The clinical ramifications of CIBIS III: Does the sequence of medication initiation really matter?

The development of new and innovative mechanical and pharmacologic therapies for the broad spectrum of cardiovascular disease has led to dramatic changes in the makeup of clinical practice. At the same time, an increasing percentage of the clinical cardiologist’s practice is now made up of patients with chronic congestive heart failure (CHF) secondary to both ischemic and nonischemic etiologies. The impact of this disease on the national healthcare system is staggering, with many of these patients undergoing numerous and multiple hospitalizations during the myriad phases of their treatment. Thus, determining the best strategy for both initiating and optimizing medical therapy for chronic heart failure is of paramount importance.

The present study by Willenheimer investigates this very question. In it, the authors randomized 1010 patients with mild-to-moderate chronic heart failure and left ventricular dysfunction (ejection fractions ≤ 35%). The patients in the study were truly representative of patients seen in clinical practice (mean age 74 years; New York Heart Association class II or III). Of note, the patients in the present study were in the initial phase of treatment initiation with angiotensin-converting enzyme (ACE) inhibitor medications and beta blockers. The primary question to be answered by this study was whether starting beta-blocker therapy with bisoprolol before the ACE inhibitor enalapril was beneficial in terms of both hospitalizations and long-term survival, as opposed to treatment initiation with the opposite sequence of these medications. The 2 pharmacologic strategies were blindly compared with regards to the combined primary end points of all-cause mortality or hospitalization, and with regards to each of these end points individually. The mean follow-up time for this study was 1.2 years.

The results of the study can be summarized as follows. The bisoprolol first strategy was found to be non-inferior to the enalapril-first strategy by intention-to-treat analysis; however, by the per-protocol analysis, the bisoprolol-first strategy was not proven inferior to the enalapril-first strategy. With the bisoprolol-first strategy, 63 patients had a worsening of chronic heart failure requiring hospitalization or recurrent in-hospital symptoms compared to 51 in the enalapril-first group. At the end of the monotherapy phase, 109 patients in the bisoprolol-first group had a primary end point versus 108 with the enalapril-first group. However, the bisoprolol-first study group showed a 31% lower mortality at the end of the first year. The 2 drug regimens showed similar rates of adverse effects (36.5% for the bisoprolol-first group versus 37.3% for the enalapril-first group) during the study period. Both strategies affected blood pressure similarly during the monotherapy and combined therapy phases. The final conclusion was that the 2 strategies of drug initiation were statistically similar in safety and efficacy with regard to the primary end point (mortality and all hospitalizations). There was a slight trend for increased numbers of hospitalizations and worsening of heart failure symptoms during drug initiation and up-titration in the bisoprolol-first group. However, there was a survival trend in favor of the bisoprolol-first group during the mean follow-up period.

The clinical implications and message from this study are familiar and expected to those clinicians who take care of elderly patients with chronic heart failure. Diuretics, ACE inhibitors, beta blockers, and other medications such as cardiac glycosides and angio­tensin receptor blockers have formed the mainstay of pharmacologic therapy for CHF. The clinical challenge faced by us all, however, is how to bring the patient through the initiation and up-titration phase of medical therapy to the point of optimal treatment. Often, with up-titration of beta blockers, the clinician has a sense of taking 2 steps forward and 1 step back with regards to patient tolerance of these medications. This was seen in the present study by Willenheimer, but to a lesser degree than expected. The trend towards long-term survival with the bisoprolol-first strategy suggests that despite the clinical challenges in managing heart failure patients with these drugs, this strategy is well justified by the benefits.

One must tailor drug initiation and up-titration to the individual patient. The use of beta blockers first followed by ACE inhibitor medicines may make sense in patients who have ischemic cardiomyopathies with tachy­cardia. Conversely, optimizing the ACE inhibitor medicines first may make perfect clinical sense in other situations. The overall message from this study is that both treatment strategies are safe and efficacious in the management of chronic heart failure. Thus the choice of 1 strategy over another depends greatly on the patient and their unique clinical circumstances.