Drug Criteria & Outcomes-The evidence grows regarding use of ACEIs and aspirin
By Aileen Luzier, PharmD
Assistant Professor, School of Pharmacy
University at 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 those 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 those agents. However, the clinical relevance of the interaction remains unanswered. The Warfarin-Antiplatelet Trial in Chronic Heart Failure 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 (80-160 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 trails.
o The enzyme kininase II: In addition to inhibiting the formation of angiotensin II, ACEIs also inhibit the enzyme kininase II that is responsible for the degradation of kinins. That results in potentiation of the biologic effects of kinins and enhances the production of prostaglandins. The primary mechanism of aspirin is to decrease platelet aggregation through the inhibition of prostaglandin (and thromboxane) production. Because the two agents have opposite effects on prostaglandins, concern has been raised that aspirin may nullify the beneficial effects of ACEIs. That interaction has greater significance with the recent understanding of the biologic role of kinins in the regulation of vascular tone; myocardial contractility and ventricular remodeling; modulation of neuroendocrine activation; and influence over the response to tissue injury or stress.6,7
o 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-myocar dial infarction ventricular remodeling.11
o 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 dem onstrate an interaction. Aspirin did not influence the mean blood pressure response to 25 mg of captopril or 5-10 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 et al. has invest igated the interaction in heart failure patients using pulmonary function testing. Several issues support that 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 monox ide 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.
o 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 trail who were taking aspirin had a smaller mortality benefit from enalapril compared to those who were not taking aspirin.22 In contrast to those 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) also was observed in a subgroup of patients with congestive heart failure who received the combination vs. those who only received ACEI therapy.
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 (³ 160 mg/day) reduce renal and systemic prostaglandin synthesis.25 If prostaglandins 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, considerable data support the presence of an interaction between those 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 address the question, clinicians are obligated to use the agents concurrently.
1. Konstam MA, Dracup K, Baker DW, et al. Heart failure: Evaluation and care of patients with left ventricular systolic dysfunction. Clinical Practice Guideline. No. 11. Rockville, MD: Agency for Health Care Policy and Research; 1994. (AHCPR publication No. 94-0612.)
2. Guidelines for the evaluation and management of heart failure: Report of the American College of Cardiology/Amer ican Heart Association Task Force on Practice Guidelines (committee for the evaluation and management of heart failure). Circulation 1995; 92:2,764-2,784.
3. Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81-106.
4. Teerlink JR, Goldhaber SZ, Pfeffer MA. An overview of contemporary etiologies of congestive heart failure. Am Heart J 1991; 121:1,852-1,853.
5. Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Br Heart 1995; 74:215-219.
6. Linz W, Wiemer G, Gohlke P, et al. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47:25-49.
7. Dzau VJ, Packer M, Lilly LS, et al. Prostaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia. New Engl J Med 1984; 310:347-352.
8. Moroi M, Akatsuka N, Fukazawa M, et al. Endothel ium-dependent relaxation by angiotensin-converting enzyme inhibitors in canine femoral arteries. Am J Physiol 1994; 266:H583-9.
9. Hartman JC. The role bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors. Ann Thor Surg 1995; 60:789-792.
10. Evans MA, Burnett JC Jr., Redfield MM. Effect of low dose aspirin on cardiorenal function and acute hemodynamic response to enalaprilat in a canine model of severe heart failure. JACC 1995; 25:1,445-1,450.
11. Stauss HM, Zhu YC, Redlich T, et al. Angiotensin-converting enzyme inhibition in infarct-induced heart failure in rats: Bradykinin versus angiotensin II. J Cardiovasc Risk 1994; 1:255-262.
12. Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. JACC 1992; 20:1,549-1,555.
13. Nakamura M, Funakoshi T, Arakawa N, et al. Effect of angiotensin-converting enzyme inhibitors on endothelium-dependent peripheral vasodilation in patients with chronic heart failure. JACC 1994; 24:1,321-1,327.
14. Spaulding C, Charbonnier B, Cohen-Solal A, et al. Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: Results of a double-blind, randomized comparative trial. Circulation 1998; 98:757-765.
15. Van Wijngaarden J, Smit AJ, de Graeff PA, et al. Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1994; 23:240-245.
16. Baur LH, Schipperheyn JJ, van der Laarse A, et al. Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J 1995; 73:227-236.
17. Riegger GA, Kahles HW, Elsner D, et al. Effects of acetylsalicylic acid on renal function in patients with chronic heart failure. Am J Med 1991; 90:571-575.
18. Dietz R, Nagel F, Osterziel KJ. Angiotensin-converting enzyme inhibitors and renal function in heart failure. Am J Cardiol 1992; 70:119C-125C.
19. Guazzi M, Marenzi G, Alimento M, et al. Improve ment of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997; 95:1,930-1,936.
20. Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin- converting enzyme inhibitors. Am Heart J 1999; 138:254-260.
21. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and survival: A cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. JACC 1998; 31:419-425.
22. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: Subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study CONSENSUS II. Am J Cardiol 1997; 79:115-119.
23. Leor J, Reicher-Reiss H, Goldbourt U, et al. Aspirin and mortality in patients treated with ACE inhibitors: A cohort study of 11,575 patients with coronary artery disease. JACC 1999; 33:1,920-1,925.
24. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1,366-1,372.
25. FitzGerald GA, Oates JA, Hawiger J. Endogenous biosynthesis of prostocyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71:676-688.