As the health care system transitions to a precision medicine approach that tailors clinical care to the genetic profile of the individual patient, there is a potential tension between the clinical uptake of new technologies by providers and the legal system's expectation of the standard of care in applying such technologies. We examine this tension by comparing the type of evidence that physicians and courts are likely to rely on in determining a duty to recommend pharmacogenetic testing of patients prescribed the oral anti-coagulant drug warfarin. There is a large body of inconsistent evidence and factors for and against such testing, but physicians and courts are likely to weigh this evidence differently. The potential implications for medical malpractice risk are evaluated and discussed.
E.Marshall, “Waiting for the Revolution,”Science331, no. 6017 (2011): 526-529, at 526; E. J. Stanek et al., “Adoption of Pharmacogenomic Testing by US Physicians: Results of a Nationwide Survey,” Clinical Pharmacology & Therapeutics 91, no. 3 (2012): 450-458, at 454.
3.
A. L.Greer, “The State of the Art versus the State of the Science: The Diffusion of New Medical Technologies into Practice,”International Journal of Technology Assessment in Health Care4, no. 1 (1988): 5-26, at 5.
4.
J. PEvans, W.Burke, and M.Khoury, “The Rules Remain the Same for Genomic Medicine: The Case against ‘Reverse Genetic Exceptionalism,’”Genetics in Medicine12, no. 6 (2010): 342-343; A. C. J. W. Janssens and P. A. Deverka, “Useless Until Proven Effective: The Clinical Utility of Preemptive Pharmacogenetic Testing,” Clinical Pharmacology & Therapeutics 96, no. 7 (2014): 652–654.
5.
H. R.Arkes, “The Consequences of the Hindsight Bias in Medical Decision Making,”Current Directions in Psychological Science22, no. 5 (2013): 356–360.
6.
K.De Ville, “Medical Malpractice in Twentieth Century United States: The Interaction of Technology, Law, and Culture,”International Journal of Technology Assessment in Health Care14, no. 2 (1998): 196-211, at 200.
7.
G. J.Annas, “Is a Genetic Screening Test Ready When the Lawyers Say It Is?”The Hastings Center Report15, no. 6 (1985): 16-18, at 18.
8.
J. A.Roth, “Genetic Risk Factors for Major Bleeding in Patients Treated with Warfarin in a Community Setting,”Clinical Pharmacology & Therapeutics95, no. 6 (2014): 636-643, at 636; M. Pirmohamed et al., “Oral Anticoagulation: A Critique of Recent Advances and Controversies,” Trends in Pharmacologic Sciences 36, no. 3 (2015): 153–163.
9.
I. A.Choonara, “The Relationship between Inhibition of Vitamin K1 2,3-Epoxide Reductase and Reduction of Clotting Factor Activity with Warfarin,”British Journal of Clinical Pharmacology25, no. 1 (1998): 1-7, at 4–5.
10.
D. A.Flockhart, ‘Pharmacogentic Testing of CYP2C9 and VKORC1 Alleles for Warfarin,”Genetics in Medicine10, no. 2 (2008): 139-150, at 139.
11.
In-hospital mortality of intracranial bleeding associated with warfarin is 42.3%, and many of those who survive are severely disabled. D.Dowlatshahi, “Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal,”Stroke43, no. 7 (2012): 1812-1817, at 1815.
12.
M. C.Fang, “Death and Disability from Warfarin-Associated Intracranial and Extracranial Hemorrhages,”American Journal of Medicine120, no. 8 (2007): 700-705; L.-A. Linkins, “Bleeding Risks Associated with Vitamin K Antagonists,” Blood Reviews 27, no. 3 (2013): 111-118, at 112.
13.
D. K.Wysowski, P.Nourjah, and L.Swartz, “Bleeding Complications with Warfarin Use: A Prevalent Adverse Effect Resulting in Regulatory Action,”Archives of Internal Medicine167, no. 13 (2007): 1414–1419.
14.
D. S.Budnitz, “Emergency Hospitalizations for Adverse Drug Events in Older Americans,”New England Journal of Medicine365, no. 21 (2011): 2002-2012, at 2008.
15.
Roth et al., supra note 8, at 636.
16.
E. A.Sconce, “The Impact of CYP2C9 and VKORC1 Genetic Polymorphism and Patient Characteristics Upon Warfarin Dose Requirements: Proposal for a New Dosing Regimen,”Blood106, no. 7 (2005): 2329-2333, at 2332; C. Carnes, “What Is the Role of Pharmacogenetics in Optimization of Warfarin Dosing?” Trends in Cardiovascular Medicine 25, no. 1 (2015): 42–43.
17.
Flockhart et al., supra note 10, at 140.
18.
Id.
19.
S.Chatterjee, “New Oral Anticoagulants and the Risk of Intracranial Hemorrhage: Traditional and Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials of New Oral Anticoagulants in Atrial Fibrillation,”JAMA-Neurology70, no. 12 (2014): 1486-1490; A. Liew et al., “Assessment of Anticoagulation Intensity and Management of Bleeding with Old and New Oral Anticoagulants,” Canadian Journal of Cardiology 29, no. 7, Supp. (2013): S34-S44, at S34, S36.
