Hypothesis formulation from subgroup analyses: nonadherence or nonsteroidal
anti-inflammatory drug use explains the lack of clinical benefit of aspirin on
first myocardial infarction attributed to "aspirin resistance".
Author(s): Hennekens CH, Schneider WR, Hebert PR, Tantry US, Gurbel PA.
Affiliation(s): Florida Atlantic University, Boca Raton, 33431-0991, USA. profchhmd@prodigy.net
Publication date & source: 2010, Am Heart J. , 159(5):744-8
BACKGROUND: "Aspirin resistance" has been defined as the occurrence of
cardiovascular events despite regular intake of aspirin. One major analytic study
suggesting that "aspirin resistance" is a clinical reality was unable to control
for confounding by nonadherence or nonsteroidal anti-inflammatory drugs (NSAIDs).
METHODS: We formulated a hypothesis from subgroup analyses in the Physicians'
Health Study, a randomized double-blind placebo-controlled trial testing 325 mg
of aspirin every other day among 22,071 apparently healthy US male physicians. We
classified participants by nonadherence or NSAIDs and used time-varying Cox
proportional hazard models to adjust for confounding.
RESULTS: After 5 years, the blinded aspirin component was terminated early based
on the unanimous recommendation of the Data and Safety Monitoring Board. Of 378
confirmed first myocardial infarctions (139 aspirin and 239 placebo), the
relative risk (RR) was 0.56 (95% CI 0.45-0.70, P < .00001). There was no
statistically significant reduction among aspirin <150/180 pills/y (RR = 0.91,
95% CI 0.61-1.35, P = .62) or NSAID users >60 days per year (RR = 1.54, 95% CI
0.68-3.47, P = .31). There was a statistically significant reduction among
aspirin >150/180 pills/y and NSAID users <60 days/y (RR = 0.55, 95% CI 0.44-0.70,
P < or = .0001) and an increase among aspirin <150/180 pills/y and NSAID users
>60 days/y (RR of 3.43, 95% CI 1.41-8.33, P = .007).
CONCLUSIONS: In subgroup analyses useful to formulate hypotheses from a large
randomized trial in apparently healthy men, aspirin nonadherence or NSAID use
explained the lack of clinical benefit of aspirin on first myocardial infarction
that has been attributed to "aspirin resistance." Direct randomized comparisons
are necessary in trials designed a priori to test this hypothesis.
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