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β-BLOCKER THERAPY IN HEART FAILURE
DRUG THERAPY IN CARDIOVASCULAR DISEASE
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P-BLOCKER THERAPY IN HEART FAILURE Peter Carson, MD
Congestive heart failure remains a complex pathophysiologic syndrome associated with significant morbidity and mortality. Although advances in therapy, particularly with vasodilators, have improved prognosis, progression of heart failure occurs in most patients, and the role of neurohormonal stimulation has taken on increasing importance. The reninangiotensin system is activated in heart failure and has been the target of the angiotensin-converting enzyme inhibitors, the most proven drugs in heart fai1~re.l~. 44 Increasingly the crucial role of the sympathetic nervous system has been recognized: Catecholamines are markers for advanced heart failure but also exert toxic effects.37More recently, there has been increasing attention to the pathologic remodelingz3in heart failure that contributes to the progression of the syndrome. pBlocker drugs are neurohormonal antagonists and also appear to remodel the failing ventri~ l eEarly . ~ ~reports suggested clinical efficacy7 and subsequent data have shown evidence that the progression of heart failure might be prevented or even reversed.8 The effect of P-blockade on these processes has added to growing interest in these agents for the therapy of heart failure. Portions of this article appeared in The Cardiology Clinics: Annual of Drug Therapy, Vol. 3, 1999.
HEART FAILURE AND MYOCARDIAL CONTRACTION
Conceptually, heart failure is usually initiated by factors that impair the heart's ability to respond to circulatory need. This may involve peripheral effects such as increased afterload as in hypertension, but for most patients the initiating event impairs myocardial systolic function either by ischemic events or by a usually undefined process (idiopathic). When heart failure ensues with inadequate circulatory function, the body initiates a series of compensatory responses, such as neurohormonal activation4as well as myocardial and vascular hypertrophy. These mechanisms may be initially beneficial in aiding the failing myocardium but soon become pathologic responses. The renin-angiotensin system activation causes increased afterload, causes salt and water retention, and modulates cellular growth. The sympathetic nervous system increases afterload and heart rate and may also impair myocardial response through receptor down-reg~lation.~ In response to these ongoing stimuli, myocardial hypertrophy occurs and may lead to pathologic remodeling with a dilated ventricle, which functions on a lower pressure volume curve. It is not surprising then that therapeutic
From the Department of Veterans Affairs Medical Center, Georgetown University Hospital, Washington, District of Columbia
CARDIOLOGY CLINICS VOLUME 19 * NUMBER 2 * MAY 2001
267
268
CARSON
efforts have attempted to improve myocardial contraction. Unfortunately, direct attempts, such as with inotropic agents, have been uniformly neutral or unfavorable. Other ways of effecting contraction may be more beneficial. It is worth remembering that the contraction of the heart is governed by three mechanisms: (1)intrinsic contractile function, as indicated by the Frank-Starling relationship, in which increased myocardial stretch results in increased force of contraction; (2) heart rate, the Bowditch-Treppe reflex, in which increased heart rate results in increased contractile force; and (3) sympathetic nervous system, which modulates the myocardial response for increased circulatory functional requirements. In heart failure, the remodeled dilated heart functions on a lower pressure volume curve, which worsens as heart failure progresses. Remodeling occurs when the ventricle dilates and becomes less spherical with a resulting further fall in ejection fraction. Part of this remodeling process may involve angiotensin 11. Although the relationship is not entirely clear, angiotensin I1 appears to be atrophic substance with properties promoting myocardial and vascular hypertrophy.22The success of converting enzyme inhibitors is increasingly believed to be related to the antiremodeling effects such as noted in Studies of Left Ventricular Dysfunction (SOLVD), in which changes in left ventricular size and mass were attenuated by e n a l a ~ r i l P-blockers .~~ may be even more effective in influencing remodeling. Hall et alZ4found that metoprolol therapy was associated with regression of left ventricular mass and a more favorable myocardial shape. Therefore the path to improving the Frank-Starling relationship in heart failure may be through reversing remodeling rather than through direct stimulation. The second important mechanism for contraction involves heart rate. The BowditchTreppe phenomenon indicates that in the normal heart the force of contraction increases with heart rate. In heart failure, however, increasing heart rate results in a diminished force of contraction. Slowing of heart rate appears to increase the force of contraction as in the work of Hasenfuss et al.25This phenomenon is called rate-dependent inotropism and suggests that agents that slow heart rate may
be beneficial by this property alone in improving contractile force. The third mechanism, the sympathetic nervous system, is the most complex. The sympathetic nervous system is stimulated in heart failure, and one of its clinical indicators, plasma norepinephrine, has been associated with increased mortality. Plasma norepinephrine has usually been elevated in more advanced heart failure and therefore may be a marker for more significant disease; however, norepinephrine can also induce myocyte necrosis e~perimentally~l and may therefore contribute to progression of heart failure. Despite the peripheral catecholamine overload, cardiac norepinephrine stores are decreased, perhaps because of defective reuptake mechanisms. Myocardial contractility is mediated through beta-adrenergic receptors ( P1, P2), which are linked by stimulating (Gs) proteins to the effector enzymes.39The adrenergic and angiotensin I1 receptors are also present and interact through G proteins to effect regulaFurther cardiac-beta tory enzymes (Fig. l).50 receptors are decreased overall, but particularly this is a P1 receptor decrease, and the ratio of p receptors is altered. In normal subtype hearts, the ratio is approximately P1:pz 80:20, whereas in failing hearts it is 60:40. This p1 receptor decrease appears to be a downregulation with decreased RNA synthesis, although an increase in receptor degradation may also be operative.50Additionally an uncoupling of the beta receptor from pharmacologic response may occur in ischemic cardiomyopathy. The physiology of adrenergic blockade is complicated and not always consistent, however. Decreases in peripheral norepinephrine have been noted in uncontrolled studies2with metoprolol and in a controlled study with bucindolol. Interestingly, data with carvedilol showed no change in peripherally measured norepinephrine, whereas coronary sinus norepinephrine decreased ~ignificantly.~~ The relationship of P-blockade to cardiac receptors also has not proven to be straightforward. Data with metoprolol have consistently demonstrated increases in P receptor density posttreatment that correlated with increased ejection fraction.18 These changes in receptor density, however, occurred well be-
P-BLOCKER THERAPY IN HEART FAILURE
269
AMP PLMBN
Figure 1. Receptor-G AC pathway.
fore the rise in ejection fraction.43Further data with the newer agents, bucindolol and carvedilol, have not shown an effect on PI receptor density, whereas ejection fraction has increased in similar degree to metoprol01.~~ The pathophysiologic consequences of pblockade remain to be clearly elucidated. The improvement in ejection fraction, the most consistent P-blocker finding in heart failure, is difficult to explain entirely in relation to the above-mentioned mechanisms. An effect on remodeling and subsequent improvement in the Frank-Starling mechanism is least proven and perhaps also has the least contradictory data. Ejection fraction improves gradually, which is consistent with a structural effect. An effect on contractility mediated by heart rate is possible but is not consistent with the temporal relationship-heart rate decreases early in therapy, whereas ejection fraction rises later. The relationship to the sympathic nervous system is complex-the receptor data vary with different P-blockers, but even when P receptors are increased in number, it is an earlier finding than ejection fraction change. Finally the sympathetic nervous system blockade might be expected to prevent further damage but perhaps not improve function. In addition to effects on remodeling and contractility, P-blockers do have potential antifibrillatory and anti-ischemic effects, which may influence mortality. Protection from sudden death may relate to these effects
but may also relate to the degree of adrenergic blockade not only in terms of dose, but also degree of receptor selectivity.
PHARMACOLOGIC DIFFERENCES IN P-BLOCKERS
The most relevant difference among Pblockers relates to the specificity of receptor blockade. The cardioselectivity of selected P-blockers is shown in Table l.50 Bisoprolol and metoprolol are highly cardioselective, whereas carvedilol and bucindolol are nonselective. Additionally the latter agents have modest vasodilating properties. It is postulated that greater adrenergic blockade provides greater survival benefit, but this remains unproven. Carvedilol also has important antioxidant properties,5l which have been apparent in animal models of myocardial infarction; however, the significance of this property in heart failure has not been established.
