Editorial

Reza Tabrizchi, PhDAssociate Professor of PharmacologyDivision of Basic Medical Sciences, Faculty of MedicineMemorial University of Newfoundland, St. John’s, NL, A1B 3V6, Canadartabrizc@mun.ca

© Future Drugs Ltd. All rights reserved. ISSN 1476-0584 157

Should β-blockers form the cornerstone for the treatment of congestive heart failure?‘Recent data from a number of clinical studies seem to suggest that the addition of a β-blocker to standard therapy in patients with heart failure will further reduce mortality and death associated with cardiovascular complications’Expert Rev. Cardiovasc. Ther. 1(2), 157–160 (2003)

It is recognized that the use of angiotensinconverting enzyme (ACE) inhibitors as atreatment in patients with congestive heartfailure reduces the rate of hospitalization andmortality [1]. However, recent data from anumber of clinical studies seem to suggest thatthe addition of a β-blocker to standard ther-apy in patients with heart failure will furtherreduce mortality and death associated withcardiovascular complications.

In a population of patients with establishedheart failure, coronary artery disease seems toaccount for two-thirds of patients with left ven-tricular systolic dysfunction and the remainderappear to have nonischemic causes of systolicdysfunction with an identifiable cause, such ashypertension, valvular disease or myocarditis [2].Epidemiological studies indicate that themedian survival after the onset of heart failure is1.7 and 3.2 years in males and females, respec-tively [3]. Moreover, the overall 1-year and 5-yearsurvival rates were found to be 57 and 25%,respectively, in males and 64 and 38%, respec-tively, in females [3]. In addition, it is estimatedthat heart failure accounts for as many as500,000 new admissions to hospitals in the USA[2]. Thus, morbidity and mortality associatedwith congestive heart failure is of significant pro-portion in the population at large. Presently, theCanadian Cardiovascular Society guidelines forthe management of heart failure recommendsneuro/endocrine control with the use of ACEinhibitors, β-blockers and diuretic therapy asrequired [4]. However, in many quarters, it seems

that the use of β-blockers is not considered to beone of the primary choices in pharmacotherapyof patients with heart failure and certainly thecurrent published evidence in the medicalliterature indicates that it should be.

Based on published medical literature the firstindication that the use of β-blockers may resultin improved hemodynamics in patients withheart failure secondary to idiopathic dilated car-diomyopathy came in the late 1970s [5,6]. Thefirst organized placebo-controlled, double-blindclinical trial with the prime objective of investi-gating the beneficial effects of β-blockers inpatients with heart failure with dilated cardio-myopathy was conducted in the early 1990s [7].The evidence from the latter clinical trial other-wise labeled as the Metoprolol in Dilated Cardi-omyopathy trial indicated that a starting dose of10 mg daily and titrated up to 100–150 mgdaily of metoprolol versus placebo could reducethe primary end point as defined by death or theneed for cardiac transplantation by 34%(p = 0.058). This relatively positive and provoca-tive discovery planted the seeds which resulted inseveral well-organized clinical trials to assess thebeneficial effects of β-blockers in patients withdeficiency in left ventricular ejection [8–11].Thus, the additional studies with β-blockers cor-roborated and extended the observations of theearlier studies with metoprolol. Among these tri-als was the landmark clinical trial with metopro-lol (Metoprolol Randomized Intervention Trialin Congestive Heart Failure; MERIT-HF) thatalso had the power to prove survival benefit [11].

