doi: 10.1161/CIRCULATIONAHA.105.586545
(Circulation. 2005;112:2380-2382.)
© 2005 American Heart Association, Inc.
Editorial |
Angiotensin-Converting Enzyme Inhibitors or ß-Blockers in Heart Failure
Does It Matter Who Goes First?
From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.
Correspondence to James C. Fang, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail jfang{at}partners.org
Key Words: Editorials • heart failure • drugs • adrenergic beta-antagonists • angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors and ß-blockers are potent therapies in heart failure. They lower total mortality and heart failure hospitalizations by 25% to 40% across all ages, functional capacities, degrees of left ventricular dysfunction, and causes.1,2 But does it matter which intervention is given first? There are 2 primary reasons why clinicians initiate heart failure therapy with ACE inhibitors for patients with systolic dysfunction: (1) ACE inhibitors were the first agents to demonstrate a mortality benefit in heart failure and therefore have since served as background therapy for all heart failure trials, and (2) heart failure is a hemodynamic as well as a neurohormonal condition that acutely improves with vasodilation.3 In acutely decompensated patients, initial hemodynamic stabilization through vasodilation improves the neurohormonal profile, including a reduction in norepinephrine levels.4 This stabilization may allow the subsequent introduction of ß-blockers, which are acutely associated with a decline in ventricular function.5,6
Article p 2426
However, when a patient has compensated heart failure, would a ß-blocker first be tolerated, safe, and even better? There are putative reasons why ß-blockers first may lead to greater survival and improved quality of life. The adrenergic system is activated earlier than the renin-angiotensin system (RAS)7 and is an important stimulus for RAS activation. Norepinephrine is a potent predictor of mortality.8 Enhanced sympathetic renal activity may contribute to sodium and water avidity.9 Evidence suggests that there is less "escape" and greater suppression of angiotensin II by ACE inhibitors when the adrenergic system is also blocked.10 Cardiorenal complications of heart failure may be avoided because rises in serum creatinine with ACE inhibitors may be decreased by pretreatment with a ß-blocker.11 ß-Blockers may have a greater impact on ventricular remodeling than ACE inhibitors.12 In contrast to ACE inhibitors,2 ß-blockers also appear to have a greater impact on the lowering of sudden death risk, which accounts for one half to two thirds of total mortality in moderate heart failure.13 Finally, in clinical practice the first drug rather than the second drug started is more likely to be titrated to target doses used in the clinical trials. Therefore, the benefits of effective ß-blockade, which are dose related,14 may be attenuated. Being first no longer appears to be sufficient rationale to justify the optimal sequence to initiate these agents. After all, digoxin, once favored as a first-line agent (and certainly our oldest agent in heart failure), is now considered second-line therapy with a Class II recommendation in the 2005 American College of Cardiology/American Heart Association heart failure guidelines.
Two previous trials have suggested that a ß-blocker–first strategy is safe and potentially beneficial. In the multicenter Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation (CARMEN) trial,12 572 patients with mild heart failure and clinically stable for 2 weeks were randomly assigned in a blinded fashion to carvedilol 25 mg twice daily, enalapril 10 mg twice daily, or the combination (with titration first of carvedilol) for 18 months. Combination therapy led to a greater improvement in end systolic volume followed by carvedilol and enalapril monotherapy. Most importantly, safety, mortality, hospitalizations, and withdrawal rates were comparable in all 3 trial arms. In a smaller single-center nonblinded study,15 78 NYHA class II/III patients with newly diagnosed idiopathic dilated cardiomyopathy were randomized to 6 months of either carvedilol or perindopril first followed by titration of the second agent with functional class and ejection fraction as primary end points. The carvedilol-first group reached a greater total carvedilol dose (43±17 mg versus 33±18 mg, P=0.03), had greater improvement in symptoms, had a greater ejection fraction (15±16% versus 6±13%, P<0.05), and experienced greater lowering of plasma N-terminal pro-brain natriuretic protein (166±142 pg/mL versus 51±384 pg/mL, P<0.02).
