Interaction of Angiotensin-Converting Enzyme Inhibition and Aspirin in Congestive Heart Failure: Long Controversy Finally Resolved?

Abstract

Not long after the initial findings of the positive effects of angiotensin-converting enzyme (ACE) inhibition on prognosis for patients with congestive heart failure (CHF), a controversy commenced as to whether there is a negative interaction between ACE inhibition and aspirin.1Hall D Zeitler H Rudolph W Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure.J Am Coll Cardiol. 1992; 20: 1549-1555Abstract Full Text PDF PubMed Scopus (228) Google ScholarSince one of the most important underlying causes of CHF is coronary artery disease, this question is of utmost clinical importance. The fact that this topic is still relevant > 10 years after the initiation of the controversy indicates the difficulty inherent in resolving the question. In this issue of CHEST (see page 1250), Aumégeat et al present their data showing no negative interaction in their CHF cohort. Does this mean that the controversy is finally resolved? It is important to understand the theoretic basis for this potential interaction. ACE not only converts angiotensin I to angiotensin II, but it is also responsible for the degradation of kinins. Thus, the inhibition of ACE increases bradykinin levels. Bradykinin, a potent vasodilator on its own, activates vascular endothelial B2-kinin receptors, which promote the formation of vasodilatory prostaglandins through the action of phospholipase-A2 and cyclooxygenase (COX).2Blais Jr, C Drapeau G Raymond P et al.Contribution of angiotensin-converting enzyme to the cardiac metabolism of bradykinin: an interspecies study.Am J Physiol. 1997; 273: H2263-H2271PubMed Google Scholar3Gainer JV Morrow JD Loveland A et al.Effect of bradykinin- receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects.N Engl J Med. 1998; 339: 1285-1292Crossref PubMed Scopus (426) Google ScholarAccordingly, drugs that inhibit endothelial COX, such as aspirin, may reduce the synthesis of vasodilatory prostaglandins. Accordingly, the inhibition of COX may reduce the efficacy of ACE inhibition, if this pathway is of importance. Indeed, although it is also a matter of controversy, there is some indirect evidence that this is the case. Thus, the clinical benefits of ACE inhibition persist despite the fact that angiotensin II levels may return to pretreatment levels.4Jorde UP Ennezat PV Lisker J et al.Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure.Circulation. 2000; 101: 844-846Crossref PubMed Scopus (191) Google ScholarThese findings suggest that mechanisms other than the inhibition of angiotensin II formation (ie, increased levels of bradykinin and vasodilatory prostaglandins) are at least in part responsible for the effects of ACE inhibitors. Similarly, the lack of superiority of angiotensin II receptor type 1 blockade compared to ACE inhibition in patients with CHF,5Pitt B Poole-Wilson PA Segal R et al.Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial; the Losartan Heart Failure Survival Study ELITE II.Lancet. 2000; 355: 1582-1587Abstract Full Text Full Text PDF PubMed Scopus (1802) Google Scholardespite the more complete inhibition of the angiotensin II-transmitted effects, suggests that additional mechanisms are responsible for the effects of ACE inhibitors. Furthermore, experimental data suggest that the positive effects of ACE inhibition on postmyocardial remodeling are mediated by bradykinin,6Stauss 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: 255-262Crossref PubMed Scopus (83) Google Scholar7Zhu P Zaugg CE Hornstein PS et al.Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.J Cardiovasc Pharmacol. 1999; 33: 785-790Crossref PubMed Scopus (30) Google Scholaralthough the data in this regard are not consistent.8Duncan AM Burrell LM Kladis A et al.Effects of angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptides in rats with myocardial infarction.J Cardiovasc Pharmacol. 1996; 28: 746-754Crossref PubMed Scopus (42) Google ScholarCardioprotection against free radicals by ACE inhibition depends on the activation of bradykinin type 2 receptors and prostaglandin synthesis.9Jin ZQ Chen X Pretreatment with ramiprilat induces cardioprotection against free radical injury in guinea-pig isolated heart: involvement of bradykinin, protein kinase C and prostaglandins.Clin Exp Pharmacol Physiol. 2000; 27: 257-262Crossref Scopus (16) Google ScholarIn humans, several hemodynamic studies showed that the inhibition of endothelial COX by nonsteroidal antirheumatic drugs may result in a substantial reduction of the effects of ACE inhibition.10Townend JN Doran J Lote CJ et al.Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril.Br Heart J. 1995; 73: 434-441Crossref PubMed Scopus (46) Google ScholarAlso, the antihypertensive potential of ACE inhibitors was found to be reduced with concomitant use of nonsteroidal antirheumatic drugs.11Morgan TO Anderson A Bertram D Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril.Am J Hypertens. 2000; 13: 1161-1167Crossref PubMed Scopus (101) Google ScholarHowever, for obvious reasons, the issue of whether long-term endothelial COX inhibition is prognostically harmful in patients with cardiovascular diseases has never been prospectively evaluated. There are, however, also reasons for a positive rather than negative interaction between ACE inhibition and aspirin. Thus, angiotensin II may exert its vasoconstrictive effect in part via the COX product thromboxane-A2.12Lin L Nasjletti A Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction.Hypertension. 