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Tabrizchi

158 Expert Rev. Cardiovasc. Ther 1(2), (2003)

The MERIT-HF trial was stopped prematurely as it becameapparent that metoprolol controlled release (CR)/extendedrelease (XL) was beneficial in patients with congestive heartfailure prior to the completion date for the trial (the studybeing started in April of 1998 and stopped in October of 1998)[11]. The patient cohort for MERIT-HF were those withchronic heart failure and based on the New York Heart Associa-tion (NYHA) functional class II–IV with ejection fraction of40% or less, stabilized with optimum standard therapy. Thestudy was carried out in multiple centres in a double-blind andrandomized fashion and with the sample size of 3991. Evidenceobtained from the MERIT-HF investigation revealed that all-cause mortality was reduced in the metoprolol CR/XL groupversus placebo. The mortality rates were 7.2 and 11% perpatient-year of follow-up for metoprolol and placebo, respec-tively, with a reported relative risk (RR) of 0.66 (95% CI:0.53–0.81; p = 0.00009), the actual number of deaths being145 and 217 in metoprolol and placebo groups, respectively.Mortality due to cardiovascular events in the metoprolol versusplacebo groups was 128 versus 203 patients, respectively(RR = 0.62; 95% CI: 0.5–0.78; p = 0.0002). Death due toworsening heart failure was 30 and 58in metoprolol and placebo groups,respectively (RR = 0.51; 95% CI:0.33–0.79; p = 0.0023). Thus, it wasclear that metoprolol CR/XL once dailyin addition to optimum standard ther-apy improved survival and it was alsowell-tolerated [11]. Interestingly, sinceits premature termination, theMERIT-HF trial has yielded some veryuseful information through post hocanalysis of sub-groups and follow-upstudies. Further valuable information has been gathered andpublished in the medical literature in relation to effectiveness,dose, gender, functional state and time-course from theMERIT-HF investigation.

Effect of metoprolol on frequency of hospitalization, symptoms & quality of life in patients with heart failureA cohort of patients from the MERIT-HF trial were followedfor up to 1 year [12]. In comparison to placebo, metoprololCR/XL reduced the total number of hospitalizations. Theactual number of days in hospital for all-causes, cardiovascularcauses and worsening heart failure was reduced by 17%(p = 0.004), 22% (p < 0.001) and 36% (p < 0.001), respec-tively. In addition, physician and patient assessment of treat-ment effect indicated that improvement occurred in 28.6 ver-sus 25.8% in the metoprolol CR/XL and placebo group.Furthermore, overall treatment evaluation scores indicated sig-nificant improvement in the metoprolol CR/XL-treated groupcompared with placebo (p = 0.009). More importantly, treat-ment with the β1-blocker significantly reduced combined endpoint (total mortality or all-cause hospitalization time) whencompared with placebo treatment [12].

In the metoprolol CR/XL group, total mortality for all-causehospitalization (RR = 19%; 95% CI: 10–27%; p < 0.001), totalmortality or hospitalization for worsening heart failure(RR = 31%; 95% CI: 20–40%; p < 0.001), death or heart trans-plantation (RR = 32%; 95% CI: 16–45%; p < 0.001), cardiacdeath or nonfatal acute myocardial infarction (RR = 39%;95% CI: 25%-51; p < 0.001) were reduced. Total mortality, orhospitalization or emergency department visits due to worseningheart failure was reduced (-32%; 95% CI: 21–41%; p < 0.001)compared with placebo [13]. Here, the sub-group analysis fromthe MERIT-HF trial clearly demonstrated that metoprololCR/XL in addition to conventional therapy in patients withheart failure resulted in improved survival and reduced the needfor hospitalization due to worsening heart failure.

Response titration & dose-response effectsIt must be recognized that MERIT-HF was not designed as adose-response study for the actions of metoprolol CR/XL inpatients with heart failure. However, two subpopulations ofpatients could be identified that were administered a low dose(mean dose of 76 mg; n = 604) and a high dose (mean dose of

192 mg; n = 1202) of metoprolol in thistrial. The post hoc analysis of the effects oftwo doses of metoprolol on heart rate in acohort of patients in MERIT-HF investi-gation has resulted in some notable andspellbinding observations [13].

