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

Hans Peter Brunner-La Rocca
Author and Funding Information

Affiliations: Basel, Switzerland
 ,  Dr. Brunner-La Rocca is Assistant Professor of Cardiology, University Hospital.

Correspondence to: Hans Peter Brunner-La Rocca, MD, Division of Cardiology, University Hospital, Petersgraben 4, 4031 Basel, Switzerland; e-mail: brunnerh@uhbs.ch



Chest. 2003;124(4):1192-1194. doi:10.1378/chest.124.4.1192
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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.1 Since 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).23 Accordingly, 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.4 These 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,5 despite 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,67 although the data in this regard are not consistent.8 Cardioprotection against free radicals by ACE inhibition depends on the activation of bradykinin type 2 receptors and prostaglandin synthesis.9 In 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.10 Also, the antihypertensive potential of ACE inhibitors was found to be reduced with concomitant use of nonsteroidal antirheumatic drugs.11 However, 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-A2.12 Opposing 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.13 This may be particularly important in the heart since cardiac sympathetic activation is related both to the progression of CHF and to sudden cardiac death.14 Whether 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.15 Accordingly, 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),,1,16 but not with low doses of aspirin (ie, ≤ 100 mg).18

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.1924 It 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.,1921,2324 The 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 studies1921,2324 were 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.26 Less 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.27 Thus, 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.

References

Hall, D, Zeitler, H, Rudolph, W (1992) Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure.J Am Coll Cardiol20,1549-1555. [CrossRef] [PubMed]
 
Blais, C, Jr, Drapeau, G, Raymond, P, et al Contribution of angiotensin-converting enzyme to the cardiac metabolism of bradykinin: an interspecies study.Am J Physiol1997;273,H2263-H2271. [PubMed]
 
Gainer, 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 Med1998;339,1285-1292. [CrossRef] [PubMed]
 
Jorde, 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.Circulation2000;101,844-846. [CrossRef] [PubMed]
 
Pitt, 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.Lancet2000;355,1582-1587. [CrossRef] [PubMed]
 
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 Risk1994;1,255-262. [PubMed]
 
Zhu, P, Zaugg, CE, Hornstein, PS, et al Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.J Cardiovasc Pharmacol1999;33,785-790. [CrossRef] [PubMed]
 
Duncan, 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 Pharmacol1996;28,746-754. [CrossRef] [PubMed]
 
Jin, 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 Physiol2000;27,257-262. [CrossRef] [PubMed]
 
Townend, 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 J1995;73,434-441. [CrossRef] [PubMed]
 
Morgan, 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 Hypertens2000;13,1161-1167. [CrossRef] [PubMed]
 
Lin, L, Nasjletti, A Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction.Hypertension1991;18,158-164. [CrossRef] [PubMed]
 
Seyedi, 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 Res1997;81,774-784. [CrossRef] [PubMed]
 
Brunner-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 J2001;22,1136-1143. [CrossRef] [PubMed]
 
Weksler, BB, Pett, SB, Alonso, D, et al Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients.N Engl J Med1983;308,800-805. [CrossRef] [PubMed]
 
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.Circulation1998;98,757-765. [CrossRef] [PubMed]
 
Guazzi, MD, Campodonico, J, Celeste, F, et al Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction.Clin Pharmacol Ther1998;63,79-86. [CrossRef] [PubMed]
 
Boger, 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 Pharmacol1996;42,721-727. [PubMed]
 
Teo, 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.Lancet2002;360,1037-1043. [CrossRef] [PubMed]
 
Latini, 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 Cardiol2000;35,1801-1807. [CrossRef] [PubMed]
 
Flather, 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.Lancet2000;355,1575-1581. [CrossRef] [PubMed]
 
Oosterga, 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 Cardiol1998;81,1178-1181. [CrossRef] [PubMed]
 
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 II (CONSENSUS II).Am J Cardiol1997;79,115-119. [CrossRef] [PubMed]
 
Leor, 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 Cardiol1999;33,1920-1925. [CrossRef] [PubMed]
 
Cleland, JG, Semple, P, Hodsman, P, et al Angiotensin II levels, hemodynamics and sympathoadrenal function after low-dose captopril in heart failure.Am J Med1984;77,880-886. [CrossRef] [PubMed]
 
Cleland, 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 J1985;54,305-312. [CrossRef] [PubMed]
 
Packer, 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.Circulation1999;100,2312-2318. [CrossRef] [PubMed]
 

Figures

Tables

References

Hall, D, Zeitler, H, Rudolph, W (1992) Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure.J Am Coll Cardiol20,1549-1555. [CrossRef] [PubMed]
 
Blais, C, Jr, Drapeau, G, Raymond, P, et al Contribution of angiotensin-converting enzyme to the cardiac metabolism of bradykinin: an interspecies study.Am J Physiol1997;273,H2263-H2271. [PubMed]
 
Gainer, 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 Med1998;339,1285-1292. [CrossRef] [PubMed]
 
Jorde, 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.Circulation2000;101,844-846. [CrossRef] [PubMed]
 
Pitt, 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.Lancet2000;355,1582-1587. [CrossRef] [PubMed]
 
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 Risk1994;1,255-262. [PubMed]
 
Zhu, P, Zaugg, CE, Hornstein, PS, et al Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.J Cardiovasc Pharmacol1999;33,785-790. [CrossRef] [PubMed]
 
Duncan, 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 Pharmacol1996;28,746-754. [CrossRef] [PubMed]
 
Jin, 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 Physiol2000;27,257-262. [CrossRef] [PubMed]
 
Townend, 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 J1995;73,434-441. [CrossRef] [PubMed]
 
Morgan, 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 Hypertens2000;13,1161-1167. [CrossRef] [PubMed]
 
Lin, L, Nasjletti, A Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction.Hypertension1991;18,158-164. [CrossRef] [PubMed]
 
Seyedi, 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 Res1997;81,774-784. [CrossRef] [PubMed]
 
Brunner-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 J2001;22,1136-1143. [CrossRef] [PubMed]
 
Weksler, BB, Pett, SB, Alonso, D, et al Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients.N Engl J Med1983;308,800-805. [CrossRef] [PubMed]
 
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.Circulation1998;98,757-765. [CrossRef] [PubMed]
 
Guazzi, MD, Campodonico, J, Celeste, F, et al Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction.Clin Pharmacol Ther1998;63,79-86. [CrossRef] [PubMed]
 
Boger, 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 Pharmacol1996;42,721-727. [PubMed]
 
Teo, 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.Lancet2002;360,1037-1043. [CrossRef] [PubMed]
 
Latini, 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 Cardiol2000;35,1801-1807. [CrossRef] [PubMed]
 
Flather, 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.Lancet2000;355,1575-1581. [CrossRef] [PubMed]
 
Oosterga, 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 Cardiol1998;81,1178-1181. [CrossRef] [PubMed]
 
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 II (CONSENSUS II).Am J Cardiol1997;79,115-119. [CrossRef] [PubMed]
 
Leor, 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 Cardiol1999;33,1920-1925. [CrossRef] [PubMed]
 
Cleland, JG, Semple, P, Hodsman, P, et al Angiotensin II levels, hemodynamics and sympathoadrenal function after low-dose captopril in heart failure.Am J Med1984;77,880-886. [CrossRef] [PubMed]
 
Cleland, 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 J1985;54,305-312. [CrossRef] [PubMed]
 
Packer, 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.Circulation1999;100,2312-2318. [CrossRef] [PubMed]
 
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