beta-blockers in heart failure - The 'new wave' of clinical trials

There is now considerable clinical trial data to support the use of beta-bl ockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the l ast 20 years supporting the benefits of these agents on ventricular functio n and clinical status. In addition, morbidity and mortality benefits have b een suggested, specifically with the non-selective vasodilating agent, carv edilol. More recently, a "new wave" of clinical trials have been conducted to defin itively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questio ns. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powe red studies; whether the benefits of carvedilol in systolic heart failure a re due to its beta-blocking properties alone or to a combination of the bet a-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class III B-TV CHF; and, whether beta-blockers are of benefit (additional to ACE inhi bitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions . Most are still underway but 3 studies have recently reported their result s: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Resear ch in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/X L Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These st udies have demonstrated that blockade with beta(1)-selective, non-vasodilat ing agents (i.e. bisoprolol and metoprolol) improve survival in patients wi th CHF Comparison of relative risk reduction in these recent studies with t he earlier carvedilol studies raises mechanistic questions, specifically wh ether non-selectivity, vasodilation and other ancillary properties of carve dilol are critical to its benefit in CHF patients. This question is current ly being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of othe r agents in this condition. Open-label prescribing of beta-blockers is incr easing in these studies and this is having an impact on event rates and thu s required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied c lass of agents in the treatment of CHE with a database of over 6000 patient s in placebo-controlled studies, and ongoing clinical and mechanistic studi es. Despite this, further questions remain regarding the use of these agent s in CHE including their role in the extreme elderly, in patients with diab etes mellitus and in patients with renal impairment.