An Overview of Genetic Testing for Clopidogrel Responsiveness

Clopidogrel is the generic name of an antiplatelet drug known by the trade name Plavix. This medication is used to decrease platelet aggregation, and by extension prevent blood clot formation, in the aftermath of a heart attack or stroke. Plavix also decreases the risk of thrombotic complications following stent placement in patients with atherosclerosis of the coronary or carotid arteries.

Until the late 1990’s, relatively few medications were available for people who could not tolerate long term therapy with aspirin or anticoagulants like warfarin. Besides aspirin, the main antiplatelet drug in use then was called ticlopidine, marketed as Ticlid. Unfortunately, a number of patients on Ticlid suffered a life threatening side effect called TTP (Thrombotic Thrombocytopenia Purpura), marked by platelet aggregation, trapping of platelets in the spleen, and internal bleeding. Rather than stop platelets from clumping together, Ticlid apparently had the opposite effect in these patients; it is also possible that the drug triggered the production of autoantibodies, which in turn caused TTP. Although Ticlid remains on the market, it has long since fallen into disuse.

Plavix received FDA approval in 1997. It achieved nearly overnight success in hospitals across the U.S., in spite of its high cost compared to aspirin and their similar efficacy profiles. Like aspirin, Plavix is contraindicated primarily in patients with active bleeding and remains in widespread use today. Over the years, relatively few safety issues have emerged with Plavix; however, another trend has raised concern: Some patients seem to exhibit little or no response to the drug.

The reason for this is that Plavix is a prodrug, meaning it must be metabolized by the liver to its active form. Although this finding was not entirely unexpected, it may not have been detected during clinical trials, partially due to the small number of patients (relative to the size of the adult U.S. population) who participate in these studies. However, a second, more important factor came into play: pharmacogenetics, or genetic variations underlying individual metabolic responses to different medications. As will be explained shortly, most people have no problem converting Plavix to its active form, but a significant number cannot.

Studies of Plavix demonstrate the drug is a substrate of the liver enzyme Cytochrome P450 2C19. People with two copies of a certain CYP2C19 polymorphism called 2C19*2 metabolize Plavix slowly or not at all. This genetic variant occurs in approximately 5% of Caucasians and African-Americans but in upward of 20% of people of East Asian ancestry. Some Pacific Islanders and natives of New Guinea are believed to have an even higher frequency of this 2C19 polymorphism. Since most Americans, including cardiac patients enrolled in clinical trials, are of non-Asian ancestry, relatively few are homozygous for the 2C19*2 gene. As such, very few people who metabolize Plavix poorly were represented in U.S. clinical trials of the drug.

The story does not end there. As of 2010, European scientists claim to have elucidated a second gene involved in the response to Plavix. An article in Nature Medicine describes how different forms of the PON-1 gene, which encodes the enzyme paraoxonase, were associated with better or worse clinical outcomes among a group of patients treated with Plavix following coronary artery stent placement. Patients with certain gene polymorphisms, especially those with two copies of the variant PON QQ192, suffered a higher number of thrombotic complications, which the researchers attributed to poor metabolism of Plavix. On the other hand, patients homozygous for the RR192 variant of PON-1 seemed to benefit most from the drug.

Given these findings, it seems prudent to test patients for both the 2C19*2 and QQ192 polymorphisms prior to initiating therapy with Plavix. Currently, the most widely available genetic screening tests detect CYP2C19 variants only. Whether a single study implicating PON-1 in Plavix responsiveness leads to a demand for additional genetic tests remains to be seen. In the larger picture, physicians, pharmacists, and other health care providers have become far more aware of the importance of pharmacogenetics in anticipating individual responses to medication therapy.