Will the Fda’s 2010 Warfarin Label Changes Finally Provide the Legal Impetus for Warfarin Pharmacogenetic Testing?

• Publication year: 2010

Susan A. Fucks⁰

Due to newer clinical utility study results and the recent availability of warfarin pharmacogenetic testing, the Food and Drug Administration ("FDA") has modified warfarin's prescription labeling twice in the past three years. Yet, despite numerous warfarin dosing adverse events resulting from trial and error dosing, many clinicians have been reluctant to prescribe warfarin pharmacogenetic testing to increase dosing accuracy. This disparity stems from conflicts over the interpretations and results of warfarin pharmacogenetic clinical utility studies. Until the federal government implements independent clinical effectiveness testing authorized by the 2010 Patient Protection and Affordable Care Act, manufacturers, health care institutions, and health care clinicians have the unenviable task of sorting through this morass. This article examines the clinical utility of warfarin pharmacogenetic tests, the FDA's role, and other contributing factors that have an impact on the liability and practice of those responsible for the tests' implementation.

I. Introduction

In a 2006 national pharmaceutical survey, 74% of consumers admitted that they had not followed their prescribers' directions for taking their prescription medications, including 31% who had not gotten a prescription filled.¹ This prescription noncompliance may be related to the fact that 25% to 50% of medications are ineffective in a given patient, necessitating costly and inefficient trial and error prescribing.²

In contrast to this scatter-shot, trial and error approach, the goal of personalized medicine is to more accurately predict an individual's response to therapy based on unique individual characteristics, such as the patient's genetic makeup.³ Accurate, clinically useful, pharmacogenetic tests⁴ allow a health care clinician to individually target patient medication and dosages. Such targeted therapy may improve patient medication adherence because the medication and dosage are more likely to be effective and less likely to have adverse effects.⁵

Due to increasing evidentiary support for warfarin⁶ pharmacogenetic testing, the Food and Drug Administration ("FDA") has modified warfarin prescription labeling twice in the past three years.⁷ Yet, despite numerous warfarin dosing adverse events resulting from the trial and error approach, many clinicians have been reluctant to prescribe warfarin pharmacogenetic testing to increase dosing accuracy.⁸ Few question the analytical validity of FDA approved warfarin pharmacogenetic tests, but there is considerable disagreement over whether the tests offer any real clinical usefulness or utility for the medical practitioner. Numerous concerns have hampered widespread adoption of pharmacogenetic testing by clinicians: high costs, health insurance coverage issues, slow test result turnaround times, time constraints for clinician office visits, lack of informed consent, availability of genetic resources, and insufficient patient and clinician education. Independent clinical effectiveness testing, authorized by the 2010 Patient Protection and Affordable Care Act ("PPACA"),⁹ might help to clarify the above concerns, but the Act's measures will not be implemented for several years.¹⁰ Meanwhile, pharmaceutical manufacturers, pharmacists, health care institutions, and health care clinicians have the unenviable task of sorting through warfarin pharmacogenetic testing concerns without the benefit of PPACA's independent clinical effectiveness testing. This article focuses on warfarin pharmacogenetic testing as an example of both the promises and the limitations of genetic personalized medicine. It examines the clinical utility of warfarin pharmacogenetic tests and the consequences that the FDA's and health insurers' actions have on the liability and practice of those responsible for implementation of the tests.

II. Warfarin and Pharmacogenetic Testing

Warfarin is a prescription medication within the class of anticoagulant drugs.¹¹ Without sufficient anticoagulation in a patient susceptible to blood clots, the patient risks death or tissue damage, depending upon where in the body the blood clot blocks or ruptures a blood vessel.¹² A drug in this class can prevent a stroke from a coagulation that restricts blood flow in the brain,¹³ limits lung damage that would have resulted from a clot induced pulmonary embolism,¹⁴ and discourages other blood starved tissue injuries from clots that migrate and block blood vessels elsewhere in the body.¹⁵ Anticoagulants are often prescribed when blood pools in a patient's heart, a byproduct of ineffective heartbeats from atrial fibrillation. Avoidance of clotting in the pooled blood helps to protect the patient from a myocardial infarction or stroke.¹⁶ Anticoagulants are also indicated to prevent the clotting process ("thrombosis") in patients with a history of thrombosis, or in patients who are more likely to have increased clotting due to cardiac valve and joint replacements.¹⁷

