Responding to the FDA’s addition of a boxed warning on the Plavix (clopidogrel) label, the ACC and the AHA have released a clinical alert intended to provide guidance to clinicians. David Holmes, Jr, the chair of the writing group, said in a press release (below) that “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.”
The ACC and the AHA do not offer specific recommendations relating to genetic testing. They note that “many questions remain about how and when to use genetic tests, which tests to use, as well as whether they will be reimbursed.” Holmes also noted that newer agents such as prasugrel “appear to have fewer genetic issues, but have the potential for more bleeding and higher costs.”
“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 Dr. Holmes.
The document provides seven recommendations for practice, as summarized here:
- “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, health care 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.”
- “The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined.”
- “Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies.
- The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. There is no information that routine testing improves outcome in large subgroups of patients.”
- Therapeutic options for patients who experience an adverse event while taking clopidogrel include switching to prasugrel, increasing the dose of clopidogrel, and employing functional testing to determine if patients are clopidogrel nonresponders.
- For high risk patients who respond poorly to standard loading and maintenance doses, higher LDs (600 mg versus 300 mg), double-dose loading (600 mg twice over 2 hours), and higher MDs of clopidogrel (150 mg daily) may be considered.
Here is the press release from the AHA and the ACC:
ACC/AHA Release Clinical Alert in Response to FDA Boxed Warning About Anti-Platelet Agent, Clopidogrel
Report provides guidance for clinicians caring for patients with heart disease on genetic variability, risk-benefit analysis and other issues
Newly available information indicating that some patients vary in their genetic makeup in ways that may affect their response to clopidogrel (Plavix), and can prevent the medication from reducing their risk for heart attack, stroke and even death, the Food and Drug Administration (FDA) recently added a warning to the information for this drug. To help clinicians interpret the new FDA warning for this widely prescribed anti-platelet agent, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) today released a joint clinical alert, shedding light on key issues for consideration and recommendations for practice.
“Just as some people have red hair and others have blonde, our genetic makeup can also affect the way we respond to certain drugs, such as clopidogrel,” says David Holmes, Jr, M.D., chair of the six-member writing group. “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.”
Drugs like clopidogrel work by making platelets less likely to form blood clots, and have been shown to lower the risk of heart attack, unstable angina (new or increased heart pain), stroke and heart-related death in patients. However, because anti-platelet 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, 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. “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 Dr. 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 thoughtfully reviews the backdrop for the new prescribing information, including the multiple unknown factors that can influence individual patient outcomes. It also sets forth broad recommendations for practice:
1. 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, health care providers should help ensure that patients take it as prescribed.
2. 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.
3. Careful 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.
4. 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.
5. 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).
6. 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.
These recommendations are intended to help guide health care providers in devising the best treatment plan for each patient.
“Genetic testing, use of alternate drugs or using alternate dosing strategies with clopigogrel 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 Dr. Holmes. He reinforces the responsibility of the health care team to use “careful clinical judgment” in each patient and ensure compliance with existing antiplatelet therapy guidelines.
Authors caution that patients currently taking clopidogrel should not stop the drug unless advised by their health care provider.
The American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions and the Society for Thoracic Surgeons have also endorsed the recommendations presented in the ACCF/AHA advisory.
Full text of this report will be published in the July 20, 2010, issue of the Journal of the American College of Cardiology and co-published in the July 20, 2010, issue ofCirculation: Journal of the American Heart Association. The document will also be available on the ACC (www.cardiosource.org) and AHA (www.americanheart.org) web sites.
Dr. Holmes reports no conflicts of interest.
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