1991; 18: 158-164Crossref PubMed Scopus (80) Google ScholarOpposing the production of angiotensin II by ACE inhibition may result in vasodilation, in part by the attenuation of thromboxane-A2 production. Since aspirin inhibits COX and thereby thromboxane A2 production, the two agents may act synergistically. Furthermore, bradykinin has been described as enhancing the release of norepinephrine by sympathetic nerve endings.13Seyedi N Win T Lander HM et al.Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings: mediation by autocrine/paracrine mechanisms.Circ Res. 1997; 81: 774-784Crossref PubMed Scopus (89) Google ScholarThis may be particularly important in the heart since cardiac sympathetic activation is related both to the progression of CHF and to sudden cardiac death.14Brunner-La Rocca HP Esler MD Jennings G et al.Effect of cardiac sympathetic nervous activity on mode of death in chronic heart failure.Eur Heart J. 2001; 22: 1136-1143Crossref PubMed Scopus (189) Google ScholarWhether this is a direct effect of bradykinin receptor stimulation or it is mediated by prostaglandins is unknown. Still, it may be hypothesized that the increase in bradykinin is detrimental in CHF patients and that aspirin may inhibit this potentially negative effect of ACE inhibition. Taken together, these considerations suggest that even if an interaction between ACE inhibition and aspirin exists, such an interaction may be both negative and positive. Another important issue is the impact of the aspirin dose used. Thus, low doses of aspirin seem to primarily inhibit platelet COX, but endothelial COX much less so. This is partly because platelets cannot restore COX, while endothelial cells quickly restore COX after inhibition. Furthermore, platelet COX may be more susceptible to inhibition by aspirin.15Weksler BB Pett SB Alonso D et al.Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients.N Engl J Med. 1983; 308: 800-805Crossref PubMed Scopus (363) Google ScholarAccordingly, the negative hemodynamic effects may be seen with high doses of aspirin only. Indeed, several studies have found that a negative interaction with ACE inhibitors is present with high doses of aspirin (ie, ≥ 325 mg),1Hall D Zeitler H Rudolph W Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure.J Am Coll Cardiol. 1992; 20: 1549-1555Abstract Full Text PDF PubMed Scopus (228) Google Scholar16Spaulding 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: 757-765Crossref PubMed Scopus (110) Google Scholarbut not with low doses of aspirin (ie, ≤ 100 mg).17Guazzi MD Campodonico J Celeste F et al.Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction.Clin Pharmacol Ther. 1998; 63: 79-86Crossref PubMed Scopus (61) Google Scholar18Boger RH Bode-Boger SM Kramme P et al.Effect of captopril on prostacyclin and nitric oxide formation in healthy human subjects: interaction with low dose acetylsalicylic acid.Br J Clin Pharmacol. 1996; 42: 721-727Crossref PubMed Scopus (27) Google Scholar The important question is whether the potential interaction is of clinical importance. The study by Aumégeat et al in this issue suggests that it is not. Most of their patients were treated with low-dose aspirin, which is in line with the theoretical considerations delineated above. However, the previously published data are, again, not completely consistent.19Teo KK Yusuf S Pfeffer M et al.Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review.Lancet. 2002; 360: 1037-1043Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar20Latini R Tognoni G Maggioni AP et al.Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients; Angiotensin-Converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.J Am Coll Cardiol. 2000; 35: 1801-1807Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar21Flather MD Yusuf S Kober L et al.Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients: ACE-Inhibitor Myocardial Infarction Collaborative Group.Lancet. 2000; 355: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar22Oosterga M Anthonio RL de Kam PJ et al.Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction.Am J Cardiol. 1998; 81: 1178-1181Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar23Nguyen 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 II (CONSENSUS II).Am J Cardiol. 1997; 79: 115-119Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar24Leor J Reicher-Reiss H Goldbourt U et al.Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease.J Am Coll Cardiol. 1999; 33: 1920-1925Abstract Full Text Full Text PDF PubMed Scopus (100) Google ScholarIt is important to note that all of the studies investigating the clinical importance on outcome in cardiovascular diseases were post hoc analyses of large trials or were retrospective cohort studies. Therefore, none of these studies was free from considerable imbalance of the baseline characteristics of patients who were and were not receiving therapy with aspirin. Thus, none of these studies is able to conclusively resolve the controversy, despite the fact that some of these studies included a very large number of patients.19Teo KK Yusuf S Pfeffer M et al.Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review.Lancet. 2002; 360: 1037-1043Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar20Latini R Tognoni G Maggioni AP et al.Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients; Angiotensin-Converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.J Am Coll Cardiol. 2000; 35: 1801-1807Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar21Flather MD Yusuf S Kober L et al.Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients: ACE-Inhibitor Myocardial Infarction Collaborative Group.Lancet. 2000; 355: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar23Nguyen 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 II (CONSENSUS II).Am J Cardiol. 1997; 79: 115-119Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar24Leor J Reicher-Reiss H Goldbourt U et al.Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease.J Am Coll Cardiol. 1999; 33: 1920-1925Abstract Full Text Full Text PDF PubMed Scopus (100) Google ScholarThe study by Aumégeat et al has the same limitations and included only 755 patients, thereby lowering the statistical power significantly. However, this study has some special features that may deserve consideration. Thus, it included consecutive, unselected patients from a single center. In contrast, most of the other studies19Teo KK Yusuf S Pfeffer M et al.Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review.Lancet. 2002; 360: 1037-1043Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar20Latini R Tognoni G Maggioni AP et al.Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients; Angiotensin-Converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.J Am Coll Cardiol. 2000; 35: 1801-1807Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar21Flather MD Yusuf S Kober L et al.Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients: ACE-Inhibitor Myocardial Infarction Collaborative Group.Lancet. 2000; 355: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar23Nguyen 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 II (CONSENSUS II).Am J Cardiol. 1997; 79: 115-119Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar24Leor J Reicher-Reiss H Goldbourt U et al.Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease.J Am Coll Cardiol. 1999; 33: 1920-1925Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholarwere post hoc analyses of multicenter trials, excluding a significant proportion of patients. Moreover, the assessment of the patients was comprehensive, including coronary angiography, echocardiography, and ergospirometry in most patients. Importantly, this improves the value of the data because undetected confounding factors are much less likely to be present. Although it is not possible to record all of the potential confounders, the more completely they are recorded, the less likely it is that an important confounding factor remains undetected. The study by Aumégeat et al found that these potential confounders did not influence the results. Also, doses of ACE inhibitors and aspirin were recorded not only at study entry, but also later on. As delineated above, the dose of aspirin may be crucial in this regard. Additionally, the dose of ACE inhibition also may be important, since the inhibition of angiotensin II formation in the long term may be dose-dependent, being present with the use of high doses only.25Cleland JG Semple P Hodsman P et al.Angiotensin II levels, hemodynamics and sympathoadrenal function after low-dose captopril in heart failure.Am J Med. 1984; 77: 880-886Abstract Full Text PDF PubMed Scopus (56) Google Scholar26Cleland JG Dargie HJ Ball SG et al.Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state.Br Heart J. 1985; 54: 305-312Crossref PubMed Scopus (246) Google ScholarLess is known about the dose-response relationship of the non-angiotensin II-mediated effects of ACE inhibitors. However, the positive prognostic effect of ACE inhibition at doses without sufficient angiotensin II suppression may indicate that these effects occur at lower doses, although the beneficial effect is enhanced at high doses.27Packer M Poole-Wilson PA Armstrong PW et al.Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure: ATLAS Study Group.Circulation. 1999; 100: 2312-2318Crossref PubMed Scopus (1093) Google ScholarThus, the interaction may be, in theory, more important with low-dose ACE inhibition. The study by Aumégeat et al suggests that this was not the case in their CHF population. Taken together, the evidence for a significant interaction between aspirin and ACE inhibitors in CHF patients is minimal, as long as low-dose aspirin (ie, ≤ 100 mg) are used. This seems to be the case not only with maximal ACE inhibitor doses, but also with moderate doses that are commonly used in clinical practice. Because aspirin significantly improves prognosis in atherosclerotic patients, all these patients should receive low-dose aspirin therapy together with full-dose ACE inhibition therapy, even though the controversy has not yet been resolved. Whether other antiplatelet therapy (ie, with clopidogrel) or oral anticoagulation is superior in these patients will be answered by ongoing studies (eg, WATCH and PLUTO-CHF). However, the controversy will probably never be resolved since these studies will not address the question of a clinically significant interaction between aspirin and ACE inhibition. Still, with these results, the question will be less relevant. Aspirin Does Not Adversely Affect Survival in Patients With Stable Congestive Heart Failure Treated With Angiotensin-Converting Enzyme InhibitorsCHESTVol. 124Issue 4PreviewExperimental studies and retrospective analyses of mortality trials with angiotensin-converting enzyme inhibitors (ACE-Is) have suggested that aspirin may reduce the beneficial effect of these drugs. The aim of this study was to assess a possible detrimental effect of aspirin on survival in stable patients with left ventricular systolic dysfunction who had congestive heart failure and had been treated with ACE-Is. Full-Text PDF