a Monash University/Alfred Hospital, Melbourne, Australia
b Cardiology Department, Austin Hospital, Heidelberg, Australia
* Correspondence to: Prof. H. Krum, Alfred Hospital, Clinical Pharmacology Unit, Commercial Road, Prahan, Vic 3181, Australia. Tel: +61 3 9903 0042; Fax: +61 3 9903 0556
E-mail address: henry.krum{at}med.monash.edu.au
Received 1 April 2003; accepted 20 June 2003
Dear Sir,
We read with interest the article by Simon et al.1in the Journal, examining the dose-response relationship of bisoprolol in patients with chronic heart failure in the CIBIS II study. The authors conclude that bisoprolol reduced significantly the risk of mortality in CHF patients for all tolerated dose levels. The suggestion by the authors is that this study demonstrates clinical benefit at doses of bisoprolol lower than that achieved in the overall study.
We believe these conclusions are unable to be substantiated by the data presented. The present study is a post-hoc sub-group analysis, where patients were not prospectively randomized to receive differing doses of bisoprolol a priori. Furthermore, the comparator group for each dosing level was the equivalent dose achieved by patients receiving placebo. This type of analysis is fundamentally flawed because patients not able to tolerate higher doses of placebo clearly declare themselves as being the sickest patients within the cohort. Therefore, when compared to those unable to tolerate higher doses of bisoprolol (which may occur for many reasons), the active drug would appear to provide clinical benefit. The inequity of this comparison is underscored by the disparity in the number of patients in the low and moderate dose groups amongst patients randomised to bisoprolol versus placebo.
What is unambiguous from this data is that low doses of bisoprolol are significantly inferior to those of high doses in prolonging survival in CIBIS II. There are of course many reasons for these differences, but this merely highlights the pitfalls of attempting to interpret data obtained from non-randomized groups.
Based on the above, we believe it is misleading and potentially sub-optimal patient management to suggest that prescribing of bisoprolol should be based on the individual patient's tolerability. The CIBIS I study2(a larger cohort of bisoprolol patients than the low dose group in the present analysis) did not observe significant benefit with bisoprolol compared to placebo at a target dose of 5mg/day. Furthermore, in the MOCHA study,3a positive dose-dependent relationship was observed between carvedilol dose and subsequent improvements in ventricular function and survival.
Based on the above, there is a clear need for a properly-powered, prospectively-randomized study comparing beta-blockade at differing dosing levels. However, until that time, recommendations regarding use of beta-blockers should emphasise the need to up-titrate patients to the doses observed to be of proven benefit in major prospective trials.
References