increase in plasma proprotein convertase subtilisin/kexin type 9 protein (PCSK9) levels, which may further increase Lp(a) production.[38] Another meta-analysis and systemic review found that statin therapy does not cause clinically significant changes in Lp(a) levels and may not change Lp(a) associated cardiovascular risk.[39] PCSK9 Inhibiting Medications Trials of monoclonal antibodies that inhibit PCSK9 demonstrated that besides lowering LDL levels, those medications can also reduce Lp(a) levels by 25% to 30%.[1,40] In the ODYSSEY trial, cardiac patients on statins with LDL maximized to 70mg/dL or lower started using alirocumab, which caused a lowering of Lp(a) levels that independently reduced the risk for MACE compared to controls. The investigators found that each 1mg/dL reduction in Lp(a) was associated with a 0.6% decrease in the risk of MACE events.[41] The FOURIER trial found that evolocumab reduced Lp(a) levels by 26.9% and the risk of coronary heart disease, death, myocardial infarction, or urgent revascularization by 23%.[42] Another PCSK9 directed medication is inclisiran, which is a small interfering RNA that blocks PCSK9 messenger RNA. In clinical trials it has been found to decrease Lp(a) levels by 18.6–25.6% while reducing LDL levels close to 50%. One of the advantages of inclisiran is that it is long-lasting and after a second dose administered at 3 months, recommended dose intervals are then every 6 months.[43,44] Antisense Oligonucleotides Newer medications, still in testing trials, are antisense oligonucleotides which inhibit the production of apolipoprotein(a) in the hepatocyte, the source of Lp(a). One drug, known as APO(a)-LRx , has been found to reduce Lp(a) levels up to 80%.[45] Niacin Niacin when taken daily has been shown to lower Lp(a) by 20% to 45% as well as raising HDL and lowering LDL. Niacin by itself has been found in one 15-year study to decrease mortality 11%,[46] and in another meta-analysis niacin reduced MACE 25%.[47] However, niacin when added to statins has not been associated with improved cardiac outcomes in a number of trials and appears to add no benefit to statins alone.[1,2,48-50] Hormonal drugs Hormonal drugs may improve Lp(a) levels but are not necessarily associated with improved cardiovascular outcomes. Estrogen can improve Lp(a) levels but is not currently used as a therapy to improve lipid markers. Estrogen also does carry other potential risks and is unlikely to become an established treatment. Testosterone replacement therapy has also been shown to lower Lp(a) levels, but more research is needed. Testosterone replacement therapy can lower HDL levels, which may elevate the risk of atherosclerosis.[26] Conclusion Lipoprotein (a) elevation is a known genetic risk factor for both cardiovascular disease and aortic calcification. Unfortunately, diet and lifestyle changes do not affect Lp(a) levels to any significant degree. There are differences in median Lp(a) levels in different ethnic groups which may need to be taken into consideration. There are a number of tests for Lp(a) but ELISA is considered the most accurate. Mg/dL is frequently used as the reported value for Lp(a) levels in the literature but there have been recommendations to switch to nmol/L, which is thought to provide a more accurate measurement. At a minimum, patients with premature CVD, recurrent CVD despite being on statin therapy, high risk of fatal CVD, a family history of hypercholesterolemia, elevated Lp(a), or premature CVD should probably have Lp(a) levels checked.[2] Niacin lowers Lp(a) but has not been shown to improve outcomes when added to statin therapy. Statins may actually raise Lp(a) levels and may not be completely effective in preventing MACE in patients with Lp(a) elevations. PCSK9 inhibitors and PCSK9 small interfering RNA drugs lower Lp(a) levels and have demonstrated improved cardiac outcomes. Antisense oligonucleotides, which dramatically decrease Lp(a) levels, are currently being evaluated. Lipoprotein apheresis is a definitive treatment usually reserved for patients with an Lp(a) level over 60 mg/dL. “Thank you to Dr. Theodor Feigelman and Julie Sandler for their assistance editing this article” 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 References [1] Reyes-Soffer G et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Oct 14,2021. Retrieved from: https://www.ahajournals.org/doi/10.1161/ATV.0000000000000147#R101 [2] Kronenberg F. Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases. Cardiovasc Drugs Ther. 2016;30(1):87-100. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789197/ [3] Enkhmaa B, Petersen KS, Kris-Etherton PM, Berglund L. Diet and Lp(a): Does Dietary Change Modify Residual Cardiovascular Risk Conferred by Lp(a)? Nutrients. 2020; 12(7):2024. Retrieved from: https://www.mdpi.com/2072-6643/12/7/2024 [4] Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction. JAMA. 2009;301(22):2331–2339. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/184063 [5] Watanabe J, Hamasaki M, Kotani K. Risk of cardiovascular disease with lipoprotein(a) in familial hypercholesterolemia: a review. Arch Med Sci Atheroscler Dis. 2020;5:e148-e152. Published 2020 Jul 11. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433790/ [6] Kamstrup PR, Nordestgaard BG. Elevated Lipoprotein(a) Levels, LPA Risk Genotypes, and Increased Risk of Heart Failure in the General Population. JACC: Heart Failure. Volume 4, Issue 1, Pages 78-87. 2016. Retrieved from: https://www.sciencedirect.com/science/article/pii/S2213177915006502?via%3Dihub [7] Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-2853. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295201/ [8] Madsen CM et al. Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:255–266. Retrieved from: https://www.ahajournals.org/doi/full/10.1161/ATVBAHA.119.312951 [9] Capoulade R, Chan KL, Yeang C, et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015;66(11):1236-1246. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0735109715044654?via%3Dihub [10] Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503-512. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766627/ [11] Liu Q, Yu Y, Xi R, et al. Association Between Lipoprotein(a) and Calcific Aortic Valve Disease: A Systematic Review and Meta-Analysis. Front Cardiovasc Med. 2022;9:877140. Published 2022 Apr 25. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082602/ [12] Connor A. Emdin CA et al. Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. Journal of the American College of Cardiology. Volume 68, Issue 25, Pages 2761-2772. 2016. Retrieved from: https://www.sciencedirect.com/science/article/pii/S073510971636781X?via%3Dihub [13] Genser B, Dias KC, Siekmeier R, Stojakovic T, Grammer T, Maerz W. Lipoprotein (a) and risk of cardiovascular disease--a systematic review and meta-analysis of prospective studies. Clin Lab. 2011;57(3-4):143-156.Retrieved from: https://pubmed.ncbi.nlm.nih.gov/21500721/ [14] von Depka M et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood. 2000; 96:3364–3368. Retrieved from: https://ashpublications.org/blood/article/96/10/3364/181027/Increased-lipoprotein-a-levels-as-an-independent [15] Nowak-Göttl U et al. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation. 1999; 100:743–748. Retrieved from: https://www.ahajournals.org/doi/10.1161/01.CIR.100.7.743 [16] Marcucci R et al. Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism. Am J Med. 2003; 115:601–605. Retrieved from: https://www.amjmed.com/article/S0002-9343(03)00541-2/fulltext [17] Vormittag R et al. Lipoprotein (a) in patients with spontaneous venous thromboembolism. Thromb Res. 2007. Retrieved from: https://www.thrombosisresearch.com/article/S0049-3848(06)00087-9/fulltext [18] Sofi F et al. Lipoprotein (a) and Venous Thromboembolism in Adults: A Meta-Analysis. The American Journal of Medicine. Volume 120, Issue 8, 2007. Pages 728-733. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0002934307002434 [19] Kunutsor SK, SCANDINAVIAN CARDIOVASCULAR JOURNAL VOL. 53, NO. 3, 125–132. 2019. Retrieved from: https://www.tandfonline.com/doi/full/10.1080/14017431.2019.1612087 [20] Dentali F et al. Lipoprotein(a) as a Risk Factor for Venous Thromboembolism: A Systematic Review and Meta-analysis of the Literature. Semin Thromb Hemost. 2017;43(6):614-620. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/28346964/ [21] Mora S et al. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem. 2010;56(8):1252-1260. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912456/ [22] Ding L, Song A, Dai M, et al. Serum lipoprotein (a) concentrations are inversely associated with T2D, prediabetes, and insulin resistance in a middle-aged and elderly Chinese population. J Lipid Res. 2015;56(4):920-926. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373748/ [23]Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes. 2014;63(1):332-342. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246060/ [24] Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1046-e1081. Retrieved from: https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000624?