Multiple Choice Rx

As much as I try to second-guess my thoughts, I cannot yet shake my newfound interest passion for Neurology, especially the subcategory of cerebrovascular diseases. It’s possible that I may be overcompensating for my previous wariness of Neurology and Neuroscience; indeed, I feel a compulsion to “catch up,” which has included subscribing to Stroke on my RSS feed, reading new research on stroke treatments, and reading selections of a Neuropathology text and Pourmand’s Practicing Neurology before going to sleep. However, in the past two years of medical school and previous years as a premedical student, I haven’t found myself as excited about any other field of medicine: at least, excited enough to feel content reading beyond class requirements rather than feeling what I now recognize as ambivalence. For the time being, I am content to use stroke as a springboard for my possible career development in Neurology, Interventional Neurology, and Critical Care Neurology. Here are my thoughts on some of the new data from the field:

Today, the NEJM has an early release article comparing the efficacy of two popular antiplatelet agents, aspirin-dipyramidole (ASA-ERDP, extended-release) (also known as Aggrenox by Boehringer Ingelheim) and clopidogrel (also known as Plavix/Iscover/Clopilet by Bristol-Meyers Squibb, Sanofi-Aventis, and Sun Pharmaceuticals, respectively). Aspirin, the oldest agent, reduces the incidence of a second stroke by approximately 23% vs. placebo. Previously, ASA-ERDP had been shown to be superior to aspirin alone in reducing the recurrence of ischemic strokes (20-23% relative risk reduction) while clopidogrel had demonstrated a smaller benefit over aspirin (8% relatively risk reduction). Given these results, the expectation for this most recent study was that ASA-ERDP would prove superior to clopidogrel. However, the study showed no significant difference between the two treatments in reducing the incidence of stroke recurrence or bleeding events (recurrent stroke in 9.0% ASA-ERDP vs. 8.8% clopidogrel), and ASA-ERDP even had a greater percentage of hemorrhagic vs. ischemic strokes (though the number of fatal or severely disabling hemorrhagic strokes between the two treatment groups were comparable). This new data, combined with the potential adverse effect of intolerable headaches in ASA-ERDP and the increased incidence of potentially fatal bleeding in combined clopidogrel and aspirin therapy over aspirin or clopidogrel alone, further complicates the treatment decisions regarding the secondary prevention of stroke. Has the efficacy of clopidogrel been underestimated in previous studies? Or is ASA-ERDP not as efficacious as previously indicated? Of the three agents, there appears to be no clear winner, although aspirin, the oldest agent, is much cheaper than the two newer antiplatelet medications. (Notably, this negative study was authored by physician-researchers with financial connections to pharmaceutical companies on both sides of the competition.)

One of my attending physicians in Neurology, a Vascular Neurology specialist, asked my team a question that highlights a simple, underemphasized fact: “If a patient was on aspirin before having a stroke, did she fail aspirin treatment?” All medications that prevent a catastrophic event do so in incomplete measures: it is rarely, if ever, possible to decrease the risk of an occurrence by 100%. So, did the patient have a stroke because the medication (aspirin, clopidogrel, or ASA-ERDP) did not work, or did she have a stroke because her fate did not roll the dice in her favor despite the efficacy of her medication? If nothing else, it gives me pause when considering switching a patient from aspirin to a more expensive antiplatelet agent with questionable improvements in efficacy.

1 comment
  1. Ben said:

    The result is a little puzzling, especially if both trials were designed effectively to have statistical power. It is possible, though, that none of our clinical trials actually have sufficient statistical power to resolve certain differences in efficacy (an analogy to this would be how its difficult to see any noticeable difference between the gallons needed in a car that runs at 200mpg versus a car that runs at 300mpg if considering the fuel needed to go 5 miles — its a very small difference), especially when you consider that these trials sort of peanut butter over all the significant genetic differences between different groups of people.

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