Beta-Blocker Therapy and Severe Heart Failure: Myth or Reality?

Transcription

1 BETA BLOCKERS AND HF CHF JULY/AUGUST Beta-Blocker Therapy and Severe Heart Failure: Myth or Reality? The medical management of heart failure has undergone remarkable progress in the past 10 years. The paradigm shift is toward long-term reparative strategies that help in altering the biologic properties of the failing heart. Together with angiotensin-converting enzyme inhibitors, β blockers have emerged as standard therapy for heart failure, especially for patients with mild to moderate heart failure. Since most of the clinical trials demonstrating the benefits of β blockers have been done in patients with mild to moderate heart failure, some controversy exists about the utility of β-blocking agents in patients with advanced heart failure. This review will summarize the rationale and the use of β blockers, a very challenging therapeutic strategy, in patients with severe heart failure. (CHF. 2003;9: ) 2003 CHF, Inc. Thomachan Kalapura, MD, MRCP; Hector O. Ventura, MD From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA Address for correspondence: Hector O. Ventura, MD, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA hventura@ochsner.org ID: 1467 The failing human heart is adrenergically activated, which helps in maintaining an adequate cardiac performance in the short term by increasing contractility and heart rate. 1 However, this chronic hyperadrenergic state in the long term damages the failing heart. There are three types of adrenergic receptors (β 1, β 2, and α 1 ) in the human cardiac myocytes that have been associated with a positive inotropic response and cell growth (Table I). 2 Beta-adrenergic (β 1 and β 2 ) receptors are coupled via the stimulatory G protein to the effector enzyme, adenyl cyclase, which increase the intracellular concentration of the second messenger cyclic adenosine monophosphate (camp). It has been shown that camp leads to an increase in contractility and, in addition, is strongly growth promoting. Heart failure is characterized by desensitization of the β receptor pathway due in part to a sustained cardiac adrenergic stimulation. When this occurs, the β receptor pathways have several abnormalities, which ultimately produce a reduced response to adrenergic stimulation. In nonfailing human hearts, the β 1 /β 2 receptor ratio is 75% 80% to 25% 30%. Conversely, in failing hearts this ratio is altered (60% 65% to 35% 40%), due to the selective down-regulation of the β 1 subtype with no change in the number of β 2 receptors. 3 Norepinephrine is an extremely cardiotoxic substance that produces cardiac myocyte injury in the concentrations seen in failing human hearts. 4 This cytotoxicity appears to be mediated through the β rather than the α-adrenergic receptors. Animal experiments with transgenic mice have shown that chronic cardiac overexpression of human β 1 and β 2 receptors produces an overtly cardiomyopathic phenotype with chamber dilatation, hypertrophy, systolic dysfunction, and increased markers of apoptosis. 5,6 In the failing heart, β-adrenergic signal transduction is reduced due to certain adaptive changes in the β receptors, inhibitory G protein, β adrenergic receptor kinase, and the enzyme adenyl cyclase. 3 In endstage heart failure, 50% 60% of the signal transducing potential is lost. These β-adrenoreceptor desensitization changes are adaptive and strategies to inhibit the receptor signal transduction would add to this endogenous antiadrenergic strategy. 7

2 198 BETA BLOCKERS AND HF CHF JULY/AUGUST 2003 The continuous adrenergic drive in the failing human heart delivers adverse biologic signals to the cardiac myocyte through the β 1, and likely β 2 receptors. This is the fundamental basis for use of anti-adrenergic agents in the treatment of chronic heart failure. From Bench to Bedside: Evidence From Randomized Trials The US Carvedilol Program (USCP), Cardiac Insufficiency Bisoprolol Study (CIBIS-II), and Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). Even though β blockers were used in heart failure care in Sweden in the 1970s, it was not until 1996, with the publication of the USCP, 8 that β-blocker therapy was shown to be beneficial in a prospective, randomized, controlled trial. Most of the patients enrolled in this study had mild to moderate heart failure. This trial reported a reduction in mortality and in cardiovascular hospitalizations in patients with heart failure. Subsequently, two landmark clinical trials demonstrating a survival benefit from β blockers have been reported: the CIBIS-II 9 and MERIT-HF. 10 These two prospective, randomized, placebo-controlled studies showed convincingly that, in patients with stable chronic heart failure with symptoms of mild to moderate severity, β blockers added to full conventional therapy (digoxin, diuretics, angiotensin-converting enzyme [ACE] inhibitors) reduce mortality by about one third and the risk of hospitalization for any reason by 12% 20%. 