CLINICAL STUDIES Background
The first report of P-blocker use in heart failure came from Waagstein et a14'j in 1975, in which seven patients showed clinical and echocardiographic improvement. Subsequent
4.6 f 3.5
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9.7 f 1.7
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2.7 f 1-1
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3.8 f 1.91
-
-
2.2 f 0.6
64 f 32
4-4 f 1-5
70 f 38
48 f 22
-
2.0
1398 +. 236
-
-
-
2.0 f 1.3
1.2 f 0.3
Pi
3333
-
-
-
-
1.0 f 0.7
2.3 f 1.4
P2
Recombinant Systems
4412 f 1816
4.4 f 1.5
7135 +. 3383
3777 f 1709
5.2 f 2-0
*
* 5.2 f 2.0
P2
Pi
ICYP Competition Curves, Failing Heart
From Yoshikawa T, Port JD, Asano K, et al: Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 17(suppl B): 8-16, 1996; with permission.
*Competition curve data unreliable with
-
-
-
-
-
-
12.6
-
-
-
4.3 f 1.0
36 f 24
P2
-
6.2 f 2-2
49 f 16
4.5 f 1.2
Pi
Carvedilol (n = 5-8) Bucindolol (n = 2-10) Metoprolol (n = 5) Bisoprolol (n = 3) Propranolol (n = 1 4 ) Xamoterol (n = 5) CGP 207124
P2
PI
Cardiac Function Assays
Compound
ICYP Competition Curves, Nonfailing Heart vs Lymph
Table 1. SELECTIVITY FOR HUMAN p1 VERSUS p2 RECEPTORS (K, OR KB,nM f SEM), IN PRESENCE OF Gpp (NH) P
2.1
64
4.1
69
50
3.6
4.0
Pi
2366
4412
8.5
7135
3825
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29-1
P2
Average Values
1126
69
2.1
102
79
1.4
7.3
P1:P2
Selectivity
271
R-BLOCKER THERAPY IN HEART FAILURE
studies from the same group, although open label, also indicated clinical benefit. Clinical evaluation of p-blockers has moved slowly, however, particularly in the United States. In 1985, however, Engelmeier et all8 published data in a double-blind, placebo-controlled trial with metoprolol showing improvement in exercise capacity, functional classification, and ejection fraction. Subsequently, other clinical trials have shown similar results using a variety of P-blockers (Table 2). Hemodynamics
These clinical results indicate that ejection fraction improves reproducibly if sequential measurements are obtained after at least 2 months of therapy. The studies of Ikram and Fitzpatrickz6and Currie et all5are noteworthy for a 1-month follow-up with no change in ejection fraction. The time course of change in ejection fraction was well studied by Hall et alZ4who noted an initial deterioration at 1 week in metoprolol-treated patients followed by a return to baseline value by 1 month. There was a 10 ejection fraction point rise by
3 months. Heart failure cause, however, may have an impact on this response. Woodley et a148demonstrated that nonischemic heart failure patients treated with bucindolol showed greater ejection fraction improvement than ischemic patients. More recent work by Brisbev et a18 indicates that a dose range exists with bucindolol and that ischemic patients improve comparably to nonischemic patients at higher but not lower dosages. Improvement in ejection fraction has occurred with both cardioselective (P1) and nonselective (P1 and p2) agents. Multiple studies with metoprololl, 18, 24 have shown ejection fraction improvement. The study by Engelmeier et all8 is an example: Ejection fraction on active drug improved from 0.13 2 to 0.21 k 10.10 at 1 year ( P = .02), whereas no change was seen in the placebo group. Little investigation has occurred with nonselective agents such as propranolol because the early depression of ejection fraction described by Hall et aP4makes nonselective p-blockers difficult for the continuation of therapy. Cardioselective agents leave pz receptors unblocked, potentially allowing a minor vasodilatory action, which improves tolerability. Newer non-
Table 2. PUBLISHED TRIALS OF BETA-BLOCKERS IN HEART FAILURE Effect No. of Patients
Author
Agent
Currie (1984)15 Ikram (1984)26 Anderson (1985)' Engelmeier (1985)18 Sano (1989)41 Gilbert (1990)20 Leung (1990)29 Pollack (1990)m Woodley (1991)@
Metoprolol Acebutolol Metoprolol Metoprolol Metoprolol Bucindolol Labetalol Bucindolol Bucindolol
10 28 50 25 30 24
MDC (1992)" Paolisso (1992)38 Krum (1993)27 Olsen (1993)33 Wisenbaugh (1993)47 Bristow (1994)8 CIBIS (1994)'O Eichhom (1994)17 Fisher (1994)19 Metra (1994)33 ANZ (1995)3 Hall (1995)24 US Carv (1996)35
Metoprolol Metoprolol Carvedilol Carvedilol Nebivolol Bucindolol Bisoprolol Metoprolol Metoprolol Carvedilol Carvedilol Metoprolol Carvedilol
383
EF = Ejection fraction; ETT = exercise tolerance test.
€77
f f
f
NA
c
-
+ + + +
12 20 50
+ + c + +
+ idiopathic ? ischemic + + + + + + + + + +
10 49 60 24 139 641 25 50 40 415
c
f
+ c
-
+
-
=unfavorable effect;
Symptoms f
+ c
-
+ + + + +
+ idiopathic f ischemic + + + + f
+ + +
f
+
1096
+ =favorable effect;
EF
t ?
=equivocal effect.
-c
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CARSON
selective agents under clinical evaluation, such as carvedilol and bucindolol, have mild vasodilatory properties involving alpha antagonism. Data with carvedilolz7 demonstrated an increase in left ventricular ejection fraction from 17.2 k 11.2% to 23.7 t 12.0% on active drug, whereas values in placebo patients did not change (16.1 & 11.8% baseline, 15.7 k 11.8 months), a statistically significant ( P < .05) directional change. Data with bucindolol are similar. Gilbert et alZo showed an increase in ejection fraction in bucindolol-treated patients (pretreatment 0.26 k 10.1, posttreatment 0.35 t lo), whereas values in placebo patients did not change. Two studies done involved dose-ranging analysis with carvedilol and bucindolol. Most recently in the US Carvedilol trials? ejection fraction increased with linearly increasing drug dose ( P < .01). Previous data with bucindolo18 showed an effect on dose response that was not linear, although the highest tested dose (200 mg) showed the greatest ejection fraction increase. The improvement in ejection fraction correlated with decreased heart rate (R = .024, P < .015). It is worthwhile noting that with both carvedilol and bucindolol, a significant proportion of the ejection fraction improvement occurs with the lower dose. Multiple studies have used invasive monitoring to evaluate hemodynamic effects of pblockers in heart failure. All studies show lower heart rate. Metoprolol was studied by Eichhorn et all7 as well as in the Metoprolol Dilated Cardiomyopathy (MDC) study.@ In both studies, metoprolol lowered filling pressure and increased stroke work, whereas cardiac output changed little. Systemic vascular resistance was also unchanged. With newer agents, the pattern has been similar. Pollock et a141showed increased cardiac output with bucindolol; a larger dose-ranging trial did not.34Both studies showed decreased filling pressures and systemic vascular resistance as well as increased stroke work with bucindo101. For the other third-generation agent, carvedilol, the studies of Olsen et a P and Krum et alZ7are concordant in showing lowered filling pressure, increased stroke work index, and increased systemic vascular resistance, while cardiac index is unchanged. The consistent findings suggest that although p-
blockers increase pump efficacy, cardiac output is unchanged likely because of the heart rate lowering effect. Exercise
As seen in Table 2, exercise testing of pblockers in heart failure has yielded mixed results. Studies such as Ikram and Fitzpatrickz6 and Currie et all5 in which patients have not been followed for longer than 1 month have shown no benefit. Most data with cardioselective agents have been with metoprolol and a longer follow-up period. Engelmeier et all7 demonstrated significant improvement, although the double-blind data included only patients who tolerated 100 mg of drug (mean dose 92 mg), and the number was small (n = 88). Anderson et all studied 50 patients with lower-dose metoprolol (mean dose 61 mg). Exercise change did not reach statistical difference with metoprolol, although a trend for improvement was present. Paolisso et a138used metabolic exercise testing in evaluating metoprolol in heart failure, and a statistical increase was noted. The largest patient experience was in the MDC trial, in which no statistical difference in exercise time was seen between metoprolol and placebo at 6 months, but a small positive effect was seen at 12 months (47 5 189 seconds metoprolol versus 15 f 128 seconds placebo, P = .046)/5 Data in smaller studies with metoprolol in Japanese patients4zor with another cardioselective agent, nebivolol, have also been favorable.48 The data with nonselective agents on exercise are mixed, and positive results are fewer. Leung et alZ showed a favorable effect for labetalol in a 12-patient study. The majority of data concern the newer nonselective agents bucindolol and carvedilol. Pollock et a141studied bucindolol and demonstrated an improvement in exercise time from 445 to 630 seconds ( P = .04). Woodley et a149in a larger 50 patient study, found no difference from placebo. The most comprehensive work came from Bristow et a18 in a dose-ranging study. Bucindolol-treated patients, as a group, showed a decrease in maximal exercise ( P = .036) compared to placebo. No change was
P-BLOCKER THERAPY IN HEART FAILURE
