Sudden death prevention in heart failure: The case of CIBIS III

Abstract

CIBIS III completes a fundamental scientific phaseof a sequence of large clinical trials (1-7) which hasestablished the current therapeutic principles for themanagement of chronic heart failure (CHF) patients(8). These comprise the use of ACE inhibitors and be-ta-blockers. However, while ACE inhibitors, by an-tagonizing the synthesis of angiotensin II, found theirnatural pathway from hypertension into CHF, beta-blockers followed a controversial trail. They ap-peared effective in the BEHAT (9) trial after myocar-dial infarction (MI) even in patients with depressedleft ventricular (LV) function. Nonetheless, the gener-al view of CHF as an almost exclusively cardio-circu-latory mechanical disease/remodelling led to the useof inotropic interventions, with non-infrequent nega-tive consequences on mortality (10). Furthermore,this view prevented the conception of using anti-adrenergic interventions in CHF which consequentlyremained a strong contraindication to the use of be-ta-blockers for many years. Beginning with CIBIS II,a number of trials have proven that beta-blockertherapy improves survival in CHF, with a specific ac-tion on arrhythmic sudden cardiac death (SCD) in pa-tients with optimum background therapy, includingthe use of ACE inhibitors. This did not happen bychance, as a strong experimental ground had alreadyexisted and has further grown during the last fewyears (11); very soon after its first manifestation, is-chemic heart disease triggers a profound remodel-ling of the autonomic nervous system, resulting in re-ceptor changes and sprouting of neural fibers (12,13). In line with this background stands the hugeamount of clinical evidence documenting the anti-fibrillatory action of anti-adrenergic interventions. Incontrast to the rapid activation of the autonomic ner-vous system, the renin-angiotensin system (RAS)acts primarily by promoting the progressive myocar-dial architectural changes, leading to inefficient LVfunction and pump failure (14). The same process in-directly contributes to the genesis of an arrhythmo-genic substrate for SCD to occur (15, 16). However,despite the bulk of evidence documenting the strik-ing efficacy of ACE inhibitors and, more so, of beta-blockers in CHF, both drugs are underused. Recentsurveys indicate that ACE inhibitors are given to only60% of eligible patients (17) (Fig. 1) and the picturefor beta-blockers is even worse, as the percentage oftreated patients among those eligible is as low asaround 30%. Additionally, beta-blocker therapy ismostly given to low risk patients and as late as 6months after a first hospitalisation for HF (18). Theimmediate consequence of the mistrust in (or fear of)using adequate pharmacological therapy accordingto the international guidelines has been the boosteduse of implantable cardioverter defibrillators (ICD) inany patient with depressed LV systolic function.