CORRESPONDENCE: LETTER TO THE EDITOR
Secondary Stroke Prevention and Antiplatelet Therapy
Heather L. Horton, MD, PhD, FACC, FSCAI*
* Geisinger Wyoming Valley Heart Hospital, Geisinger Health System Cardiology, Valley Medical Building, 1000 East Mountain Drive, Wilkes-Barre, Pennsylvania 18711 (Email: hlhorton{at}geisinger.edu).
A truth that’s told with bad intent beats all the lies you can invent—William Blake (1757–1827, Auguries of Innocence)
I was very disappointed to see JACC publish an opinion piece by Dr. Gebel that is basically a cleverly disguised advertisement for Aggrenox (1). Extended-release dipyridamole (ER-DP) and aspirin is sold as Aggrenox, which is made by Boehringer Ingelheim, which (as he disclosed) gives speaker bureau support and clinical research support to Dr. Gebel.
Consider my representative patient recently admitted to the hospital with a transient ischemic attak (TIA) shortly after drug-eluting stent implantation for in-stent restenosis. The neurologist and internist stopped his aspirin and clopidogrel and put him on Aggrenox. The patient thought this sounded wrong, and he asked them to check with me but they did not. Fortunately, I walked into the patient’s room to do a consult on his roommate, discovered the error, corrected it, and the patient did well. However, if my patient had been in a private room, if I had not been on consult, if no cardiology consult had been ordered on his roommate, or if my patient had been out of the room when I arrived, he could have developed subacute stent thrombosis with its associated 50% mortality rate. But for an extremely lucky series of coincidences my patient could have died.
When I asked the other physicians why they did this, one stated that the Management of Atherothrombosis in High-risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial showed that Aggrenox was better than clopidogrel for prevention of stroke and presented handouts from a recent talk that had clearly been sponsored by the makers of Aggrenox (directly or indirectly). The handouts bore a striking resemblance to Dr. Gebel’s opinion piece. As we know, the MATCH trial did not include Aggrenox, but compared acetylsalicylic acid (ASA) to clopidogrel or clopidogrel plus aspirin (2). Interestingly, whether by oversight or for purposes of obfuscation, the 50-mg subtherapeutic aspirin dose in the Second European Stroke Prevention Study (ESPS-2) is not mentioned either in Dr. Gebel’s report (1) or in the talk handout. The clever design of the presentation leads the listener to believe Aggrenox has done the appropriate research to compare itself to clopidogrel or therapeutic doses of aspirin to demonstrate efficacy and safety in cardiovascular patients; it has not.
The widely cited ESPS-2 trial compared Aggrenox to 50 mg of aspirin daily; 50 mg of aspirin daily is not a therapeutic dose. In the Antithrombotic Trialists’ meta-analysis, no benefit was seen of aspirin over placebo with doses of aspirin <75 mg daily (3). In the Women’s Health Study, no benefit was seen of aspirin 100 mg every other day compared to placebo (4). These results suggest that the majority of the benefit seen in the ESPS-2 trial was due to subtherapeutic aspirin dosing, not to a dramatic benefit of Aggrenox. Even with this subtherapeutic dosing, aspirin had a 21% relative risk reduction (RRR) in myocardial infarctions. One would expect a greater RRR with therapeutic aspirin dosing.
Tran and Anand published a balanced review of this topic in 2004 (5). Their recommendation, based on viable therapeutic alternatives, prior adverse experiences with dipyridamole, and only a single clinical trial showing benefit of Aggrenox (in which it was compared to subtherapeutic doses of aspirin), is that Aggrenox should be avoided until data are available from ongoing clinical trials.
At last year’s cardiology meetings, there were multiple reports in verbal presentations of drug-eluting stent thrombosis in patients being treated with aspirin and dipyridamole. The implication was that these were non-U.S. patients. Under these circumstances, these data would not be reported to the Food and Drug Administration (FDA). Given the aggressive marketing campaign being run by Boehringer Ingelheim, cardiologists must be very vigilant in protecting their patients. Perhaps the FDA could withdraw Aggrenox from the market until it has shown superiority, equivalence, or noninferiority to therapeutic doses of aspirin (75 mg daily, or preferably 81 mg as is used in U.S. practice). Perhaps the FDA could do a black box warning and letter against its use in coronary stent patients. Perhaps individual institutions can remove it from their formularies or place it on restricted formularies so that a cardiologist, not a neurologist or primary care physician, must review each case to limit the potential for harm in withdrawal of effective antiplatelet therapy in high-risk patients.
Finally, this issue is likely to be more critical now that Aggrenox representatives will be carrying around copies of this opinion piece, and the neurologists and primary care providers will say that they read a study in JACC stating that "clinical trial data support the use of ER-DP plus aspirin [Aggrenox], but not clopidogrel plus aspirin, to prevent secondary vascular events after stroke of TIA" (1). Unfortunately, this is because the appropriately designed trials have not been done, not because Aggrenox has documented superiority, equivalence, or even noninferiority to any other therapeutic antiplatelet regimen.
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1. Gebel JM. Secondary stroke prevention with antiplatelet therapy with emphasis on the cardiac patient J Am Coll Cardiol 2005;46:752-755.[Abstract/Free Full Text]2. Diener HC, Bogousslavsky J, Brass M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic or transient ischaemic attack in high-risk patients (MATCH)randomized, double-blind, placebo-controlled trial. Lancet 2004;364:331-337.[CrossRef][Web of Science][Medline] 3. Antithrombotic Trialists’ Collaboration Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patient BMJ 2002;324:71-86.[Abstract/Free Full Text] 4. Ridker P, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women N Engl J Med 2005;352:1293-1304.[Abstract/Free Full Text] 5. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease JAMA 2004;292:1867-1874.[Abstract/Free Full Text]
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