noted in submaximal exercise. It is of interest to note that the baseline in exercise time was directly related to the change in maximal heart rate (R = .41, P = .001). As noted previously, an inverse relation has been noted between decrease in maximal heart rate and change in left ventricular ejection fraction (R = .24, P = .015). With carvedilol, Krum et aP7 evaluated exercise efficacy in an advanced heart failure population. This study, however, reported an improvement in the 6-minute walk with carvedilol but again no change in maximal exercise. Olsen et a135showed a trend for improvement in submaximal exercise but no change in maximal exercise with carvedilol. In the larger US Carvedilol trials (1096 patient~):~however, statistical improvement in exercise was not attained in any of the four component trials. Further, data from the Australia-New Zealand (AN-ZUS)3trial of ischemic cardiomyopathy patients also did not demonstrate exercise improvement. The exercise data on P-blockers in heart failure are mixed with modestly favorable data with cardioselective agents and predominantly neutral data with nonselective agents. No data clearly indicate why P-blockers, despite the improvement in hemodynamics and left ventricular ejection fraction, do not improve exercise. Most likely, the blunted maximal heart rate response offsets the hemodynamic improvement. Longer follow-up, however, might also lead to more favorable results, as is suggested in the MDC experien~e.~~ Symptoms
Symptom change in heart failure is often difficult to assess, and it may be more difficult with p-blocker therapy because of the decreased heart rate. The symptom data with Pblockers in heart failure are similar to exercise data in that cardioselective agents appear to provide more consistently favorable results than nonselective agents. With metoprolol, Engelmeier,ls P a o l i ~ s o ,and ~ ~ FisherI9 all showed improvement in New York Heart Association (NYHA) class. In the MDC there was also improvement in NYHA class,
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and this correlated with a patient/physician global assessment. The data with nonselective agents have once again been mixed. Leung et a130 reported favorable data on symptoms with labetalol in a small trial. Bucindolol data includes improvement in a more rigorous test, the Minnesota Living with Heart Failure, as noted by Pollock et a141;however, the larger bucindolol dose-ranging study of Bristow et a18 did not show improvement in either NYHA class or in the Minnesota test. Using carvedilol, both Olsen et aP5and Krum et alZ7 showed improved NYHA class and questionnaire results. In the US Carvedilol trials, there was improvement in NYHA class and a patient/physician global assessment; however, there was no change in the Minnesota Living with Heart Failure score.4z The P-blocker data indicate that symptom assessment by NYHA classification and a variety of questionnaires shows improvement consistently with cardioselective agents and inconsistently with nonselective agents. Assessment with the more rigorous and validated quality-of-life scoring, however, has been less favorable. These results may, in part, reflect the mixed results of the exercise trials described previously but may also reflect the difficulty of testing symptoms and well-being in this population. P-Blockers and Mortality
Although mortality data have been collected in every p-blocker heart failure study, it had been of primary interest in three early trials: MDC,45Cardiac Insufficiency Bisoprolol Study I (CIBIS 1),lo and the US Carvedilol The results are shown in Table 3. The MDC trial compared metoprolol with placebo in a population of dilated cardiomyopathy using a combined endpoint of mortality and “need for transplantation.” The latter endpoint was a series of clinical findings indicating progressive deterioration. The majority (16/21) of the patients meeting this endpoint were ultimately transplanted. The MDC results were perplexing in that although the combined endpoint showed a nearly statistically significant reduction in favor of metoprolol ( P = .058), the endpoint components
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Table 3. MORBIDITY AND MORTALITY DATA Trial
n
Study (%)
17 small trials MDC46 CIBIS’” US Carvedilo13’ ANZ3 Meta-analy sis CIBIS XI” MERIT-HF3’ COPERNICUS36
608 383 641 1096 415 3023 2647 3991 2289
4.7 11.9 16.6 3.2 9.0
7.5 11.8 7.2 11.2
tended to be in the opposite direction. Mortality, predominantly sudden death, showed no benefit for metoprolol-23 deaths versus 19 placebo deaths. The ”transplant” endpoint strongly favored metoprolol-19 events versus 2 placebo events ( P = .0001). The trial then showed evidence of reduction of progressive heart failure, but it cannot be confidently assumed that metoprolol reduced pump failure deaths because the relationship between the components of the transplant endpoint and mortality is not clear. Another study, CIBIS I, also evaluated survival with P-blockade in heart failure with the cardioselective agent bisoprolol. This trial enrolled 641 patients, predominantly NYHA class 111. In contrast to MDC, the study population included patients with both ischemic and nonischemic cardiomyopathy. Similar to MDC, however, the trial had an overall neutral result on mortality, with 67 deaths on placebo and 53 on bisoprolol ( P = 22). Sudden deaths again did not differ between groups-17 on placebo and 15 on bisoprolol. It is also worth noting that heart failure hospitalization ( P < .01) and other pump failure events were both decreased by bisoprolol. The trial did demonstrate a significant mortality reduction with bisoprolol in patients without a history of myocardial infarction, adding to the speculation that beta-blockers may be more effective in patients without significant coronary artery disease. Only 60% of the CIBIS bisoprolol patients received the target dose, which may have affected trial outcome. The results of the MDC trial and CIBIS provide suggestive but not conclusive data for P-blocker efficacy on mortality in heart failure. The trials were both hampered by
Control (%)
Hospitalization
6.9
1 1 1 1 1
10.1 20.9 7.8 9.0 11.9 17.3 11.0 16.8
1 1
1 1
relatively small sample sizes and event rates. They also used cardioselective agents, which provide less than complete adrenergic blockade and might have explained the finding that sudden death was not reduced. The US Carvedilol Trials were larger, 1096 patients, and used a less cardioselective agent, carvedi101.~~ Packer et a137reported a dramatic 65% reduction in mortality with carvedilol compared to placebo. Both pump failure and sudden deaths were decreased. These results may support the concept that more complete adrenergic blockade may be beneficial; however, carvedilol also has potent antioxidant properties, which may also be operative. The results are controversial in that the US Carvedilol Trials consisted of multiple studies: Prospective randomized evaluation of carvedilol symptoms and exercise (PRECISE)38with mild, moderate, and severe heart failure patients and Multicenter oral carvedilol heart failure assessment (MOCHA) with a doseranging design. The PRECISE trials were conducted at the same centers with a separate slate of MOCHA centers. Mortality benefits were significant with MOCHA, but the mild and severe PRECISE trials were difficult to interpret because of small numbers. The US Carvedilol Trials did show a 27% reduction in cardiovascular hospitalization by carvedilol, a finding concordant with MDC, CIBIS, and ANZ. The carvedilol data are the most favorable data on mortality with any P-blocker. Although accepted by many, questions remain because of the small event numbers (52 deaths) and short follow-up (6 months). In another large carvedilol trial, with an ischemic cardiomyopathy population, ANZ? mortality did not differ among the treatment groups.
@-BLOCKERTHERAPY IN HEART FAILURE
p-BLOCKERS
Compelling data are now available from three large mortality trials, which clearly establish that p-blockers reduce mortality in heart failure. The first to report results was Cardiac Insufficiency Bisoprolol Study I1 (CIBIS 11), which enrolled 2647 class 111-IV patients with a mean left ventricular ejection fraction (LVEF) of 27%." The trial was terminated prematurely at 13 months when the benefit of bisoprolol crossed a stopping boundary. The final results indicated that overall mortality was reduced 34% with bisoprolol compared with placebo (156 [11.84%] versus 228 [17.3%], P = .0001) and that the dominant mechanism of sudden death was reduced 44%. Measurements of morbidity also were reduced dramatically: all-cause hospitalization 20% ( P = .0006) and heart-failure hospitalization 36% ( P = 0.0001). Finally, treatment was well tolerated with a 15%withdrawal in treatment and placebo groups. Compared to CIBIS Illo CIBIS IF' was more than four times larger, enrolled a somewhat sicker population, and used a higher bisoprolo1 dose. CIBIS I1 did not confirm the seeming advantage of bisoprolol for patients with dilated cardiomyopathy seen in CIBIS I; the most striking survival advantage appeared in patients with ischemic cardiomyopathy. The results of CIBIS I1 were confirmed in MERIT-HF, which tested long acting metoprolo1 (Metoprolol XL), enrolling 3991 class 11-IV heart failure patients with an ejection fraction of 27%. MERIT-HF also was stopped early when it, like CIBIS 11, crossed a boundary for statistical benefit. The design of MERIT-HF included two primary endpoints, and benefit was apparent on both: all-cause mortality was reduced 34% versus placebo (145 [7.2% annual mortality] versus 217 [11.2%],P = 0.00009); and combined all-cause mortality and all-cause hospitalization was reduced 19% ( P = 0.00012). Among hospitalization data, long acting metoprolol XL reduced cardiovascular hospitalizations 16% ( P = 0.0003) and heart-failure hospitalization 30% ( P = 0.00001). The medication was well tolerated with a permanent discontinuation rate of 14.3% in the treatment group even though a mean dose of 159 mg was attained.
