The ACC Foundation and the American Heart Association yesterday released a joint clinical alert on clopidogrel (Plavix). The alert is intended to help CV professionals make sense of a recent FDA black box warning for the drug saying that some patients’ genetic makeup can affect their response and put them at risk for serious adverse events.

Two to 14 percent of patients are “poor metabolizers” of clopidogrel and do not benefit fully from it, according to FDA analysis. Information about the specific genetic variation that might affect clopidogrel metabolism – and thus, lead to suboptimal clinical responses – is increasing, but there still isn’t sufficient evidence available to develop specific recommendations related to genetic testing in patients. Many questions remain about how and when to use genetic tests for clopidogrel candidates, which tests to use, as well as whether tests will be reimbursed.

The new ACCF/AHA report reviews the backdrop for the black box warning, including the multiple unknown factors that can influence individual patient outcomes. Its recommendations for practice are as follows:

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. That said, care providers of course should continue to use careful clinical judgment in each patient.

Relationships With Industry

An interesting side note to this document is that it was the first major clinical document to be produced under a new set of ACC principles for relationships with industry for the development of clinical documents.  Of the many things discussed in the document, one principle outlined is that the chair of the writing committee and greater than 50% of its members must have no relevant relationships with industry.

For the clopidogrel document, only two out of the five authors have relevant relationships with industry that needed to be disclosed.  ACC Vice President and writing committee Chair David Holmes, M.D., F.A.C.C., did not. Being 2/3 of the way free of relationship represents a vast improvement over both our previous clinical documents and our new RWI guidelines. It’s important to the ACC that it be able to offer unbiased clinical documents. It’s not that we think that cardiologists who accept money from drug companies are biased  (we believe that the RWI can provide value when such relationships are ethically structured) , it’s just that we feel strongly in the importance of transparency and maintaining rigorous levels of relationship-free writing committee members helps us to do this.

I’ll be talking more about relationships with industry in the coming weeks, but I’m interested to hear what you think now. Should clinical document writing committees exclude physicians because they accept industry funding or is there an acceptable level of relationships within a writing committee?

UPDATE (7/1): Watch a CVN video with writing committee chair and ACC Vice President David Holmes, M.D., F.A.C.C., explaining the alert.

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