It is against this background that the CIBIS III investigators16 are to be congratulated for undertaking a trial with a large sample size that addresses both the safety and efficacy of a ß-blocker–first strategy in heart failure. The investigators randomized 1010 patients with mild to moderate heart failure, and an ejection fraction <35%, to open-label monotherapy with either bisoprolol (target dose 10 mg/day) or enalapril (target dose 10 mg twice daily) for 6 months followed by uptitration of the second drug for 6 to 24 months. The study randomization was not blinded, but the end point and safety committees were blinded. The investigators chose a conservative strategy of a noninferiority trial using a primary end point that combined all-cause mortality and all-cause hospitalization. In the intention-to-treat sample, there were 178 patients (35.2%) with a primary end point in the bisoprolol-first group compared with 186 (36.8%) in the enalapril-first group. Although the prespecified criteria for noninferiority was met with the intention-to-treat analysis (absolute difference –1.6%, 95% CI –7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16), it did not quite meet the requirements of the per-protocol analysis (the most rigorous analysis to use in noninferiority trials), although it was close (absolute difference –0.7%, 95%CI –6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). There were 65 all-cause deaths and 151 all-cause hospitalizations in the bisoprolol-first group versus 73 deaths and 157 hospitalizations in the enalapril-first group; neither end point reached statistical significance.
Several issues are worthy of note. By design, the patients studied were 1 decade older than those studied in most heart failure trials (ie, 72 versus 62 years old). In part, this older age led the investigators to use a 6-month period of monotherapy because rapid additions of multiple therapies are often not tolerated in elderly patients. Although some practitioners may find withholding ACE inhibitors in symptomatic but ambulatory patients troublesome, participating institutional review boards did not find fault with this practice. More important, patients were excluded if they received RAS antagonists and/or ß-blockers for >7 days in the 3 months before randomization, so the findings are not confounded by pretreatment effects. Clinical stability for 7 days was also required before enrollment, which would exclude many patients either hospitalized or recently hospitalized for heart failure. Titration of bisoprolol was also cautious and slower than the protocol used in CIBIS II (respecting the older age of the study population and the lack of concomitant vasodilator therapy). This strategy was appropriate in that bisoprolol is a ß-1 selective agent without ancillary vasodilator properties that could limit its tolerability in the absence of a vasodilator during monotherapy titration.
Despite the use of this titration protocol, there was some cause for concern. The bisoprolol-first strategy was associated with a nonsignificant trend toward worsening of heart failure requiring hospitalization or occurring in the hospital (63 versus 51, HR 1.25, 95% CI 0.87 to 1.81, P=0.23) and may be a consequence of using a ß-1 selective agent without concomitant vasodilator properties. This issue may have also resulted in a greater number of serious adverse events reported during the monotherapy phases of the bisoprolol-first arm as compared with the enalapril-first arm (192 versus 163). Particular patients may be especially prone to this issue because the percentage of patients reporting these events were similar between the 2 groups (22.4% versus 22.1%), suggesting that more than one event occurred in the same patient. Despite this issue, there was little need in either group to introduce the second agent early during monotherapy for clinical reasons (bisoprolol-first 7.7% versus enalapril-first 7.3%, P=0.81). Furthermore, few patients in either arm discontinued either drug during the monotherapy or combined-drug phases. During the entire trial, 60 bisoprolol-first patients and 59 enalapril-first patients withdrew formally from the trial.
Patients with significant renal impairment (Cr >220 µmol/L or 2.5 mg/dL) were also excluded, which is a common problem in older adults with heart failure. Furthermore, follow-up renal function was not reported but would be of great interest considering the cardiorenal limitations in the treatment of elderly patients with heart failure. There did not appear to be a difference in outcome when renal function was stratified between a baseline creatinine clearance of <60 and >80 mL/min, but these ranges may not be the most appropriate because most patients >70 years old and with heart failure will have a creatinine clearance <50 mL/min.
As anticipated, the first drug titrated resulted in a greater proportion of patients taking the target dose of that drug during the combined therapy phase. For example, 64.8% of the bisoprolol-first group was taking 10 mg/day at the end of the study compared with 53.8% of the enalapril-first group, which may explain the survival difference seen; however, the lack of blinding and open label design may have had a significant impact on these final doses. In contrast, only 42.5% of patients in CIBIS II reached this goal dose when both active and placebo arms were blinded.17
The study has other limitations and these were acknowledged by the authors. It did not meet the strictest criteria for noninferiority because the per-protocol analysis boundaries were not met. (In a per-protocol analysis, only patients who strictly followed the protocol to the end of the study are included in the analysis.) As outlined by the investigators, however, the statistical power of such an analysis was reduced because the number of patients diminished rapidly with time and brings to light that there were a significant number of protocol violations and withdrawals (thus, the need for an intention-to-treat analysis in most prospective randomized clinical trials).
