Genetic Future

i-5f8eccb3d39bc5368657cc726f456699-warfarin_bait.jpgWarfarin (a.k.a. Coumadin, Jantoven, Marevan, or Waran) is the most widely-prescribed blood-thinning agent on the market. It’s also (in the words of Howard McLeod) a “terrible drug” – it has a very narrow therapeutic window, meaning that the minimal useful dose and the maximal safe dose are very close together. (The effects of over-dosing on warfarin – reduced blood clotting – are so severe that the drug is also used as a highly effective rat poison.)

To further complicate things, the dosage of the drug that is both effective and safe differs widely between individuals, and is known to be altered both by environmental factors (e.g. smoking) and by genetics. This variation means that determining the right dosage for a patient is a fairly hit-and-miss affair, and patients often have to be tested at several different doses before a stable dose is found.

At the current time there are two genetic variants known to explain a fairly large chunk of this variation, one in a gene involved in drug metabolism (CYP2C9) and another in a gene involved in the clotting response (VKORC1). A paper in this week’s New England Journal of Medicine looked at whether the use of genetic information from these two variants could improve the ability of clinicians to predict the optimal dosage for patients.

The short answer is: yes. The authors used data from 4,043 patients to determine the optimal parameters for their prediction algorithm, and then tested the results on a validation set of 1,009 subjects. They found that the addition of genetic information significantly increased the accuracy of dose predictions, with the improvements being  seen mainly in patients at the extremes (i.e. those who required higher or lower doses of the drug than the population average).

The clinical benefits of this testing are clear: incorporating genetic data means that more patients will be placed on the correct dosage of warfarin from the outset, rather than having to go through multiple (potentially dangerous) trial runs at different doses before settling on a stable figure. Further studies on the genetic variants associated with warfarin response, as well as gene-environment interactions, should improve predictive performance even further.

The authors have made their prediction algorithm available as a nifty online calculator.

I noted in my post last week on routine whole-genome sequencing of newborns that the real clinical benefits of widespread genetic screening will come first in pharmacogenomics – these results provide a neat demonstration of this process in action.

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Comments

  1. #1 Steven Murphy MD
    February 19, 2009

    Daniel,
    Great post. This now makes 3 validated clinical algorithms for dosing. For the next 5 years Pgx will dominate clinical relevance. These genes have already been discovered and investigated thoroughly…..unlike 9p21.3 plus the pathways are known too….This IS personalized medicine for now…

    -Steve
    http://www.thegenesherpa.blogspot.com

  2. #2 Matthew Markus
    February 20, 2009

    I am passingly familiar with this research area and the people involved, so I felt the need to comment. First, this was a great research project that produced solid results along with an actual clinical tool. Unfortunately, though, the costs associated with this tool may outweigh its benefits. More specifically, Xarelto (rivaroxaban), an anticoagulant that does not require the extensive monitoring that Warfarin requires, has already been cleared for use in Europe for VTE prevention in adults undergoing elective hip or knee replacement surgery [1]. Thus, Xarelto, even on-patent, will probably be more cost-effective than cheap Warfarin coupled with its additional monitoring burden and an expensive, non-reimbursable pharmacogenetic test. All in all, I think that this tale serves as a reminder that pharmacogenetics is in constant competition with drug development.

    [1] http://www.bayer.com/en/News-Detail.aspx?id=11268

  3. #3 George Erickson
    February 23, 2009

    Matthew, this is interesting observation, which certainly will be good news for Bayer, but a major drain on the US healthcare system. Xarelto average cost online is about $12 per pill. Replacing 30 million coumadin/warfarin prescriptions per year (current US consumption) would cost the US taxpayer (many pts placed on warfarin at 65 or older) over $10 billion!

    Walmart sells a 30-day supply of warfarin for $4 and a 90-day supply for $10. INR test is reimbursed at around $18.50.

    It’s true that some insurance companies but not all reimburse PGx tests. Xarelto is not reimbursed by anyone. This and other studies will likely to accelerate broad warfarin sensitivity test reimbursement long before Xarelto does.

  4. #4 Matthew Markus
    February 24, 2009

    “Matthew, this is interesting observation, which certainly will be good news for Bayer, but a major drain on the US healthcare system.”

    Maybe, maybe not. There really is no thorough cost-effectiveness studies on the issue. Such studies must take into account:

    1.) The medical reason for prescribing a drug.
    2.) The duration of treatment under the drug.
    3.) The cost of pharmacogenetic testing associated with the drug.
    4.) The incidence of adverse events associated with the drug.

    My speculation that Xarelto (rivaroxaban) may be highly competitive with warfarin in some situations is based on the following anecdotes:

    1.) An indirect comparison of rivaroxaban versus warfarin for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement indicates that rivaroxaban is likely to reduce the incidence of costly VTE events [1].

    2.) Warfarin PGx tests are unlikely to be cost-effective for typical patients with nonvalvular atrial fibrillation due to testing costs in the $200-$500 range [2,3].

    It will be interesting to see how this plays out.

    [1] http://www.xarelto.com/html/images/events/ASH/ASH2008_Rivaroxaban_versus_Alternative_Prophylaxes_for_the_Prevention_of_VTE_after_TKR.pdf
    [2] http://www.ncbi.nlm.nih.gov/pubmed/19153410
    [3] http://www.genomeweb.com/dxpgx/warfarin-dose-dx-may-not-be-cost-effective-typical-patient-may-be-risk-cohort?page=show

  5. #5 George Erickson
    February 27, 2009

    Matthew, I commend you for taking the time to search the subject, and I really mean it with all respect. I just wish that you had read the paper you referenced above in the Ann Intern Med and the response letters the editors received before posting.

    The paper is controversial at best and should have never passed the peer review in its current form.

    Dr. Eckman and his colleagues misinterpreted the results of another clinical study in their meta-analysis. The clinical study reported total number of serious adverse clinical events in 7 different categories. Dr. Eckman and his colleagues used the results as if they were all major bleeding events (which was just one of the 7 categories the clinical study followed). This was clearly a mistake to assume all events in the clinical study to be major bleedings because the rate was much higher than major bleeding events rate reported in other clinical studies (with much larger cohorts).

    Dr. Eckman and his colleagues also made an order of magnitude mistake in estimating the number of major bleeding events that could be prevented with a genotype-guided warfarin dosing. They didn’t explain how they came up with 300 major bleeding events out of 300,000 new pts per year, but if you will follow their analysis, you will come up with 3,000 events.

    Also, the cost analysis didn’t take into account the cost savings of fewer office visits and INR tests as the results of the clinical studies they used for the meta-analysis suggested.

    I hope that this study by Dr. Eckman and his colleagues will not be misused in the coming years like the infamous 1998 study by Dr. Wakefield in the Lancet on the link between MMR vaccine and autism.

  6. #6 Matthew Markus
    February 27, 2009

    George,

    You are right, I did not fully read the Eckman paper; rather, I assumed that the data was properly vetted since Dr. Gage (warfarindosing.org) was a co-author.

    I still believe that Xarelto will be cost-competitive with warfarin when used as a prophylactic for the postoperative prevention of VTE in some surgical situations since, holding all else equal (which is arguably unfair to Xarelto), a 15-day supply of Xarelto is $180, which is less than a $200 warfarin PGx test.

    P.S. You might be interested in this article:

    PGx tests for warfarin dosing—how soon?
    http://www.cap.org/apps/portlets/contentViewer/show.do?printFriendly=true&contentReference=cap_today%2F0109%2F0109c_PGx_tests_for_warfarin.html

  7. #7 George Erickson
    February 28, 2009

    I agree that the results of rivaroxaban phase II and III studies have been positive and it has quite a positive prospect. It is hard for me though to see the pharma companies agree to a limited use such as knee replacement.

    BTW, according to a 2007 study by Agnelli, Gallus, Goldhaber, et al in Circulation, the biological half-life of rivaroxaban is between 9 (young healthy) to 12 hours (healthy elderly subjects). So a rivaroxaban therapy might require twice daily doses.

    Dr. Gage disclosed that he is a paid consultant to BMS, which has 3 oral direct Factor Xa inhibitors in various phases, including rivaroxaban. I do NOT suggest that has anything to do with the cost-effectiveness analysis or the conclusion. It is just that he disclosed it in the paper. In fairness, Dr. Altman was quoted in the media last week on the recent study in the NEJM, and he disclosed that he has received consulting fees from and holds equity in 23andMe.

  8. #8 Matthew Markus
    May 15, 2009

    Stumbled upon the following update:

    Gene Test for Dosage of Warfarin Is Rebuffed
    http://www.nytimes.com/2009/05/05/health/05thinner.html

  9. #9 Michael Fitzpatrick
    December 20, 2009

    Here is another new treatment for blood clots that may be helpful.

    New study recommends change in treating pulmonary embolisms
    October 27th, 2009

    William Kuo, MD, was the on-call interventional radiologist one Friday night three years ago when he received a call from the intensive care unit at Stanford Hospital & Clinics. He was asked to attend to a 62-year-old woman who had collapsed at home and was rushed to the emergency room with massive blood clots in her lungs.

    “I get very emotional when I think about what happened,” said Kuo, assistant professor of radiology at the Stanford University School of Medicine. “I could immediately see the patient was not doing well. She was dying, and the ICU team had notified the family that she was going to die very soon.”

    What happened that night would set Kuo on a three-year mission to design and implement studies to reveal the safety and effectiveness of a new treatment called catheter-directed therapy or catheter-directed thrombolysis for massive blood clots in the lungs.

    The results of the Stanford study, a meta-analysis of scientific data from around the world, showed that when this therapy was used to treat dangerous blood clots, it saves lives. In fact, the data indicated that the catheter procedure was life-saving in 86.5 percent of the cases studied, prompting Kuo and his co-authors to call for making the procedure the first-line treatment for pulmonary embolism. The study will be published Oct. 30 in the Journal of Vascular and Interventional Radiology.

    “I remember that night so vividly,” Kuo said of the events that led to his research. “The patient was by far the sickest I had ever seen on my angiography table. She couldn’t breathe on her own. She was barely alive. There was no time to waste.”

    As in most cases of pulmonary embolism, blood clots had first formed in the patient’s legs, then traveled to her lungs, interfering with oxygenation and the heart’s ability to pump blood into the lungs. Because of the massive blood clots, she was quickly suffocating to death. The ICU staff had already done everything they could to save her.

    She had been given an intravenous infusion of potent clot-busting medicine, a treatment called systemic thrombolysis, but that had already failed.

    Kuo was initially consulted to perform a minor procedure — placement of a special filter in the major abdominal blood vessel to prevent more clots from traveling from the legs to the lungs, but he knew it would do little to save her. And then an idea came to him.

    “I had been reading about experimental catheter-based treatments to remove these clots from the lungs,” Kuo said. “I told the staff, ‘We can do more than just insert a filter. We can go after these clots using specially-designed catheters.’ The ICU staff was at first skeptical, but I just kept insisting because I knew it might save her life. We quickly obtained consent from the family and went ahead with it.”

    As a vascular and interventional radiologist, Kuo is experienced in guiding and maneuvering catheters and wires through blood vessels using real-time radiologic imaging. He uses these techniques to reach diseased areas and to treat a variety of conditions without open surgery. Kuo knew how to perform this type of targeted, less-invasive treatment.

    He quickly made a small incision in the patient’s neck, inserted a catheter — a thin plastic tube — into the blood vessel. He then used real-time X-ray images (fluoroscopy) to guide the catheter, navigating through the heart and finally reaching the blood clots within the lungs. First, he injected clot-busting medicine through the catheter directly into the clots. Then, he used the catheter to mechanically break up the clots. Finally, he suctioned them out.

    “It was quite a rush of adrenaline,” he said.

    The results were immediate. The patient’s oxygenation improved, her blood pressure started to rise and she no longer required the potent blood-pressure drugs to keep her alive. The angiogram showed that blood was now able to flow into her lungs and the massive blood clots were much smaller.