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Two further questions of significance remained for p-blocker therapy in heart failure: (1) Because the patient populations in CIBIS I1 and MERIT-HF are mild-to-moderate heart failure populations (annual placebo mortality rates 13.2% and 119'0, respectively), can pblockers be used in advanced heart failure; and (2) do the impressive morbidity and mortality results extend to all p-blockers? The first question has been answered by the recently completed COPERNICUS This study also was prematurely terminated because the favorable effects of carvedilol at slightly more than 1 year of follow-up. COPERNICUS enrolled 2200 patients with advanced heart failure and a mean LVEF of 20%.35The results demonstrated that carvedilo1 decreased mortality by 35% compared with placebo (130 [11.4%] versus 190 [18.5%], P = 0.00014). Morbidity data was not available at the time of presentation, but the active treatment withdrawal rate (13.0%) was comparable with the other trials. The COPERNICUS results appear to extend the favorable data for @-blockadein heart failure from mild-to-moderate patients to those with advanced disease. The issue of whether all p-blockers confer mortality benefit remains uncertain. The @Blocker Evaluation of Survival Trial (BEST)I5 evaluated bucindolol in 2708 patients with class 111-IV heart failure and a mean LVEF of 23%. Unlike the above trials, bucindolol did not statistically reduce mortality: 10% reduction compared with placebo over the 2year average follow-up (bucindolol 411 [30.4%]versus placebo 449 [33.2%], P = 0.10). Bucindolol reduced total hospitalizations only modestly (9%) and CHF-related hospitalizations l6%, though time to first heartfailure hospitalization was reduced significantly ( P = .0001). The discontinuation rate per year was similar with bucindolol to the active therapy used in CIBIS 11, MERIT-HF, and COPERNICUS, and the explanation for the attenuated efficacy of bucindolol is unclear. Possibilities include the properties of the p-blocker itself or the population tested (in particular, black patients in BEST treated with bucindolol had a higher mortality rate than placebo). At present, however, placed in the context of other clinical trials, the BEST
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data indicate that the safest recommendation would be use to specific p-blockers with proven efficacy in patients with heart failure. There is currently great interest in p-blocker use in heart failure. To a large degree, this interest has been related to the data consistently showing an improvement in ventricular function, which suggest a halt or even reversal of the progression of pump failure. No other cardiovascular group has demonstrated the improvement in ejection fraction noted with P-blockers. Although most hemodynamic indices improve, however, cardiac output usually does not, and this may account for the mixed findings on improvement in exercise and symptoms. It is also true that exercise does not correlate well with ejection fraction, a finding noted in the Vasodilator in Heart Failure Trials (VHeFT) trials,12 therefore, trial results also raise the possibility that an exercise endpoint may not be an attainable indication of efficacy. For example, the widespread use of angiotensin-convertingenzyme (ACE) inhibitors may make it a difficult endpoint to demonstrate a favorable result; in fact, no therapeutic agent has yet demonstrated consistently a favorable exercise effect in a population on ACE inhibitors. Indeed, although the original ACE-inhibitor trials indicated efficacy, these agents have not been uniformly favorable in exercise. Symptoms have been even more of a dilemma as an endpoint. Most questionnaires and symptoms are subjective measures, and even the Minnesota Living with Heart Failure questionnaire, which has had extensive evaluation, has had mixed results in correlating with other measures of outcome. The current P-blocker database, however, overwhelms any ambiguity in the functional characteristics discussed above. The morbidity and mortality results now extend from clinical trials involving over 10,000 patients, and the magnitude of results consistently exceed those with any other medication tested in heart failure (excluding one smaller trial with spironolactone). Furthermore, these results have been obtained in patients almost entirely on converting enzyme inhibitor therapy. The overall power of these results should make P-blocker agents standard therapy in
heart failure for all symptomatic patients except those with clear contraindications or unstable advanced symptoms.
References 1. Anderson JL, Lutz JR, Gilbert EM, et al: A randomised trial of low-dose-blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 55:471-475, 1985 2. Andersson B, Blomstrom-Lundqvist C, Hedner T, et al: Exercise haemodynamics and myocardial metabo lism during long-term, beta-adrenergic blockade in severe heart failure. J Am Coll Cardiol 18:1059-1066, 1991 3. Australia-New Zealand Heart Failure Research Collaborative Group: Effects of carvedilol, a vasodilatorbeta blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation 92212218, 1995 4. Benedict CR, Weiner DH, Johnstone DE, et al: Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: Results of the studies of left ventricular dysfunction (SOLVD) registry. J Am Coll Cardiol 22146A153A, 1993 5. Bristow MR, Gilbert EM, Abraham WT, et al, for the MOCHA Investigators: Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA): A six-month dose response evaluation in class 11-IV patients. Circulation 92(suppl 1):I-142, 1995 6. Bristow MR, Gilbert EM, Olsen S, et al: Long-term metoprolol therapy increases myocardial beta-adrenergic receptor density relative to placebo controls [abstr]. J Am Coll Cardiol2l(suppl A):lOlA, 1993 7. Bristow MR, Ginsburg R, Umans V, et al: Beta 1- and beta 2-adrenergic subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor downregulation in heart failure. Cir Res 59:297-309, 1986 8. Bristow MR, OConnell JB, Gilbert EM, et al, for the Bucindolol Investigators: Dose-response of chronic beta blocker treatment in heart failure from either idiopathic dilated or ischaemic cardiomyopathy. Circulation 89:1632-1642, 1994 9. Bristow MR, Olsen S, Gilbert EM, et al: p-blockade with carvedilol selectively lowers cardiac adrenergic drive in the failing human heart. [abstr]. J Am Coll Cardiol 19:146A, 1992 10. CIBIS Investigators: A randomised trial of beta blockade in heart failure: The Cardiac Insufficiency Bisoprolol Study. Circulation 90:1765-1773, 1994 11. CIBIS I1 Investigators and committees: Lancet 353:913, 1999 12. Cintron G, Johnson G, Francis G, et al, for the VheFT VA Cooperative Studies Group: Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation 87(suppl):VI-17-VI-23, 1993 13. Cohn JN, Levine B, Olivari MT, et al: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311:819-823,1984
P-BLOCKER THERAPY IN HEART FAILURE 14. CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe heart failure: Results of the Co-operative North Scandinavian Enalapril Survival Studv (CONSENSUS).N End T Med 3161429-1435, 1987' ' 15. Currie PJ, Kelly MJ, McKenzie A, et al: Oral betaadrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol 3903-209, 1984 16. Eichom E: Best Results. Atlanta, American Heart Association, 1999 17. Eichhom EJ, Heejch CM, Bamett JH, et al: Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: A randomised, double-blind, placebo-controlled study. J Am Coll Cardiol24:1310-1320, 1994 18. Engelmeier RS, OConnell JB, Walsh R, et al: Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: A double-blind, randomised, placebo-controlled trial. Circulation 72:53&546,1985 19. Fisher ML, Gottlieb SS, Plotrick GD, et al: Beneficial effects of metoprolol in heart failure associated with coronary artery disease: A randomised trial. J Am Coll Cardiol 23:943-950, 1994 20. Gilbert EM, Anderson JL, Deitchman D, et a1 Longterm beta blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind, randomized study of bucindolol versus placebo. Am J Med 88:223-229, 1990 21. Gilbert EM, Olsen SL, Renlund DG, et al: Beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy. Am J Cardiol 71:23C-29C, 1993 22. Green DL, Malhotra A, Scheuer J: Angiotensin I1 increases cardiac protein synthesis in adult rat heart. Am J Physiol265:H238-H243, 1993 23. Greenberg B, Quinones MA, Koilpillai C, et al, for the SOLVD Investigators: Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Circulation 91:2573-2581,1995 24. Hall SA, Cigarroa CG, Marcous L, et al: Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol25:1154-1161,1995 25. Hasenfuss G, Holubarsh C, Hermann H-P, et al: Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with nonfailing hearts and in patients with nonfailing hearts and in patients with dilated cardiomyopathy. Eur Heart J 15:164-170, 1994 26. Ikram H, Fitzpatrick D: Double-blind trial of chronic oral beta blockade in congestive cardiomyopathy. Lancet 2:49M93, 1981 27. Krum H, Schwartz B, Sackner-Bernstein J, et al: Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe heart failure treated with converting-enzyme inhibitors [abstr]. J Am Coll Cardiol Zl(supp1 A):114A, 1993 28. Lechat P, Packer M, Chalon S, et al: Clinical effects of p-adrenergic blockade in chronic heart failure: A meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 9831184-1191, 1998 29. Leung W, Lau C, Wong C, et al: A double-blind cross over trial of labetalol in patients with dilated V
I