The study was not blinded, although the analyses of the end points were. The open study design was specifically chosen by the investigators to allow separate titration of the drugs during the follow-up combined-drug period because of a concern that side effects could not be adequately addressed if blinding were present. The lack of blinding could have lowered the threshold to hospitalize for heart failure but not for other reasons in the bisoprolol-first group (as was seen) and could have had an impact on the small difference in the numbers of deaths between groups. Although the authors address this problem, noting that blinding of the end points committee limits bias,18 such blinding does not eliminate bias.
Although there were trends toward fewer hospitalizations and fewer deaths in the bisoprolol-first group, the absolute differences were small and not conclusive (8 deaths, 6 hospitalizations). Small absolute differences have been seen before in clinical trials but not confirmed in subsequent adequately powered studies (ie, remember the supposed mortality benefit of losartan over captopril in ELITE I but not confirmed in ELITE II). Although the target doses used in the trial were the targets used in the clinical trials of these drugs, many practice environments do not have the capacity to get patients to such doses over the course of weeks. It is not clear what the results would have shown if the monotherapy duration were shorter than 6 months because many clinicians would be uncomfortable withholding ACE inhibitors for such a long period of time, despite the apparent safety of the practice in the trial. Most important, the patients studied were ambulatory, compensated, and only mild to moderately symptomatic and therefore least prone to serious hemodynamic collapse from the negative inotropic effects of ß-blockers in the absence of background vasodilator therapy with an ACE inhibitor.
What, then, should we take away from the CIBIS III trial? We can feel safe that in mild to moderately symptomatic elderly patients with heart failure who are ambulatory, clinically compensated, and appropriately supervised, the use of ß-blocker–first therapy is tolerated and appears to be as effective as an ACE inhibitor–first strategy. It would be an overstatement to conclude that starting with a ß-blocker is better; strictly speaking, CIBIS III did not meet criteria for noninferiority, much less superiority. Furthermore, vigilance for decompensated heart failure during ß-blocker monotherapy is essential if safety is to be maintained.
The key concepts, however, are compensated and supervised. ß-Blockers do not provide a hemodynamic rescue for the acutely decompensated patient with volume overload and/or low output; in fact, in such settings, ß-blockers should either be cut back or withheld. I would still prefer beginning with an ACE inhibitor in patients with moderately severe to advanced symptoms and/or a decompensated state (ie, hospitalized). It is premature to let go entirely of current practice standards because the data do not suggest that reversing the traditional order of things is especially advantageous to our patients, even if higher doses can be achieved. Although it is reasonable to extrapolate the CIBIS III findings to younger patients and to other proven ß-blockers (especially ones with vasodilator properties), it remains to be shown that routinely starting with ß-blockade is the preferred strategy in all patients. Rather, we should feel reassured that we can tailor our approach to our patients without harm. What are the principles of such a tailored approach? In patients in whom blood pressure is limiting, ACE inhibitors should be cut back to maximize ß-blocker doses, as has been done in all ß-blocker trials to date. In tachycardic patients who are clinically well perfused, euvolemic, and not hypotensive (ie, tachycardic cardiomyopathies, adriamycin cardiomyopathy19), ß-blockers can be initiated first and titrated to goal doses before the addition of an ACE inhibitor. It is imperative that such a practice be undertaken only if close and frequent follow-up can be ensured, as in the context of a disease management program. Despite the potential benefits of certain therapies in closely supervised clinical trials, indiscriminant and loosely supervised use of these therapies may result in significant harm, which was underestimated in the clinical trial. Such has been the case with spironolactone since the publication of the Randomized ALdactone Evaluation Study (RALES) study, in which an increase in clinically important hyperkalemia has been seen despite the modest rates of this life-threatening problem in the trial itself.20 These findings must also be put into the context of other proven agents in heart failure for which we do not yet know their optimal use (ie, angiotensin receptor blockers, aldosterone antagonists, diuretics).
It is important to understand that the greatest benefit for our patients is realized when both agents are used. The sobering facts are that <50% of patients with a diagnosis of heart failure are on ACE inhibitors in real life21; even in the highly supervised environment of a contemporary heart failure clinical trial, ß-blocker use ranges from 35% to 55%. It is therefore important not to lose sight of our primary challenge: to encourage physicians to use ß-blockers and RAS antagonists in patients with heart failure.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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