Angiotensin converting enzyme inhibition and aspirin in congestive heart failure

Sammanfattning: Angiotensin-converting enzyme (ACE) inhibitors act by decreasing production of angiotensin II and by potentiating the effects of bradykinin by inhibition of its breakdown. Bradykinin exerts part of its effects via vasodilating prostaglandins. Since the cyclooxygenase (COX)-inhibitors, e.g. aspirin and non-steroidal anti-inflammatory drugs, NSAIDs, block the formation of prostaglandins patients may not receive full advantage of ACE-inhibition if they are treated with an ACE-inhibitor and a COX-inhibitor. In study I the renal effects of low-dose aspirin and the NSAID diclofenac in patients with congestive heart failure treated with ACE-inhibitors were evaluated. A single dose of diclofenac was found to significantly impair the renal function. No differences were found between low-dose aspirin and placebo. In study II the negative renal effects of COX-inhibitors in elderly, healthy subjects treated with an ACE-inhibitor after activation of the renin-angiotensin system were quantified. Activation of the renin-angiotensin system was achieved by pre-treatment with a diuretic and an ACE-inhibitor. Diclofenac induced reductions in renal function and after pre-treatment the reductions were even more pronounced. Angiotensin-receptor blockers (ARBs) block the angiotensin II action with no significant effect on bradykinin. Consequently, ARBs should not affect prostaglandin synthesis and not interact with COX-inhibitors the same way as ACE-inhibitors do. In study III elderly, healthy volunteers had pre-treatment as in study II but during one of the pre-treatment periods an ARB was given together with the diuretic. Surprisingly, no significant differences were found in renal impairment between ACE-inhibitors and ARBs. Study IV investigated the dose dependency of renal effects of aspirin with ACE-inhibitor treatment. Elderly, healthy volunteers were pre-treated as in study II and were randomised into two groups: one group received doses of placebo and 160 mg, the other group received doses of 80 mg and 320 mg. The results showed a clear dose dependency for the renal effects of aspirin. The renal effects were of clinical importance from a dose of at least 160 mg. In summary, this thesis suggests that NSAIDs should be avoided in patients with congestive heart failure, or only used under strict supervision. ACE-inhibitors and ARBs are equally sensitive to renal impairment from COX-inhibitors and aspirin shows a clear dose dependent interaction with ACE-inhibitors on renal function. If treatment with aspirin is mandatory a dose equal to or lower than 80 mg should be used.