Following 3 months of therapy themean reduction in heart rate in low andhigh doses of metoprolol CR/XL was13.7 (-16.9%) beats/minute and 15.9(-19.1%) beats/minute, respectively,while heart rate was reduced in the pla-

cebo group by 2.8 (-3.3%) beats/minute. The median plasmaconcentrations after 3 months for metoprolol were 95 mM and247 mM, for low and high doses, respectively. Of interest wasthe fact that the mean reduction in heart rate per mg of meto-prolol was significantly greater (p < 0.0001) for the low dose(0.21 beats/minute per mg) than the high dose (0.08beats/minute per mg) after 3 months of therapy. It is recognizedthat the latter difference is not due to differences in body size orbody mass index of the patients, as these were found to be com-parable in the low dose and high dose group of patients. More-over, the difference cannot be readily explained on the basis ofplasma concentrations of metoprolol in the two groups. There-fore, the basis for this difference was not due to disparity inpharmacokinetics of the drug in the two cohorts [13].

Therefore, possibly, differences in pharmacodynamics mayexplain the differential effects of the low and high dose of meto-prolol on heart rate. Indeed, it is apparent that the low-dosegroup includes a high proportion of the high-risk patients and itis in this group that the heart rate was reduced more per mg ofmetoprolol. Therefore, it is possible that the increased sensitivityto the β1-adrenoceptor blockade in the low-dose group was aresult of the downregulation of desensitized receptors in the

‘It must be recognized that in patients with heart failure,

treatment with metoprolol does not immediately translate into

an improvement in systolic performance… however, long-

term therapy with metoprolol will result in an increased left

ventricular ejection fraction’

β-blockers for the treatment of congestive heart failure

www.future-drugs.com 159

myocardium, which possibly had occurred due to advancedheart failure and as a consequence of intense activation of thesympathetic nervous system. Alternatively, it is possible that thehigher dose provided a greater protection to β1-adrenoceptors inthe myocardium, resulting in a faster rate of recovery of down-regulated and desensitized receptors and this ultimately mani-fested itself as a lower reduction in heart rate per mg of metopro-lol (in the higher dose group). Admittedly, significant reductionin mortality with metoprolol CR/XL compared with placebowas similar, 38% (95% CI: 16–55%; p = 0.0022) in high doseand also 38% (95% CI: 11–57%; p = 0.010) in low dose [13].

Effect of metoprolol on survival in womenThere has been some uncertainty about the beneficial effects ofβ-blockers in female patients with heart failure. The most con-founding problem has been an under-representation of femaleswith heart failure in clinical trials involving β-blockers. Simply,this has limited meaningful conclusions as to the effectiveness ofthis class of agents on survival in women with heart failure. TheMERIT-HF clinical trial has pro-vided the largest database of womenwith heart failure to be treated with aβ-blocker. Thus, the subgroup analy-sis of the data from this clinical trialhas revealed some useful informationin this population of patients [14].

Post hoc subgroup analysis indi-cated that female patients (n = 898)were older than men and thatfemales enrolled in the trial weremore often in NYHA functional class III and IV, with the ejec-tion fraction of 25% or less. Results from this analysis haverevealed a reduction in all-cause hospitalization by 19% (209versus 252 patients; p = 0.044), cardiovascular hospitalization by29% (120 versus 164 patients; p = 0.013) and hospitalizationfor worsening heart failure by 42% (56 versus 95 patients;p = 0.021) in metoprolol CR/XL in comparison with placebo,respectively. The number of deaths (patient-years of follow-up)were 31 (6.9%) and 33 (7.5%) (p = not significant [NS]) inmetoprolol and placebo groups, respectively. Furthermore, theincidence of sudden death, cardiovascular death or death due toworsening heart failure was not significantly different in the twogroups. Nonetheless, treatment of female patients with metopro-lol CR/XL in comparison with placebo significantly reduced thecombined end point of all-cause mortality and all-cause hospital-ization by 21% (137 versus 164 patients; p = 0.044) withdivergence occurring 3 months into the treatment [14].

Within the cohort of female patients with severe heart failure(n = 183), metoprolol CR/XL decreased all-cause hospitaliza-tion by 44% (56 versus 89 patients; p = 0.016); cardiovascularhospitalization by 57% (30 versus 63 patients; p = 0.005) andhospitalization due to worsening heart failure by 72% (14 ver-sus 46 patients; p = 0.0004). The number of deaths in this sub-group was 9 and 12 in metoprolol and placebo groups(p = NS), respectively [14].

