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Genetic Testing for Patients on Coumadin

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 in: Clinical Trials, Pharmaceuticals

Leave a Comment (18) ↓

18 thoughts on “Genetic Testing for Patients on Coumadin

  1. Shelley says:

    Coumadin has been around forever, and despite the need for management and testing, it is highly effective and predictable. (Frankly, with a home monitor, it isn’t difficult to manage Coumadin at all with a little practice).

    I can see little benefit in genetic testing (unless there is some reason to believe the patient has a bleeding or clotting disorder) since ongoing management and testing will be required in any event.

  2. BillyJoe says:

    The reported 29% reduction of re-hospitalization for bleeding or clotting complications is a relative risk. What was the absolute risk?

    I always smell a rat when relative risk is used instead of absolute risk. If the icidence of a complication is 3 in 10,000 and the intervention reduces it to 2 in 10,000, the absolute risk reduction is 1 in 10,000. But the relative risk reduction is 33%. That sounds much more impressive but is misleading. In fact, from a clincal viewpoint, the statistic is almost meaningless.

  3. windriven says:

    The Healthday News is terribly murky. The item states N=896 and that they were separated into two groups based on genetic sensitivity to warfarin. One might infer that the ‘control’ group was some historical cohort of warfarin users. That in itself should set off alarms; the improvement may simply reflect a more rigorous titration protocol in the test group than in the ‘control’ cohort.

  4. moderation says:

    I was over at the blog healthnewsreview.org and they had an interesting description of relative risk … “Relative risk is like having a 50% off coupon, but not knowing if it is for a Lexus or a lollipop.”

  5. weing says:

    By heparin, I think you are referring to low molecular weight heparin, this is given SQ and does not require blood testing. Regular heparin, used as an IV drip requires PTT monitoring.

  6. Harriet Hall says:

    weing,

    Yes, I was referring to low molecular weight heparin, which seems to be the standard treatment today. Thanks for the clarification.

  7. Interesting article. I wonder if quicker genetic test results could make any difference in the usefulness? I’m under the impression that much of the wait in genetic testing is due to backlog. Am I wrong in this?

    Would be interested to see a follow up article on this study when more info is available.

    Also, if Coumadin does not look like a good match, what are some other up and coming possibilities for individual treatment based on genetic testing?

  8. weing says:

    “Also, if Coumadin does not look like a good match, what are some other up and coming possibilities for individual treatment based on genetic testing?”

    Checking for CYP 2C19 alleles for Clopidogrel resistance.

  9. weing “Checking for CYP 2C19 alleles for Clopidogrel resistance.”

    It is clear. I need to get a copy of “Genetics for Dummies” or “Cardiology for Idiots” to comprehend that. : )

  10. Meaning – my understanding of genetics and cardiology is so remedial I’d have to start to educate myself at a very elementary level.

    Re-reading my comment, I thought it might sound as if I thought weing’s comment was “for dummies”. (I hope that’s not how it sounded :(

  11. Harriet Hall says:

    For those who want to know more about genetics and about personalized medicine, I highly recommend Francis Collins’ book “The Language of Life.” He covers everything from the basics of DNA to cutting edge research on stem cell therapy.

  12. weing says:

    micheleinmichigan,

    This test would be great if it was cheaper. About 2 percent of the population has alleles of the gene for CYP2C19 and cannot activate clopidogrel. This drug is used after coronary stenting to prevent clotting of the stent. If you identify those patients you can use a different and more expensive medication. Otherwise you’re stuck waiting for stent thrombosis, which can be fatal.

  13. Thanks for the explanation weing and the book recommendation Dr. H.

  14. Chris says:

    I have nothing profound to add to this discussion. But I did first hear about genetic responses to coumadin when I attended this lecture:
    http://www.gs.washington.edu/wednesdays/2007/speakers/nickerson.html

  15. Newcoaster says:

    While genetic testing may be valuable for the next generation of doctors, I don’t foresee it changing my practice much in the next decade, and I agree with your comments about genetic testing for warfarin sensitivity; it’s just unnecessary. I have always taken the high dose and taper approach to start patients on warfarin, and I thought one of the concerns was the significantly higher cost of LMWH.

    Of course there is the possibility that dabigatran may be as effective and safe as warfarin, though cost may still be an issue for widespread use.

  16. Harriet Hall says:

    The complete study is now available at http://content.onlinejacc.org/cgi/content/full/j.jacc.2010.03.009v1

    I still have a lot of reservations.

  17. Daniel M says:

    Dr. Hall,

    I’d love to see you do a thorough review of Collins’ book “The Language of Life” in a future post. I read it as soon as it came out and really enjoyed it, but I did wonder what other doctors might think about it. Did it seem overly optimistic on the future of genetic medicine to you?

    Do you have any other book recommendations on genetic medicine? Hopefully I’ll be starting medical school in 2011 and I’m trying to learn as much as I can about this field, because right now I’m most interested in a clinical geneticists residency (due in large part to Dr. Collins book).

  18. Harriet Hall says:

    Daniel M,

    I don’t have any other book recommendations, and I do highly recommend Collins’ book. I thought he tempered his optimism about future developments with explanations of factors that will make such developments difficult to achieve. My only problem with his optimism is that he is pushing direct-to-consumer genetic testing in its present very imperfect state. He accurately describes its limitations but recommends it anyway. I think this is misguided.

    He was tested himself and claims that knowing his risk of diabetes was 29% rather than the average 23% was enough to motivate him to a healthy lifestyle. Two different labs interpreted his genome as showing he was at high risk and at average risk of high sensitivity to Coumadin, and he was told his genome indicated brown eyes – but his are blue! IMHO this suggests that the tests are not yet ready for prime time.

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