BY OUR PHARMA CORRESPONDENT
8 September, 2005: Merck KGaA reports that initiating treatment with beta blocker and adding an ACE-inhibitor after six months was clinically comparable to starting with an ACE-inhibitor and adding bisoprolol after six months, in treating chronic heart failure.
Starting therapy with bisoprolol (ConcorCOR) rather than with the ACE-inhibitor enalapril showed a similar incidence of the primary endpoint of all-cause death or hospitalization with a favorable trend toward mortality reduction during the monotherapy phase and during the first year of treatment. The trial involving 1,010 patients with chronic heart failure conducted at 128 centers in 20 countries, was sponsored by the drug maker Merck KGaA.
CIBIS III (Cardiac Insufficiency Bisoprolol Study III) was the first large prospective study to compare starting treatment with a beta-blocker rather than with an ACE-inhibitor. The study results were presented during the European Society of Cardiology Congress in Stockholm, Sweden.
"While current guidelines recommend initiating treatment with an ACE-inhibitor and then adding a beta-blocker, this strategy is based on tradition and not evidence," said Professor Ronnie Willenheimer, director of the Research Unit at the Department of Cardiology, University Hospital Malmö, Sweden, and co-chairman of the CIBIS III steering committee. "There has been no appropriate evidence on which to make this critical decision on how to best initiate treatment of chronic heart failure. CIBIS III addresses this vitally important clinical question."
The trend towards a benefit of a bisoprolol-first strategy in relation to early survival may be clinically important, Professor Willenheimer said. "To date, studies of heart failure have focused on the benefits of combination (add-on) therapy in chronic management of progressive heart failure, where significant advances have been made. However, during the initial treatment of chronic heart failure, the risk of sudden death is high. At this early stage, when patients cannot be given combinations of several drugs, beta-blockade may be particularly valuable in improving survival through its action on the sympathetic nervous system."
In CIBIS III, the survival benefits of early beta-blocker treatment were somewhat in contrast with increased hospitalization due to worsening of heart failure. "This was probably due to the known biphasic action of a beta-blocker seen in some patients with a slight and brief initial worsening followed by improvement. It is an issue that can be addressed by greater experience in starting with the beta-blocker and by a better identification of patients who are potentially more sensitive to such an adverse outcome during initiation of beta-blocker therapy," Professor Willenheimer said.
Professor Philippe Lechat, Service de Pharmacologie, Hôpital Pitié-Salpêtrière, Paris, France, and chairman of the CIBIS III steering committee, said that for the first time clinicians have a large, randomized study on which to make evidence-based decisions when initiating treatment of heart failure.
"Until now, the sequence of starting drugs in heart failure (i.e. diuretic plus ACE-inhibitor followed by beta-blocker) has reflected the situation where ACE-inhibitors were the first to demonstrate their beneficial effects," said Professor Lechat. "CIBIS III shows that beta-blockade can be safely used to start therapy and, following the addition of an ACE-inhibitor, will produce similar efficacy and safety in chronic management to a regimen in which the ACE-inhibitor precedes the beta-blocker. Clearly, the underlying mechanism of the beta-blocker may offer advantages in early treatment where sympathetic nervous system activity is particularly important."
A total of 1,010 patients with a mean age of 72 years, mild-to-moderate chronic heart failure (NYHA class II and III) and left ventricular ejection fraction (LVEF) = 35% were randomized to bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months followed by combination therapy for 6-24 months.
By the end of the study, there were no clinically significant differences in the efficacy or tolerability of the two treatment arms (measured by a combined endpoint). In addition, analysis suggested a potential benefit on survival with a 28% mortality reduction during the Concor COR monotherapy phase and 31% mortality reduction during the first year of treatment. Although non-significant from a strictly statistical point of view, these results may argue in favor of initiating therapy with a beta-blocker.
Chronic heart failure has become one of the largest medical and epidemiological problems. In terms of five-year survival after diagnosis, CHF is more deadly than most cancers. Its prevalence is increasing rapidly, due to the aging population and the much-publicized diabetes and obesity epidemics. It affects approximately 18.5 million individuals (7 biggest markets: US, Jap, F, UK, Ger, It, Sp); and this number may increase to 33.2 million by 2015, according to Datamonitor (2005). Moreover, CHF treatment is associated with high costs. The estimated direct and indirect costs of heart failure in the United States are US $ 27.9 billion in 2005 (AHA's 2005 Statistical Update).
Merck KGaA is the maker of ConcorCOR (bisoprolol), one of the world's leading ß1-selective beta-blockers. It is indicated in chronic heart failure (CHF) management, currently on top of ACE inhibition.
The landmark study CIBIS II contributed to establish beta-blockers such as bisoprolol as a leading treatment option in CHF: bisoprolol reduces mortality by 34% as well as a reduction in hospitalization, improvement of NYHA class and reduction of heart failure worsening.
BY OUR PHARMA CORRESPONDENT