COMBINING SALICYLATE AND ENALAPRIL IN PATIENTS WITH CORONARY-ARTERY DISEASE AND HEART-FAILURE

Objective-To study the effects of adding a salicylate to the angiotens in converting enzyme inhibitor enalapril in patients with heart failur e due to coronary artery disease. Design-Double blind, crossover study for three days in hospital followed by an extended similar study outs ide hospital over two months of once daily enalapril plus salicylate a nd enalapril plus placebo. Setting-Tertiary referral centre. Patients- 20 patients with heart failure due to myocardial infarction (New York Heart Association class II or III) and an ejection fraction less than 0.40. Twelve patients completed the two parts of the study. Main outco me measures-Blood pressure, plasma converting enzyme activity; plasma angiotensin II and noradrenaline concentrations; excretion of metaboli tes of renal and systemic prostanoids. Results-The unloading effect of first and second dose of enalapril in the morning lasted only during the day; in the extended study it lasted 24 hours because of the drug' s accumulation. Converting enzyme inhibitors attenuate the breakdown o f bradykinin and therefore enhance prostaglandin E(2), synthesis media ted by bradykinin. Evidence was found of such a prostaglandin E(2) med iated contribution to ventricular unloading by enalapril, which was bl ocked by salicylate. The contribution, however, was small and variable , and salicylate addition had on average no significant de-unloading e ffect during the day. Unloading was abolished in only three of the 20 patients in the short term study and in one of the 12 in the extended study. At night, when other effects of enalapril on brood pressure had waned and the bradykinin induced effect persisted, salicylate signifi cantly reduced the remaining small unloading effect. No effect was see n of salicylate addition on reversal of remodelling. Enalapril reduced angiotensin II induced synthesis of systemic and renal prostaglandin I-2 and thromboxane A(2), initially only during the day, but later als o at night. It thereby masked suppression of thromboxane A(2) synthesi s by salicylate, which is the effect to which reinfarct prevention by salicylate is attributed. Conclusion-The risk is low that salicylate w ill substantially reduce the benefit of enalapril in patients with hea rt failure by de-unloading the ventricle. Like other effects induced b y bradykinin significant de-unloading occurs in only a minority of the patients. In the presence of enalapril, however, salicylate will prob ably not be as effective as expected in reducing reinfarction risk, be cause enalapril already reduces thromboxane A, synthesis effectively i n patients with heart failure and no further reduction by salicylate w as found.