Increased understanding of pathophysiological mechanisms of cardiovascular diseases has shown that the renin-angiotensin-aldosterone system (RAAS) is activated in this setting and suggests a central role for the angiotensin-converting enzyme (ACE). ACE transforms angiotensin I (Ang I) to angiotensin II (Ang II), and also promotes the degradation of bradykinin into inactive metabolites. These bradykinins stimulate nitric oxide synthesis and vasodilatator prostaglandin synthesis via a cyclooxygenase (COX) pathway.
COX inhibitors may therefore be deleterious in cardiovascular disease and/or counteract part of ACE inhibitor (ACE-I) efficacy. This has been clearly demonstrated with non-steroidal anti-inflammatory drugs (NSAIDs), including high-dose aspirin, in avoiding their use in such patients. hypertension, coronary artery disease and chronic heart failure (CHF); most guidelines recommend avoiding their use in such patients.
Theoretically, this effect is dose-mediated and the existence of an identical deleterious effect with low-dose aspirin has been an area of intense debate. In this article, we review studies, most of them conducted in CHF, that pointed out such a possible deleterious effect and a counteraction of ACE-Is with low-dose aspirin , using various criteria of assessment.
However, there are no prospective long-term studies that have validated such an effect, and the role of other anti-aggregating agents has not been evaluated. Until such studies are published, the use of low-dose aspirin (100 mg/day) in such patients can be recommended.
Packer M.The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol1992;20:248-54.
2.
Mann DLMechanisms and models in heart failure. 3 Circulation1999;100:999-1008.
3.
Erdös EGAngiotensin I converting enzyme and the changes in our concepts through the years. Hypertension1990;16:363-70.
4.
Dzau VJ, Packer M., Lilly LS, Swartz SL, Hollenberg NK, Williams GHProstaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia. N Engl J Med1984;310:347-52.
5.
Cheng CP, Onishi K., Ohte N., Suzuki M., Little WCFunctional effects of endogenous bradykinin in congestive heart failure . J Am Coll Cardiol1998;31:1679-86.
6.
Schrör K.Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol1992;20:S68-S73.
7.
Cannon PJProstaglandins in congestive heart failure and the effects of nonsteroidal anti-inflammatory drugs. Am J Med1986;82:123-32.
8.
Cleland JGF , Bulpitt CJ, Falk RH et al. Is aspirin safe for patients with heart failure?Br Heart J1995;74:215-19.
9.
Mahé I., Meune C., Diemer M., Caulin C., Bergmann JFInteraction between aspirin and ACE inhibitors in patients with heart failure . Drug Safety2001;24:167-82.
10.
Spaulding C. , Charbonnier B., Cohen-Solal A. et al. Acute heamodynamic interaction of aspirin and ticlodipine with enalapril. Circulation1998;98:757-65.
11.
Schwieler JH , Kahan T., Nussberger J. et al. Converting enzyme inhibition modulates sympathetic neurotransmission in vivo via multiple mechanisms . Am J Physiol1993;264:E631—E637.
Pellacani A. , Brunner HR, Nussberger J.Plasma kinins increase after angiotensin-converting enzyme inhibition in human subjects. Clin Sci1994;87:567-74.
14.
Minshall RD , Tan F., Nakamura F. et al. potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells. Circ Res1997;81:848-56.
15.
Regoli D., Rhaleb NE, Drapeau G. et al. Basic pharmacology of kinins:pharmacologic receptors and other mechanisms. In: Abe K, Moriya H, Fuji S.New York: Plenum, 1989 ;398-407.
16.
Bönner G.The role of kinins in the antihypertensive and cardioprotective effects of ACE inhibitors. Drugs1997; 54(suppl 5):23-30.
17.
Gainer JV, Morrow JD, Loveland A., King DJ, Brown NJEffect of bradykinin-receptor blockade on the response to angiotensin-converting enzyme inhibitor in normotensive and hypertensive subjects. NEnglJMed1998;339:1285-92.
18.
Townend JN, Doran J., Lote CJ, Davies MKPeripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril. Br Heart J1995;73:734-41.
19.
Emanueli C. , Maestri R., Domenico C. et al. Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice. Circulation1999;100:2359-65.
20.
Vane JRInhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature1971;231:232-5.
21.
Needleman P. , Isakson PCThe discovery and function of COX-2 . J Rheumatol1997;24(suppl 49):6-8.
22.
Meade EA, Smith WL, DeWitt DLDifferential inhibition of prostaglandin endoperoxydase synthase (cyclooxygenase) isoenzymes by aspirin and other non-steroidal antiinflammatory drugs. JBiol Chem1993;268:6610-14.
23.
Patrignani P., Filabozzi P., Patrono C.Selective inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects . J Clin Invest1982;69:1366-72.
24.
Weskler BB, Pett SB,Alonso D. et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients.NEnglJMed1983;308:800-05.
25.
Baur LHB , Schipperheyn JJ, Van der Laarse A. et al. Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J1995;73:227-36.
26.
Fitzgerald GA, Oates JA, Hawiger OJ et al. Endogenous biosynthesis of prostacycline and thromboxane and platelet function during chronic administration of aspirin in men. J Clin Invest1983;71:976-88.
27.
The SOLVD investigators.Effects of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med1991;325:293-302.
28.
Yusuf S., Sleight P., Pogue J., Bosch J., Davies R., Daguenais G.for The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med2000;342:145-53.
29.
Garg R., Yusuf S., for the Collaborative Group on ACE Inhibitor trials. Overview of randomized trials of angiotensin-converting enzyme inhibitor on mortality and morbidity in patients heart failure. JAMA1995;273:1450-6.
30.
