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Effects of coadministration of aspirin or clopidogrel on exercise testing in patients with heart failure receiving angiotensin-converting enzyme inhibitors*

      Angiotensin-converting enzyme (ACE) inhibitors are effective drugs that have been shown to lower morbidity and mortality in patients with heart failure who have left ventricular systolic dysfunction.
      The SOLVD Investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      ,
      • Pfeffer M.A.
      • Braunwald E.
      • Moye L.A.
      • Basta L.
      • Brown E.J.
      • Cuddy T.E.
      • Davis B.R.
      • Geltman E.M.
      • Goldman S.
      • Flaker G.C.
      • et al.
      Effects of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction results of the Survival and Ventricular Enlargement Trial.
      ,
      The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      Patients with congestive heart failure (CHF) often have indications for using both ACE inhibitors and antiplatelet agents. Various clinical trials have suggested that an adverse interaction exists from the combined use of aspirin and an ACE inhibitor in patients with CHF, but few studies have measured this effect directly.
      The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      ,
      • Hall D.
      • Zeitler H.
      • Rudolph W.
      Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure.
      ,
      • Spaulding C.
      • Charbonnier B.
      • Cohen-Solal A.
      • Juilliere Y.
      • Kromer E.P.
      • Benhamda K.
      • Cador R.
      • Weber S.
      Acute hemodynamic interaction of aspirin and ticlopidine with enalapril results of a double-blind, randomized comparative trial.
      ,
      • Guazzi M.
      • Marenzi G.
      • Alimento M.
      • Contini M.
      • Agostoni P.
      Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effects of aspirin.
      ,
      • 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.
      ,
      • Guazzi M.
      • Melzi G.
      • Agostoni P.
      Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
      ,
      • Nakamura M.
      • Funakoshi T.
      • Arakawa N.
      • Yoshida H.
      • Makita S.
      • Hiramori K.
      Effect of angiotensin-converting enzyme inhibitors on endothelium-dependent peripheral vasodilation in patients with chronic heart failure.
      ,
      • Al-Khadra A.S.
      • Salem D.N.
      • Rand W.M.
      • Udelson J.E.
      • Smith J.J.
      • Konstam M.A.
      Antiplatelet agents and survival a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial.
      ,
      • Nguyen K.N.
      • 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).
      ,
      • Song K.H.
      • Fedyk R.
      • Hoover R.
      Interaction of ACE inhibitors and aspirin in patients with congestive heart failure.
      The most compelling evidence of a potential adverse interaction between ACE inhibitors and aspirin stems from the Studies Of Left Ventricular Dysfunction (SOLVD)
      The SOLVD Investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      ,
      • Al-Khadra A.S.
      • Salem D.N.
      • Rand W.M.
      • Udelson J.E.
      • Smith J.J.
      • Konstam M.A.
      Antiplatelet agents and survival a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial.
      and Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)
      • Nguyen K.N.
      • 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).
      trials. In SOLVD, although enalapril and aspirin when used alone were associated with lower mortality rates, retrospective analysis revealed that the addition of enalapril did not reduce mortality in patients already taking aspirin, and conversely, neither did the addition of aspirin in patients receiving enalapril. In a post hoc analysis of CONSENSUS II, aspirin and enalapril, when utilized alone, were associated with lower mortality rates. However, the relative risk of death at the end of the study was 1.23 (95% confidence interval [CI] 0.99 to 1.53) for patients taking aspirin and enalapril, and 0.86 (95% CI 0.63 to 1.16) for patients taking enalapril without aspirin (p = 0.047). Guazzi et al,
      • 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.
      in a small prospective study, measured maximal exercise oxygen uptake (VO2max) in patients with CHF, and demonstrated an adverse effect when ACE inhibitors were combined with aspirin, but not with ACE inhibitors alone. Therefore, we hypothesized that exercise duration and VO2max would not be attenuated by clopidogrel compared with aspirin in patients with CHF who are taking ACE inhibitors.
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      References

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