Comparatively, risk reduction by metoprolol of the total mor-tality or all-cause hospitalization was 21% (p = 0.044) and 18%(p = 0.0011) in women and men, respectively. However, the rela-tive risk in placebo-treated women was significantly lower than inplacebo-treated men (RR = 0.63; 95% CI: 0.43–0.91; p = 0.015)[14]. Nevertheless, the outcome from this subgroup analysis didindicate that metoprolol as an addition to conventional therapywas of benefit in women with heart failure [14].

Functional classFor some time, the usefulness of β-blockers in patients withsevere heart failure has been the subject of some discussion andmuch debate. The obvious dilemma being whether blockade ofβ-adrenoceptors in such a population of patients will be benefi-cial or detrimental to their well-being.

A subgroup analysis of data from the MERIT-HF trial of acohort of patients with NYHA functional class III/IV heart fail-ure (ejection fraction ≤ 25%; n = 795) indicated there were 72(19.1%) deaths in the placebo group in comparison with 45

(11.7%) deaths in the metoprolol group[15]. Treatment with metoprolol CR/XLreduced total mortality by 39%(95% CI: 11–58%; p = 0.0086), deathsdue to worsening heart failure by 55%(95% CI: 13–77%; p = 0.015) and sud-den death by 45% (95% CI: 7–67%;p = 0.024). Treatment with metoprololalso resulted in risk reduction (time-to-first-event) of combined end points(time-to-first-event) by 29% (95% CI:

13–43%; p = 0.0012), all-cause mortality or hospitalizationdue to worsening heart failure by 44% (95% CI: 27–57%;p < 0.0001) and cardiac death or nonfatal acute myocardialinfarction by 46% (95% CI: 21–63%; p = 0.0014) [15].

Indeed, subgroup analysis of data for the female cohorts ofpatients with severe heart failure also indicated that metoprololCR/XL compared with placebo reduced the combined endpoint of all-cause mortality and hospitalization by 44%(95% CI: 12–65%; p = 0.01) and all-cause mortality and/orhospitalization due to worsening heart failure by 63%(95% CI: 33–80%; p = 0.0008) [14].

Time-courseThe data from the MERIT-HF trial was used to determinewhich patients are at risk for deterioration following the initia-tion of treatment with the β1-blocker. To this end, an assess-ment of the effectiveness of the protocol was conducted over90 days in patients with NYHA functional classification II andIII/IV heart failure. This analysis revealed that the curve diver-gence in favor of metoprolol treatment occurred after 60 dayswith the only limiting factor against the titration to a higherdose being low heart rate. At day 90, the RR for all-cause mor-tality/hospitalization for all the patients was 0.81 (95% CI:0.73–0.9). Further breakdown of data and analysis indicatedthat RR at 90 days for all-cause mortality/hospitalization for

‘The information generated from the MERIT-HF trial on the basis of

sub-group and post hoc analyses provides compelling evidence in

support of the inclusion of a β1-blocker as part of any

therapeutic strategy for treating patients with heart failure.’

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160 Expert Rev. Cardiovasc. Ther 1(2), (2003)

NYHA functional class II versus III/IV was 0.78 (95% CI:0.65–0.94) and 0.83 (95% CI: 0.73–0.94), respectively. Theoverall indication was that metoprolol CR/XL could beemployed safely to treat the majority of patients with stablemild-to-moderate heart failure with minimal side effects onworsening heart failure [16].

It must be recognized that in patients with heart failure,treatment with metoprolol does not immediately translate intoan improvement in systolic perform-ance and within 1 month of therapy,there may indeed be a mild reduction infunction [17]. However, long-term ther-apy with metoprolol will result in anincreased left ventricular ejection frac-tion by as much as 39% (p = 0.013) ver-sus standard therapy within 3 months.More importantly, within 18 months of therapy, metoprololwill continue to improve ejection fraction (+83% versus base-line; p = 0.0004) and reverse remodeling, reducing leftventricular volume leading to regression of left ventricular massas well as improving geometry [17].