9,10 These data suggest that dual neurohormonal inhibition (i.e., β blocker and ACE inhibitor combination therapy) may reduce the annual mortality rate in patients with New York Heart Association (NYHA) class II and III congestive heart failure by about 50%. Although a beneficial effect of bisoprolol and metoprolol-xl was observed in patients with heart failure NYHA functional class IV, the numbers of patients in this category were too small. Beta Blockers in Severe Heart Failure Because of the degree to which the failing heart is dependent on adrenergic support, there is also a potential for adverse effects of β-blocking agents in patients with advanced heart failure. Thus, these patients might not tolerate the initiation or up-titration of β blockers; additionally, some patients might have a reduction in left ventricular function. Since most of the clinical trials of β-blocking agents have been conducted in patients with heart failure NYHA functional class II/III, until recently there was limited information regarding safety Table I. Biologic Responses Mediated by Adrenergic Receptors in the Human Heart BIOLOGIC RESPONSE ADRENERGIC RECEPTOR MEDIATION Cardiac myocyte growth β 1, β 2, α 1 Positive inotropic response Positive chronotropic response β 1, β 2 Myocyte toxicity β 1, β 2 Myocyte apoptosis β 1 β 1, β 2, α 1 (minimal) and efficacy of β blockers in patients with heart failure NYHA functional class IV. We will summarize some of the new evidence regarding their use in patients with more advanced heart failure and we will also discuss the utility of the combination between β blockers and inotropic agents (phosphodiesterase inhibitors). Observational Studies. The tolerability and efficacy of carvedilol in patients with heart failure and functional class IV symptoms were recently reported. 11 The authors retrospectively analyzed the outcomes of 230 patients with heart failure treated with carvedilol who were stratified according to baseline functional class: 63 patients were NYHA class IV and 167 were NYHA class I, II, or III. Carvedilol was started at mg twice a day and titrated to 25 mg twice a day as tolerated. The results of the study demonstrated that patients in functional class IV taking carvedilol had a higher degree of nonfatal adverse events (43% vs. 24%; p<0.0001) when compared to patients in lower functional classes. In addition, the adverse events more often resulted in permanent withdrawal of the drug (25% vs. 13%; p<0.01). Thirty-seven (59%) patients who were NYHA class IV at baseline had improved by one or more functional classes at 3 months, 8 (13%) were unchanged, and 18 (29%) had deteriorated or died. Among the less symptomatic group, 62 (37%) patients had improved their NYHA status at 3 months, 73 (44%) were unchanged, and 32 (19%) had deteriorated or died. The differences in symptomatic outcome at three months between the two groups were statistically significant (p=0.001, chi-square analysis). Both groups demonstrated similar significant improvements in left ventricular dimensions and systolic function. Clinical predictors of which patients in functional class IV would tolerate β blockers poorly were hyponatremia and baseline hypotension. The authors concluded that patients with chronic NYHA class IV heart failure are more likely to develop adverse events