20.
Liew et al., supra note 19, at S34.
21.
J. D.Rockoff and R.Winslow, “New Medicines Emerge, but Few Blockbusters,”Wall Street Journal, December15, 2013.
22.
For example, Pradaxa resulted in the most reports of adverse effects of any drug monitored by FDA in 2012, and over 2400 lawsuits have been filed by alleged victims of Pradaxa bleeding side effects. Wright & Schulte LLC, New Order in Pradaxa Lawsuits Sets Dates for Jury Selection in First Federal Pradaxa Trial (May 5, 2014), available at <http://www.prweb.com/releases/2014/05/prweb11823340.htm> (last visited February 24, 2016). Xarelto has now surpassed Pradaxa in the number of serious adverse effects reported to FDA, and there are also multiple lawsuits pending against this alternative to warfarin. J. Steinberg, “Xarelto Plaintiffs Seek to Consolidate Injury Suits in Southern Illinois,” Product Safety & Liability Reporter (Bloomberg BNA) 42 (October 16, 2014): 1176.
23.
G. M.Arepally and Thomas L.Ortel, “Changing Practice of Anticoagulation: Will Target-Specific Anticoagulants Replace Warfarin?”Annual Review of Medicine66 (2015): 241-253, at 246–248.
24.
J. A.Johnson and L. H.Cavallari, “Warfarin Pharmacogenetics,”Trends in Cardiovascular Medicine25, no. 1 (2015): 33-41; D. S. Kazi and M. A. Hlatky, “Warfarin, Genes, and the (Health Care) Environment,” JAMA Internal Medicine 174, no. 8 (2014): 1338-1339, at 1338.
25.
Linkins, supra note 12, at 111; Arepally and Ortel, supra note 23, at 242.
26.
N. A.Limdi, “Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic Complications in African-American and European-American Patients on Warfarin,”Clinical Pharmacology & Therapeutics83, no. 2 (2008): 312-321; M. Wadelius et al., “The Largest Prospective Warfarin-Treated Cohort Supports Genetic Forecasting,” Blood 113, no. 4 (2009): 790-791; J. Yang, et al., “Influence of CYP2C9 and VKORC1 Genotypes on the Risk of Hemorrhagic Complications in Warfarin-Treated Patients: A Systematic Review and Meta-analysis,” International Journal of Cardiology 168, no. 4 (2013): 4234–4243.
27.
Johnson and Cavallari, supra note 24.
28.
Roth et al., supra note 8, at 639.
29.
FDA, “FDA Approves Updated Warfarin (Coumadin) Prescribing Information; New Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients,”August6, 2007, available at <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967> (last visited February 24, 2016).
The International Warfarin Pharmacogenetics Consortium, “Estimation of the Warfarin Dose with Clinical and Pharmaccogenetic Data,”New England Journal of Medicine360, no. 8 (2009): 753-764; B. S. Finkelman et al., “Genetic Warfarin Dosing: Tables Versus Algorithms,” Journal of the American College of Cardiology 57, no. 5 (2011): 612–618.
M. M.Mello, “Of Swords and Shields: The Use of Clinical Practice Guidelines in Medical Malpractice Litigation,”University of Pennsylvania Law Review149, no. 3 (2001): 645-710, at 662–667.
35.
A.Holbrook, “Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence Based Clinical Practice Guidelines,”Chest141, no. 2, Suppl. (2012): e152S-184S, at 159s-161s.
36.
PharmGKB, “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Information for Warfarin and CYP2C9, VKORC1,”available at <https://www.pharmgkb.org/guideline/PA166104949> (last visited February 24, 2016).
37.
J. L.Anderson, , “Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation,”Circulation116, no. 22 (2007): 2563–2570.
38.
J. K.Burmester, “A Randomized Control Trial of Geno-type-Based Coumadin Initiation,”Genetics in Medicine13, no. 6 (2011): 509–518.
39.
S. E.Kimmel, “A Pharmacogenetic Versus Clinical Algorithm for Warfarin Dosing,”NEJM369, no. 24 (2013): 2283–2293.
40.
L. H.Cavallari and E. A.Nutescu, “Warfarin Pharmacogenetics: To Genotype or Not to Genotype, That Is the Question,”Clinical Pharmacology & Therapeutics96, no. 1 (2014): 22-24, at 22–23.
41.
Id., at 23.
42.
Id.
43.
Id.
44.
Johnson and Cavallari, supra note 24.
45.
M.Pirmohamed, “A Randomized Trial of Genotype Guided Dosing for Warfarin,”NEJM369, no. 24 (2013): 2294–2303.
46.
See, e.g., Johnson and Cavallari, supra note 24.
47.
S. AScott and S. A.Lubitz, “Warfarin Pharmacogenetic Trials: Is There a Future for Pharmacogenetic-Guided Dosing?”Pharmacogenomics15, no. 6 (2014): 719-722, at 720.
48.
Id., at 721.
49.
E. J.Do, “Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT): Rationale and Study Design,”Pharmacogenomics Journal12, no. 5 (2012): 417–424.
