Research Original Investigation

Genotype-Guided Dosing of Warfarin

47. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989;87(2):144-152.

48. Roden DM, Johnson JA, Kimmel SE, et al. Cardiovascular pharmacogenomics. Circ Res. 2011; 109(7):807-820.

Invited Commentary

Warfarin, Genes, and the (Health Care) Environment Dhruv S. Kazi, MD, MSc, MS; Mark A. Hlatky, MD

Despite the introduction of several novel oral anticoagulants, warfarin remains the most widely used anticoagulation agent worldwide. Physicians have extensive experience with warfarin, it is inexpensive, its effects are easily reversible, and its activity Related article page 1330 c an be monitored with a simple blood test. However, warfarin has a narrow therapeutic index and requires active management. Day-to-day variability in an individual’s response to warfarin is partially determined by diet, comorbidities, and interactions with other medications. Genetic variation also affects warfarin dosing; carriers of reduced-function polymorphisms of CYP2C9 have decreased clearance of warfarin and therefore require lower maintenance doses, and carriers of polymorphisms in VKORC1 have altered sensitivity to vitamin K antagonists.1 Traditionally, warfarin therapy has been initiated with a relatively arbitrary starting dose and then adjusted based on the international normalized ratio (INR) of the prothrombin time. An INR below the therapeutic range is associated with more thromboembolic events, and an INR above the therapeutic range is associated with more bleeding. Knowledge of a patient’s genotype might be used to make a better prediction of the maintenance dose of warfarin and thereby shorten the time needed to reach the therapeutic range and reduce the chance of overshooting the target. In 2010, the US Food and Drug Administration2 recommended that pharmacogenomic data, if available, should be used to inform warfarin dosing. Nearly 4 years later, use of genotyping is still low, perhaps because of the challenges of obtaining genotyping rapidly, scant evidence that use of genetic information improves clinical outcomes, and the reluctance of insurers to pay for genetic testing. In the past year, several randomized trials have tested the role of using genotyping to choose the dose of warfarin or its analogues. These trials varied in size, duration of follow-up, characteristics of the participants, and comparator (usual care vs clinical algorithms), yet each examined the effect of genotype-guided dosing on the outcome of time that the INR is within the therapeutic range. None of these trials was powered to detect differences in “hard” clinical outcomes, such as strokes or bleeding, so a metaanalysis of the evidence on whether genotype-guided warfarin dosing improves clinical outcomes is timely and appropriate. In this issue, Stergiopoulos and Brown3 do just that with an analysis of 2812 patients from 9 randomized trials conducted in Europe, North America, and Israel. 1338

Approximately half of the patients were women; most were white. Genotype-guided dosing had marginal effects on the time that the INR was within the therapeutic range (increased by 14%, P = .25), major bleeding (0.9% vs 1.6%, P = .16), and thromboembolism (1.1% vs 1.2%, P = .93). Genotype-based warfarin dosing did not significantly improve either laboratory-based outcomes (ie, INR time within therapeutic range) or clinical outcomes (ie, bleeding and strokes). Proponents of genetic testing will undoubtedly criticize the design of the trials included in the meta-analysis, point out that the outcome trends are in the right direction, and speculate that larger studies might demonstrate a significant improvement. Skeptics will counter that the absolute reduction in events was small, corresponding to a “number needed to test” of 142 to prevent 1 bleeding event, and that genotyping is unlikely to be cost-effective.4 Why did genotype-guided warfarin dosing fail to improve outcomes in the trials analyzed? One potential explanation is that outcomes among patients receiving warfarin depend on many environmental variables in addition to genetic factors. In addition, patients differ in adherence to warfarin, which is particularly challenging because of the need for frequent monitoring and dose adjustment; 26% of patients who began warfarin therapy for nonvalvular atrial fibrillation discontinued it within a year.5 Furthermore, genotype guidance may not have improved outcomes in randomized trials because patients in control groups were monitored at state-ofthe-art anticoagulation clinics where INRs were tested frequently and doses were adjusted using an algorithm. There may be little room for genotype guidance to improve outcomes in settings where patients are closely monitored and therapy is carefully managed. Finally, the primary use of genotyping is in identifying the starting dose of warfarin, and because patients’ genes do not change while their environment does, there is only a narrow window of time in which genetic testing might be useful in warfarin management. We doubt that even a large pragmatic randomized trial comparing genotype-guided therapy with usual management of warfarin therapy could demonstrate a meaningful difference in hard clinical outcomes. Routine use of genetic testing to guide warfarin management cannot be recommended. Pharmacogenomics, that is, the use of genetic information to individualize pharmacologic therapy, is touted as a gateway to the new world of personalized medicine. The “Holy Grail” is finding genetic variants that identify the subset of patients most likely to benefit from a specific drug

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Genotype-Guided Dosing of Warfarin

Original Investigation Research

(eg, mutations in a receptor that make a tumor susceptible to a targeted biologic therapy) or be harmed (eg, mutations that increase the risk of a life-threatening adverse drug effect). A step removed are genetic variants that affect drug pharmacokinetics and hence a drug’s concentration at its receptor. Bringing pharmacogenomics into routine practice will require the buy-in of patients, providers, and payers. We would argue that an effect on surrogate markers, such as drug levels and other laboratory test results, or process measures, such as drug dose adjustment, is insufficient evidence to recommend widespread adoption of a genetic test. The key consideration in establishing the value of a

test is whether it provides information that changes choice of treatment and improves clinically meaningful outcomes.6,7 The journey to a world of personalized medicine is exciting but bumpy. We hope that future well-designed, adequately powered studies will help clinicians leverage pharmacogenomics to target therapy, improve clinical outcomes, and lower health care costs. Although the failure of genotypeguided warfarin dosing to improve outcomes should not be generalized to other genetic tests, it does offer a cautionary tale. Evidence of improved clinical outcomes, not biological plausibility or hype, should drive the adoption of genetic tests into practice.

ARTICLE INFORMATION

REFERENCES

Author Affiliations: Department of Medicine, University of California, San Francisco (Kazi); Department of Epidemiology and Biostatistics, University of California, San Francisco (Kazi); Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California (Hlatky); Department of Medicine, Stanford University School of Medicine, Stanford, California (Hlatky).

1. Furie B. Do pharmacogenetics have a role in the dosing of vitamin K antagonists? N Engl J Med. 2013;369(24):2345-2346.

Corresponding Author: Mark A. Hlatky MD, Department of Health Research and Policy, Stanford University School of Medicine, HRP Redwood Bldg, Room 150, Stanford, CA 94305 ([email protected]). Published Online: June 16, 2014. doi:10.1001/jamainternmed.2014.1227. Conflict of Interest Disclosures: None reported.

2. US Food and Drug Administration. Safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER)—January 2010: Coumadin (warfarin sodium) tablet and injection. http://www.fda.gov/Safety/MedWatch /SafetyInformation/ucm201100.htm. Published January 2010. Accessed April 1, 2014. 3. Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials [published online June 16, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.2368. 4. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic

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information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150(2):73-83. 5. Fang MC, Go AS, Chang Y, et al. Warfarin discontinuation after starting warfarin for atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2010;3 (6):624-631. 6. Hlatky MA, Greenland P, Arnett DK, et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119(17):2408-2416. 7. Kazi DS, Garber AM, Shah RU, et al. Cost-effectiveness of genotype-guided and dual antiplatelet therapies in acute coronary syndrome. Ann Intern Med. 2014;160(4):221-232.

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Warfarin, genes, and the (health care) environment.

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