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org [25] Mach et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal (2020) 41, 111188. Retrieved from: https://air.unimi.it/retrieve/dfa8b9a1-0b7d-748b-e053-3a05fe0a3a96/European%20Heart%20Journal%202020_41_%20111.pdf [26] Farzam K, Senthilkumaran S. Lipoprotein A. [Updated 2022 Sep 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570621/ [27] Khera AV et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129(6):635-642. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946056/ [28] Leitersdorf E et al. Diverse effect of ethnicity on plasma lipoprotein[a] levels in heterozygote patients with familial hypercholesterolemia. J Lipid Res. 1991;32(9):1513-1519. Retrieved from: https://www.jlr.org/article/S0022-2275(20)41918-2/pdf [29] Guan W, Cao J, Steffen BT, et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35(4):996-1001. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377643/ [30] Virani SS, Brautbar A, Davis BC, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125(2):241-249. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760720/ [31] Moliterno DJ et al. No Association Between Plasma Lipoprotein(a) Concentrations and the Presence or Absence of Coronary Atherosclerosis in African-Americans. Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:850–855 Retrieved from: https://www.ahajournals.org/doi/full/10.1161/01.ATV.15.7.850 [32] Coronary Heart disease in Asian Indians. Lp (a) and Ethnicty (sic). CADI Research Foundation. 2012. Retrieved from: https://cadiresearch.org/topic/lipoproteina/lp-a-and-ethnicty [33] Paultre F, Pearson TA, Weil HF, et al. High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men. Arterioscler Thromb Vasc Biol. 2000;20(12):2619-2624. Retrieved from: https://www.ahajournals.org/doi/10.1161/01.atv.20.12.2619?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [34] Nugent AK et al. Lipoprotein Apheresis: First FDA Indicated Treatment for Elevated Lipoprotein(a). J Clin Cardiol. 2020; 1(1):16-21 Retrieved from: https://www.scientificarchives.com/article/lipoprotein-apheresis-first-fda-indicated-treatment-for-elevated-lipoprotein [35] Jaeger, B., Richter, Y., Nagel, D. et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Rev Cardiol 6, 229–239 (2009). Retrieved from: https://pubmed.ncbi.nlm.nih.gov/19234501/ [36] Leebmann J, Roeseler E, Julius U, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. 2013;128(24):2567-2576. Retrieved from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.113.002432?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [37] Safarova MS, Ezhov MV, Afanasieva OI, et al. Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl. 2013;14:93–9. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S1567568812000268?via%3Dihub [38] Tsimikas S et al. Statin therapy increases lipoprotein(a) levels, European Heart Journal , Volume 41, Issue 24, 21 June 2020, Pages 2275–2284. Retrieved from: https://academic.oup.com/eurheartj/article/41/24/2275/5492355?login=false [39] de Boer LM, Oorthuys AOJ, Wiegman A, et al. Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis. Eur J Prev Cardiol. 2022;29(5):779-792. Retrieved from: https://academic.oup.com/eurjpc/article/29/5/779/6439180?login=false [40] Navarese EP et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Jul 07;163(1):40-51. Retrieved from: https://www.acpjournals.org/doi/full/10.7326/M14-2957?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org [41] Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, et al; ODYSSEY OUTCOMES Committees and Investigators. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020; 75:133–144. https://www.sciencedirect.com/science/article/pii/S0735109719384645?via%3Dihub [42] O’Donoghue ML et al. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019;139:1483–1492. Retrieved from: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.037184 [43] Cupido AJ, Kastelein JJP. Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res . 2020;116(11):e136-e139. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449556/ [44] LEQVIO prescribing information. Novartis. 2021. Retrieved from: https://www.novartis.com/us-en/sites/novartis_us/files/leqvio.pdf [45] Tsimikas S et al. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease N Engl J Med, 382:244-255. January 16, 2020. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1905239?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed [46] Canner PL et al. Fifteen-year mortality in Coronary Drug Project patients: Long-term benefit with niacin. Journal of the American College of Cardiology. Volume 8, Issue 6, Pages 1245-1255. 1986. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0735109786802935?via%3Dihub [47] Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;210(2):353-361. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0021915009010314\ [48] Boden WE, Sidhu MS, Toth PP. The Therapeutic Role of Niacin in Dyslipidemia Management. Journal of Cardiovascular Pharmacology and Therapeutics . 2014;19(2):141-158. Retrieved from: https://journals.sagepub.com/doi/10.1177/1074248413514481?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [49] Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1107579?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov [50] Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1300955?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov initially published February 2023

The Pros and Cons of Robotic-Assisted Surgery Continuing Medical Education Overview: This article will discuss the pros and cons of robotic-assisted surgery for various procedures.  It will also touch on credentialling issues and the future of robotic-assisted surgery.  ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 By   Stuart M. Caplen, MD Reviewed and Edited by Brian Housman, MD How Is Robotic-assisted Surgery Performed? Robotic-assisted surgery uses a console located away from the bedside where the operating surgeon is seated.  The console is connected to a robotic cart that is beside the patient.  The console typically contains two binocular lenses that magnify and create a three-dimensional image for the surgeon.[1]  A dual-camera endoscope on a robotic arm transmits 3-D images to the surgeon[1].  During the surgery, two handpieces transmit the surgeon's hand movements, allowing manipulatio of surgical instruments which are attached to robotic arms.[1,2]  A motion filtration system minimizes tremor, and foot pedals control different types of monopolar or bipolar energy used to cut and coagulate during the surgery and also control movement of the different robotic instruments including suction, irrigation and stapler devices needed for the procedure.[2]  Some robotic systems have the ability to automatically reposition the robotic arms to keep the instruments in the same relative position in the operating field when the patient’s stretcher is moved to allow better surgical field exposure.  This permits a smooth transition when repositioning a patient, as opposed to needing to undock the robotic platform and then reposition the robotic arms.[3] An assistant, located at the bedside, can retract, remove specimens, suction and deliver equipment as needed.  Some advantages of robotic-assisted surgery for the surgeon include improved dexterity, allowing the surgeon a better ergonomic operating position with lessened muscle fatigue, and the elimination of the need to stand, possibly for hours.[1] Robotic-assisted Surgery Procedures The first recorded use of robotics was in a brain biopsy procedure in 1985.[4]  Since then, the FDA has cleared or approved robotic-assisted surgery for a broad variety of surgery indications across specialties such as cholecystectomy,[5] thoracic surgery[6], hysterectomy, atrial septal defect closure,[7] mitral valve repair,[8] coronary artery anastomosis during cardiac revascularization,[7] spinal pedicle screw insertion,[9] hip replacement, total knee replacements[10], simple and radical prostatectomy,[11,12] transoral otolaryngology procedures,[13] and bronchoscopic lung biopsy[14].  The FDA removed its clearance for robotic-assisted thyroidectomy in 2011 which will be discussed later.[15] In 2001, doctors in New York City performed a telerobotic-assisted gallbladder removal on a patient located in France.[4] Robotic-Assisted Surgery Complications The reported complication rate due to robotic malfunction is approximately 0.1% to 0.5%.  When robotic errors do occur, rates of permanent injury reported range from 4.8% to 46.6% in the medical literature.  In 2016 less than 800 complications directly attributable to a robotic operating system were reported to the FDA for the previous 10-year period.[2]  However, almost 57% of respondents in an internet survey of urologists had experienced an irrecoverable intraoperative malfunction of the robot while performing a robot-assisted radical prostatectomy.  The most common issues reported were malfunctioning of the robotic arms, arm joint problems and camera issues, followed by electrical power issues, instrument malfunction, and a broken console handpiece.[2,16] Some possible disadvantages of robotic-assisted surgery include increased procedure time, human error in operating the apparatus, mechanical failure, accidental burn injuries, lack of tactile feedback, and nerve palsies due to direct nerve compression or extreme body positioning required for some robotic-assisted surgical procedures.