WASHINGTON, DC - Public Citizen is petitioning the FDA to add a boxed warning to clopidogrel alerting patients to the bleeding risks associated with taking clopidogrel on top of aspirin beyond 12 months after drug-eluting-stent (DES) treatment[1].
The consumer watchdog group also wants the agency to request that companies to send "Dear Doctor" letters and distribute an updated medication guide to patients warning of these "preventable adverse effects that occur with use for greater than one year."
The petition is already stoking a long-simmering debate around the need for antiplatelet therapy after DES implantation to mitigate stent-thrombosis risk.
Dr Sidney Wolfe , the group's founder and senior advisor, and Dr Neil Holtzman (Johns Hopkins University School of Medicine) sent the letter today to the FDA directors and commissioner. In it, they summarize the recent evidence supporting shorter-duration dual antiplatelet therapy (DAPT), noting also that more than one million DES were implanted in 2012 in the US alone. More than 2.2 million prescriptions for clopidogrel were written in October 2012 (the last month for which data are available).
Importantly, note Wolfe and Holtzman, "The FDA has not revised its recommendation since 2008, despite mounting data that little benefit in terms of cardiac end points is to be gained by 12 or more months of clopidogrel therapy and the risks of bleeding persist as long as patients are on the drug."
The FDA's current medication guide (2011) notes that clopidogrel "can cause bleeding, which can be serious and can sometimes lead to death."
Public Citizen's petition is asking that the new labeling, medication guide, and Dear Doctor letters "address the increased risks of major and minor bleeding with use beyond 12 months following implantation of DES. . . . Such warning is made necessary both by a lack of evidence of a further reduction of thrombotic cardiovascular events, such as MI or stroke, as well as existing evidence of continued risk of major bleeding with prolonged use."
Accompanying today's letter was a Public Citizen press release noting that Holtzman’s involvement in the petition stems from the death of his wife, prescribed clopidogrel and aspirin following a DES implantation in January 2009. In June 2011, still taking DAPT, she died from an acute, massive cerebral hemorrhage, age 78.
"The doctor didn’t know, and we didn't know, that this drug that had significant risks was providing no additional benefit at that point," Holtzman is quoted in the press release. "It's absurd that doctors are now still prescribing and people are still taking this drug for more than a year after a stent when it turns out the research shows this is putting people at serious risk unnecessarily."
Science or Conjecture?
Reacting to the letter and press release, Dr Dean Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati) dismissed the calls for an updated warning, noting that there is no evidence yet to suggest that bleeding events outweigh the benefits in terms of reducing stent thrombosis.
"At this point, there has obviously not been an adequate safety signal to prompt termination of the trial. I honestly believe that a blanket statement like this is irresponsible. There is currently an FDA-sanctioned, adequately powered, large-scale randomized controlled clinical trial designed to answer this question that is supervised by an independent data and safety monitoring board [DSMB]," he told heartwire .
Kereiakes, along with Dr Laura Mauri (Brigham and Women's Hospital, Boston, MA), are the principal investigators for the 20 000-patient, multisponsor DAPT randomized clinical trial testing 12 vs 30 months of dual antiplatelet therapy in patients post-DES implantation. The reason for the DAPT trial, he argues, "is so we can definitely answer these questions [of risk vs benefit] and appropriately script the process of care based on science, not conjecture or empiricism. Now, has anyone seen someone who has had a bleeding event beyond one year? Yes but that's not the point. The point is that we have an ongoing RCT, costing over $100 million, with an independent DSMB: I want my care defined by that process, not Sidney Wolfe."
A Tragic Death
Also speaking with heartwire , Dr David Kandzari, whose work is cited in the letter, notes that the petition is one of the first public reports warning against long-term clopidogrel use in this setting.
"Even though the data would now suggest that there is no benefit in reducing stent thrombosis beyond six to 12 months of DAPT with new-generation DES, clinicians are still driven by their anecdotal experiences--a patient who stops and has an abrupt event," he commented.
Yet, clinical trials, including DAPT and the now-defunct SEASIDE study, have actually struggled to enroll patients who were willing to stop dual antiplatelet therapy at 12 months, based largely on their physicians' trepidations of doing so, Kandzari points out.
"I don't mean to dismiss this patient event, which was tragic, but these types of letters sensationalize the bleeding events with antiplatelet therapy. In a way, the announcement itself is a good thing, to remind physicians that it's not risk-free to routinely advise patients to continue clopidogrel along with aspirin, even if they are doing fine with it."
In Europe and other regions, Kandzari notes, physicians are already using much shorter durations of DAPT, with some guideline support, and several trials are looking at DAPT duration even shorter than six months. And, he reminded heartwire , just as the cutoff of 12 months was arbitrary in terms of reducing thrombotic events, it is equally non–evidence-based for limiting major and minor bleeding events, since "these can occur at any time."
When DES stent thrombosis was first making headlines, interventionalists invariably told heartwire that if they themselves received a DES, they would remain on clopidogrel "indefinitely."
Now, says Kandzari, "I think interventionalists would probably answer in a more reserved way by saying it might depend on the type of stent they had received, and if they received a newer-generation stent, they might feel better staying on aspirin alone or clopidogrel without aspirin. But a lot of clinicians might still say they would stay on it for life because they fear a large heart attack or death more than a bleeding event that could be managed or controlled, but not life-threatening. Although as this petition reminds us, bleeding events can be life-threatening."
Dr Roxana Mehran (Mount Sinai School of Medicine, New York, NY) will present new two-year results addressing cessation of DAPT post-PCI from the PARIS registry at the upcoming European Society of Cardiology 2013 Congress.
Results from the large DAPT randomized clinical trial are expected in late 2014, Kereiakes confirmed for heartwire .
Heartwire from Medscape © 2013 Medscape, LLC
Cite this: Public Citizen to FDA: No More Clopidogrel 1 Year Post-DES - Medscape - Aug 22, 2013.
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