Lorel BHPericardial disease. In: Braunwald E (ed.). Heart Disease. A textbook of cardiovascular medicine . 5th edition Philadelphia: W.B. Saunders Company, 1997;1478-534.
31.
Albert DA, Harel L., Karrisson T.The treatment of rheumatic carditis:A review and meta-analysis. Medicine1995;74:1-12.
32.
Brooks PM, Day RONon-steroidal anti-inflammatory drugs: differences and similarities . N Engl J Med1991;324: 1716-25.
33.
Antiplatelet Trialists Collaboration.Collaborative overview of randomised, controlled trials of antiplatelet therapy. I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ1994 ;308:81-106.
34.
Hansson L., Zanchettti S., Carruthers SG et al. for the HOT study group.Effect of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet1998;351:1755-62.
35.
Ho KK, Pinsky JL, Kannel WB, Levy D.The epidemiology of heart failure: the Framingham study. J Am Coll Cardiol1993; 22:6A-13A.
36.
Brater DCEffect of indomethacin on salt and water homeostasis. Clin Pharmacol Ther1979;25:322-30.
37.
Pope JE, Anderson JJ, Felson DTA meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Int Med1993;153:477-84.
38.
Collins R., Peto R., MacMahon S. et al. Blood pressure, stroke, and coronary health disease. Part 2, Short term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet1990 ;335:827-38.
39.
Gottlieb SS , Robinson S., Krichten CM, Fisher MLRenal response to indomethacin in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol1992 ;70:890-3.
40.
Page J., Henry D.Consumption of NSAIDs and the development of congestive heart failure in elderly patients. Arch Intern Med2000;160:777-84.
41.
Nawarskas JJ , Spinler SADoes aspirin interfere with the therapeutic efficacy of angiotensin-converting enzyme inhibitors in hypertension or congestive heart failure?Pharmacotherapy1998;18:1041-52.
42.
Bhagat K., Collier J., Vallance P.Vasodilatation to arachidonic acid in humans.An insight into endogenous prostanoids and effects of aspirin. Circulation1995;92:2113-18.
43.
Davie AP, Love MP, McMurray JJV.Even low-dose aspirin inhibits arachidonic acid-induced vasodilatation in heart failure. Clin Pharmacol Ther2000 ;67:530-7.
44.
Galatius S. , Wroblewski H., Kastrup J.Does aspirin treatment influence vascular resistance and fluid filtration in patients with congestive heart failure?Heart1999;81:330.
45.
Guazzi MD, Campodonico J., Celeste F. et al. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clin Pharmacol Ther1998;63:79-86.
46.
Meune C., Mahe I., Mourad JJ et al. Interaction between angiotensin-converting enzyme inhibitors and aspirin: a review. Eur J Clin Pharmacol2000;56:609-20.
47.
Latini R., Santoro E., Masson S. et al. for the GISSI-3 investigators.Aspirin does not interact with ACE inhibitors when both are given early after acute myocardial infarction. Results of the GISSI-3 trial. Heart Disease2000;2:185-90.
48.
Zanetti G., Latini R., Maggioni AP, Franzosi MG, Santoro L., Tognoni G., for the GISSI-3 investigators.Effects of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction. Circulation1997;96:4239-45.
49.
Latini R., Tognoni G., Maggioni AP et al. on behalf of the Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence or absence of aspirin. J Am Coll Cardiol2000;35:1801-07.
50.
Hall D.The aspirin-angiotensin-converting enzyme inhibitor tradeoff: to halve and halve not. J Am Coll Cardiol2000;35:1808-12.
51.
Takkouche B. , Etminan M., Caamaño , Rochon PAInteraction between aspirin and ACE inhibitors.Resolving discrepancies using a meta-analysis . Drug Safety2002;25:373-8.
52.
Krumholz HM , Chen Y.-T, Wang Y., Radjford MJAspirin and angiotensin-converting enzyme inhibitors among elderly survivors of hospitalization for an acute myocardial infarction. Arch Intern Med2001 ;161:538-44.
53.
Garcia-Dorado D., Rami JV, Lamela AV et al. Interaction between antiplatelet agents and ACE inhibitors in patients with acute myocardial infarction . Eur Heart J Supplements1999 ;1(suppl F):F24-F28.
54.
Al-Khadra AS , Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MAAntiplatelet agents and survival: a cohort analysis from the Studies Of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol1998;31:419-25.
55.
Nguyen KN, Aursnes I., Kjekshus J.Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroups analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol1997;79:115-19.
56.
Teo KKYusuf S., Pfeffer M. et al. for the ACE inhibitors collaborative group.Effects of long-term treatment with angiotensinconverting enzyme inhibitors in the presence or absence of aspirin: a systematic review . Lancet2002;360:1037-43.
57.
Hall D., Zeitler H., Rudolph W.Counteraction of the vasodilatator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol1992;20:1549-55.
58.
Aumégeat V. , De Groote P., Meurice T., Millaire A., Ducloux G., Lablanche JMAspirin and angiotensin converting enzyme inhibitors in 445 patients with moderate congestive heart failure. J Am Coll Cardiol1999;33:214A.
59.
Harjai KJ, Nunez E.,TurgutT.,Newman J.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 Cardiol2001;87: 483-7.
60.
Jones CG, Cleland JGF.The LIDO, HOPE, MOXCON and WASH studies. Eur J Heart Fail1999;1:425-31.
61.
Tenenbaum A. , Grossman E., Shemesh J., Fizman EZ, Nosraty I., Motro M.Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. Am J Hypertens2000;13:776-82.
62.
Meune C., Mahé I., Mourad JJ et al. Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors :a dose-mediated deleterious effect. Eur J Heart Fail2003;5:271-9.