A. Advantages and Disadvantages of Available Anticoagulants¹⁸

1. Warfarin

a. Warfarin's Moldy Origins

Scientist Karl Paul Link and his colleagues fractionated a concentrate of the active hemorrhagic ingredient in spoiled hay that was responsible for killing cattle.¹⁹ After testing the concentrate on laboratory rabbits, they discovered that it increased the rabbits' blood clotting time ("prothrombin time"), resulting in hemorrhages.²⁰ Link realized that vitamin K-deficient animals and dicumarol-fed laboratory rabbits had similar hemorrhages, noting that vitamin K has a similar structure to dicumarol. This led to Link's use of vitamin K to reverse dicumarol's anticoagulation properties.²¹

b. Warfarin's Mechanism of Action as an Anticoagulant

Warfarin is the only vitamin K antagonist available in the United States.²² Vitamin K is a cofactor that activates several of the proteins that cause blood to coagulate ("clotting factors").²³ The body has limited stores of vitamin K, so the body cyclically regenerates existing vitamin K for reuse.²⁴ During this regeneration process, the enzyme vitamin K epoxide reductase ("VKoR") converts the inactive form of vitamin K ("vitamin K epoxide") into the active form of vitamin K.²⁵ Warfarin inhibits the VKoR enzyme's ability to change vitamin K epoxide back into vitamin K. This results in less vitamin K available to facilitate the activation of clotting factors such as Factor II ("prothrombin").²⁶ ultimately, this creates an increase in prothrombin time: less prothrombin activation slows the conversion of prothrombin into thrombin,²⁷ making less thrombin available to alter fibrinogen into fibrin to form blood clots.

2. Heparin and Low Molecular Weight Heparin Mechanisms of Action

Heparin ("heparin" or "unfractionated heparin") and low-molecular-weight heparin ("LMW heparin" or "fractionated heparin") enhance the effect of antithrombin to inhibit factors Xa and IIa ("thrombin").²⁸ When antithrombin inactivates these factors, it prevents fibrinogen from clotting.²⁹ Both heparin and LMW heparins are associated with increased risks of heparin-induced thrombocytopenia ("HIT") syndrome, which can be fatal, and osteoporosis.³⁰

3. Differences between Warfarin and Heparin/LMW Heparin

Although the anticoagulation result is the same using warfarin as it is with fractionated or unfractionated heparin, warfarin and heparins make thrombin unavailable to fibrinogen through different pathways. Since heparins are not vitamin K antagonists, clinicians can prescribe warfarin and heparin concurrently.³¹ A clinician may start a patient on one of the heparins because their anticoagulant affects are quite rapid, often occurring within 24 hours.³² it can take four to five days to get a warfarin international normalized ratio ("INR") response within the therapeutic range.³³

The advantage of warfarin over heparins is that warfarin is available orally as a pill,³⁴ while the others are only available as injectables.³⁵ The warfarin pill allows a patient to easily self-administer the medication as an outpatient.³⁶ LMW heparin is not as convenient as warfarin, but usually more so than unfractionated heparin. A patient can self-administer most LMW heparins subcutaneously instead of requiring a hospital stay for intravenous heparin.³⁷

The issue of hospitalization is important for managing the cost of anticoagulation therapy. Though heparin and some LMW heparins are off-patent, hospital stays for intravenous anticoagulation therapy are costly. in data collected from December 2006 through June 2008, an average hospital stay to obtain a therapeutic INR range or to treat a bleeding episode is 4.8 days. ³⁸ The median 4.8 day hospital cost is $10,419; patient costs are higher.³⁹ In contrast, warfarin is available generically and is 1,000 times less costly, at $10.83 for 100 7.5 milligram tablets of warfarin.⁴⁰ Warfarin's ease of self-administration and cost savings have contributed to clinicians writing more than 30 million warfarin prescriptions in 2004 alone.⁴¹

B. Genetic Factors Affecting Warfarin Dosing

All anticoagulants have bleeding risks if a patient receives too much, and clotting risks if a patient receives too little.⁴² Warfarin has a narrow therapeutic range (a target INR of 2.5 with a range of 2.0-3.0).⁴³ A number of risk factors, including age, weight, sex, drug and food interactions, and genetic factors, affect achieving that narrow therapeutic range.⁴⁴ Several known genetic factors that affect warfarin dosage are in the CYP2C9 and VKORC1 genes.⁴⁵

1. CYP2C9 DNA Sequence Variants

The Cytochrome P450 enzyme, in subfamily IIC, polypeptide 9, is also known as CYP2C9.⁴⁶ It is the body's main metabolizing enzyme for warfarin.⁴⁷ Two frequent polymorphisms in the genes that encode the enzyme, CYP2C9*2⁴⁸ and CYP2C9*3, are found primarily in Caucasians.⁴⁹ These polymorphisms are known to affect how a person's body metabolizes warfarin.⁵⁰

CYP2C9*1 is the unmodified allele that does not...