Overall, there is still some resistance to incorporating the useof β1-blockers into clinical care. There is perhaps even more

concern about their benefits in patients with severe heart failure.Notwithstanding these facts, the information generated fromthe MERIT-HF trial on the basis of subgroup and post hoc anal-yses provides compelling evidence in support of the inclusion ofa β1-blocker as part of any therapeutic strategy for treatingpatients with heart failure. Needless to say that it can easily beargued that such a therapeutic approach is beneficial on anumber of grounds which include:

• Making the patient live longer

• Reducing hospitalization due to worseningheart failure

• Reducing all-cause hospitalization

Arguably, an extension of the latter benefit iscost-saving in terms of patient care.

In final analysis, it seems prudent to treat patients afflictedwith congestive heart failure with a β-blocker in concomitancewith conventional therapy, the caveat being tolerance to thisform of pharmacotherapy and an absence of pathology that con-tradicts the use of a β-blocker. This may mean that the start-updose may have to be quite small and the subsequent titration toa higher dose should proceed on a case-by-case basis.

References

1 The SOLVD investigation. Effect of enalapril on survival in patients with reduced left ventricular ejections fraction and congestive heart failure. N. Engl. J. Med. 325, 293–302 (1991).

2 Hunt SA, Baker DW, Marshall HC et al. ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. Circulation 104, 2996–3007 (2001).

3 Ho KK, Anderson KM, Kannel WB et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 88, 107–115 (1993).

4 Liu P, Arnold JM, Belenkie I et al. The 2002/3 Canadian Cardiovascular Society: consensus guideline update for the diagnosis and management of heart failure. Can. J. Cardiol. 19, 347–356 (2003).

5 Waagstein F, Hjalmarson Å, Varnauskas E et al. Effect of chronic β-adrenergic receptor blockade in congestive cardiomyopathy. Br. Heart J. 37, 1022–1036 (1975).

6 Swedberg K, Hjalmarson Å, Waagstein F et al. Prolongation of survival in congestive cardiomyopathy by β-receptor blockade. Lancet 1, 1374–1376 (1979).

7 Waagstein F, Bristow MR, Swedberg K et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 342, 1441–1446 (1993).

8 Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med. 334, 1340–1355 (1996).

9 Packer M, Coats AJS, Fowler MB et al. Effect of carvedilol on survival in severe chronic heart failure. N. Engl. J. Med. 344, 1651–1658 (2001).

10 CIBIS-II Investigation and Committee. The Cardiac Insufficiency Bisoprolol Study II (CIBSI II). Lancet 353, 9–13 (1999).

11 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 353, 2001–2007 (1999).

12 Hjalmarson Å, Goldstein S, Fagerberg B et al. Effects of controlled-release metoprolol on total mortality, hospitalizations and well-being in patients with heart failure. JAMA 283, 1295–1302 (2000).

13 Wikstrand J, Hjalmarson Å, Waagstein F et al. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J. Am. Coll. Cardiol. 40, 491–498 (2002).

14 Ghali JK, Piña IL, Gottlieb SS et al. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in metoprolol extended-release randomized intervention trial in heart failure (MERIT-HF). Circulation 105, 1585-1591 (2002).

15 Goldstein S, Fagerberg B, Hjalmarson Å et al. Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study. J. Am. Coll. Cardiol. 38, 932–938 (2001).

16 Gottlib SS, Fisher ML, Kjekshus J et al. Tolerability of β-blocker initiation and titration in the metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Circulation 105, 1182–1188 (2002).

17 Hall SA, Cigarroa CG, Marcoux L et al. Time course of improvement in left ventricular function, mass geometry in patients with congestive heart failure treated with β-adrenergic blockade. J. Am. Coll. Cardiol. 25, 1154–1161 (1995).

‘It seems prudent to treat patients afflicted with

congestive heart failure with a β-blocker in

concomitance with conventional therapy.’