LETTERS TO THE EDITOR
Reply
James M. Gebel, Jr., MD, MS, FAHA*
* Department of Neurology, Jewish Hospital, 250 East Liberty Street, Suite 500, Louisville, Kentucky 40026 (Email: j.gebel{at}att.net).
Stick to the obvious.—Dennis Whitehead (my 11th-grade biology teacher)
It was with surprise and disappointment that I read the "letter" to the editor authored by Dr. Horton.
If I am interpreting Dr. Horton's missive correctly, the following summarize her major points of concern or contention, which I will respond to respectively:
- 1 It is inappropriate to withdraw aspirin plus clopidogrel therapy in patients in the periprocedural period following coronary artery stent placement, even if they suffer a periprocedural stroke/transient ischemic attack (TIA). My report (1) was not intended to comment on the appropriate use of antiplatelet medications in patients undergoing recent coronary artery angioplasty and stenting, or patients with acute coronary syndromes, for whom data overwhelmingly support at least the short-term use of aspirin plus clopidogrel. Furthermore, I am not an expert in this area and feel it would be inappropriate for me as a neurologist to publish an editorial review in a cardiology journal on such a topic. Most cardiologists are quite familiar with these data, whereas many cardiologists (in my community at least) are not aware of the results of Management of Atherothrombosis in High-Risk Patients with Recent Ischemic Attack or Ischemic Stroke (MATCH) trial, which were presented and published outside America, nor of the Second European Stroke Prevention Study (ESPS-2) trial, a stroke-focused clinical trial also conducted abroad. It is evident, in fact, that Dr. Horton herself has either not read or has misunderstood the MATCH trial, because she states incorrectly in her letter that the MATCH trial "compared acetylsalicylic acid (ASA) to clopidogrel or clopidogrel plus aspirin." The trial, in fact, compared aspirin plus clopidogrel to clopidogrel alone. I cannot respond to Dr. Horton's unreferenced overseas case report presentations regarding any association between aspirin plus extended-release dipyridamole causing in-stent thrombosis, other than to reiterate that it is important to differentiate clinical trials of acute cardiovascular and cerebrovascular event therapy from long-term secondary prevention trials. I did at one point discuss the possibility of a multiple patient scenario review with the JACC editorial board; however, word limitations would require a scant and inadequate review of multiple scenarios as opposed to a more thorough review focused on what I regard as a common and highly relevant single scenario.
My review was an effort to communicate formally as a stroke neurologist and clinical trialist to my cardiology colleagues an evidence-based perspective on a very important topic, hoping it would stimulate the kind of productive discourse between colleagues, which is apparently lacking at times in Dr. Horton's own clinical practice. I would think that a similar editorial and review of antithrombotic therapy use in acute coronary syndrome and/or post-stenting data published in a leading neurological journal by an intellectually honest cardiologist interested in continuing such discourse would be a much more appropriate and productive response to my editorial rather than a rant to the editor of JACC impugning my scientific integrity and ironically filled with the sorts of half-truths and inaccuracies that its author is insinuating were present in my review.
- 2 I am a hack for Boehringer-Ingelheim, and my editorial was based on an "Aggrenox" (aspirin plus extended-release dipyridamole) handout of some sort and is a covert "advertisement" for this product. Let me begin by pointing out that I did not see any conflict-of-interest disclosures in Dr. Horton's letter. The sole research support that I (and thousands of other investigators) receive from Boehringer-Ingelheim is for enrollment of patients into the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, a study that is seeking to answer exactly the criticism that Dr. Horton complains about in her letter, namely a lack of direct comparison between clopidogrel and aspirin plus extended-release dipyridamole. We will know soon enough whether any of these preparations is "subtherapeutic." No handouts from any pharmaceutical company were utilized in the preparation of my manuscript, and the opinions regarding data interpretation are entirely my own.
- 3 A 50-mg dose of aspirin is ineffective and is an invalid comparison dose against another antiplatelet drug/drug combination. This is a point that has been and will be debated for decades, and it depends on what end points and study population one focuses upon. Numerous trials support the efficacy of 50-mg and even lower doses of aspirin for stroke/TIA prevention, including the Dutch and British TIA studies. It is my opinion that 50 mg/day of aspirin is, if anything, a more than adequate dose to prevent subsequent vascular events in most TIA/stroke patients, because the majority of recurrent vascular events in such patients are recurrent ischemic strokes, at least during the 1.5- to five-year time frame investigated by modern-era antiplatelet drug clinical trials.
Additionally, the American Stroke Association, National Stroke Association, American Heart Association, American College of Chest Physicians, and the Food and Drug Administration (FDA) all disagree with Dr. Horton's interpretation of these data and include 50 mg/day in their recommended acceptable dose range of aspirin for stroke/TIA prevention. Ever since I submitted my manuscript, the important Women's Health Study (2) has indeed been published, and contrary to Dr. Horton's assertions of no benefit, it showed a statistically significant 24% relative risk reduction in ischemic stroke (p = 0.03) in this primary prevention cohort of women using 100 mg of aspirin every other day, which is otherwise irrelevant to the focus of my manuscript, namely secondary vascular event prevention in TIA and stroke patients. It does, once again, demonstrate Dr. Horton's unfamiliarity with the data she is citing to support her arguments; and contrary to her assertions, this in fact adds another piece of strong evidence supporting the efficacy of 50 mg of aspirin per day in preventing ischemic stroke (albeit not myocardial infarction [MI] or vascular death). For those physicians uncomfortable with a 50-mg dose of aspirin in patients with known coronary artery disease and the lack of sufficient data to establish efficacy in MI prevention for aspirin doses below 75 mg/day, the obvious simple solution is to prescribe additional aspirin for such a patient.
- 4 The FDA should require a warning for "Aggrenox" regarding it not being used postacute coronary syndrome/stent. Again, it is obvious that Dr. Horton has not read the Aggrenox package insert, which already does and always has included such a warning. The "precautions" section of the package insert specifically states the following: "Coronary Artery Disease: Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction). ... For stroke or TIA patients for whom aspirin is indicated to prevent recurrent MI or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications." To the best of my knowledge, this product is neither FDA-approved nor marketed for any cardiac indication.
- 5 Boehringer-Ingelheim is engaged in an aggressive marketing campaign for "Aggrenox." I cannot speak for Boehringer-Ingelheim or its marketing practices or comment on any "handout" that I have not seen, but I will mention what I have seen first-hand, namely that the manufacturers of clopidogrel continued to air direct-to-consumer television commercials advising patients to ask their doctor about adding Plavix to aspirin to prevent another heart attack or stroke, even subsequent to the publication of the MATCH trial.
I look forward to the results of the many ongoing clinical trials that will further define the role of antiplatelet medications in vascular-event prevention, acute stroke, and carotid stenting. In the interim, I will continue to respect the opinions of colleagues whose interpretation of currently available data differs from my own even when they do not respect mine.
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References
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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. 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]
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