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cardiomyopathy [abstr]. Circulation SO(supp1 1I):II118, 1990 30. Leung W, Lau C, Wong C, et al: Improvement in exercise performance and hemodvnamics bv labetalol in patiehts with idiopathic dilated cardiomyopathy. Am Heart J 119:884-890, 1990 31. Mann DL, Cooper G: Propranolol prevents the myopathic effects of catecholamines in vitro: Implications for patients with congestive heart failure. Circulation 78(suppl 1I):II-576, 1988 32. MERIT-HF STUDY GROUP: Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 353:2001-2007, 1999 33. Metra M, Nardi M, Giubbini R, Dei Cas L: Effects of short term and long term carvedilol administration on rest and exercise hemodynamic variable, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 24:1678-1687, 1994 34. Newton GE, Parker JD: 81 vs nonselective P-blockade in human congestive heart failure: Acute effects on cardiac sympathetic activity [abstr]. Circulation 9 2 ( ~ ~ pI):I-395, pl 1995 35. Olsen SL, Gilbert EM, Renlund DG, et a1 Carvedilol improves symptoms and left ventricular function in patients with congestive heart failure due to ischaemic or idiopathic delated cardiomyopathy [abstr]. J Am Coll Cardiol Zl(supp1. A):114A, 1993 36. Packer M: Oral COPERNICUS results. [oral presentation]. Amsterdam, European Society of Cardiology, August, 2000 37. Packer M, Bristow MR, Cohn JN, et al, for the U.S. Carvedilol Heart Failure Study Group: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 33413491355, 1996 38. Packer M, Colucci WS, Sackner-Bemstein J, et al, and the PRECISE Study Group: Prospective randomized evaluation of carvedilol on symptoms and exercise tolerance in chronic heart failure: Results of the PRECISE Trial. Circulation 923-143, 1995 39. Paolisso G, Gambardella A, Marrazzo G, et al: Metabolic and cardiovascular benefits deriving from padrenergic blockade in chronic congestive heart failure. Am Heart J 123:1397-1404, 1992 40. Petch MC, Nayler WG: Uptake of catecholamines in human cardiac muscle in vitro. Br Heart J 41:336339, 1979 41. Pollock SG, Lystash J, Tedesco C, et al: Usefulness of bucindolol in congestive heart failure. Am J Cardiol 66:603-607,1990 42. Sano H, Kawabata N, Yonezawa K, et al: Metoprolol was more effective than captopril for dilated cardiomyopathy in Japanese patients. Circulation 8O(suppl II):II-118, 1989 43. Shape N Beta blockers in heart failure. Heart Failures Reviews 1:5-12, 1996 44. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 325:293-302, 1991 45. Waagstein F, Bristow MR, Swedberg K, et al, for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 34214411446,1993 46. Waagstein F, Hjalmarson A, Vamauskas E, et al: Ef-
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fect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 371022-1036, 1975 47. Whyte K, Jones CR, Howie CA, et al: Haemodynamic metabolic and lymphocyte beta 2 adrenoceptor changes following chronic beta-adrenoceptor antagonism. Eur J Clin Pharmacol32:237-243, 1987 48. Wisenbaugh T, Katz I, Davis J, et a1 Long-term (3 month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol21:1094-1100, 1993
49. Woodley SL, Gilbert EM, Anderson JL, et al: Betablockade with bucindolol in heart failure caused by ischaemic versus idiopathic dilated cardiomyopathy. Circulation 849426-2441, 1991 50. Yoshikawa T, Port JD, Asano K, et al: Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 17 (suppl B):8-16, 1996 51. Yue T-L, Cheng H-Y, Lysko PG, et a1 Carvedilol, a new vasodilator and beta adrenoreceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 263:92-98, 1992
Address reprint requests to Peter Carson, MD Department of Veterans Affairs Medical Center 50 Irving Street NW Washington, DC 20422
0733-8651/01 $15.00
+
.OO
P-BLOCKER THERAPY IN HEART FAILURE Peter Carson, MD
Congestive heart failure remains a complex pathophysiologic syndrome associated with significant morbidity and mortality. Although advances in therapy, particularly with vasodilators, have improved prognosis, progression of heart failure occurs in most patients, and the role of neurohormonal stimulation has taken on increasing importance. The reninangiotensin system is activated in heart failure and has been the target of the angiotensin-converting enzyme inhibitors, the most proven drugs in heart fai1~re.l~. 44 Increasingly the crucial role of the sympathetic nervous system has been recognized: Catecholamines are markers for advanced heart failure but also exert toxic effects.37More recently, there has been increasing attention to the pathologic remodelingz3in heart failure that contributes to the progression of the syndrome. pBlocker drugs are neurohormonal antagonists and also appear to remodel the failing ventri~ l eEarly . ~ ~reports suggested clinical efficacy7 and subsequent data have shown evidence that the progression of heart failure might be prevented or even reversed.8 The effect of P-blockade on these processes has added to growing interest in these agents for the therapy of heart failure. Portions of this article appeared in The Cardiology Clinics: Annual of Drug Therapy, Vol. 3, 1999.
HEART FAILURE AND MYOCARDIAL CONTRACTION
Conceptually, heart failure is usually initiated by factors that impair the heart's ability to respond to circulatory need. This may involve peripheral effects such as increased afterload as in hypertension, but for most patients the initiating event impairs myocardial systolic function either by ischemic events or by a usually undefined process (idiopathic). When heart failure ensues with inadequate circulatory function, the body initiates a series of compensatory responses, such as neurohormonal activation4as well as myocardial and vascular hypertrophy. These mechanisms may be initially beneficial in aiding the failing myocardium but soon become pathologic responses. The renin-angiotensin system activation causes increased afterload, causes salt and water retention, and modulates cellular growth. The sympathetic nervous system increases afterload and heart rate and may also impair myocardial response through receptor down-reg~lation.~ In response to these ongoing stimuli, myocardial hypertrophy occurs and may lead to pathologic remodeling with a dilated ventricle, which functions on a lower pressure volume curve. It is not surprising then that therapeutic
From the Department of Veterans Affairs Medical Center, Georgetown University Hospital, Washington, District of Columbia
CARDIOLOGY CLINICS VOLUME 19 * NUMBER 2 * MAY 2001
267
268
CARSON
efforts have attempted to improve myocardial contraction. Unfortunately, direct attempts, such as with inotropic agents, have been uniformly neutral or unfavorable. Other ways of effecting contraction may be more beneficial. It is worth remembering that the contraction of the heart is governed by three mechanisms: (1)intrinsic contractile function, as indicated by the Frank-Starling relationship, in which increased myocardial stretch results in increased force of contraction; (2) heart rate, the Bowditch-Treppe reflex, in which increased heart rate results in increased contractile force; and (3) sympathetic nervous system, which modulates the myocardial response for increased circulatory functional requirements. In heart failure, the remodeled dilated heart functions on a lower pressure volume curve, which worsens as heart failure progresses. Remodeling occurs when the ventricle dilates and becomes less spherical with a resulting further fall in ejection fraction. Part of this remodeling process may involve angiotensin 11. Although the relationship is not entirely clear, angiotensin I1 appears to be atrophic substance with properties promoting myocardial and vascular hypertrophy.22The success of converting enzyme inhibitors is increasingly believed to be related to the antiremodeling effects such as noted in Studies of Left Ventricular Dysfunction (SOLVD), in which changes in left ventricular size and mass were attenuated by e n a l a ~ r i l P-blockers .~~ may be even more effective in influencing remodeling. Hall et alZ4found that metoprolol therapy was associated with regression of left ventricular mass and a more favorable myocardial shape. Therefore the path to improving the Frank-Starling relationship in heart failure may be through reversing remodeling rather than through direct stimulation. The second important mechanism for contraction involves heart rate. The BowditchTreppe phenomenon indicates that in the normal heart the force of contraction increases with heart rate. In heart failure, however, increasing heart rate results in a diminished force of contraction. Slowing of heart rate appears to increase the force of contraction as in the work of Hasenfuss et al.25This phenomenon is called rate-dependent inotropism and suggests that agents that slow heart rate may
be beneficial by this property alone in improving contractile force. The third mechanism, the sympathetic nervous system, is the most complex. The sympathetic nervous system is stimulated in heart failure, and one of its clinical indicators, plasma norepinephrine, has been associated with increased mortality. Plasma norepinephrine has usually been elevated in more advanced heart failure and therefore may be a marker for more significant disease; however, norepinephrine can also induce myocyte necrosis e~perimentally~l and may therefore contribute to progression of heart failure. Despite the peripheral catecholamine overload, cardiac norepinephrine stores are decreased, perhaps because of defective reuptake mechanisms. Myocardial contractility is mediated through beta-adrenergic receptors ( P1, P2), which are linked by stimulating (Gs) proteins to the effector enzymes.39The adrenergic and angiotensin I1 receptors are also present and interact through G proteins to effect regulaFurther cardiac-beta tory enzymes (Fig. l).50 receptors are decreased overall, but particularly this is a P1 receptor decrease, and the ratio of p receptors is altered. In normal subtype hearts, the ratio is approximately P1:pz 80:20, whereas in failing hearts it is 60:40. This p1 receptor decrease appears to be a downregulation with decreased RNA synthesis, although an increase in receptor degradation may also be operative.50Additionally an uncoupling of the beta receptor from pharmacologic response may occur in ischemic cardiomyopathy. The physiology of adrenergic blockade is complicated and not always consistent, however. Decreases in peripheral norepinephrine have been noted in uncontrolled studies2with metoprolol and in a controlled study with bucindolol. Interestingly, data with carvedilol showed no change in peripherally measured norepinephrine, whereas coronary sinus norepinephrine decreased ~ignificantly.~~ The relationship of P-blockade to cardiac receptors also has not proven to be straightforward. Data with metoprolol have consistently demonstrated increases in P receptor density posttreatment that correlated with increased ejection fraction.18 These changes in receptor density, however, occurred well be-
P-BLOCKER THERAPY IN HEART FAILURE
269
AMP PLMBN
Figure 1. Receptor-G AC pathway.
