Beating the Black Box

skoktandemowyWhen the FDA adds a “Boxed Warning” to a drug – known casually and more dramatically as a “black box” – it can have dramatic consequences. The information is intended to warn physicians of potential adverse effects associated with the drug, issues that are not deemed serious enough to pull the drug from the market but which should prompt extra attention and care. Antidepressants, the diabetes drug Avandia, and Depo-Provera birth control have all received black boxes in recent years, prompting widespread media coverage and medical comment.

Earlier this year, the anticoagulant medication clopidogrel (marketed as Plavix) became the latest drug to be black-boxed by the FDA. The warning fit the purported age of genetic medicine, as it was meant to draw attention to certain patients for whom the anti-clotting drug is less effective due to the presence of a gene variant for an important enzyme. These “poor metabolizers” exhibited reduced ability to convert the drug into its active components, and the black box warned that physicians should run genetic tests and consider alternative treatments in patients with the polymorphism.

But clopidogrel has become an important medical tool, used in millions of patients at high risk for heart attack, stroke, and other cardiovascular events. The drug has increasingly been incorporated into the long-term care of patients with drug-eluting stents – devices implanted to keep arteries open that secrete medication to prevent the vessels from re-narrowing. In patients where genetics renders clopidogrel less effective, the lost protection can lead to a stent thrombosis (where a clot forms on the device and blocks the artery) or other grave problems. Those concerns, and the expense of conducting genetic tests in every patient, have sent ripples through the field of interventional cardiology, said Sandeep Nathan, assistant professor of medicine at the University of Chicago Medical Center.

“There’s a growing recognition that this sort of formulaic approach to anti-platelet therapy is probably not a good idea,” Nathan said. “What has been brewing as a suspicion for well over a decade has come to an explosive head in the past one or two years.”

In response, Nathan has launched a two-pronged research and clinical effort to rethink current use of clopidogrel while seeking the best possible way to address risk in the future. Instead of waiting for a post-stent adverse event to tragically prove a patient’s insensitivity to clopidogrel, Nathan’s group has become one of the first to offer anti-platelet testing before the stent is implanted in patients at high-risk for the drug being ineffective.

“I view this as testing a parachute. You better be sure that the pack you just strapped on before you jumped out of a plane actually contains a parachute and not camping gear,” Nathan said. “If somebody implanted a drug-eluting stent in me, you better believe that I’m going to want to know if the drug that is my sole protection against a catastrophic, potentially life-ending event, is working.”

The chance of clopidogrel insensitivity is especially high in minority patients, who show a higher incidence of the genetic variants associated with reduced drug effectiveness. As many as one-third of African-Americans may carry the variant, Nathan said, and that percentage may be even higher for South Asians and other ethnic populations. Since clinical trials have largely tested the drug’s effectiveness in predominantly white populations, the additional risk to minorities – and how to address it – has not been well quantified.

So the second part of Nathan’s efforts is to measure genetic data and closely study the response in 100 patients receiving stents – a project he hopes will begin later this month. The resulting database can be a tool for physicians to determine the best way to adjust treatment in patients who exhibit reduced sensitivity to clopidogrel, an approach recently shown to be effective in reducing adverse outcomes in a small group of French patients. With the diverse patient population seen at the University of Chicago, Nathan hopes that biomarkers and treatment strategies can be generated for the minority populations that need them the most.

“What we want to know in our population, which is very ethnically diverse and enriched for African-American patients, is where is the ‘sweet spot’ for anti-platelet treatments?” Nathan said.

However, Nathan does not believe that genetic testing will become a mandatory procedure before stent implantation any time soon. Instead, genetic testing will complement anti-platelet testing for patients whose family history or ethnic background suggests a reasonable chance of low clopidogrel sensitivity, he said. The results of those tests can trace the ineffectiveness of clopidogrel in each patient back to its true source, allowing physicians to determine the best personalized alternative therapy.

“It’s not binary,” Nathan said, pointing out that there is probably more than one gene that determines clopidogrel’s success or failure. “That’s a very crude way of handling a very intricate problem. I think we need a much more sophisticated solution than that, and that’s the thrust of this research and the complementary clinical endeavor.”

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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