    “We just stood there,” Kuo said, “and we were amazed that the treatment had saved her life. She walked out of the hospital nine days later.”

    But that was just the beginning for Kuo.

    “That one case changed my views on the existing treatment algorithm for this deadly disease, and I suddenly realized the limited options available for life-threatening pulmonary embolism. At that moment three years ago, I recognized that this was a potentially life-saving procedure; but I also realized that few physicians were aware of it. The experience from that case really inspired me to begin my clinical research.”

    The labor-intensive study involved collaboration with other expert interventional colleagues, a pulmonologist adept at meta-analysis, statisticians, medical librarians and interpreters to initiate a global search of scientific literature. The researchers sifted through 18 years of data collecting information on cases involving the use of catheter-directed therapy for treating massive pulmonary embolism.

    “I wanted to know if other interventional physicians had recorded this experience,” Kuo said. “Were they getting the same results we were seeing at Stanford?”

    Kuo’s research team discovered 594 patients in 18 countries who had undergone this therapy between 1990 and 2008. After statistically analyzing the data, they found that not only was the treatment effective, but it also appeared much safer than injecting the high-dose thrombolytic drug systemically or directly into the bloodstream where it can circulate throughout the body and cause dangerous bleeding in up to 20 percent of patients. By targeting blood clots directly, the catheter-based procedure was associated with only a 2.4 percent chance of major complications, and the procedure was life-saving in 86.5 percent of the 594 patients dying from PE.

    The catheter-based technique involves targeted drug delivery, which typically uses a much lower dose of the potent thrombolytic drug because it is injected directly into diseased areas. Thus, it can be useful in patients who cannot tolerate the high-dose systemic drug treatment, which carries a significant risk of bleeding.

    The researchers concluded that “modern catheter-directed therapy is a relatively safe and effective treatment for acute massive pulmonary embolism and should be considered as a first-line treatment.”

    Among the 530,000 to 600,000 cases of massive pulmonary embolism diagnosed each year in the United States, an estimated 300,000 patients die. If initiated early, catheter-directed therapy could save many of those lives. According to Kuo, “It’s a matter of life and death. Catheter-directed therapy for acute pulmonary embolism saves lives, and we need to raise awareness not only among the general public but also within the medical community. This treatment saves lives.”

    Source: Stanford University Medical Center (news : web)

    http://www.physorg.com/news175867194.html

  10. #10 Janet Smith
    December 20, 2009

    Ultrasound Waves Aid In Rapid Treatment Of Deep Vein Thrombosis

    ScienceDaily (Nov. 23, 2008) — The use of ultrasound waves for deep vein thrombosis (DVT) may help dissolve blood clots in less time than using clot-busting drugs alone, according to researchers at Emory University. The study will be presented Nov. 23, 2008 at the annual VEITHsymposium in New York City.

    http://www.sciencedaily.com/releases/2008/11/081123150253.htm

  11. #11 Murfomurf
    May 16, 2010

    I think there is not enough taken into account when looking at the “cost effectiveness” of using PGX testing before warfarin dosing- from speaking to friends and patients who have recently been prescribed warfarin for the first time, the experience of adverse bleeding events is terrifying for some people, life threatening in a few and expensive and inconvenient for the remainder. If warfarin caused a bleed into the brain in your average recipient with hypertension, it could mean some disability in the future- and that’s from merely starting on the wrong dose of a medication meant to protect you from a clotting problem! I’m sure if you asked people what each was willing to trade off, most would not mind $200 now (in Australia) vs. possibly disabling effects from a stroke plus future hospitalisation. The cost of warfarin itself is negligible and it potentially adds many years of life for many people. Waiting for a cheap enough substitute with a wider therapeutic range may be a long process- meanwhile how to best help current patients needing anti-clotting? I’m currently looking at the number of preventable adverse events vs. the number of warfarin prescriptions for my MPH. I’d like some empirical evidence that might lead to recommendations to perform PGX before warfarin for particular groups of patients and have those tests paid for by the state. I’m also looking at a number of other medications for which PGX testing is available here.