fore the rise in ejection fraction.43Further data with the newer agents, bucindolol and carvedilol, have not shown an effect on PI receptor density, whereas ejection fraction has increased in similar degree to metoprol01.~~ The pathophysiologic consequences of pblockade remain to be clearly elucidated. The improvement in ejection fraction, the most consistent P-blocker finding in heart failure, is difficult to explain entirely in relation to the above-mentioned mechanisms. An effect on remodeling and subsequent improvement in the Frank-Starling mechanism is least proven and perhaps also has the least contradictory data. Ejection fraction improves gradually, which is consistent with a structural effect. An effect on contractility mediated by heart rate is possible but is not consistent with the temporal relationship-heart rate decreases early in therapy, whereas ejection fraction rises later. The relationship to the sympathic nervous system is complex-the receptor data vary with different P-blockers, but even when P receptors are increased in number, it is an earlier finding than ejection fraction change. Finally the sympathetic nervous system blockade might be expected to prevent further damage but perhaps not improve function. In addition to effects on remodeling and contractility, P-blockers do have potential antifibrillatory and anti-ischemic effects, which may influence mortality. Protection from sudden death may relate to these effects
but may also relate to the degree of adrenergic blockade not only in terms of dose, but also degree of receptor selectivity.
PHARMACOLOGIC DIFFERENCES IN P-BLOCKERS
The most relevant difference among Pblockers relates to the specificity of receptor blockade. The cardioselectivity of selected P-blockers is shown in Table l.50 Bisoprolol and metoprolol are highly cardioselective, whereas carvedilol and bucindolol are nonselective. Additionally the latter agents have modest vasodilating properties. It is postulated that greater adrenergic blockade provides greater survival benefit, but this remains unproven. Carvedilol also has important antioxidant properties,5l which have been apparent in animal models of myocardial infarction; however, the significance of this property in heart failure has not been established.
CLINICAL STUDIES Background
The first report of P-blocker use in heart failure came from Waagstein et a14'j in 1975, in which seven patients showed clinical and echocardiographic improvement. Subsequent
4.6 f 3.5
-
9.7 f 1.7
-
-
2.7 f 1-1
-
-
3.8 f 1.91
-
-
2.2 f 0.6
64 f 32
4-4 f 1-5
70 f 38
48 f 22
-
2.0
1398 +. 236
-
-
-
2.0 f 1.3
1.2 f 0.3
Pi
3333
-
-
-
-
1.0 f 0.7
2.3 f 1.4
P2
Recombinant Systems
4412 f 1816
4.4 f 1.5
7135 +. 3383
3777 f 1709
5.2 f 2-0
*
* 5.2 f 2.0
P2
Pi
ICYP Competition Curves, Failing Heart
From Yoshikawa T, Port JD, Asano K, et al: Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 17(suppl B): 8-16, 1996; with permission.
*Competition curve data unreliable with
-
-
-
-
-
-
12.6
-
-
-
4.3 f 1.0
36 f 24
P2
-
6.2 f 2-2
49 f 16
4.5 f 1.2
Pi
Carvedilol (n = 5-8) Bucindolol (n = 2-10) Metoprolol (n = 5) Bisoprolol (n = 3) Propranolol (n = 1 4 ) Xamoterol (n = 5) CGP 207124
P2
PI
Cardiac Function Assays
Compound
ICYP Competition Curves, Nonfailing Heart vs Lymph
Table 1. SELECTIVITY FOR HUMAN p1 VERSUS p2 RECEPTORS (K, OR KB,nM f SEM), IN PRESENCE OF Gpp (NH) P
2.1
64
4.1
69
50
3.6
4.0
Pi
2366
4412
8.5
7135
3825
5.0
29-1
P2
Average Values
1126
69
2.1
102
79
1.4
7.3
P1:P2
Selectivity
271
R-BLOCKER THERAPY IN HEART FAILURE
studies from the same group, although open label, also indicated clinical benefit. Clinical evaluation of p-blockers has moved slowly, however, particularly in the United States. In 1985, however, Engelmeier et all8 published data in a double-blind, placebo-controlled trial with metoprolol showing improvement in exercise capacity, functional classification, and ejection fraction. Subsequently, other clinical trials have shown similar results using a variety of P-blockers (Table 2). Hemodynamics
These clinical results indicate that ejection fraction improves reproducibly if sequential measurements are obtained after at least 2 months of therapy. The studies of Ikram and Fitzpatrickz6and Currie et all5are noteworthy for a 1-month follow-up with no change in ejection fraction. The time course of change in ejection fraction was well studied by Hall et alZ4who noted an initial deterioration at 1 week in metoprolol-treated patients followed by a return to baseline value by 1 month. There was a 10 ejection fraction point rise by
3 months. Heart failure cause, however, may have an impact on this response. Woodley et a148demonstrated that nonischemic heart failure patients treated with bucindolol showed greater ejection fraction improvement than ischemic patients. More recent work by Brisbev et a18 indicates that a dose range exists with bucindolol and that ischemic patients improve comparably to nonischemic patients at higher but not lower dosages. Improvement in ejection fraction has occurred with both cardioselective (P1) and nonselective (P1 and p2) agents. Multiple studies with metoprololl, 18, 24 have shown ejection fraction improvement. The study by Engelmeier et all8 is an example: Ejection fraction on active drug improved from 0.13 2 to 0.21 k 10.10 at 1 year ( P = .02), whereas no change was seen in the placebo group. Little investigation has occurred with nonselective agents such as propranolol because the early depression of ejection fraction described by Hall et aP4makes nonselective p-blockers difficult for the continuation of therapy. Cardioselective agents leave pz receptors unblocked, potentially allowing a minor vasodilatory action, which improves tolerability. Newer non-
Table 2. PUBLISHED TRIALS OF BETA-BLOCKERS IN HEART FAILURE Effect No. of Patients
Author
Agent
Currie (1984)15 Ikram (1984)26 Anderson (1985)' Engelmeier (1985)18 Sano (1989)41 Gilbert (1990)20 Leung (1990)29 Pollack (1990)m Woodley (1991)@
Metoprolol Acebutolol Metoprolol Metoprolol Metoprolol Bucindolol Labetalol Bucindolol Bucindolol
10 28 50 25 30 24
MDC (1992)" Paolisso (1992)38 Krum (1993)27 Olsen (1993)33 Wisenbaugh (1993)47 Bristow (1994)8 CIBIS (1994)'O Eichhom (1994)17 Fisher (1994)19 Metra (1994)33 ANZ (1995)3 Hall (1995)24 US Carv (1996)35
Metoprolol Metoprolol Carvedilol Carvedilol Nebivolol Bucindolol Bisoprolol Metoprolol Metoprolol Carvedilol Carvedilol Metoprolol Carvedilol
383
EF = Ejection fraction; ETT = exercise tolerance test.
