01/11/2012 - There's no need to perform a certain genetic test before deciding whether to prescribe the anti-clotting drug clopidogrel (Plavix), according to a new study published in the Journal of the American Medical Association.

However, doctors at Scripps Health who have pioneered the use of this test say Plavix testing is indeed helpful in preventing heart attacks and deaths in coronary stent patients, and that the JAMA study is flawed.

Who's right is a matter of extreme interest to the estimated 1 million patients who get coronary stents each year in the United States, including this reporter, who got five of them in August 2010. But for patients, there's no obvious answer, in part because the answer hinges on what question you ask. Is the Plavix test useful for all heart patients, or just for those getting coronary stents? That's something you and your doctor will need to decide.

Plavix inhibits the clumping of platelets, blood-cell fragments that start the clotting process. The Plavix test screens patients for a gene variant, or genotype, called CYP2C19. This genotype is known to be less responsive to Plavix's anti-clotting effect.

Patients with this genotype are at higher risk of stent thrombosis, the formation of a blood clot in their stent, said cardiologist Matthew Price, director of the Cardiac Catheterization Laboratory at Scripps Green Hospital.

Since stent thrombosis is extremely serious, Scripps tests patients for this genotype before coronary stents, which hold blood vessels open, are implanted. Patients with the genotype can be placed on a stronger antiplatelet drug, Price said.

The JAMA article said the study found no "clinically significant" relationship between the genotype, Plavix therapy and cardiovascular problems.

That study included an analysis of other studies, or a meta-analysis, which the authors said provided firm evidence that there was no need for routine testing. The potential association with stent thrombosis was found in studies with small numbers of patients and may have been subject to biases, the JAMA article stated.

An accompanying editorial in the magazine suggested that the genotype test was an example of "irrational exuberance" for genetically personalized medicine. The editorial recommended trying a larger-scale study of the genotype test for coronary stent patients to see whether the weak association detected was real or coincidence.

"In the absence of such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution," stated the editorial by Steven E. Nissen, a cardiologist with the Cleveland Clinic Foundation. "It is still likely that pharmacogenomics has a bright future in cardiovascular medicine, but the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies. Overzealous adoption based on limited biochemical data does not serve the public interest."

Scripps's Price said the study cast too wide a net by considering all cardiovascular disease, losing focus on the proven association between the genotype and coronary stenting. Since stent-associated clots are so serious, he said, even a small increase in them should be avoided.

"The analysis includes a large number of patients from trials that had nothing to do with coronary stenting," wrote Price and Scripps cardiologist colleagues Eric Topol and Paul Teirstein, along with other doctors, in a response to the JAMA study.

A more formal response to be published in JAMA is in the works, Price said.

The study itself showed that among patients receiving coronary stents, there was an extra 14 per 1,000 increase in stent thrombosis among those with the genotype, compared with those who didn't have it, the Scripps doctors' response stated. "With over 1 million patients undergoing coronary stenting per year in the United States, this extrapolates to over 14,000 stent thrombosis events per year."

Clotting from a stent "is almost a purely platelet-driven issue," Price said. So it makes sense that patients receiving coronary stents would be the most at risk of a stent clot associated with a reduced response to Plavix. Studies that examined outcomes of patients in whom Plavix was used in other conditions, such as atrial fibrillation, wouldn't be pertinent to this issue, he said.

Preventing stent thrombosis is extremely important because the event is so serious, Price said.

"It is an important public health problem," Price said. "It shows up either as a big heart attack or you drop dead."

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