3 BETA BLOCKERS AND HF CHF JULY/AUGUST during initiation and dose titration than less symptomatic patients and are more likely to show symptomatic improvement in the long term. Randomized Clinical Trials. The effect of β blockers on mortality utilized in the different randomized clinical trials 9,10,13,14 in patients with NYHA functional class IV heart failure are summarized in Figure 1. We will focus on two of those clinical trials since they enrolled a great number of patients with more advanced heart failure. Beta Blocker Evaluation Survival Trial (BEST). Design. The BEST study was designed as a doubleblind placebo-controlled trial testing the hypothesis that the addition of a β blocker, bucindolol, to standard therapy reduced all-cause mortality in patients with class III and IV congestive heart failure. 12 Twenty-three of the patients were African Americans, 22% were women, 92% were in NYHA functional class III, and 8% were in NYHA functional class IV. The annual placebo mortality rate was 16.6%. Results. The results of BEST revealed that the allcause mortality was reduced by 10% with bucindolol, but this did not reach statistical significance (p=0.109). There was a borderline 12.5% reduction in cardiovascular deaths and a reduction in hospital admissions. A subgroup analysis showed a heterogeneous response. Patients with NYHA class III heart failure or left ventricular ejection fractions (LVEF) >20% showed improved survival with bucindolol, whereas NYHA Class IV patients and those with LVEF <20% did not benefit. Regarding race, this study demonstrated a disparate survival with bucindolol in non-african Americans vs. African Americans. Most of the survival benefits were in the non- African American patients whereas the African American patients had a 17% excess mortality. The latter suggested either a lack of benefits of bucindolol in this population or perhaps a deleterious effect. The benefits of bucindolol were fewer in women than men. 13 This trial raises a number of interesting, yet unanswered questions. First, are there racial differences in the response of β blockers? Second, is it safe to use bucindolol in patients with advanced heart failure? And, third, are there real differences in the efficacy among the various classes of β blockers in the treatment of heart failure? Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS). Design. The COPERNICUS trial 14 was designed as a multicenter, multinational trial in patients with severe heart failure, randomized to carvedilol vs. placebo. This trial included patients with Figure 1. Summary of the effect of β blockers on mortality in four clinical trials. Trial acronyms are provided in text. Adapted from Eur J Heart Fail. 2001;3: , 15 with permission from the European Society of Cardiology. ischemic or nonischemic cardiomyopathy and an LVEF <25% who had symptoms of dyspnea and/or fatigue at rest or on minimal exertion for at least 2 months, despite optimal conventional therapy with ACE inhibitors and diuretics. Hospitalized patients who were not in the intensive care unit were eligible for inclusion, but must not have received IV therapy with inotropes or vasodilators within 4 days of randomization. Eligible patients must have been clinically euvolemic, although mild peripheral edema was not an exclusion criterion. The primary end point of COPERNICUS was allcause mortality. The main secondary end points were all-cause death or hospitalization for heart failure, all-cause death or cardiovascular hospitalizations, and death or hospitalization from any cause. Therapy with carvedilol or placebo was initiated at a dose of mg b.i.d. and up-titrated, as tolerated, to 25 mg b.i.d. over a 12-week period. The data and safety monitoring board terminated the study prematurely on March 14, 2000 because of a significant survival benefit from therapy with carvedilol. Results. A total of 2289 patients were randomized in COPERNICUS and the average follow-up was less than 1 year (Table II). The very low LVEF and the fact that 66% of patients were hospitalized for heart failure within 1 year of randomization, was evidence to the advanced nature of disease in the enrolled patients. In addition, the 19% annual placebo mortality rate attests to the presence of advanced heart failure in these patients. Seventy-four percent of patients treated with carvedilol and 82% of placebo-treated patients achieved the target dose of 25 mg b.i.d. Table III depicts the data on primary outcome. Therapy with carvedilol was associated with a 35% reduction in allcause mortality. This mortality reduction was observed

4 200 BETA BLOCKERS AND HF CHF JULY/AUGUST 2003 Table II. Baseline Characteristics of Patients in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Trial PLACEBO N=1133 Age (years) Male LVEF (%) CARVEDILOL N=1156 Blood pressure (mm Hg) 123/76 123/75 Heart failure hospitalization within 1 year in all subgroups stratified according to age, gender, LVEF, and heart failure hospitalization within 1 year. There was also a striking effect of carvedilol on allcause hospitalizations (mainly due to a reduction in hospitalizations for heart failure). The safety concerns associated with β blocker usage in patients with advanced heart failure were addressed by analyzing the outcome data in three groups of patients with perceived higher risk, as shown in Table IV. The mortality reduction ranged from 42% 50% in all three groups, suggesting that in this trial there were no patients whose disease was too advanced to benefit from carvedilol therapy. Also, it is important to note that 87% of carvedilol-treated and 84% of placebo-treated patients were on the study drug at the end of the follow-up period. The results of COPERNICUS demonstrate that even in patients with advanced heart failure, carvedilol exerts a beneficial effect on all-cause mortality and on all-cause hospitalizations. Based on these findings, treating 1000 patients with stable, advanced heart failure with a β blocker, such as carvedilol, for 3 years would save 200 lives. In contrast to the BEST study, there tended to be a greater reduction in mortality in the 5% of African Americans with carvedilol in COPERNICUS (but not statistically significant due to small numbers). The β Blocker Inotropic Combination The disparate results of BEST and COPERNICUS indicate a certain degree of controversy in the use of β blockers in patients with advanced heart failure. Thus, some patients with advanced heart failure do not tolerate the initiation and up-titration of β blockers, while others exhibit a decrease in left ventricular function. In addition, some patients with advanced heart failure in whom β blockade improves their functional class will later decompensate. These three clinical scenarios, which are associated with a clinically significant low output state, often require the use of inotropic support to improve hemodynamic parameters. For optimal management of patients with advanced heart failure in the β blocker era, it is important to understand the interaction between positive inotropic agents and β blockers. Mechanisms of Action of Inotropic Agents. Beta agonists exert their effects through β 1 - and β 2 -adrenergic receptor occupancy and subsequent activation of the enzyme adenyl cyclase. When a β agonist is administered in the presence of full dose β blockade, no effect of the agonist will be seen until the antagonist has been displaced from the receptor. 16 Conversely, the phosphodiesterase (PDE) inhibitors, such as milrinone and enoximone, selectively inhibit the PDE type 3 (PDE3), which is anchored to the sarcoplasmic reticulum. This results in increased intracellular concentration of camp, which leads to increases in inotropism and peripheral vasodilatation. Because the site of action of PDE inhibitors is beyond the β- adrenergic receptors, the presence of β blockade will not attenuate their favorable hemodynamic effects. The hemodynamic changes and potential adverse effects of β blockers and PDE inhibitors are depicted in Table V. In addition, this table summarizes the effects of both β blockers and PDE inhibitors when given in combination. The combination of both therapies underscores the fact that potential adverse effects of β blockers might be neutralized by PDE inhibitors and vice versa. Dobutamine vs. PDE Inhibitors in Patients Treated With β Blockers. The effects of both dobutamine and milrinone were recently compared in patients with heart failure treated with mg/d of carvedilol. The patients were matched for a comparable increase in cardiac index. 17 The intravenous infusion of dobutamine at doses ranging between 5 15 µgm/kg/min increased cardiac index; however, dobutamine significantly increased the heart rate, mean systemic pressure, and mean pulmonary artery pressure, without significantly altering the pulmonary capillary wedge pressure. In contrast, milrinone at very small doses (25 µg/kg given over 10 min) achieves a similar increase in cardiac output associated with a decrease in capillary pressure and afterload. This study is of clinical importance because it supports the concept that patients who had decompensated heart failure and were treated with β blockers should be treated with PDE inhibitors to support hemodynamics instead of dobutamine.

5 BETA BLOCKERS AND HF CHF JULY/AUGUST Oral Combination Therapy With PDE Inhibitors and β Blockers in Patients With Advanced Heart Failure. The concept of the combination of a β-blocking agent and a PDE inhibitor was recently reported by Shakar et al. 18 The authors utilized enoximone, an oral PDE inhibitor, as a bridge to initiation of metoprolol in patients with NYHA functional class IV heart failure. Thirty patients (NYHA functional class IV; LVEF, 17.2%±1.2%; cardiac index, 1.6±0.1 l/min/m 2 ; pulmonary capillary wedge pressure 25.2±1.5 mm Hg) were enrolled in the study and received enoximone orally <1 mg/kg/body weight three times a day. After clinical stability, 80% of the patients tolerated the addition of a slow titration of metoprolol up to mg/day and subsequently 50% were successfully weaned off enoximone. Patients demonstrated a significant improvement in LVEF, from 17.7%±1.6% to 27.6%±3.4%, a decrease in mean heart rate from 101±4.0 beats/min to 80±4.0 beats/min, an improvement in the NYHA class from 4 to 2.8±0.1, and a Table III. Primary Outcome in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Trial PLACEBO CARVEDILOL HAZARD RATIO (95% CI) P VALUE All-cause mortality (number of events/total patients) 190/ / ( ) Annual mortality rate 18.5% 11.4% CI=confidence interval Table IV. Analysis of High-Risk Patients (COPERNICUS) LVEF <20%, and heart failure hospitalization within 1 year PLACEBO CARVEDILOL HAZARD RATIO (95% CI) Annual mortality rate 22.5% 17.9% 0.58 ( ) LVEF <15%, or three heart failure hospitalizations within 1 year Annual mortality rate 25% 19% 0.64 ( ) Signs of fluid retention, use of intravenous inotropes or vasodilators within 2 weeks, or three heart failure hospitalizations within 1 year Annual mortality rate 25.3% 16.7% 0.50 ( ) COPERNICUS=Carvedilol Prospective Randomized Cumulative Survival; CI=confidence interval; LVEF=left ventricular ejection fraction Table V. Cardiovascular Effects of β Blockers, PDE Inhibitors, or Their Combination in Subjects With Heart Failure EFFECT β BLOCKER PDE INHIBITOR β BLOCKER + PDE INHIBITOR Heart rate or Systolic function then Diastolic function Arterial vasodilatation, or Venodilation, or LV filling pressure or, then MVO 2 or Exercise capacity or Proarrythmia or or PDE=phosphodiesterase; LV=left ventricular; MVO 2 =myocardial oxygen consumption; =increase; =significant increase; = decrease; = no change

6 202 BETA BLOCKERS AND HF CHF JULY/AUGUST 2003 decrease in the number of hospitalizations. In addition, combination therapy showed a promising effect on the survival of this cohort. The authors concluded that this combination is beneficial for the treatment of heart failure in patients with NYHA functional class IV. Thus, long-term oral inotropic therapy serves as a bridge to β blockade, while β blockade decreases the adverse side effects of inotropic therapy and in addition improves the clinical and economic outcomes of these challenging patients. As a result of this study, the use of combination therapy (PDE inhibitors and β blockers) is under investigation in a large randomized multicenter trial (Enoximone Plus Metoprolol in Subjects With Advanced Chronic Heart Failure [EMPOW- ER]). Additionally, a large, multicenter, double-blind, randomized trial of intravenous milrinone vs. placebo as a therapeutic tool to allow the initiation of metoprolol orally in patients hospitalized with class III/IV heart failure (Primacor for Optimization of Beta Blocker Efficacy [PROBE]) is also underway. 15 Conclusions Antiadrenergic therapy with β-blocking agents has evolved over a 25-year period from being a contraindicated therapy to an established treatment for patients with mild to moderate heart failure. Several randomized clinical trials have demonstrated that when β blockers are added to ACE inhibitors there is a substantial reduction in morbidity and mortality in patients with heart failure. The role of β-blocking agents in patients with advanced heart failure remains challenging. The results of COPERNICUS are very promising; they demonstrate that all stable patients with advanced heart failure should be considered for β-blocker therapy with carvedilol. Conversely, in patients with severe heart failure, more specifically African Americans, bucindolol did not show any benefit in survival. The role of PDE inhibitors as a bridge to β blockade in patients with advanced heart failure is a very interesting theory. Further studies are underway to test this hypothesis. Because of the risk of deterioration upon withdrawal of β blockers, these agents should be maintained indefinitely in patients with heart failure who achieved a maintenance dose. Therefore, in case of decompensated heart failure in patients on β blockers, the use of PDE inhibitors for inotropic support should be advocated, since the hemodynamic effects of the PDE inhibitors are not antagonized by β blockade. In conclusion, β blockade in patients with advanced heart failure is more a reality than a myth. However, since not all the β-blocking agents are created equal and might differ in efficacy, one should be cautious and judicious in their use in these challenging patients. 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