ACC/AHA elucidate FDA boxed warning on Plavix for practices

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Based on new information indicating that some patients vary in their genetic makeup in ways that may affect their response to clopidogrel (Plavix, Bristol-Myers Squibb), the FDA has added a warning to the information for this drug. Today, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) released a joint clinical alert for consideration and recommendations for practice.

“The majority of patients do very well with standard guideline-based clopidogrel, but for the small number of patients who have problems, these are big problems,” said David Holmes, Jr, MD, chair of the six-member writing group.

Because antiplatelet effects don’t occur unless the body converts or metabolizes the drug into its active form, patients with certain differences in their genetic makeup will not derive clinical benefit and instead remain at risk for serious adverse events. The FDA estimates that 2 to 14 percent of patients are “poor metabolizers” of the drug, thereby not benefiting fully from it.

Although there is increasing information about specific genetic variations that might affect clopidogrel metabolism, leading to suboptimal clinical responses in some patients, the ACCF and the AHA said there is “not sufficient evidence upon which to develop specific recommendations related to genetic testing in patients.” Since the FDA warning, many questions remain about how and when to use genetic tests, which tests to use, as well as whether they will be reimbursed, the agencies said. In fact, researchers at the University of North Carolina at Chapel Hill began a clinical trial to further develop reasons for patient resistance and test other forms of treatment.

Further complicating the issue are new medications that appear to have fewer genetic issues, but have the potential for more bleeding and higher costs,” added Holmes.

“We have pieces of information, but we need to try to connect the dots, and that’s what we have tried to do [in this report],” he said. “While it would be nice to match a specific drug to each patient, the science for personalized medicine isn’t there yet. What we are left with are different groups of patients, different medicines and an attempt by clinicians to carefully balance the risks and benefits of all the different therapeutic strategies to optimize outcomes.”

The report reviewed the backdrop for the new prescribing information, including the unknown factors that can influence individual patient outcomes. It also set forth recommendations for practice:

  • Adherence to existing evidence-based guidelines from ACC, AHA or other professional societies for using antiplatelet therapies should remain the foundation of care. If clopidogrel is prescribed, healthcare providers should help ensure that patients take it as prescribed.
  • Clinicians must be aware that in certain patients with either acute or chronic coronary artery disease, genetic variability in response to clopidogrel can affect its inhibition of platelet function.
  • Clinical judgment, including weighing the risks and benefits, is needed in considering all therapies. The new boxed warning points out that for clopidogrel, if there is a lack of efficacy, the consequences can potentially result in fatal outcomes.
  • Results from ongoing clinical trials in large groups of patients will provide more information about the predictive value of genetic testing and better inform the role genotyping might play in personalizing medicine and optimizing outcomes.
  • Genetic testing to determine if a patient is a poor metabolizer may be considered before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes (e.g., patients undergoing elective high-risk PCI procedures).
  • Using alternative antiplatelet therapies or altering the dosing of clopidogrel may be reasonable options in patients who experience an adverse event while taking clopidogrel and have been taking the drug as prescribed.

“Genetic testing, use of alternate drugs or using alternate dosing strategies with clopidogrel might be reasonable in some patients who have taken the drug as directed, but have experienced an adverse event either because the drug did not work or worked too well and caused bleeding,” said Holmes. He reinforced the responsibility of the healthcare team to use “careful clinical judgment” in each patient and ensure compliance with existing antiplatelet therapy guidelines.

The American Academy