€77
f f
f
NA
c
-
+ + + +
12 20 50
+ + c + +
+ idiopathic ? ischemic + + + + + + + + + +
10 49 60 24 139 641 25 50 40 415
c
f
+ c
-
+
-
=unfavorable effect;
Symptoms f
+ c
-
+ + + + +
+ idiopathic f ischemic + + + + f
+ + +
f
+
1096
+ =favorable effect;
EF
t ?
=equivocal effect.
-c
272
CARSON
selective agents under clinical evaluation, such as carvedilol and bucindolol, have mild vasodilatory properties involving alpha antagonism. Data with carvedilolz7 demonstrated an increase in left ventricular ejection fraction from 17.2 k 11.2% to 23.7 t 12.0% on active drug, whereas values in placebo patients did not change (16.1 & 11.8% baseline, 15.7 k 11.8 months), a statistically significant ( P < .05) directional change. Data with bucindolol are similar. Gilbert et alZo showed an increase in ejection fraction in bucindolol-treated patients (pretreatment 0.26 k 10.1, posttreatment 0.35 t lo), whereas values in placebo patients did not change. Two studies done involved dose-ranging analysis with carvedilol and bucindolol. Most recently in the US Carvedilol trials? ejection fraction increased with linearly increasing drug dose ( P < .01). Previous data with bucindolo18 showed an effect on dose response that was not linear, although the highest tested dose (200 mg) showed the greatest ejection fraction increase. The improvement in ejection fraction correlated with decreased heart rate (R = .024, P < .015). It is worthwhile noting that with both carvedilol and bucindolol, a significant proportion of the ejection fraction improvement occurs with the lower dose. Multiple studies have used invasive monitoring to evaluate hemodynamic effects of pblockers in heart failure. All studies show lower heart rate. Metoprolol was studied by Eichhorn et all7 as well as in the Metoprolol Dilated Cardiomyopathy (MDC) study.@ In both studies, metoprolol lowered filling pressure and increased stroke work, whereas cardiac output changed little. Systemic vascular resistance was also unchanged. With newer agents, the pattern has been similar. Pollock et a141showed increased cardiac output with bucindolol; a larger dose-ranging trial did not.34Both studies showed decreased filling pressures and systemic vascular resistance as well as increased stroke work with bucindo101. For the other third-generation agent, carvedilol, the studies of Olsen et a P and Krum et alZ7are concordant in showing lowered filling pressure, increased stroke work index, and increased systemic vascular resistance, while cardiac index is unchanged. The consistent findings suggest that although p-
blockers increase pump efficacy, cardiac output is unchanged likely because of the heart rate lowering effect. Exercise
As seen in Table 2, exercise testing of pblockers in heart failure has yielded mixed results. Studies such as Ikram and Fitzpatrickz6 and Currie et all5 in which patients have not been followed for longer than 1 month have shown no benefit. Most data with cardioselective agents have been with metoprolol and a longer follow-up period. Engelmeier et all7 demonstrated significant improvement, although the double-blind data included only patients who tolerated 100 mg of drug (mean dose 92 mg), and the number was small (n = 88). Anderson et all studied 50 patients with lower-dose metoprolol (mean dose 61 mg). Exercise change did not reach statistical difference with metoprolol, although a trend for improvement was present. Paolisso et a138used metabolic exercise testing in evaluating metoprolol in heart failure, and a statistical increase was noted. The largest patient experience was in the MDC trial, in which no statistical difference in exercise time was seen between metoprolol and placebo at 6 months, but a small positive effect was seen at 12 months (47 5 189 seconds metoprolol versus 15 f 128 seconds placebo, P = .046)/5 Data in smaller studies with metoprolol in Japanese patients4zor with another cardioselective agent, nebivolol, have also been favorable.48 The data with nonselective agents on exercise are mixed, and positive results are fewer. Leung et alZ showed a favorable effect for labetalol in a 12-patient study. The majority of data concern the newer nonselective agents bucindolol and carvedilol. Pollock et a141studied bucindolol and demonstrated an improvement in exercise time from 445 to 630 seconds ( P = .04). Woodley et a149in a larger 50 patient study, found no difference from placebo. The most comprehensive work came from Bristow et a18 in a dose-ranging study. Bucindolol-treated patients, as a group, showed a decrease in maximal exercise ( P = .036) compared to placebo. No change was
P-BLOCKER THERAPY IN HEART FAILURE
noted in submaximal exercise. It is of interest to note that the baseline in exercise time was directly related to the change in maximal heart rate (R = .41, P = .001). As noted previously, an inverse relation has been noted between decrease in maximal heart rate and change in left ventricular ejection fraction (R = .24, P = .015). With carvedilol, Krum et aP7 evaluated exercise efficacy in an advanced heart failure population. This study, however, reported an improvement in the 6-minute walk with carvedilol but again no change in maximal exercise. Olsen et a135showed a trend for improvement in submaximal exercise but no change in maximal exercise with carvedilol. In the larger US Carvedilol trials (1096 patient~):~however, statistical improvement in exercise was not attained in any of the four component trials. Further, data from the Australia-New Zealand (AN-ZUS)3trial of ischemic cardiomyopathy patients also did not demonstrate exercise improvement. The exercise data on P-blockers in heart failure are mixed with modestly favorable data with cardioselective agents and predominantly neutral data with nonselective agents. No data clearly indicate why P-blockers, despite the improvement in hemodynamics and left ventricular ejection fraction, do not improve exercise. Most likely, the blunted maximal heart rate response offsets the hemodynamic improvement. Longer follow-up, however, might also lead to more favorable results, as is suggested in the MDC experien~e.~~ Symptoms
Symptom change in heart failure is often difficult to assess, and it may be more difficult with p-blocker therapy because of the decreased heart rate. The symptom data with Pblockers in heart failure are similar to exercise data in that cardioselective agents appear to provide more consistently favorable results than nonselective agents. With metoprolol, Engelmeier,ls P a o l i ~ s o ,and ~ ~ FisherI9 all showed improvement in New York Heart Association (NYHA) class. In the MDC there was also improvement in NYHA class,
273
and this correlated with a patient/physician global assessment. The data with nonselective agents have once again been mixed. Leung et a130 reported favorable data on symptoms with labetalol in a small trial. Bucindolol data includes improvement in a more rigorous test, the Minnesota Living with Heart Failure, as noted by Pollock et a141;however, the larger bucindolol dose-ranging study of Bristow et a18 did not show improvement in either NYHA class or in the Minnesota test. Using carvedilol, both Olsen et aP5and Krum et alZ7 showed improved NYHA class and questionnaire results. In the US Carvedilol trials, there was improvement in NYHA class and a patient/physician global assessment; however, there was no change in the Minnesota Living with Heart Failure score.4z The P-blocker data indicate that symptom assessment by NYHA classification and a variety of questionnaires shows improvement consistently with cardioselective agents and inconsistently with nonselective agents. Assessment with the more rigorous and validated quality-of-life scoring, however, has been less favorable. These results may, in part, reflect the mixed results of the exercise trials described previously but may also reflect the difficulty of testing symptoms and well-being in this population. P-Blockers and Mortality
Although mortality data have been collected in every p-blocker heart failure study, it had been of primary interest in three early trials: MDC,45Cardiac Insufficiency Bisoprolol Study I (CIBIS 1),lo and the US Carvedilol The results are shown in Table 3. The MDC trial compared metoprolol with placebo in a population of dilated cardiomyopathy using a combined endpoint of mortality and “need for transplantation.” The latter endpoint was a series of clinical findings indicating progressive deterioration. The majority (16/21) of the patients meeting this endpoint were ultimately transplanted. The MDC results were perplexing in that although the combined endpoint showed a nearly statistically significant reduction in favor of metoprolol ( P = .058), the endpoint components
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Table 3. MORBIDITY AND MORTALITY DATA Trial
n
Study (%)
17 small trials MDC46 CIBIS’” US Carvedilo13’ ANZ3 Meta-analy sis CIBIS XI” MERIT-HF3’ COPERNICUS36
608 383 641 1096 415 3023 2647 3991 2289
4.7 11.9 16.6 3.2 9.0
7.5 11.8 7.2 11.2