[2]  It is uncommon for mechanical failure to result in uncontrolled motion of the arms, due to safety protocols now built into modern robotic-assisted systems that prevent instrument use or restrict motion.*  Experience Required to Gain Technical Proficiency  There is currently no consensus of how many procedures a surgeon would need to perform to gain proficiency in robotic-assisted surgery.  While standardized credentialing is gaining attention in the literature, proficiency varies significantly based on the specialty and technical complexity.  It has been demonstrated that there is a learning curve when surgeons use these tools.[2,17]  A learning curve is the rate of progress in learning a new skill.  There are no national standards but it is common practice for hospitals to require certification to perform robotic-assisted surgery.  Online and in-person training courses by the manufacturers are typically required, and one reference cited 20 bedside and 50 console procedures for residents and 5 proctored procedures for attendings with 50 tracked procedures as being a common standard.[17]  However, an issue that may be problematic is that a hospital’s credentialing process relies on the manufacturers of the equipment.[17]  Various studies defining mastery of robotic-assisted colorectal surgery reported that a surgeon needed 15 to 20 cases to overcome the learning curve.[18]  However, in one study it was reported that technical competence occurred after 44 cases and expert performance occurred after 75 cases.[19]  In another study the initial learning curve was 35 cases but it took 128 cases to reach expert performance.[20]   At one academic center, the failure rate for robotic-assisted mitral valve replacement was 7% for the first 100 cases and fell to 4.5% in the next 200 cases.  The need to convert robotic-assisted to open surgery occurred in 5% to 9.1% during the early part of the learning curve, compared to 0.7% to 1.3% in the later part of the curve.[21,22]   In a study of 326 patients who received totally endoscopic coronary artery bypass graft (CABG) surgery, 14% needed a larger incision during the robotic-assisted procedure, which was found to be dependent on where the surgeon was on the learning curve with the equipment.[23]   An appraisal of the robotic-assisted surgery learning curve in the medical literature concluded that there are few guidelines on dealing with the learning curve.  The number of cases needed to achieve peak performance varied by type of surgery and the learning curve may have several phases, as surgeons perform more complex cases with growing experience.  The literature also lacks a uniform assessment of outcomes and complications that could be used to decide when expertise had been achieved.[24] A Review of Some Robotic-assisted Procedures Abdominopelvic Surgery A systematic review of 50 studies concluded that while robotic-assisted abdominopelvic surgery was safe with slight decreases in complications, it failed to find a significant advantage over traditional open or laparoscopic surgery.[17]  In that review, 9% of conventional laparoscopies led to complications requiring further surgical intervention, compared to 8% of robotic-assisted operations.  In studies of gastrointestinal surgery, life-threatening complications ranged from 0 to 2% for robot-assisted surgery, from 0 to 3% for standard laparoscopy and from 1 to 4% for open surgeries.  In up to 8% of robotic-assisted surgeries and up to 12% in standard laparoscopic surgery the surgeon had to convert to an open surgical procedure.  Robotic-assisted surgery was found to  have increase costs and time duration compared with standard surgery.[17,25]  The authors also point out that in the published literature two-thirds of the authors have received honoraria, speaking or consulting fees from the manufacturer.  They also stated that the lack of high-quality data supporting robot-assisted surgery over laparoscopy or open surgery has not affected its rapid growth due in part to aggressive marketing by manufacturers, the belief that technology will improve outcomes, and demand from patients, surgeons, and health care systems.[17] Radical Prostatectomy  Up to 85% of all radical prostatectomies performed in the U.S. are done using robotic-assisted surgery.  There are high initial upfront costs of one to two million dollars associated with purchasing a robot.  There are also annual maintenance contracts which can cost $150,000 or more per robot, and the cost of disposable instruments which results in much greater direct costs of robotic-assisted prostatectomy compared to open prostatectomy.  In the U.S., most hospitals receive little or no additional payment from insurers for robotic-assisted surgery to offset these added costs.  Many hospitals have marketed robotic-assisted surgery to patients, possibly as a way to recoup the increased costs of using robot surgical equipment.[26] A meta-analysis of robotic-assisted versus open radical proctectomy reported that there were significantly less postoperative complications as well as a lower incidence of postoperative urinary incontinence at one year.  There was no difference between the two techniques with respect to the amount of blood loss and finding cancer-free margins in the tissue removed.  The authors stated that “in the narrow pelvic space, the flexible robotic arm makes the anatomical operation finer than the human hand, and it is easier to preserve the integrity of the nerve.”*[27] (*cavernous nerve)  Another meta-analysis found that robotic-assisted radical prostatectomy was associated with less blood loss and need for blood transfusion, and a shorter length of hospitalization compared to standard surgery.  There was no proof of the superiority of either surgical technique with respect to postoperative complications, cancer-free margins of tissue removed, cancer reoccurrence, urinary incontinence or sexual function.  Robotic-assisted surgery was found to take more operative time and was more expensive than open surgery.[28] Radical Cystectomy A study of robotic-assisted surgery versus open surgery for radical cystectomy (urinary bladder removal) in patients with bladder cancer reported that there were significantly less thromboembolic complications, wound complications, and days spent in the hospital within the first 90 days after surgery with robotic-assisted surgery compared to open surgery.  At 18-month follow-up, there was no significant difference in the recurrence of cancer or mortality between the two groups.[29]  Thyroidectomy In 2011, the FDA withdrew approval of robotic-assisted thyroidectomy surgery and the manufacturer stopped supporting the procedure.[15]  This was due to reports that low-volume medical centers performing less than five cases per year were found to have a significantly higher complication rate than high-volume centers.[30]  While robotic-assisted remote access thyroidectomy is still performed in other countries, it is rarely done in the U.S.[31]  Knee Arthroplasty A meta-analysis of robotic-assisted vs open total knee arthroplasty reported that there was more precise prosthesis positioning and less blood loss with robotic-assisted surgery.  There were no statistically significant differences in the two groups in range of motion and complications after surgery.  Several of the included studies found that the surgeons needed some experience with the equipment to perform the procedure optimally.[32]  Hip Arthroplasty  The literature regarding robotic-assisted hip arthroplasty is mixed.  A meta-analysis of robotic-assisted total hip arthroplasty compared to open surgery reported that robotic-assisted surgery improved component placement and reduced intraoperative complications.  However, robotic-assisted surgery increased the risks of postoperative heterotopic ossification, dislocation, and the need for revision.  Robotic-assisted surgery was found to increase surgical time by 20 minutes compared to standard surgery.[33]  Another meta-analysis reported similar results.[34]  However, a study of over 2,000 patients reported less postoperative dislocations with robotic-assisted surgery.[35]  A different meta-analysis reported that robotic-assisted hip arthroplasty had significantly better component placement, less limb length discrepancies and no significant differences in the number of revision surgeries needed or long-term clinical outcomes compared to standard surgery.[36]  It is possible the different outcomes might be due to where the surgeons were on the learning curve or which manufacture’s device was used.  A systematic review reported that the surgeons’ learning curve for robotic-assisted total hip arthroplasty was between 12 and 35 cases.[37] Mitral Valve Replacement Robotic-assisted mitral valve replacement was first performed in 1998 and received FDA approval in 2002.  The 3-D imaging used in robotic-assisted surgery according to one author allows better visualization of the valve area and may obviate the need for a sternotomy.[38]  In one study of 759 patients, robotic-assisted surgery took longer than open surgery, and the quality of mitral valve repair was judged to be equivalent for robotic-assisted surgery versus partial and complete sternotomy, and right mini-anterolateral thoracotomy.  