Elsevier

Progress in Cardiovascular Diseases

Volume 44, Issue 4, January–February 2002, Pages 275-292
Progress in Cardiovascular Diseases

Is aspirin ″the weakest link” in cardiovascular prophylaxis? The surprising lack of evidence supporting the use of aspirin for cardiovascular disease

https://doi.org/10.1053/pcad.2002.31597Get rights and content

Abstract

It is currently fashionable to prescribe aspirin, long-term to people with or at high risk of vascular events due to atherosclerosis. There is a moderately conclusive evidence for a short-term benefit after an acute vascular event. However, there is remarkably little evidence that long-term aspirin is effective for the prevention of vascular events and managing side effects may be expensive. Reductions in nonfatal vascular events may reflect an ability of aspirin to alter cosmetically the presentation of disease without exerting real benefit. Cardiovascular medicine appears prone to fads and fashions that are poorly substantiated by evidence. The current fashion for prescribing aspirin is reminiscent of the now discredited practice of widespread prescription of class I anti-arrhythmic drugs for ventricular ectopics. We should learn from experience. Copyright 2002, Elsevier Science (USA). All rights reserved.

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

References (126)

  • M Guazzi et al.

    Modulation of alveolar-capillary sodium handling as a mechanism of protection of gas transfer by enalapril, and not by losartan, in chronic heart failure

    J Am Coll Cardiol

    (2001)
  • M Guazzi et al.

    Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors

    Am Heart J

    (1999)
  • H Wunsch

    COX provides missing link in mechanism of aspirin in colon cancer

    Lancet

    (1998)
  • L Hansson et al.

    Effect of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the hypertension optimal treatment (HOT) randomised trial

    Lancet

    (1998)
  • PM Rothwell et al.

    Meta-analysis of randomised controlled trials

    Lancet

    (1997)
  • MJ Domanski et al.

    Relative role of meta-analysis and randomised controlled trials in the assessment of medical therapies

    Am J Cardiol

    (1994)
  • The RISC Group

    Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease

    Lancet

    (1990)
  • LC Wallentin

    Aspirin (75mg/day) after an episode of unstable coronary artery disease: Long-term effects on the risk ofor myocardial infarction, occurrence of severe angina and the need for revascularisation

    J Am Coll Cardiol

    (1991)
  • PC Elwood et al.

    Aspirin and secondary prevention after myocardial infarction

    Lancet

    (1979)
  • S Juul-Moller et al.

    Double blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris

    Lancet

    (1992)
  • R Manfredini et al.

    An uncommon case of fluid retention simulating a congestive heart failure after aspirin consumption

    Am J Med Sci

    (2000)
  • KJ Harjai et al.

    Effect of combined aspirin and angiotensin-converting enzyme inhibitor therapy versus angiotensin-converting enzyme inhibitor therapy alone on readmission rates in heart failure

    Am J Cardiol

    (2001)
  • The SALT Collaborative Group

    Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events

    Lancet

    (1991)
  • H Diener et al.

    European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of strokes

    J Neurol Scien

    (1996)
  • BB Weksler et al.

    Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients

    N Engl J Med

    (1983)
  • C Patrono et al.

    Clinical pharmacology of platelet cyclooxygenase inhibition

    Circulation

    (1985)
  • AP Davie et al.

    Even low-dose aspirin inhibits arachidonic acid-induced vasodilatation in heart failure

    Clin Pharm Ther

    (2000)
  • AK Pedersen et al.

    Dose-related kinetics of aspirin

    N Engl J Med

    (1984)
  • DJ Heavey et al.

    Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man

    Nature

    (1985)
  • MT Santos et al.

    Prothrombotic effects of erythrocytes on platelet reactivity

    Circulation

    (1997)
  • CM O'Connor et al.

    The importance of aspirin dose in the protection of non-haemorrhagic stroke following acute myocardial infarction:Insights from the coumadin aspirin reinfarction study (CARS)

    Circulation

    (1996)
  • AM Richards et al.

    Plasma alpha natriuretic peptide in cardiac impairement

    Br Med J

    (1986)
  • VJ Dzau et al.

    Prostaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia

    N Engl J Med

    (1984)
  • JN Townend et al.

    Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril

    Br Heart J

    (1993)
  • G Haynes et al.

    Endothelium-dependent modulation of responses to endothelin-1 in human veins

    Clin Sci

    (1993)
  • JGF Cleland et al.

    Bradykinin and ventricular function

    Eur Heart J

    (2000)
  • JGF Cleland et al.

    Sudden death in heart failure: Vascular or electrical?

    Eur J Heart Failure

    (1999)
  • C Spaulding et al.

    Acute hemodynamic interaction of aspirin and ticlopidine with enalapril. Results of a double-blind, randomised comparative trial

    Circulation

    (1998)
  • JGF Cleland et al.

    Is aspirin safe for patients with heart failure?

    Br Heart J

    (1995)
  • JGF Cleland

    Anticoagulant and antiplatelet therapy in heart failure

    Curr Opinion Cardiol

    (1997)
  • SD Katz et al.

    Aspirin does not inhibit the vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure

    Am Heart J

    (1997)
  • M Jeserich et al.

    Effect of long-term angiotensin-converting enzyme inhibition on vascular function in patients with chronic congestive heart failure

    Am J Cardiol

    (1999)
  • AC Yeung Laiwah et al.

    Antagonistic effect of non-steroidal anti-inflammatory drugs on frusemide-induced diuresis in cardiac failure

    Br Med J

    (1981)
  • J Page et al.

    Consumption of NSAIDs and the development of congestive heart failure in elderly patients. An underrecognised public health problem

    Arch Intern Med

    (2000)
  • ER Heerdink et al.

    NSAIDs associated with risk of congestive heart failure in elderly patients taking diuretics

    Arch Intern Med

    (1998)
  • DM Clive et al.

    Renal syndromes associated with non-steroidal anti-inflammatory drugs

    N Engl J Med

    (1984)
  • The Persantine-Aspirin Reinfarction Study (PARIS) Research Group

    Persantine and aspirin in coronary heart disease

    Circulation

    (1980)
  • Aspirin Myocardial Infarction Study Research Group

    A randomised, controlled trial of aspirin in persons recovered from myocardial infarction

    JAMA

    (1980)
  • The Aspirin Myocardial Infarction Study Research Group

    The aspirin myocardial infarction study: Final results

    Circulation

    (1980)
  • R Brambrilla et al.

    Worsening of morbidity and renal function in angiotensin-converting enzyme- inhibited heart failure patients taking aspirin

    Eur J Heart Failure

    (2001)
  • Cited by (57)

    View all citing articles on Scopus
    View full text