1. C. Reassessing clinical management of heart failure:
Interpreting evidence-based clinical trials
Survival studies of b-blockade in heart failure
Content points:
Current recommendations for the use of b-blockers in HF reflect the evolution from a hemodynamic to a neurohormonal model of the pathogenes is of progressive ventricular remodeling. The substantial benefit of b-blockade on survival has been demonstrated in a series of major clinical trials.1-4
CIBIS-II1 showed that treatment with bisoprolol (a b1--receptor blocker) improved survival 34% in symptomatic patients with NYHA class III or IV HF and ejection fraction ≤35%.
MERIT-HF2 results showed ER metoprolol succinate reduced total mortality 34% in patients with NYHA class II to IV HF and ejection fraction ≤35%.
COPERNICUS3 evaluated the effect of carvedilol on survival in 2889 patients with severe HF (NYHA class III and IV) and ejection fraction <25%. The results demonstrated that carvedilol improved survival 38%.
Only one large-scale trial failed to demonstrate a benefit with b-blockade. In BEST (Beta-blocker Evaluation of Survival Trial), treatment with bucindolol did not significantly reduce all-cause mortality in patients with NYHA class III (92%) or IV (8%) HF and ejection fraction ≤35%. However, treatment achieved short-term benefits, including improved ejection fraction and reductions in heart rate and HF symptoms.4
1 CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet. 1999;353:9-13.
2 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:
3 Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med.2001;344:
4 BEST Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:

2. MERIT-HF: Reduction in total mortality and hospitalizations in women
receiving b-blockade
Content points:
Because there have not been enough women enrolled in HF trials there has been a lack of knowledge about the effect of various management strategies on survival in women.
The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) study in patients with class II to IV HF and LV ejection fraction ≤0.40 included 898 women (22%), of which 183 had severe HF (class III/IV and LV ejection fraction <0.25). In a post hoc analysis, the beneficial effects of ER metoprolol succinate were also seen in women with HF and LV dysfunction, including women with clinically stable, severe HF.
Treatment resulted in a 21% reduction in the primary combined endpoint of all-cause mortality/all-cause hospitalizations (P = 0.044). Cardiovascular hospitalizations were reduced 29% (P = 0.013) and hospitalization for worsening heart failure was reduced 42% (P = 0.021).
In the subgroup of women with severe HF (not shown), there were reductions of 57% in cardiovascular hospitalizations (P = 0.005) and 72% reduction in hospitalization due to worsening HF (P = ).
1 Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: Analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation. 2002;105:

3. MERIT-HF: Efficacy of b-blockade in elderly patients with heart failure
Content points:
A subgroup analysis of the MERIT-HF study examined the efficacy and tolerability of b-blockade in patients with HF aged ≥65 versus ages <65 years.1 There were no significant differences in baseline variables among older patients except for a higher prevalence of AF, history of MI, and NYHA class III HF.
In the group aged ≥65 years there were significant risk reductions of 37% in total mortality, 43% in sudden death, and 30% in death or hospitalizations for worsening HF, which were comparable to those in younger patients (ie, <65 years).
Fewer patients aged ≥65 years reached the target 200-mg dose (54%) compared with those <65 years (71%), although they tolerated b-blockade as well.
The results show no notable differences in the efficacy and tolerability of b-blockade between older and younger patients. These results indicate that elderly patients can be expected to benefit substantially from b-blockers.
1 Deedwania PC, Wikstrand J, Gottlieb SS, Wedel H, Klibaner M. Efficacy and tolerability of treatment with metoprolol CR/XL in elderly patients with heart failure. Circulation. 2001;104(suppl II):II-753. Abstract 3547.

4. COPERNICUS: Effect of b-blockade in patients with severe HF by
sex and age
Content points:
OPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study) evaluated 2289 patients with symptoms of HF at rest who were clinically euvolemic and had an ejection fraction <25%.1 Patients who required intensive care, had marked fluid retention, or receiving intravenous vasodilators or positive inotropic drugs were excluded.
Patients were randomly assigned to treatment with carvedilol (n = 1156) or placebo (n = 1133) for a mean period of 10.4 months, during which standard therapy for HF was continued.
There were 190 deaths in the placebo group and 130 deaths in the carvedilol group, representing a 35% adjusted risk reduction (P = ). There was also a 24% difference in the number of patients who died or were hospitalized for worsening HF in the carvedilol group (P < 0.001).
The benefits of treatment were seen in women as well as men, in elderly patients, ie, those ≥65 years as well as in patients aged <65 years.
1 Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:

5. MERIT-HF: Effects of b-blockade on mortality in post-MI and
Hypertensive patient subgroups
Content points:
The first and second most common etiologies for HF are ischemic heart disease and hypertension.1 Approximately 50% of the MERIT-HF population had a history of acute MI and 44% had a history of hypertension.2,3
A prespecified subgroup analysis was done to determine the effects of b-blocker therapy in patients with MI who developed HF (n = 1926).2 Compared with placebo, the group taking ER metoprolol succinate had risk reductions of 40% in total mortality (P = ); 50% in sudden death (P = ); and 49% in death due to worsening HF (P < 0.021).
A subgroup analysis of MERIT-HF patients with a history of hypertension (n = 1747) showed that ER metoprolol succinate reduced the risk of total mortality 39% (P = ), mainly because of reductions of 49% in sudden death (P = ) and 51% in mortality from worsening HF (P = 0.042).3
The mean dose for the ER metoprolol succinate group was 146 mg once daily.
1 Wilson PWF. An epidemiologic perspective of systemic hypertension, ischemic heart disease, and heart failure. Am J Cardiol. 1997;80(9B):3J-8J.
2 Ghali JK, Janosi A, Herlitz J, Czuriga I, Klibner M, Wikstrand J, Hjalmarson A. Metoprolol CR/XL in post-myocardial infarction patients with chronic heart failure: Experiences from MERIT-HF. Circulation. 2002;106(Suppl). Abstract 3382.
3 Herlitz J, Wikstrand J, Denny M, Fenster P, Heywood T, Masszi G, et al. Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension. J Card Fail. 2002;8:8-14.

6. in diabetic and nondiabetic patients
MERIT-HF: Effect of b-blockade on total mortality or HF hospitalization
in diabetic and nondiabetic patients
Content points:
Although the benefits of b-blockers in HF have been established, they continue to be underutilized because of concerns about efficacy and safety in high-risk patients, including patients with diabetes.
In the MERIT-HF study, 25% of the patients had diabetes (n = 984). A post hoc analysis in the diabetic subgroup demonstrated the safety and efficacy of ER metoprolol succinate in these patients.1
The diabetic patients taking ER metoprolol succinate had a 29% reduction in the combined outcome of death from any cause or hospitalization for worsening HF (P = 0.007), which was comparable to the 31% reduction in nondiabetic patients (P < 0.001).2
At the end of the study, the mean b-blocker dose in the diabetic cohort was 162 mg. The rates of both discontinuation due to an adverse event or worsening HF were significantly lower in the ER metoprolol succinate group compared with placebo
1 Deedwania P, Giles T, Ghali JK, Gottlieb SS. Safety and efficacy of treatment with metoprolol CR/XL in diabetic patients with heart failure. Circulation. 2000;102(Suppl II). Abstract 3760.
2 Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al, for the MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA. 2000;283:

7. b-Blocker titration in major HF trials Content points:
There has been concern that b-blockade may lead to worsening HF when b-blocker therapy is initiated. Therefore, many physicians are reluctant to inititate these agents. However, experience in major HF trials has shown that b-blockers can be initiated safely in the overwhelming majority of patients with stable mild-to-moderate HF, with minimal side effects or deterioration.1-3
In recent b-blocker HF survival trials, including MERIT-HF,1 CIBIS-II,2 and COPERNICUS,3 b-blocker treatment began at low doses and was titrated at intervals of ≥2 weeks over approximately 3 months to the target or highest tolerated dose.
As this indicates, b-blockers therapy should begin with low doses and proceed cautiously, gradually increasing the dose every 1 to 2 weeks to the full b-blocker dose or the maximum tolerated dose.
Treatment should be tailored to the individual patient. Patients with more severe HF need to be monitored carefully. For example, in MERIT-HF, patients in NYHA class III and IV HF began treatment with ER metoprolol succinate 12.5 mg once daily compared with a 25-mg dose for class II.4 In COPERNICUS, patients weighing ≤187 pounds were targeted at a lower dose of carvedilol (25 mg bid) than patients ≥188 pounds (50 mg).
At the end of the titration phase, approximately two thirds of patients were on the target doses of carvedilol and ER metoprolol succinate. In MERIT-HF, 80% patients tolerated ≥100 mg ER metoprolol succinate. In the CIBIS-II study, 43% patients were on the target dose, bisoprolol 10 mg, but 67% were taking at least 5 mg of bisoprolol.
1 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. 1999;353:
2 CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomized trial. Lancet.1999;353:9-13.
3 Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:
4 Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure. J Am Coll Cardiol. 2002;40:

8. MERIT HF: Discontinuation from study medicine during follow-up
Content points:
The results of MERIT-HF show that b-blockade can be initiated safely in the overwhelming majority of patients with stable mild-to-moderate HF with minimal side effects or deterioration.1
Among patients with NYHA class II HF, more patients in the placebo group than in the b-blocker group discontinued treatment. In the group with NYHA class III and IV, fewer than 3% more patients on b-blockade than placebo discontinued treatment. Among patients with class III and IV HF and an ejection fraction <25%, there was less than 1% excess discontinuation in the b-blocker group.
In all NYHA classes, from day 90 until the end of the study, more patients in the placebo group discontinued treatment than with b-blockade.
Discontinuation does not necessarily reflect important adverse effects. Heart rate was the most common reason given for discontinuation, which suggests that the drug may have been well tolerated in many patients in whom it was nevertheless discontinued.
1 Gottlieb SS, Fisher ML, KjekshusJ, Deedwania P, Gullestad L, Vitovec J, Wikstrand J. Tolerability of ß -blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Circulation. 2002;105:

9. MERIT-HF: Consistent heart rate reduction with lower vs higher
b-blocker dose
Content points:
Clinical trials in patients with HF show b-blockers reduce mortality and improve outcomes. Because not all patients reached the maximum dose, clinicians have questioned whether maximum doses are necessary to benefit from treatment. In a post hoc analysis of MERIT-HF, Wikstrand et al1 investigated heart rate during titration phase in two dosage groups. This analysis produced additional information on this issue.
The high-dose subgroup (n = 1202) reached >100 mg of ER metoprolol succinate once daily (mean dose 192 mg).
The low-dose subgroup (n = 412) reached ≤100 mg once daily (mean dose 76 mg).
Starting from a similar heart rate of 81 and 83 beats/min (high- vs low-dose, respectively), both groups reached a heart rate of 67 beats/min. This indicates that the low-dose group had a higher sensitivity for b-blockade. For each milligram of b-blocker, heart rate was reduced 0.21 beats/min in the low-dose group versus 0.08 beats/min in the high-dose group.
This observation is important to understanding the clinical benefits of treatment in the two subgroups. Greater sensitivity to b-blockade in the low-dose group might be caused by downregulation and densensitization of myocardial b1-receptors in patients with more advanced disease,2 which predominated in the low-dose subgroup. The low-dose group had more patients in class III and IV HF.
Clinical outcomes in the high- and low-dose groups are discussed on the next slide.
1 Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: Analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). J Am Coll Cardiol. 2002;40:
2 Bristow MR, Ginsburg R, Mintobe W, Cubicciotti RS, Sageman WS, Lurie K, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:

10. MERIT-HF: Flexible dosing achieves consistent results Content points:
Results of MERIT-HF subgroup analysis1 showed that, compared with patients in the high-dose group (>100 mg ER metoprolol succinate once daily), patients in the low-dose group (≤100 mg once daily) were slightly older, had somewhat lower BP, and were more likely to have ischemic HF and a history of MI.
Despite being at higher risk, patients in the low-dose group still derived benefit from b-blocker treatment. Total mortality per patient-year of follow-up was 10.8% in the placebo group compared with 6.8% in the two b-blocker groups, corresponding to a risk reduction of 38%. The low- and high-dose groups had similar risk reductions in sudden death (44%) and death from worsening HF (48%).
This analysis of achieved dose and outcomes in MERIT-HF supports the concept that b-blocker dose should be tailored according to the individual patient’s response. Although the target dose of 200 mg ER metoprolol succinate once daily was well tolerated and effective for most patients, for those patients who cannot tolerate high doses, lower doses can be given with the knowledge that they are of substantial benefit.
1 Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: Analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). J Am Coll Cardiol. 2002;40:

11. b-Blockade modifies circadian pattern of ventricular tachyarrhythmias
Content points:
Sudden cardiac death exhibits a circadian variation and commonly peaks in the morning. This study showed that b-blockers blunt the morning peak in life-threatening ventricular tachyarrhythmias.1
This study of 87 patients with ICDs included patients who were and were not receiving b-blockers. There were 344 tachyarrhythmia episodes in patients without b-blockers and they exhibited a circadian pattern, peaking at 38 episodes between 6 am and 12 pm. In contrast, episodes of tachyarrhythmias (104) were equally distributed throughout the day in patients who were taking b-blockers.
The blunted morning peak of ventricular tachyarrhythmias by b-blockers supports the hypothesis that the circadian rhythm of tachyarrhythmias and sudden death is due to a morning surge in sympathetic tone that results in an elevation in catecholamines, heart rate, and BP.
1 Behrens S, Ehlers C, Bruggemann T, Ziss W, Dissmann R, Galecka M, et al Modification of the circadian pattern of ventricular tachyarrhythmias by betablocker therapy. Clin Cardiol. 1997;20:

12. Sudden death: Risk reduction with b-blockade Content points:
Placebo-controlled studies have shown significant reductions in sudden death with b-blockade.
Primary prevention. About 50% of men and 63% of women who die suddenly have no previous symptoms of coronary disease.1
MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) demonstrated a 30% reduction in sudden death in patients with mild-to-moderate uncomplicated hypertension who were treated initially with a b-blocker (metoprolol, mean dose 176 mg daily) compared with a diuretic.2
Secondary prevention. The risk of sudden death is increased 4 to 6 in people who have had a heart attack.1
Pooled results of five double-blind randomized studies that included more than 5000 post-MI patients show that b-blockade (metoprolol 100 mg twice daily) reduced sudden deaths 42% compared with placebo.3
Heart failure. The risk of sudden death increases 6 to 9 with HF compared with the general population.1
In the MERIT-HF study, b-blockade (ER metoprolol succinate 200 mg once daily) reduced sudden death 41%. The benefits of b-blockade were apparent within 2 months.4
1 American Heart Association Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association
2 Olsson G, Tuomilehto J, Berglund G, Elmfeldt D, Warnold I, Barber H, et al. Primary prevention of sudden cardiovascular death in hypertensive patients. Mortality results from the MAPHY Study. Am J Hypertens. 1991;4(2 Pt 1):
3 Olsson G, Wikstrand J, Warnold I, Manger Cats V, McBoyle D, Herlitz J, et al. Metoprolol-induced reduction in postinfarction mortality: Pooled results from five double-blind randomized trials. Eur Heart J. 1992;13:28-32.
4 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:

13. MADIT II: Survival with prophylactic ICD in MI patients with EF ≤30%
Content points:
Recently the Centers for Disease Control and Prevention reported that more than 460,000 sudden deaths occur annually in the United States. Sudden death accounts for 63% of all cardiac mortality.1
MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) showed that prophylactic implantation of a defibrillator improves survival in patients with prior MI and reduced LV ejection fraction (EF).2 MADIT-II enrolled 1232 patients with prior MI and a LV ejection fraction ≤30%. They were randomly assigned to receive either an implantable cardiac defibrillator (ICD) (n = 742) or conventional therapy (n = 490).
During an average follow-up of 20 months, the mortality rate from any cause was 19.8% with conventional therapy and 14.2% in the ICD group, representing a 31% risk reduction (P = 0.016). The effect was consistent regardless of age, sex, ejection fraction, NYHA functional class, and the QRS interval. Over 70% of patients in both treatment arms were receiving b-blockers and ACE inhibitors.
MADIT-II concluded ICDs improve survival in patients with coronary heart disease and moderate to severe LV dysfunction and recommends its widespread use.
The clinical benefit of ICDs is convincing. However, widespread use will be very expensive-currently, the device alone costs $20,000 (US$). An evaluation of the cost effectiveness of ICD treatment in MADIT-II is underway. At present, it is estimated that 11 high-risk coronary patients need to be treated over a 3-year period to save one life.3
1 Centers for Disease Control and Prevention. State specific mortality from sudden cardiac death—United States MMWR. 2002;51:
2 Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:
3 Moss AJ. MADIT-II and its implications. Eur Heart J. 2003;24:16-18.

14. Predictive power of BNP for HF hospitalization or death
Content points:
This study showed that B-type natriuretic peptide (BNP) levels in patients with dyspnea were a predictor of future cardiac events.1
BNP levels were measured in 324 patients presenting to the emergency department with dyspnea. The group was followed for 6 months to determine outcomes, including death (cardiac and noncardiac), hospital admissions (cardiac), and repeat emergency department visits for HF.
Higher BNP level indicated a progressively worse prognosis. Patients with BNP >480 pg/mL had a 42% 6-month cumulative probability of being admitted to the hospital for HF or death. By comparison, those with BNP levels <230 pg/mL had only a 2% chance of such events.
The relative risk of HF death in patients with BNP levels >230 pg/mL was 24%.
1 Harrison A, Morrison LK, Krishnaswamy P, Kazanegra R, Clopton P, Dao Q, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med. 2002;39: