In the treatment of congestive heart failure with left ventricular (LV) dysfunction, beta-blocking agents are traditionally administered after optimal therapy with angiotensin-converting enzyme (ACE) inhibitors has been achieved. This is done because clinical trials demonstrating the therapeutic benefits of beta blockers were conducted in patients receiving ACE inhibitors as background therapy.1-3 In congestive heart failure, however, sympathetic activation precedes that of the renin-angiotensin system.4 With the introduction and proven benefits of beta blockers in heart failure, do ACE inhibitors still deserve their role as a primary component of standard background therapy? Will more substantial benefits be realized when maximal doses of beta blockers are achieved before initiating ACE inhibitor therapy? The present study evaluated the order of initiation of beta-blocker therapy relative to ACE inhibitor therapy on LV function, New York Heart Association (NYHA) functional class, and biochemical indexes of heart failure (plasma
NT-pro-brain natriuretic peptide [NT-pro-BNP] concentrations) in patients with heart failure.
Patients and methods
This was a randomized, prospective, single-center, open-label study in 78 consecutive patients with newly diagnosed idiopathic dilated cardiomyopathy in NYHA functional class II to III heart failure. Patients were randomly assigned to receive either the ACE inhibitor perindopril (Aceon, ACE inhibitor-first group,
n = 40) or the beta blocker (BB) carvedilol (Coreg, BB-first group, n = 38) in addition to diuretics and digoxin for 6 months. After 6 months, carvedilol was added to the regimen in those receiving the ACE inhibitor and perindopril was added to the therapeutic regimen in those receiving carvedilol. We titrated both study drugs to maximum tolerable doses (systolic blood pressure was maintained at 85 mm Hg or greater, no dizziness was reported, and orthostatic hypotension did not occur). Data are presented as mean ± standard deviation. Significance was assumed at a two-tailed probability value of less than .05.
There were no differences in hemodynamic or cardiac function, and biochemical or demographic characteristics between patients enrolled, completing 6 months of the study, and completing 12 months of the study (data not shown). There were no differences between the groups in age (ACE inhibitor-first group = 51 ± 11 years, BB-first group = 48 ± 10 years) or percentage of men (ACE inhibitor-first group = 47%, BB-first group = 44%). During the 12-month study period, 11 patients died (six in the ACE inhibitor-first group); 10 patients were not available for follow-up (5 in the ACE inhibitor-first group).
There was an improvement in NYHA functional class at 6 and 12 months in both study groups (Table 1). The majority of the improvement occurred in the first 6 months, with minimal additional changes noted between 6 and 12 months in both groups. Improvement in functional class was consistently greater in the BB-first group, however (Table 1).
A significant reduction in heart rate was noted at both 6 and 12 months in the BB-first group (Table 1). In the ACE inhibitor-first group, however, a reduction in heart rate was only noted at 12 months.
Left ventricular ejection fraction (LVEF) increased in the BB-first group after both 6 and 12 months (Figure). No significant changes were noted in the first 6 months of therapy in the ACE inhibitor-first group (Figure), but there was an increase in LVEF after 12 months.
Concentrations of plasma NT-pro-BNP were markedly raised compared with normal values for healthy, age-matched volunteers from the same population in both groups (BB-first group: 219 ± 141 pg/mL; ACE inhibitor-first group: 222 ± 254 pg/mL; normal volunteers: 12 pg/mL, P < .001). The reduction in plasma NT-pro-BNP concentrations was greater, and final plasma NT-pro-BNP concentrations at 12 months were lower in the BB-first group versus the ACE inhibitor-first group (166 ± 142 pg/mL versus 51 ± 384 pg/mL, P = .01).
In the BB-first group the mean dose of furosemide was lower (Table 2). Compared with those in the ACE inhibitor-first group, patients in the BB-first group were able to tolerate a higher dose of carvedilol at 12 months (Table 2). There were no differences between groups in the dose of perindopril achieved (Table 2).
We have shown in this study that left ventricular function and symptoms, as well as laboratory responses, were substantially better if beta blockade preceded, rather than followed therapy with an ACE inhibitor in the initial sequence of treatment of patients with newly diagnosed conges-tive cardiac failure. Patients who were given carvedilol first were able to tolerate a higher dose of carvedilol and needed lower doses of diuretic agents at 1 year after initiating therapy. Starting with beta blockade first produced more favorable responses, including better functional class, higher achievable dose of beta blocker, lower dose of furosemide, and more marked changes in LV systolic (left ventricular ejection fraction) and diastolic function and a biochemical index of raised filling pressures (plasma NT-pro-BNP concentrations).
There are a number of possible theoretical and scientific reasons that could explain our findings. Patients who were prescribed carvedilol as initial therapy were able to tolerate a higher dose of carvedilol after 1 year of therapy. This higher dose of the beta-adrenoreceptor blocker achieved in the group receiving carvedilol first could partly explain the differences in hemodynamic and symptomatic improvement between the two groups. This is consistent with data that demonstrate a better outcome following the use of higher doses of both ACE inhibitors and beta-adrenoreceptor blockers in heart failure.5,6
Beta-adrenoreceptor blocker therapy could simply be more effective than ACE inhibitor therapy in newly diagnosed heart failure. Sympathetic activation precedes the activation of the renin-angiotensin-aldosterone system in heart failure, as demonstrated by measurements of plasma neurohormonal levels in the Studies of Left Ventricular Dysfunction trial.4 Therefore, prevention of the deleterious effects of beta-adrenergic stimulation should be achieved as early as possible LV if dysfunction is present. This hypothesis is supported by the marked differences in changes in measures of LV systolic function and functional class between the two groups that were noted after 6 months of therapy.
Reverse remodeling is regarded as one of the important determinants of long-term outcome in the treatment of heart failure. Although ACE inhibitors slow the remodeling process, no reverse remodeling has been observed with this class of agents.7 However, studies with carvedilol administered to patients with heart failure reversed LV remodeling.8 In our study, LV diastolic chamber dimensions were reduced in the group of patients in whom carvedilol was initiated first, whereas in those patients receiving the ACE inhibitor as initial therapy, only a trend for a reduction was noted.
The present study had several limitations that include the lack of mortality data, an outcome that cannot be adequately assessed in a single-center study. It was an open-label rather than a double-blind study. However, in the present study, assessments of hemodynamic function were conducted by investigators and laboratory technicians unaware of medication received by patients.
In conclusion, this study provides the first proof that initiating therapy with carvedilol before an ACE inhibitor results in higher tolerable doses of carvedilol and better improvement in functional class and LV function, opposed to the conventional sequence of drug use in the treatment of heart failure. These results are encouraging and suggest an alternative therapeutic approach in patients with newly diagnosed heart failure.