Does aspirin interfere with benefits of ACEI?
By Aileen Luzier, PharmD
Assistant Professor
School of Pharmacy
University at Buffalo
Buffalo, NY
The impact of aspirin on the therapeutic benefits of angiotensin converting enzyme inhibitors (ACEI) has been a topic of intense research for nearly two decades. ACEIs are considered first-line therapy in the treatment of heart failure and are recommended for the prevention of heart failure in post-myocardial infarction patients.1,2
Aspirin is widely recommended for both primary and secondary prevention of cardiovascular events, particularly in ischemic heart disease — a significant etiologic factor in heart failure.3,4 Thus many patients are appropriately treated with both of these agents. However, there is a growing body of evidence that questions the simultaneous use of ACEIs and aspirin.5
The weight of some recent studies supports the presence of an interaction between these agents. However, the clinical relevance of the interaction remains unanswered. The Warfarin-Antiplatelet Trial in Chronic Heart Failure (WATCH) is a large clinical trial currently in progress that will provide important insight into this issue. Until the answers are available, the clinician should be aware of the potential for aspirin to attenuate the beneficial effects of ACEIs. However, given the weight of evidence that supports the use of ACEI and aspirin therapy, clinicians are obligated to use the agents together in appropriate patients. Clinicians should be encouraged to titrate ACEIs to doses recommended by current guidelines. As lower doses of aspirin theoretically may interfere less with the effects of ACEIs than higher doses, it may be prudent to use smaller doses of aspirin (80 mg to 160 mg daily) for the prevention of cardiovascular events in these patients.
The evidence for a pharmacologic interaction between ACEIs and aspirin is in the form of theoretical mechanistic considerations, animal data, small drug interaction studies, and clinical trials.
Theoretical
In addition to inhibiting the formation of angiotensin II, ACEIs also inhibit the enzyme kininase II that is responsible for the degradation of kinins. This results in potentiation of the biologic effects of kinins and enhances the production of prostaglandins.
The primary mechanism of aspirin is to de-crease platelet aggregation through the inhibition of prostaglandin (and thromboxane) production. As the two agents have opposite effects on prosta-glandins, concern has been raised that aspirin may nullify the beneficial effects of ACEIs.
This interaction has greater significance with the recent understanding of the biologic role of kinins in the regulation of vascular tone, myo-cardial contractility and ventricular remodeling, modulation of neuroendocrine activation, and influence over the response to tissue injury or stress.6,7
Animal studies
The interaction of aspirin and ACEIs has been investigated in animal models. Aspirin reduced endothelium-dependent relaxation induced by captopril in the canine model.8
The role of prostaglandins in maintaining renal function has been clearly shown; however, conflicting results have been reported on the effects of aspirin on renal responses in ACEI-treated animals.9,10 The beneficial effects of ACE inhibition, and specifically the role of bradykinin on ventricular remodeling — the hallmark of heart failure — also has been studied in animal models. Aspirin administration was shown to attenuate the beneficial effects of ACEIs on post-myocardial infarction ventricular remodeling.11
Interaction studies
Several small studies in heart failure patients have investigated the effects of the combination of aspirin and ACEIs on hemodynamics, renal function, and pulmonary dynamics. A 350 mg dose of aspirin abolished enalapril-induced decreases in left ventricular filling pressures, systemic and vascular resistances, and increases in cardiac output.12 Subsequent studies also showed decreased vasodilatory activity of ACEIs with concomitant aspirin.13,14
In contrast, several studies that only assessed peripheral hemodynamics (rather than central hemodynamics or cardiac output) did not demonstrate an interaction. Aspirin did not influence the mean blood pressure response to 25 mg of captopril or 5 mg to 10 mg of enalapril when administered at a dose of 236 mg and 250 mg, respectively.15,16 Other investigations have demonstrated that co-administration of aspirin and ACEIs can be detrimental to renal function in patients with heart failure.17,18
A series of studies by Guazzi and fellow researchers has investigated the interaction in heart failure patients using pulmonary function testing. Several issues support this methodology. The lungs are an important site for prostaglandin production, release, and metabolism, and ACEIs improve pulmonary function and thus exercise performance in heart failure patients, an effect thought to be due to prostaglandin activation. Guazzi has demonstrated a counteracting effect of aspirin (325 mg) on ACEI-induced improvements, assessed through changes in exercise tolerance, pulmonary carbon monoxide diffusion, and oxygen consumption.19,20
The interaction was not observed with losartan, an angiotensin II antagonist that does not influence bradykinin or prostaglandin production. In addition, the interaction was demonstrated with chronic dosing of the agents, in contrast to the acute dosing used by many of the previously mentioned studies.
Clinical trials
Subanalyses of large clinical trials also have suggested a negative interaction between aspirin and ACEIs. Enalapril did not improve survival among a subgroup of heart failure patients taking aspirin in the SOLVD trial.21
Similarly, patients in the CONSENSUS II trial who were taking aspirin had a smaller mortality benefit from enalapril compared to those who were not taking aspirin.22 In contrast to this data, a subanalysis of the Benzafibrate Infarction Prevention (BIP) study observed lower five-year mortality in coronary artery disease patients who were treated with both aspirin and ACEIs.23
Lower mortality (24% vs. 34%, p=0.001) was also observed in a subgroup of patients with congestive heart failure who received the combination vs. those who only received ACEI therapy.
Why discrepancies in literature?
There may be several explanations for the discrepancies in the literature. The dose of aspirin used may influence the results. Aspirin exhibits dose-dependent inhibition of platelet thromboxane A2 synthesis. At low doses (£100 mg/day) aspirin selectively inhibits platelet thromboxane A2 synthesis.24
Higher doses (³160 mg/day) reduce renal and systemic prostaglandin synthesis.25 If prosta-glandins are partially responsible for the clinical effects of ACEIs, higher daily doses of aspirin should be more prone to blunting their effects than lower doses.
Differences may be related to the different populations studied, as the role of kinins may be more significant in post-myocardial infarction and heart failure patients (CONSENSUS II and SOLVD, respectively) than in chronic ischemic heart disease (BIP registry). Also, it must be emphasized that the clinical trial data presented are retrospective subanalyses and caution must be exercised in their interpretation.
At this time, there are considerable data to support the presence of an interaction between these agents. However, it is difficult to draw any conclusions about the clinical significance of the interaction.
Until answers are provided by large controlled clinical trials of long-term therapy that directly addresses this question, clinicians are obligated to use the agents concurrently.
References
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