50.
See Pirmohamed et al., supra note 8, at 156–157.
51.
J. L.Anderson, “A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II),”Circulation125, no. 16 (2012): 1997–2005.
52.
R. S.Epstein, “Warfarin Genotyping Reduces Hospitalization Rates: Results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study),”Journal of the American College of Cardiology55, no. 25 (2010): 2804–2812.
53.
J. L.Mega, “Genetics and the Clinical Response to Warfarin and Edoxaban: Findings from the Randomised, Double-Blind ENGAGE AF_TIMI 48 Trial,”The Lancet385, no. 9984 (2015): 2280–2287.
54.
M. S.Wen, “Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes,”Clinical Pharmacology & Therapeutics84, no. 1 (2008): 83-89; P. A. Lenzini et al., “Laboratory and Clinical Outcomes of Pharmacogenetic vs. Clinical Protocols for Warfarin Initiation in Orthopedic Patients,” Journal of Thrombosis and Haemostasis 6, no. 10 (2008): 1655-1662; G. A. McMillin et al., “Gene-Based Warfarin Dosing Compared with Standard of Care Practices in an Orthopedic Surgery Population: A Prospective, Parallel Cohort Study,” Therapeutic Drug Monitoring 32, no. 3 (2010): 338–345.
55.
K.Stergiopoulos and D. L.Brown, “Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues: Meta-analysis of Randomized Clinical Trials,”JAMA Internal Medicine174, no. 8 (2014): 1330–1338.
56.
Z.Liao, “Meta-analysis of Randomized Controlled Trials Reveals an Improved Clinical Outcome of Using Geno-type Plus Clinical Algorithm for Warfarin Dosing,”Journal of Thrombosis and Thrombolysis39, no. 2 (2015): 228–234.
57.
L. M.Meckley, “A Policy Model to Evaluate the Benefits, Risks and Costs of Warfarin Pharmacogenomic Testing,”Pharmacogenomics28, no. 1 (2010): 61-74, at 70–71.
58.
M. H.Eckman, “Cost-Effectiveness of Using Pharmaco-genetic Information in Warfarin Dosing for Patients with Nonvalvular Atrial Fibrillation,”Annals of Internal Medicine150, no. 2 (2009): 73-83, at 80.
59.
Id., at 78.
60.
J. A.Leey, “Cost-Effectiveness of Genotype-Guided Warfarin Therapy for Anticoagulation in Elderly Patients with Atrial Fibrillation,”American Journal of Geriatric Pharmaco-therapy7, no. 4 (2009): 197–203.
61.
T.Sweezy and S. A.Mousa, “Genotype-Guided Use of Oral Antithrombotic Therapy: A Pharmacoeconomic Perspective,”Personalized Medicine11, no. 2 (2014): 223–235.
62.
Id.
63.
P. J.Neumann, J. T.Cohen, and M. C.Weinstein, “Updating Cost-Effectiveness — The Curious Resilience of the $50,000-per-QALY Threshold,”NEJM371, no. 9 (2014): 796–797.
64.
FDA News Release, FDA Approves Updated Warfarin (Coumadin) Prescribing InformationNew Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients, Press Release, August 16, 2007, available at <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm> (last visited February 24, 2016).
65.
FDA Warfarin Press Conference Transcript, supra note 33, at 2 (statement of Larry Lesko, FDA) (emphasis added).
Sweezy and Mousa, supra note 60; Kazi and Hlatky, supra note 24, at 1338.
70.
E. A.Nutescu, “Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service,”Pharmacotherapy33, no. 11 (2013): 1156–1164.
71.
See, e.g., Johnson and Cavallari, supra note 24; Kazi and Hlatky, supra note 24, at 1338.
72.
Scott and Lubitz, supra note 47, at 721; A. H.Maitland-van der Zee, “Patients Benefit from Genetics-Guided Coumarin Anticoagulant Therapy,”Clinical Pharmacology & Therapeutics96, no. 1 (2014): 15-17; Pirmohamed et al., supra note 8, at 161.
73.
Cavallari and Nutescu, supra note 40, at 24.
74.
Johnson and Cavallari, supra note 24.
75.
Kazi and Hlatky, supra note 24, at 1338.
76.
N. A.Limdi, “Race Influences Warfarin Dose Changes Associated with Genetic Factors,”Blood126, no. 4 (2015): 539–545.
77.
See P. G.Peters, Jr., “The Role of the Jury in Modern Malpractice Law,”Iowa Law Review87, no. 3 (2002): 909-969, at 914.
78.
See, e.g., A. W.O’Neill, “GM Ordered to Pay $4.9 Billion in Crash Verdict,”Los Angeles Times, July10, 1999.
79.
Arkes, supra note 5, at 358.
80.
E.g., Jeffries v. United States, No. C08-1514RSL (W.D. Wash., Oct. 28, 2009), 30 No. 1 Verdicts, Settlements & Tactics art 12 ($3.8 million verdict for negligent provision of anti-coagulation therapy); “388,000 Awarded to Family of Patient Who Died after Failure to Monitor Administration of Coumadin,” Physician Risk Management, July 1, 2013.