Neurologic, pulmonary, and renal complications were similar among groups.  The robotic-assisted surgery arm had the lowest occurrences of atrial fibrillation, pleural effusion, and shorter hospital stays.[39] Coronary Revascularization Surgery A robotic-assisted CABG (coronary bypass graft) is where robotic arms and camera are placed in chest wall incisions and the left internal mammary artery is harvested using the robotic arms.  This artery is then grafted onto the blocked coronary artery either through the incisions already in place or hand-sewn in place through a mini-thoracotomy. The procedures can be performed on both the beating heart (off-pump) and the arrested heart (on-pump).[38,40] In one study of 326 patients receiving totally endoscopic coronary artery bypass graft surgery, 14% needed a larger incision.  The need for a larger incision was found to be dependent on where the surgeon was on the learning curve with the equipment.[23] Pulmonary Lobectomy Robotic-assisted pulmonary lobectomy for cancer treatment is estimated to be used in about 20% of lobectomies in the U.S.[41]  Additional surgical approaches include open lobectomy and video-assisted thoracoscopic surgery (VATS).   A meta-analysis of robotic-assisted lobectomy versus open lobectomy for cancer reported that robotic-assisted lobectomy had lower 30-day mortality rates than open surgery or video-assisted thoracoscopic surgery.  Robotic-assisted lobectomy also had less complications and shorter durations of hospitalization than open surgery.  In one study in the meta-analysis, blood transfusions requirements were lower with the robotic-assisted approach.  Surgical times were found to be longer in the robotic-assisted group.[42]   A systematic review reported that blood loss and length of hospital stay were similar between robotic-assisted lobectomy and video-assisted thoracoscopic surgery.  Robotic-assisted lobectomy was superior to thoracotomy and equivalent to video-assisted thoracoscopic surgery for the incidence of persistent air leaks and hospital length-of-stay.  There was no difference in survival between robotic-assisted lobectomy and video-assisted thoracoscopic surgery, however, robotic-assisted lobectomy was found to be more costly than video-assisted thoracoscopic surgery.  The authors cautioned that large prospective studies were needed to confirm or refute those findings.[43] Telerobotic Surgery  Benefits of telerobotic-assisted surgery, where a surgeon operates on a patient from another site include providing healthcare to remote areas, allowing top specialists to participate in a patients care,[44] and its use in battlefield hospital units.   Issues include needing rapid data transmission to allow a safe procedure, mechanical failures,[44] and not having personnel at the bedside who can convert robotic-assisted surgery to open surgery which may prove to be problematic in some cases. Conclusions Robotic-assisted surgery has created a revolutionary change in surgical procedures.  In some areas, such as prostate surgery, there appear to be some significant advantages in using robotic-assisted surgery.  However, a large systematic review of abdominopelvic surgery reported that many of the studies failed to find a significant difference in outcomes between robotic-assisted surgery and standard laparoscopic or open surgery.    Advantages of robotic-assisted surgery over open surgery include smaller incisions, in some cases less blood loss, and decreased hospitalization days.  Some authors also felt that manipulation of surgical instruments in an anatomically small area might be better with robotic-assisted surgery.    Disadvantages of robotic-assisted surgery include longer operative times, the need for a significant learning curve to gain proficiency, and higher costs.  There is also the possible need to change to an open technique, or the possibility of causing an injury during surgery due to mechanical or technical issues.  There may be differences in outcomes of robotic-assisted surgery between academic centers and general hospitals.  In the U.S., the FDA revoked approval/clearance for robotic-assisted thyroid surgery.  The approval was based on data from academic centers where many procedures were performed.  However, when general hospitals doing a lower number of robotic-assisted thyroid procedures were allowed to perform the procedure, outcomes were much worse. Another issue is that there is currently no consensus on agreed upon credentialling requirements for proficiency in robotic-assisted surgery, although hospitals can set up their own credentialling processes.  Using the manufacturer as a necessary part of the credentialling process may potentially be a conflict of interest.   With the significant learning curve required to become proficient with these devices, it is possible not having those standardized guidelines may put some patients at risk for a complication or increased need to convert to an open procedure, especially if the surgeon is at the beginning of the learning curve. There appears to be some selection bias inherent in the medical literature in studies of robotic-assisted surgery that may affect results.  Patients with favorable anatomy, health, and pathology tend to be chosen by surgeons to undergo procedures robotically.  Conditions that favor the choice of robotic surgery may also skew outcomes positively.  By contrast, hazardous conditions will often require open surgery and may be more frequently associated with poorer outcomes.[45,46] It is possible that in the future with the addition of artificial intelligence, improved technology, and surgeons who trained on these devices when they were residents that outcomes with robotic-assisted surgery will continue to improve over time.[17,47] Finally, telerobotic-assisted surgery with the ability of having surgeons able to operate on patients in remote geographic areas or in battlefield hospital units, may improve care to some patients, although communications and mechanical failures, or not having personnel at the bedside who can convert robotic-assisted surgery to open surgery may prove to be problematic in some cases. 🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Relevant Financial Relationships Statement Dr. Caplen has disclosed stock ownership in Intuitive Surgical. His relevant financial relationship was mitigated via slide review and the content found to be evidence-based, balanced, and non-promotional.  All other faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they have no relevant financial relationships with ineligible companies that could constitute a conflict of interest concerning this CME activity. References [1] Goh EZ, Ali T, Robotic surgery: an evolution in practice, Journal of Surgical Protocols and Research Methodologies, Volume 2022, Issue 1, January 2022. Retrieved from: https://academic.oup.com/jsprm/article/2022/1/snac003/6533488 [2] Kirkpatrick T, LaGrange C. Robotic Surgery: Risks vs. Rewards. Patient Safety Network. February 1, 2016. Retrieved from: https://psnet.ahrq.gov/web-mm/robotic-surgery-risks-vs-rewards#references [3] Morelli L. et al. Use of a new integrated table motion for the da Vinci Xi in colorectal surgery. Int J Colorectal Dis 31, 1671–1673 (2016). Retrieved from: https://link.springer.com/article/10.1007/s00384-016-2609-3 [4] The History of Robot-Assisted Surgery. The Surgical Clinic. 2017. Retrieved from: https://thesurgicalclinics.com/history-of-robot-assisted-surgery/ [5] George EI, Brand TC, LaPorta A, Marescaux J, Satava RM. Origins of Robotic Surgery: From Skepticism to Standard of Care. JSLS. 2018;22(4):e2018.00039. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261744/ [6] Prasad SM. Robotic thoracic surgery: an evolution in progress for the treatment of lung cancer. Mo Med. 2012;109(4):307-311. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179787/ [7] FDA Clearance of da Vinci Surgical System for Intracardiac Surgery Now Encompasses ``ASD'' Closure. Intuitive Surgical. January 30, 2003. Retrieved from: https://isrg.intuitive.com/node/7356/pdf [8] Intuitive Surgical Receives FDA Clearance for Cardiac Revascularization. Intuitive surgical.  July 8, 2004.  https://isrg.gcs-web.com/node/7481/pdf   [9] Karthik K, Colegate-Stone T, Dasgupta P, Tavakkolizadeh A, Sinha J. Robotic surgery in trauma and orthopaedics. Bone Joint J. 2015;97-B(3):292-299. Retrieved from: https://boneandjoint.org.uk/article/10.1302/0301-620X.97B3.35107 [10] FDA Clears Zimmer Biomet's Rosa Hip for Robotic Hip Replacement. MDDI. August 19, 2021. Retrieved from: https://www.mddionline.com/robotics/fda-clears-zimmer-biomet-s-rosa-hip-for-robotic-hip-replacement [11] Munver R et al. Transition from open to robotic-assisted radical prostatectomy: 7 years experience at Hackensack University Medical Center. J Robot Surg. 2007;1(2):155-159. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247446/ [12] Intuitive receives FDA clearance of da Vinci SP for simple prostatectomy. Intuitive website. April 28, 2023. Retrieved from: https://investor.intuitivesurgical.com/news-releases/news-release-details/intuitive-receives-fda-clearance-da-vinci-sp-simple [13] Vianini M et al. Experience in Transoral Robotic Surgery in Pediatric Subjects: A Systematic Literature Review. Front Surg. 2021;8:726739. Published 2021 Aug 12. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387868/ [14] Kelly S. Noah Medical lung biopsy robot exceeds expectations in first-in-human trial. MedTechDIve. Sept. 1, 2023. https://www.medtechdive.com/news/noah-medical-lung-biopsy-robot-first-human-trial/692615/ [15] Rossi L, De Palma A, Fregoli L, et al. Robotic transaxillary thyroidectomy: time to expand indications?. J Robot Surg. 2023;17(4):1777-1785. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374780/ [16] Dharam K et al. Malfunction of the da Vinci Robotic System During Robot-Assisted Laparoscopic Prostatectomy: An International Survey.Journal of Endourology.Apr 2010.571-575. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/20192613/ [17] Dhanani NH et al. The Evidence Behind Robot-Assisted Abdominopelvic Surgery, A Systematic Review. Annals of Internal Medicine. 2021;174:1110-1117. Retrieved from: https://www.acpjournals.org/doi/pdf/10.7326/M20-7006 [18] Wong SW, Crowe P. Factors affecting the learning curve in robotic colorectal surgery. J Robot Surg. 2022;16(6):1249-1256. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606100/ [19]Park EJ, et al. Multidimensional analyses of the learning curve of robotic low anterior resection for rectal cancer: 3-phase learning process comparison. Surg Endosc 28:2821–2831.Retrieved from: https://pubmed.ncbi.nlm.nih.gov/24902812/ [20] Sng KK, Hara M, Shin J-W, Yoo B-E, Yang K-S, Kim S-H (2013) The multiphasic learning curve for robot-assisted rectal surgery. Surg Endosc 27:3297–3307. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/23508818/ [21] Toolan C et al. "Robotic mitral valve surgery: a review and tips for safely negotiating the learning curve." Journal of Thoracic Disease [Online], 13.3 (2021): 1971-1981. Web. 28 Dec. 2023. Retrieved from: https://jtd.amegroups.org/article/view/45078/html [22] Chitwood WR Jr, Rodriguez E, Chu MW, et al. Robotic mitral valve repairs in 300 patients: a single-center experience. J Thorac Cardiovasc Surg 2008;136:436-41. Retrieved from: https://www.jtcvs.org/article/S0022-5223(08)00858-1/fulltext [23] Schachner T, Bonaros N, Wiedemann D, et al. Predictors, causes, and consequences of conversions in robotically enhanced totally endoscopic coronary artery bypass graft surgery. Ann Thorac Surg. 2011;91(3):647-653. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/21352972/ [24] Pernar LIM et al. An appraisal of the learning curve in robotic general surgery. Surg Endosc. 2017;31(11):4583-4596. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/28411345/ [25] Bakalar N. Are Robotic Surgeries Really Better? The New  York Times. Aug. 16, 2021.  Retrieved from: https://www.nytimes.com/2021/08/16/well/live/robotic-surgery-benefits.html [26]. Stitzenberg KB et al. Trends in radical prostatectomy: centralization, robotics, and access to urologic cancer care. Cancer. 2012;118(1):54-62. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184375/ [27] Wang T, Wang Q, Wang S. A Meta-analysis of Robot Assisted Laparoscopic Radical Prostatectomy Versus Laparoscopic Radical Prostatectomy. Open Med (Wars). 2019;14:485-490. Published 2019 Jun 11. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572386/ [28] Cao L, Yang Z, Qi L, Chen M. Robot-assisted and laparoscopic vs open radical prostatectomy in clinically localized prostate cancer: perioperative, functional, and oncological outcomes: A Systematic review and meta-analysis. Medicine (Baltimore). 2019;98(22):e15770. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709105/ [29] Catto JWF, Khetrapal P, Ricciardi F, et al. Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial. JAMA. 2022;327(21):2092-2103. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/35569079/ [30] Berber E, Bernet V, Fahey TJ 3rd, et al. American Thyroid Association Statement on Remote-Access Thyroid Surgery. Thyroid. 2016;26(3):331-337. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994052/ [31] Rossi L, De Palma A, Fregoli L, et al. Robotic transaxillary thyroidectomy: time to expand indications?. J Robot Surg. 2023;17(4):1777-1785. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374780/ [32] Onggo JR, Onggo JD, De Steiger R, Hau R. Robotic-assisted total knee arthroplasty is comparable to conventional total knee arthroplasty: a meta-analysis and systematic review. Arch Orthop Trauma Surg. 2020;140(10):1533-1549. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/32537660/ [33] Kort N, Stirling P, Pilot P, Müller JH. Clinical and surgical outcomes of robot-assisted versus conventional total hip arthroplasty: a systematic overview of meta-analyses. EFORT Open Rev . 2021;6(12):1157-1165. Published 2021 Dec 10. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693228/ [34] Peng-fei H et al. Robotics-assisted versus conventional manual approaches for total hip arthroplasty: A systematic review and meta-analysis of comparative studies. The International Journal of Medical Robotics and Computer Assisted Surgery. June 2019. Volume15, Issue 3. Retrieved from: https://onlinelibrary.wiley.com/doi/full/10.1002/rcs.1990 [35] Shaw JH et al. Comparison of Postoperative Instability and Acetabular Cup Positioning in Robotic-Assisted Versus Traditional Total Hip Arthroplasty. The Journal of Arthroplasty. Volume 37, ISSUE 8, SUPPLEMENT , S881-S889, August 2022. Retrieved from: https://www.arthroplastyjournal.org/article/S0883-5403(22)00113-9/fulltext [36]Kumar V et al. Does robotic-assisted surgery improve outcomes of total hip arthroplasty compared to manual technique? A systematic review and meta-analysis, Postgraduate Medical Journal, Volume 99, Issue 1171, May 2023, Pages 375–383. Retrieved from: https://academic.oup.com/pmj/article/99/1171/375/7192094 [37] Ng N et al. Robotic arm-assisted versus manual total hip arthroplasty. Bone Joint J. 2021;103-B(6):1009-1020. Retrieved from: https://boneandjoint.org.uk/article/10.1302/0301-620X.103B6.BJJ-2020-1856.R1 [38]Harky A, Hussain SMA. Robotic Cardiac Surgery: The Future Gold Standard or An Unnecessary Extravagance?. Braz J Cardiovasc Surg. 2019;34(4):XII-XIII. Published 2019 Aug 27. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713378/ [39] Mihaljevic T et al. Robotic repair of posterior mitral valve prolapse versus conventional approaches: Potential realized. Acquired cardiovascular disease.  Volume 141, Issue 1 , P72-80.e4, January 2011. Retrieved from: https://www.jtcvs.org/article/S0022-5223(10)01051-2/fulltext [40] Cao C, Harris C, Croce B, Cao C. Robotic coronary artery bypass graft surgery. Ann Cardiothorac Surg. 2016 Nov;5(6):594. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135554/ [41] Mazzei M, Abbas AE. Why comprehensive adoption of robotic assisted thoracic surgery is ideal for both simple and complex lung resections. J Thorac Dis. 2020;12(2):70-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061192/ [42] O'Sullivan KE, Kreaden US, Hebert AE, Eaton D, Redmond KC. A systematic review and meta-analysis of robotic versus open and video-assisted thoracoscopic surgery approaches for lobectomy. Interact Cardiovasc Thorac Surg. 2019;28(4):526-534. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/30496420/ [43] Agzarian J e tal. The Use of Robotic-Assisted Thoracic Surgery for Lung Resection: A Comprehensive Systematic Review. Semin Thorac Cardiovasc Surg. 2016;28(1):182-192. Retrieved from:  https://pubmed.ncbi.nlm.nih.gov/27568159/ [44] Mohan A et al. Telesurgery and Robotics: An Improved and Efficient Era. Cureus. 2021;13(3):e14124. Published 2021 Mar 26. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075759/ [45] Housman B, Flores RM. Minimally Invasive vs Open Lobectomy for Lung Cancer: Safety Is the Selection Bias.  The Annals of Thoracic Surgery. Volume 115, ISSUE 1, P191, January 2023. Retrieved from: https://www.annalsthoracicsurgery.org/article/S0003-4975(22)00188-6/fulltext [46] Housman B, Flores RM. Minimally Invasive vs Open Lobectomy for Lung Cancer: Safety Is the Selection Bias. Ann Thorac Surg. 2023;115(1):191. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/35176263/ [47] McCartney J. Robotic Surgery Is Here to Stay— and So Are Surgeons. American College of Surgeons. May 10, 2023. Retrieved from: https://www.facs.org/for-medical-professionals/news-publications/news-and-articles/bulletin/2023/may-2023-volume-108-issue-5/robotic-surgery-is-here-to-stay-and-so-are-surgeons/ * Personal observation of Dr. Housman  ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇

This CME article examines the development of personalized oncology medications, with a focus on their application in breast cancer treatment. Read Article, Take Test , Get FREE 🎓 CME Certificate with Valid Email We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Unlocking the Potential of Targeted Cancer Therapy for Precision Medicine by Leila Haghani, MD Edited and reviewed by Rich Strongwater, MD , Stuart M. Caplen, MD and Nancy Mills, MD Two novel targeted therapy drugs that have shown significant promise in treating certain types of metastatic cancers will also be discussed. It is important for clinicians to have awareness of these therapies as more cancer patients gain access to them. Targeted Cancer Therapy  In the ever-evolving landscape of medical advancements, targeted therapy drugs have emerged as transformative agents in the fight against various cancers. Unlike traditional chemotherapy which kills rapidly dividing cells, targeted therapies specifically go after cancer cell vulnerabilities and spare more healthy cells. Personalized cancer therapy is a treatment strategy that tailors interventions to individual patients based on the  unique characteristics of the tumor. It involves the use of genetic, immunological, and further “downstream” proteomic profiling (The proteome is the entire set of proteins that can be expressed by a genome, cell, tissue, or organism) to provide therapeutic alternatives and prognostic information about cancer.[1] This approach can help identify potential therapy options for patients with known specific genomic alterations.[2] Personalized therapy can be targeted to inhibit the oncogenic drivers of a tumor. It is additionally used for immunotherapies that harness the antitumor potential of a patient's immune cells.[3] The goal is to match the right drug to the right patient, taking into account factors such as prognosis, genetic characteristics of the cancer, response to past treatment, and monitoring of therapy. Predicting Response to Treatment Treatment response to different targeted breast cancer therapies (as well as other cancers), can now be predicted using clinical data and machine learning algorithms. These approaches utilize multiple measurements, such as histopathology, imaging results, and molecular profiling, to create personalized multiscale models of breast cancer treatment regimens and responses.[4,5] Next-generation sequencing (NGS) is a new technology for DNA and RNA sequencing that can sequence large amounts of genes rapidly. Recent studies have shown NGS of circulating tumor DNA (ctDNA) may reveal potential genomic alterations in breast cancers, allowing for more precise individual treatments.[6]  Artificial intelligence Can Predict  Response to Therapy Artificial intelligence (AI) models have been developed to predict the response to breast cancer targeted therapy. These models utilize various data sources such as imaging data, molecular data, and demographic data in an attempt to accurately predict the outcome of therapy prior to treatment.[7] AI-based pipelines* have been used to extract histopathologic features from whole slide images and develop machine learning models to predict neoadjuvant chemotherapy (NAC)** response in human epidermal  growth factor receptor 2 (HER2)-positive breast cancers.***[8] Another AI-based approach, called the CDK4/6i Response Model (CRM), combines genomic data and signaling pathway activity profiles to evaluate a breast cancer patient’s sensitivity to CDK4/6 inhibitor-based therapies.****[9] Additionally, AI has been used to predict the effect of preoperative chemotherapy from histopathologic images, achieving high accuracy in predicting the response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).*****[10,11] These AI models and pipelines have the potential to guide personalized medicine and improve therapeutic decision-making in breast cancer treatment. * AI-based pipelines are an interconnected series of operations that control how data moves through artificial intelligence. **Neoadjuvant chemotherapy (NAC) is treatment given as a first step to shrink a tumor before surgery. ***A cancer that tests positive for HER2, a protein which promotes the growth of cancer cells. ****Cyclin-dependent kinase 4 (CDK4) and CDK6 may become overactive and lead to increased growth of some cancers *****Triple-negative breast cancer (TNBC) does not have  estrogen, progesterone or HER2 receptors on the cancer cells. By incorporating drug pharmacokinetics and pharmacodynamics, these models can simulate the effects of different therapy regimens on tumor growth and response.[12] Predictive biomarkers, identified through genomic, proteomic, and machine learning approaches are essential tools for selecting the most effective treatment for individual patients.[13]  The use of personalized classifiers on subsets of patients with similar characteristics, has shown improved prediction accuracy for breast cancer metastasis.[14] Early molecular profiling and the identification of treatment targets plays a crucial role in personalized treatment, particularly for aggressive subtypes such as TNBC. Bayesian optimization (a method used to help evaluate and improve machine learning) and likelihood-free inference methods help probability models in estimating the likelihood   that therapeutic parameters will function as intended. This can help evaluate individualized parameters and assist in making reliable predictions for the outcome of personalized therapy. Organoid Cells Breast cancer organoids (miniaturized in vitro organ models developed from a patient’s tumor cells), are valuable tools for studying breast cancer.[15–18] Organoids mimic the characteristics of the original tissue, and retain expression patterns, mutations, and responses to treatments, making them suitable for preclinical drug testing, guiding personalized therapy decisions and disease modeling. Advances in organoid technology have led to the development of living biobanks, allowing for the cryopreservation of organoids to test treatment options and provide personalized medicine platforms. Additionally, the development of micro-organospheres (MOS), which are much smaller than typical organoids, allows drug sensitivity and dosing studies for a patient’s specific cancer type with much faster turnaround times. Studies have shown that MOS can be generated from patient biopsies within 10-14 days.[19,20] New Targeted Therapies for Breast Cancer Recently discovered targeted therapies, including differentiated targeted and immunotherapies, for breast cancer have shown promise in improving patient outcomes.[21] Studies have identified potential therapeutic targets such as histamine receptors , transforming growth factors, cyclin-dependent kinases, and poly (ADP-ribose) polymerase. Additionally, the activation of endoplasmic reticulum stress(ERS)* and its downstream signaling pathways have been implicated in breast cancer progression, making them potential targets for therapy. Other potential targets and inhibitors for the treatment of breast cancer include PI3K (phosphoinositide 3-kinases) inhibitors, AKT (serine/threonine kinase) inhibitors, m-TOR (mammalian target of rapamycin) inhibitors, tyrosine kinase inhibitors, CDK inhibitors, DDR (DNA damage response), angiogenesis, the cell cycle, HDAC (histone deacetylases) inhibitors, and drugs targeting breast cancer stem cells, monoclonal antibodies and PARP (poly (ADP-ribose) polymerase) inhibitors.[22–26] *Endoplasmic reticulum stress (ERS) occurs when the endoplasmic reticulum starts misfolding proteins which can lead to cell death. Additionally, targeting breast cancer stem cells (BCSC) using nanoparticle-based systems appears to be a promising strategy to deliver anti-BCSC medications to targeted locations thus overcoming biodistribution obstacles.[27] Antibody-drug Conjugates  Antibody-drug conjugates (ADCs) have shown promise in breast cancer therapy, as well as other types of cancer. They consist of a monoclonal antibody combined with a chemotherapy drug. The monoclonal antibody attaches to a specific receptor on the cancer cell’s surface and then enters the cell where the chemotherapy drug is released. This allows directed therapy against the cancer with less destruction of normal cells. There has been some research with innovative non-internalizing ADCs, where the monoclonal antibody does not enter the cell, which may decrease drug resistance and enhance effectiveness.[28] Two novel ADC targeted therapy drugs have shown significant promise in treating certain types of metastatic cancers are sacituzumab govitecan-hziy (brand name Trodelvy) and fam-trastuzumab deruxtecan-nxki (brand name Enhertu). It is important for primary care physicians and clinicians to be aware of these therapies to allow more cancer patients to gain access to them. Sacituzumab govitecan (Trop-2-directed antibody-drug conjugate) Sacituzumab govitecan is FDA approved for the treatment of adult patients with unresectable locally advanced and metastatic cancer for both TNBC and hormone receptor-positive, HER2-negative breast cancer who have received two or more prior therapies.[29] It is also approved for bladder cancer and cancers of the urinary tract that have spread or cannot be removed by surgery, and who have received a platinum-containing chemotherapy medicine and also received an immunotherapy medicine. It is an antibody-drug conjugate (ADC), which permits specific targeting of cancer cells while limiting the exposure of healthy cells.  Mechanism of Action Sacituzumab govitecan-hziy consists of a monoclonal antibody targeting human trophoblast cell-surface marker 2 (Trop-2). Trop-2 is a transmembrane protein involved in calcium signal transduction that is overexpressed in many epithelial cancers including TNBC.  Sacituzumab govitecan-hziy also contains a chemotherapy drug, SN-38, that damages cancer cell DNA and prevents further cell division. First, the monoclonal antibody binds to Trop-2 proteins on cancer cells and then enters the cells. SN-38 is then released inside the cell to attack the cancer cell’s DNA. Approved Uses Metastatic TNBC after two or more prior systemic therapies Metastatic hormone receptor-positive, HER2-negative breast cancer after two or more prior systemic therapies Locally advanced or metastatic urothelial cancer (cells from the bladder, urethra or ureters) after receiving platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor (programmed cell death protein 1, programmed cell death-ligand 1) Still Investigational - other solid tumors expressing Trop-2   Benefits and Advantages Higher response rates and longer survival compared to standard chemotherapy More targeted, so lower rates of severe neutropenia than standard chemotherapy Can provide a benefit after multiple previous treatments have failed Clinical Success and Efficacy Recent studies have demonstrated a significant improvement in progression-free survival and overall response rates in patients receiving Sacituzumab govitecan-hziy, providing more hope for those facing advanced or metastatic breast cancer. In a phase 3 ASCENT trial Sacituzumab govitecan-hziy extended median survival to 12.1 months compared to 6.7 months on standard chemotherapy in previously treated metastatic TNBC. [30] Side Effects to Monitor Low blood cell counts, nausea, fatigue, alopecia Monitor closely for neutropenia Diarrhea is common but generally manageable Patients who carry the gene for UGT1A1*28, can have increased risk of getting side effects, especially neutropenia (low white blood cell counts), with or without a fever, and anemia (low red blood cell counts).[31] Patients receive treatment until disease progression or unacceptable toxicity occurs In summary, Sacituzumab govitecan-hziy is a newer ADC bringing targeted chemotherapy delivery to hard-to-treat metastatic breast and bladder cancers.  Fam-Trastuzumab Deruxtecan-nxki (HER2-directed antibody-drug conjugate) Fam-trastuzumab deruxtecan-nxki   is another ADC, that is FDA approved for adult patients with unresectable or metastatic HER2-positive solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. It is currently used to treat HER2-positive breast and gastric cancers.  Fam-trastuzumab deruxtecan-nxki is a targeted therapy used for HER2-positive breast cancer, a subtype that often poses significant challenges in treatment. By specifically targeting HER2 receptors, fam-trastuzumab deruxtecan-nxki aims to disrupt the signaling pathways that drive cancer growth, offering a promising avenue for patients resistant to traditional HER2-targeted therapies. Fam-trastuzumab deruxtecan-nxki   is an ADC, that allows precise targeting of cancer cells and direct cytotoxicity. This approach maximizes the therapeutic impact on cancer cells while minimizing harm to surrounding healthy tissues. Approved  Uses  HER2-positive metastatic breast cancer HER2-positive metastatic gastric/GE junction adenocarcinoma Still investigational for lung, colorectal, and other HER2-positive cancers Benefits and Advantages Significantly higher response rates and survival benefit compared to lapatinib plus capecitabine (two HER-2 blockers) Delivers chemotherapy directly to cancer cells sparing healthy cells May provide benefit after previous treatments that are no longer working Clinical Success and Efficacy The clinical breakthroughs associated with fam-trastuzumab deruxtecan-nxki are reshaping the treatment paradigm for HER2-positive breast cancer. Studies have demonstrated favorable response rates, even in patients who have experienced disease progression on other HER2-targeted therapies. In the DESTINY-Breast 02 trial, fam-trastuzumab deruxtecan-nxki extended progression-free survival to 17.8 months compared to 6.9 months on the treating physician's choice of other chemotherapy.[32] The DESTINY-Gastric 02 trial showed clinically meaningful improvement in objective response rate and overall survival compared to standard chemotherapy for gastric and gastro-esophageal junction cancers.[33] Trials have consistently shown significant response rates and durable remissions in patients with HER2-positive breast cancer who have either stopped responding or not responded to prior therapies.  The drug's ability to traverse the blood-brain barrier adds an extra layer of promise for patients with brain metastases. Side Effects to Monitor Low blood cell counts, nausea, fatigue, alopecia (hair loss)  Interstitial lung disease (ILD) is rare but may increase mortality if it occurs. Monitor pulmonary function and watch for signs of ILD.  Patients receive treatment until disease progression or unacceptable toxicity occurs. Monitoring Treatment and Follow-Up of Both ADC Drugs During and after treatment with Sacituzumab govitecan-hziy or fam-trastuzumab deruxtecan-nxki, clinicians should: Monitor blood cell counts, electrolytes, liver/kidney function Specifically, watch for ILD with fam-trastuzumab deruxtecan-nxki   Watch for signs of infection Assess clinical response with imaging every 3 months (CT scan of the chest/abdomen/pelvis and either bone scan or PET/CT scan.)  Provide supportive care for side effects  Check for late effects of chemotherapy (including  adverse cardiac and hematologic effects) Primary Care Clinicians Should Consider Referring Eligible Patients Including: Those with metastatic triple negative breast cancer after 2 or more different courses of therapy Patients with metastatic hormone receptor-positive, HER2-negative breast cancer after 2 or more different courses of therapy Cases of urothelial cancer post-platinum chemotherapy/immunotherapy HER2-positive breast cancer or gastric/gastroesophageal junction  adenocarcinoma progressing after other anti-HER2 options have been tried. Indicators That Patients Could Benefit from ADC Treatment  Disease progression despite multiple treatments Presence of actionable genetic markers like HER2 mutations or Trop-2 overexpression Patient has a strong cancer performance status and adequate organ function to tolerate intravenous therapy with the ADC medication.  FAQs Question 1: How are these drugs administered? Both fam-trastuzumab deruxtecan-nxki and sacituzumab govitecan-hziy are given as intravenous infusions, typically in outpatient infusion centers. Treatment is repeated every 1-3 weeks depending on protocol. Question 2 : How long is treatment given? Patients receive treatment until disease progression or unacceptable toxicity occurs. Some people have prolonged responses measured in years. Question 3 : What kind of testing is needed before starting treatment?  Testing for HER2 or Trop-2 biomarkers via immunohistochemistry or by FISH (fluorescence in situ hybridization) is required to determine if the cancer will respond.  Question 4: What are costs and coverage? These are newer therapies that can be expensive and coverage varies based on indication and insurer which needs to be confirmed. Question 5 : What should patients expect from treatment? Most patients tolerate treatment relatively well and can expect stabilization or tumor reduction for a period of time before the cancer develops resistance. Quality of life is often maintained or improved. Patient Education and Empowerment Educating patients about the availability and efficacy of Sacituzumab govitecan-hziy and fam-trastuzumab deruxtecan-nxki is a crucial aspect of family and primary care medicine. Empowering patients with knowledge about these targeted therapies fosters informed decision-making and facilitates a collaborative approach to treatment planning. Conclusion   Newer methodologies such as the use of AI and NGS is allowing the creation of  more individualized cancer therapies.  The antibody-drug conjugates sacituzumab govitecan-hziy and fam-trastuzumab deruxtecan-nxki have transformed the treatment landscape for certain types of metastatic breast cancer, gastric cancer, and urinary tract cancers. By precisely targeting cancer cells and mostly sparing healthy cells, they offer better efficacy and tolerability than conventional chemotherapy. Primary care physicians should be aware that these targeted therapies may extend patient survival by over a year.  🎓  Want Free CME Credit for This Article? Take the quiz now at www.FibonacciMD.app . It only takes a few minutes! Your certificate will be emailed to you after you pass the quiz and complete a short evaluation We’ll send you occasional updates. Your email stays private—never sold or shared.  😇 Download PDF: References ✅ Earn Free CME Credit for Reading This Article Eligible for 0.5 PRA Category 1 Credit Click the button below to take a short quiz. A valid email is required to send your certificate. We’ll send you occasional updates. Your email stays private—never sold or shared.  😇

References for CME Article " Unlocking the Potential of Targeted Cancer Therapy for Precision Medicine " References Kurnit KC, Bailey AM, Zeng J, Johnson AM, Shufean MdA, Brusco L, et al. “Personalized Cancer Therapy”: A Publicly Available Precision Oncology Resource. Cancer Research [Internet]. 2017 Oct 31 [cited 2024 May 7];77(21):e123–6. Retrieved from:  https://typeset.io/papers/personalized-cancer-therapy-a-publicly-available-precision-4a0jvev7yx Nair L, Gonzalez-Angulo AM. Chapter 13 - Personalized Therapies for Cancer Treatment. In: Singh M, Salnikova M, editors. Novel Approaches and Strategies for Biologics, Vaccines and Cancer Therapies [Internet]. San Diego: Academic Press; 2015 [cited 2024 May 7]. p. 317–46. Retrieved from: https://typeset.io/papers/personalized-therapies-for-cancer-treatment-wi5xgscufk Kumar A, Weller KP, Vilgelm AE. Chapter Twelve - Personalized cancer immunotherapy. In: Amiji MM, Milane LS, editors. Engineering Technologies and Clinical Translation [Internet]. Academic Press; 2022 [cited 2024 May 7]. p. 399–426. Retrieved from: https://typeset.io/papers/personalized-cancer-immunotherapy-3rxoo14qtf Lai X, Geier OM, Fleischer T, Garred Ø, Borgen E, Funke SW, et al. Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data. Cancer Res. 2019 Aug 15;79(16):4293–304. Retrieved from:  https://typeset.io/papers/data-from-toward-personalized-computer-simulation-of-breast-1ikjin4o Rodrigues-Ferreira S, Nahmias C. Predictive biomarkers for personalized medicine in breast cancer. Cancer Lett. 2022 Oct 1;545:215828. Retrieved from: https://typeset.io/papers/predictive-biomarkers-for-personalized-medicine-in-breast-h09fgxma Shatsky R, Parker BA, Bui NQ, Helsten T, Schwab RB, Boles SG, et al. Next-Generation Sequencing of Tissue and Circulating Tumor DNA: The UC San Diego Moores Center for Personalized Cancer Therapy Experience with Breast Malignancies. Mol Cancer Ther. 2019 May;18(5):1001–11. Retrieved from:  https://typeset.io/papers/data-from-next-generation-sequencing-of-tissue-and-19e8isbi Verma M, Abdelrahman L, Collado-Mesa F, Abdel-Mottaleb M. Multimodal Spatiotemporal Deep Learning Framework to Predict Response of Breast Cancer to Neoadjuvant Systemic Therapy. Diagnostics (Basel). 2023 Jul 3;13(13):2251. Retrieved from:  https://typeset.io/papers/multimodal-spatiotemporal-deep-learning-framework-to-predict-rt3eipz1 Huang Z, Parwani AV, Huang K, Li Z. Abstract 5436: Developing artificial intelligence algorithms to predict response to neoadjuvant chemotherapy in HER2-positive breast cancer. Cancer Research [Internet]. 2023 Apr 4 [cited 2024 May 7];83(7_Supplement):5436. Retrieved from: https://doi.org/10.1158/1538-7445 . Available from: https://typeset.io/papers/abstract-5436-developing-artificial-intelligence-algorithms-2m55vh44 Yang M, Liu Y, Zhang C, Hsueh YC, Zhang Q, Fan Y, et al. A Genome-Informed Functional Modeling Approach to Evaluate the Responses of Breast Cancer Patients to CDK4/6 Inhibitors-Based Therapies and Simulate Real-World Clinical Trials [Internet]. medRxiv; 2023 [cited 2024 May 7]. p. 2023.05.15.23289976. Retrieved from:  https://www.medrxiv.org/content/10.1101/2023.05.15.23289976v2 Shen B, Saito A, Ueda A, Fujita K, Nagamatsu Y, Hashimoto M, et al. Development of multiple AI pipelines that predict neoadjuvant chemotherapy response of breast cancer using H&E-stained tissues. J Pathol Clin Res. 2023 May;9(3):182–94. Retrieved from: https://typeset.io/papers/development-of-multiple-ai-pipelines-that-predict-2e1f3nld Krishnamurthy S, Jain P, Tripathy D, Basset R, Randhawa R, Muhammad H, et al. Predicting Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy Using a Deep Convolutional Neural Network-Based Artificial Intelligence Tool. JCO Clin Cancer Inform. 2023 Mar;7:e2200181.Retrieved from:  https://typeset.io/papers/predicting-response-of-triple-negative-breast-cancer-to-jou5dlc1 Adnan N, Najnin T, Ruan J. A Robust Personalized Classification Method for Breast Cancer Metastasis Prediction. Cancers (Basel). 2022 Oct 29;14(21):5327. Retrieved from: https://typeset.io/papers/a-robust-personalized-classification-method-for-breast-18dd68lk Klocker EV, Balic M, Steger G. Molecular profiling leading to personalized treatment in breast cancer. memo [Internet]. 2022 Sep 1 [cited 2024 May 7];15(3):196–200. Retrieved from:  https://typeset.io/papers/molecular-profiling-leading-to-personalized-treatment-in-3i20ovt9 Köhn-Luque A, Lai X, Frigessi A. Towards personalized computer simulations of breast cancer treatment [Internet]. arXiv; 2020 [cited 2024 May 7]. Retrieved from:  https://typeset.io/papers/towards-personalized-computer-simulations-of-breast-cancer-2ndi5nqsvk Graham DM, Rupprecht G, Bankaitis ED, Force JM, Watlington W, Metzger SW, et al. Abstract 192: A novel and rapid patient-derived organoid breast cancer platform for precision medicine. Cancer Research [Internet]. 2023 Apr 4 [cited 2024 May 7];83(7_Supplement):192. Retrieved from:  https://doi.org/10.1158/1538-7445.AM2023-192 Önder CE, Ziegler TJ, Becker R, Brucker SY, Hartkopf AD, Engler T, et al. Advancing Cancer Therapy Predictions with Patient-Derived Organoid Models of Metastatic Breast Cancer. Cancers [Internet]. 2023 Jan [cited 2024 May 7];15(14):3602. Retrieved from:  https://www.mdpi.com/2072-6694/15/14/3602 Ryu WJ, Park S, Lee JD, Hwang Y, Jo S, Yong KT, et al. Abstract 178: Establishment of patient-derived organoid of breast cancer. Cancer Research [Internet]. 2023 Apr 4 [cited 2024 May 7];83(7_Supplement):178. Retrieved from:  https://doi.org/10.1158/1538-7445.AM2023-178 Li  X, Zhu D. Advances in breast cancer organoid for individualized treatment. Organs-on-a-Chip [Internet]. 2023 Dec 1 [cited 2024 May 7];5:100028. Available from: https://www.sciencedirect.com/science/article/pii/S2666102023000034 Ding S, Kanikarla Marie P, Baro N, Raman R, Helman E, Hsu SD, et al. Refractory colorectal cancer patient derived MicroOrganoSpheres (MOS) to enable correlation of targeted therapy combination response with clinical outcomes. JCO [Internet]. 2023 Jun [cited 2024 May 7];41(16_suppl):e15574–e15574. Retrieved from: https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e15574 Dayanidhi DL, Rupprecht G, Watlington W, Mantyh J, Kim SY, McCall SJ, et al. MicroOrganoSpheres as a clinically applicable precision oncology platform for the discovery of novel therapies in colorectal cancer. JCO [Internet]. 2023 Jun [cited 2024 May 7];41(16_suppl):3592–3592. Retrieved from:  https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.3592 Jacobs AT, Martinez Castaneda-Cruz D, Rose MM, Connelly L. Targeted therapy for breast cancer: An overview of drug classes and outcomes. Biochemical Pharmacology [Internet]. 2022 Oct 1 [cited 2024 May 7];204:115209. Retrieved from: https://www.sciencedirect.com/science/article/pii/S0006295222003033 Więsyk PJ, Oleksa P, Chilimoniuk Z, Dobosz M, Sobczyk M, Słaboń M. Targeted therapy with histamine antagonists - New challenges to fight with breast cancer. Journal of Education, Health and Sport [Internet]. 2022 Nov 15 [cited 2024 May 7];12(12):87–93. Retrieved from: https://apcz.umk.pl/JEHS/article/view/40145 Ye  F, Dewanjee S, Li Y, Jha NK, Chen ZS, Kumar A, et al. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Molecular Cancer [Internet]. 2023 Jul 6 [cited 2024 May 7];22(1):105. Retrieved from:  https://doi.org/10.1186/s12943-023-01805-y Xu D, Liu Z, Liang MX, Fei YJ, Zhang W, Wu Y, et al. Endoplasmic reticulum stress targeted therapy for breast cancer. Cell Communication and Signaling [Internet]. 2022 Nov 7 [cited 2024 May 7];20(1):174. Retrieved from:  https://doi.org/10.1186/s12964-022-00964-7 An J, Peng C, Xie X, Peng F. New Advances in Targeted Therapy of HER2-Negative Breast Cancer. Front Oncol [Internet]. 2022 Mar 4 [cited 2024 May 7];12. Retrieved from: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.828438/full Demir Cetinkaya B, Biray Avci C. Molecular perspective on targeted therapy in breast cancer: a review of current status. Med Oncol [Internet]. 2022 Jul 14 [cited 2024 May 7];39(10):149.  Retrieved from: https://doi.org/10.1007/s12032-022-01749-1 Zhang Y, Pan H, Yu C, Liu R, Xing B, Jia B, et al. Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer. Asian Journal of Pharmaceutical Sciences [Internet]. 2023 Jul 1 [cited 2024 May 7];18(4):100827. Retrieved from: https://www.sciencedirect.com/science/article/pii/S1818087623000545 Subhan MA, Torchilin VP. Advances in Targeted Therapy of Breast Cancer with Antibody-Drug Conjugate. Pharmaceutics [Internet]. 2023 Apr [cited 2024 May 7];15(4):1242. Retrieved from:  https://www.mdpi.com/1999-4923/15/4/1242 Sacituzumab Govitecan (Trodelvy): CADTH Reimbursement Recommendation [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 [cited 2023 Nov 21]. (CADTH Reimbursement Reviews and Recommendations). Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK595400/ Bardia A, Tolaney SM, Loirat D, Punie K, Oliveira M, Rugo HS, et al. Sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): Final results from the phase 3 ASCENT study. JCO [Internet]. 2022 Jun [cited 2023 Nov 21];40(16_suppl):1071–1071.Retrieved from:  https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.1071 TRODELVY (sacituzumab govitecan-hziy) prescribing information. Gilead website. Revised 4/2024. Retrieved from:  https://www.trodelvyhcp.com/-/media/project/trodelvy/trodelvyhcp/hcp/resource-pdf/trodelvy_pi.pdf André F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773–85. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00725-0/abstract Van Cutsem E, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023 Jul;24(7):744–56. Retrieved from: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00215-2/abstract for CME article " Unlocking the Potential of Targeted Cancer Therapy for Precision Medicine "