Anticoagulation is advised for patients who have had a blood clot or who are at increased risk of blood clots because of atrial fibrillation, artificial heart valves, or other conditions. Over 30 million prescriptions are written every year in the US for the anticoagulant warfarin, best known under the brand name Coumadin. Originally developed as a rat poison, warfarin has proved very effective in preventing blood clots and saving lives; but too much anticoagulation leads to the opposite problem: bleeding. A high level of Coumadin might prevent a stroke from a blood clot only to cause a stroke from an intracranial bleed. The effect varies from person to person and from day to day depending on things like the amount of vitamin K in the diet and interactions with other medications. It requires careful monitoring with blood tests, and it is tricky because there is a delay between changing the dose and seeing the results.

In his book The Language of Life, Francis Collins predicts that Coumadin will be the first drug for which the so-called Dx-Rx paradigm — a genetic test (Dx) followed by a prescription (Rx) — will enter mainstream medical practice. FDA economists have estimated that by formally integrating genetic testing into routine warfarin therapy, the US alone would avoid 85,000 serious bleeding events and 17,000 strokes annually.
A recent news release from the American College of Cardiology described a paper at their annual meeting reporting a study of

896 people who, shortly after beginning warfarin therapy, gave a blood sample or cheek swab that was analyzed for expression of two genes — CYP2C9 and VKORC1 — that revealed sensitivity to warfarin. People with high sensitivity were put on a reduced dose of warfarin and had frequent blood tests. People with low sensitivity were given a higher dose of warfarin.

During the first six months that they took warfarin, those who underwent genetic testing were 31 percent less likely to be hospitalized for any reason and 29 percent less likely to be hospitalized for bleeding or thromboembolism than were a group that did not have genetic testing.

Epstein said that the cost of the genetic testing — $250 to $400 — would be justified by reduced hospitalization costs.

At this point, I don’t believe this study. I’ll explain why I’m skeptical.

It seems to me something is wrong with the whole idea of using genetic testing to adjust Coumadin dosage. It doesn’t matter whether a patient has low sensitivity or high sensitivity to warfarin, since the same trial-and-error process of monitoring and dose adjustment will result in a safe dose for either.

In the typical scenario for a patient who is given warfarin, he is in the hospital where he is first given heparin by injection, usually in the form of low molecular weight heparins like Lovenox. Heparin works by binding to antithrombin and does not require monitoring with blood tests. Warfarin works by an entirely different mechanism. It reduces the amount of vitamin K dependent clotting factors. The heparin provides immediate protection while the warfarin gradually takes effect, a process that lasts for several days and lags behind the blood test used to monitor it: prothrombin time with calculation of the International Normalized Ratio (INR). After the INR reaches the target levels (usually 2-3 times normal), the injectable drug is stopped.

Apparently some providers are in a hurry to get the patient stabilized on Coumadin, so they start with a high “loading” dose and then back off as needed. This may have made sense when patients had to be off the heparin before they could be discharged from the hospital; but today they are commonly taught to give themselves subcutaneous injections and they are sent home, continuing the Lovenox until the Coumadin kicks in. There’s no reason they couldn’t start everyone on a low dose of Coumadin and adjust upwards as needed. Blood tests are done very frequently at first (as often as every day or two) and then can be cut back to as infrequently as once a month if the INR remains stable on a constant dose of warfarin. In the medical facility where I get my care, a Coumadin Clinic directed by a clinical pharmacologist monitors all patients on Coumadin.

A start low/adjust upwards protocol will result in a safe dose for all patients regardless of their DNA. I don’t see how that management plan would be improved by knowing the gene expressions. It takes time to get the genetic test results, and the provider has to start the patient on Coumadin before the test results are even available. Genetics is only estimated to contribute about 70% to dose requirements, and variations in the other 30% could outweigh simplistic dose estimates based on DNA. And testing costs money that I see no need to spend.

It will be interesting to read the actual study when it is published. I will be looking closely for confounding factors that might have influenced results. Could the tested patients have been treated differently in some way because of expectations raised by the DNA test? Did the non-tested patients have optimal management by someone experienced in adjusting Coumadin dosage? Was the study population somehow different from the population the average doctor sees in his practice? How exactly was the Coumadin dose adjusted differently because of the DNA findings? What was the target INR level? Did any of the complications occur in patients who were in the target range? Was compliance assessed? Could alcohol and drug use have affected the INR? The reported 29% reduction of re-hospitalization for bleeding or clotting complications is a relative risk. What was the absolute risk? According to a review article in American Family Physician, the median annual rate of major bleeding in patients on Coumadin ranges from 0.9 to 2.7 percent, and in this study the rate of complications in the highest risk group was only 6.3%. Complications were more likely in elderly patients, patients with co-existing illnesses, and patients with INRs outside the target range. How many of these complications could have been avoided by optimal management?

My common sense tells me patients on Coumadin can be managed just as well without knowing genetic test results. Genetic testing and pharmacogenetics hold great promise for improving individualized patient care decisions, but I don’t think Coumadin is a good example of such benefits. The DNA only confirms what our patient’s response to therapy has already told us.

Posted by Harriet Hall

Harriet Hall, MD also known as The SkepDoc, is a retired family physician who writes about pseudoscience and questionable medical practices. She received her BA and MD from the University of Washington, did her internship in the Air Force (the second female ever to do so),  and was the first female graduate of the Air Force family practice residency at Eglin Air Force Base. During a long career as an Air Force physician, she held various positions from flight surgeon to DBMS (Director of Base Medical Services) and did everything from delivering babies to taking the controls of a B-52. She retired with the rank of Colonel.  In 2008 she published her memoirs, Women Aren't Supposed to Fly.