Is aspirin ″the weakest link” in cardiovascular prophylaxis? The surprising lack of evidence supporting the use of aspirin for cardiovascular disease
Section snippets
Potential biological mechanisms of aspirin benefit and harm
All treatments have the capacity to do harm. The balance of benefit to harm may vary depending on the clinical setting and concomitant medical conditions. It cannot be assumed that benefit in one group of patients applies to all, nor can it be assumed that benefit over one time period applies forever. However, it is difficult to produce outcome data for every clinical setting. Therefore, some consideration of the potential mechanisms of benefit and harm from an intervention may be useful in
Potential clinical mechanisms for the observed effects of aspirin
Enthusiastic aspirin prescribers focus mainly on the evidence that aspirin appears to reduce nonfatal vascular events. However, epidemiological data suggest that 50% of myocardial infarctions and perhaps 30% of strokes will result in death within 30 days of the event.51 Any study that shows a reduction only in nonfatal vascular events should be regarded with deep suspicion.
There are at least three ways in which an agent can bring about a reduction in nonfatal events. An agent could genuinely
Acute myocardial infarction
The recommendation that aspirin be administered routinely in the setting of acute myocardial infarction is based almost solely on the outcome of one trial, the ISIS-2 study, in which 17,187 patients were randomized to aspirin (160 mg/day) or placebo. Compared with placebo, there were 216 fewer deaths after 5 weeks on aspirin, but 501 patients were lost to follow-up.69 The Cardiff III trial, the only other large trial of aspirin after acute myocardial infarction, lost 825 (33%) patients of 2,530
Primary prevention
A series of primary prevention trials including about 250,000 patient-years of follow-up has failed to show a reduction in mortality with aspirin individually or overall (Table 3).[54], [78], [79], [80], [81]None of the studies achieved its primary endpoint. One study, the US Physicians' study,79 was stopped prematurely on the basis that an outcome other than its primary endpoint, namely fatal or nonfatal myocardial infarction, was reduced. The definition of this endpoint was curious because it
Evidence for an aspirin/ACE inhibitor interaction (fig 5, table 5)
figure
A therapeutic interaction simply means that the effects of two agents are not additive. If they are more than additive, this is termed synergy. If the interaction is less than additive, then the benefits of adding agents will be less than expected. In extreme cases, one treatment may neutralize the effect of another or cause another agent to become harmful. The most important aspect of managing an adverse interaction is to be sure that both components are required.
A series of randomized
Large observational data sets
Observational data sets, in which neither component of the interaction of interest is randomized, are an even less reliable guide to drug interactions. Predictably, these studies have come up with conflicting results, with some showing an adverse interaction and others refuting it.[37], [91], [114] Although observational data are useful for generating hypotheses about the effects and interaction of drugs, they are not a substitute for randomized controlled trials.
Side effects
Patients at risk of aspirin-induced side effects were consistently excluded from randomized controlled trials, therefore, a low rate of adverse events is not unexpected.115 The risk of major hemorrhage was about 2 per 1,000/ year for patients on low-dose aspirin in the clinical trials.115 However, these rates probably do not reflect reality. Cardiovascular prophylactic aspirin is a powerful risk factor for gastro-intestinal bleeding, increasing with age, and may account for 30% or more of all
The true cost of aspirin
In answer to the above criticisms, it is often jokingly said that at least aspirin is cheap. Cheapness is not a good reason for prescribing a potentially toxic drug. Also, aspirin is not as cheap as many believe. The only health economic analysis of aspirin suggested that it may cost up to USD $150,000 to prevent one cardiovascular event for primary prevention and up to USD $8,000 for secondary prevention (assuming that reduction in nonfatal events is real and not cosmetic).119 There are many
Conclusion
This review suggests that aspirin may not be effective, safe, or cheap. The effect of aspirin in patients with atherosclerosis may be somewhat analogous to those of class I anti-arrhythmic agents in patients with ventricular ectopics. In the CAST study, flecainide and encainide suppressed ventricular ectopics, dramatically reduced the risk of nonfatal myocardial infarction, but markedly increased the risk of sudden death.[52], [53] Aspirin, like flecainide and encainide, appears to change the
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