tended to be in the opposite direction. Mortality, predominantly sudden death, showed no benefit for metoprolol-23 deaths versus 19 placebo deaths. The ”transplant” endpoint strongly favored metoprolol-19 events versus 2 placebo events ( P = .0001). The trial then showed evidence of reduction of progressive heart failure, but it cannot be confidently assumed that metoprolol reduced pump failure deaths because the relationship between the components of the transplant endpoint and mortality is not clear. Another study, CIBIS I, also evaluated survival with P-blockade in heart failure with the cardioselective agent bisoprolol. This trial enrolled 641 patients, predominantly NYHA class 111. In contrast to MDC, the study population included patients with both ischemic and nonischemic cardiomyopathy. Similar to MDC, however, the trial had an overall neutral result on mortality, with 67 deaths on placebo and 53 on bisoprolol ( P = 22). Sudden deaths again did not differ between groups-17 on placebo and 15 on bisoprolol. It is also worth noting that heart failure hospitalization ( P < .01) and other pump failure events were both decreased by bisoprolol. The trial did demonstrate a significant mortality reduction with bisoprolol in patients without a history of myocardial infarction, adding to the speculation that beta-blockers may be more effective in patients without significant coronary artery disease. Only 60% of the CIBIS bisoprolol patients received the target dose, which may have affected trial outcome. The results of the MDC trial and CIBIS provide suggestive but not conclusive data for P-blocker efficacy on mortality in heart failure. The trials were both hampered by
Control (%)
Hospitalization
6.9
1 1 1 1 1
10.1 20.9 7.8 9.0 11.9 17.3 11.0 16.8
1 1
1 1
relatively small sample sizes and event rates. They also used cardioselective agents, which provide less than complete adrenergic blockade and might have explained the finding that sudden death was not reduced. The US Carvedilol Trials were larger, 1096 patients, and used a less cardioselective agent, carvedi101.~~ Packer et a137reported a dramatic 65% reduction in mortality with carvedilol compared to placebo. Both pump failure and sudden deaths were decreased. These results may support the concept that more complete adrenergic blockade may be beneficial; however, carvedilol also has potent antioxidant properties, which may also be operative. The results are controversial in that the US Carvedilol Trials consisted of multiple studies: Prospective randomized evaluation of carvedilol symptoms and exercise (PRECISE)38with mild, moderate, and severe heart failure patients and Multicenter oral carvedilol heart failure assessment (MOCHA) with a doseranging design. The PRECISE trials were conducted at the same centers with a separate slate of MOCHA centers. Mortality benefits were significant with MOCHA, but the mild and severe PRECISE trials were difficult to interpret because of small numbers. The US Carvedilol Trials did show a 27% reduction in cardiovascular hospitalization by carvedilol, a finding concordant with MDC, CIBIS, and ANZ. The carvedilol data are the most favorable data on mortality with any P-blocker. Although accepted by many, questions remain because of the small event numbers (52 deaths) and short follow-up (6 months). In another large carvedilol trial, with an ischemic cardiomyopathy population, ANZ? mortality did not differ among the treatment groups.
@-BLOCKERTHERAPY IN HEART FAILURE
p-BLOCKERS
Compelling data are now available from three large mortality trials, which clearly establish that p-blockers reduce mortality in heart failure. The first to report results was Cardiac Insufficiency Bisoprolol Study I1 (CIBIS 11), which enrolled 2647 class 111-IV patients with a mean left ventricular ejection fraction (LVEF) of 27%." The trial was terminated prematurely at 13 months when the benefit of bisoprolol crossed a stopping boundary. The final results indicated that overall mortality was reduced 34% with bisoprolol compared with placebo (156 [11.84%] versus 228 [17.3%], P = .0001) and that the dominant mechanism of sudden death was reduced 44%. Measurements of morbidity also were reduced dramatically: all-cause hospitalization 20% ( P = .0006) and heart-failure hospitalization 36% ( P = 0.0001). Finally, treatment was well tolerated with a 15%withdrawal in treatment and placebo groups. Compared to CIBIS Illo CIBIS IF' was more than four times larger, enrolled a somewhat sicker population, and used a higher bisoprolo1 dose. CIBIS I1 did not confirm the seeming advantage of bisoprolol for patients with dilated cardiomyopathy seen in CIBIS I; the most striking survival advantage appeared in patients with ischemic cardiomyopathy. The results of CIBIS I1 were confirmed in MERIT-HF, which tested long acting metoprolo1 (Metoprolol XL), enrolling 3991 class 11-IV heart failure patients with an ejection fraction of 27%. MERIT-HF also was stopped early when it, like CIBIS 11, crossed a boundary for statistical benefit. The design of MERIT-HF included two primary endpoints, and benefit was apparent on both: all-cause mortality was reduced 34% versus placebo (145 [7.2% annual mortality] versus 217 [11.2%],P = 0.00009); and combined all-cause mortality and all-cause hospitalization was reduced 19% ( P = 0.00012). Among hospitalization data, long acting metoprolol XL reduced cardiovascular hospitalizations 16% ( P = 0.0003) and heart-failure hospitalization 30% ( P = 0.00001). The medication was well tolerated with a permanent discontinuation rate of 14.3% in the treatment group even though a mean dose of 159 mg was attained.
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Two further questions of significance remained for p-blocker therapy in heart failure: (1) Because the patient populations in CIBIS I1 and MERIT-HF are mild-to-moderate heart failure populations (annual placebo mortality rates 13.2% and 119'0, respectively), can pblockers be used in advanced heart failure; and (2) do the impressive morbidity and mortality results extend to all p-blockers? The first question has been answered by the recently completed COPERNICUS This study also was prematurely terminated because the favorable effects of carvedilol at slightly more than 1 year of follow-up. COPERNICUS enrolled 2200 patients with advanced heart failure and a mean LVEF of 20%.35The results demonstrated that carvedilo1 decreased mortality by 35% compared with placebo (130 [11.4%] versus 190 [18.5%], P = 0.00014). Morbidity data was not available at the time of presentation, but the active treatment withdrawal rate (13.0%) was comparable with the other trials. The COPERNICUS results appear to extend the favorable data for @-blockadein heart failure from mild-to-moderate patients to those with advanced disease. The issue of whether all p-blockers confer mortality benefit remains uncertain. The @Blocker Evaluation of Survival Trial (BEST)I5 evaluated bucindolol in 2708 patients with class 111-IV heart failure and a mean LVEF of 23%. Unlike the above trials, bucindolol did not statistically reduce mortality: 10% reduction compared with placebo over the 2year average follow-up (bucindolol 411 [30.4%]versus placebo 449 [33.2%], P = 0.10). Bucindolol reduced total hospitalizations only modestly (9%) and CHF-related hospitalizations l6%, though time to first heartfailure hospitalization was reduced significantly ( P = .0001). The discontinuation rate per year was similar with bucindolol to the active therapy used in CIBIS 11, MERIT-HF, and COPERNICUS, and the explanation for the attenuated efficacy of bucindolol is unclear. Possibilities include the properties of the p-blocker itself or the population tested (in particular, black patients in BEST treated with bucindolol had a higher mortality rate than placebo). At present, however, placed in the context of other clinical trials, the BEST
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data indicate that the safest recommendation would be use to specific p-blockers with proven efficacy in patients with heart failure. There is currently great interest in p-blocker use in heart failure. To a large degree, this interest has been related to the data consistently showing an improvement in ventricular function, which suggest a halt or even reversal of the progression of pump failure. No other cardiovascular group has demonstrated the improvement in ejection fraction noted with P-blockers. Although most hemodynamic indices improve, however, cardiac output usually does not, and this may account for the mixed findings on improvement in exercise and symptoms. It is also true that exercise does not correlate well with ejection fraction, a finding noted in the Vasodilator in Heart Failure Trials (VHeFT) trials,12 therefore, trial results also raise the possibility that an exercise endpoint may not be an attainable indication of efficacy. For example, the widespread use of angiotensin-convertingenzyme (ACE) inhibitors may make it a difficult endpoint to demonstrate a favorable result; in fact, no therapeutic agent has yet demonstrated consistently a favorable exercise effect in a population on ACE inhibitors. Indeed, although the original ACE-inhibitor trials indicated efficacy, these agents have not been uniformly favorable in exercise. Symptoms have been even more of a dilemma as an endpoint. Most questionnaires and symptoms are subjective measures, and even the Minnesota Living with Heart Failure questionnaire, which has had extensive evaluation, has had mixed results in correlating with other measures of outcome. The current P-blocker database, however, overwhelms any ambiguity in the functional characteristics discussed above. The morbidity and mortality results now extend from clinical trials involving over 10,000 patients, and the magnitude of results consistently exceed those with any other medication tested in heart failure (excluding one smaller trial with spironolactone). Furthermore, these results have been obtained in patients almost entirely on converting enzyme inhibitor therapy. The overall power of these results should make P-blocker agents standard therapy in
heart failure for all symptomatic patients except those with clear contraindications or unstable advanced symptoms.
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