Beta Adrenergic Receptor Blockers

Beta blocker therapy, advocated for HF by some investigators since the 1970s,21 remains a major advance in the treatment of patients with HF and reduced LVEF. Several large-scale clinical trials, involving more than 10,000 patients, have provided unequivocal evidence of important reductions in both mortality and morbidity.22-28 The marked beneficial effects of beta blockade has been well demonstrated in large-scale clinical trials of symptomatic patients with NYHA class II-IV HF and reduced LVEF using carvedilol, bisoprolol, and metoprolol controlled release/extended release (CR/XL) (Table 7.1). 24-28 These trials added beta blockade to background therapy that included ACE inhibitors and diuretics in more than 90% of patients. The trial results support benefit from both beta1 selective and nonselective beta blockers, whether ancillary properties are present or not. Beta blocking agents with intrinsic sympathomimetic activity are likely to worsen survival and should be avoided in patients with HF.29 The beta blockers that have been shown to be effective in clinical trials and their corresponding doses are shown in Table 7.1. Whenever possible, beta blockers proven to be efficacious in clinical trials should be used. A general summary of recommendations for the successful administration of beta blockers are provided in Table 7.2.

Nebivolol is a beta1 selective beta blocker that is currently only approved for the treatment of hypertension in the United States (US.), but it does not have a Food and Drug Administration (FDA) approved indication for HF. Outcomes with nebivolol have recently been reported in the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial. The study was a randomized trial in 2128 patients >=70 years with a history of HF (a hospitalization for HF in the last year or an LVEF <=35%). The primary endpoint of all-cause mortality or cardiovascular hospitalizations was reduced with nebivolol from 35.3% to 31.1% (HR 0.86, 95% CI 0.74-0.99, p = 0.039).28 In contrast to other beta blocker trials, nebivolol did not significantly reduce all-cause mortality (HR 0.88, 95% CI 0.71-1.08, P=0.21). 28

The randomized controlled trials of beta blockers were conducted in addition to ACE-inhibitor therapy. Thus, ACE-inhibitors have generally been initiated first, followed by beta-blockade. The Cardiac Insufficiency Bisoprolol Study III (CIBIS III) trial evaluated the effect of either bisoprolol or enalapril monotherapy for 6 months, followed by combination therapy on mortality and hospitalization.30 The findings of this study suggested that the safety and efficacy of either approach (beta blocker initiation first or ACE-inhibitor initiation first) was similar.30

Randomized controlled data support the efficacy of ACE inhibitors in reducing both the likelihood of developing HF and the need for treatment or hospitalization in asymptomatic patients with an LVEF <=35%.31 Similar data are not available to support the use of beta blocker therapy in asymptomatic patients with reduced LVEF. Nevertheless, a number of arguments support the routine use of beta blockade in these patients. Guidance is provided by studies indicating the effectiveness of beta blocker therapy in patients following MI with good symptomatic and functional recovery, yet reduced LVEF. 31-33 These studies enrolled a number of patients without clinical HF. The Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) study demonstrated a reduction in all cause mortality, cardiovascular mortality, and recurrent non-fatal MI for patients with post-MI reduced LVEF randomized to carvedilol.34 Multiple studies suggest myocardial remodeling following beta blocker therapy in patients with symptomatic HF as well.35-38

Ongoing clinical experience and current trial data indicate that beginning beta blockade at low dose in the hospital is possible in patients with improved congestion and other symptoms.39,40 Initiation of therapies in hospital is known to result in better utilization and the attainment of more optimal doses of a variety of cardiovascular drugs.41,42

Beta blocker therapy should not be initiated in patients with acute decompensated heart failure (ADHF) with persistent symptoms and congestion. However, many patients hospitalized for HF are NYHA functional class IV from volume overload, and will improve sufficiently with standard therapy to allow introduction of beta blockade. The Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) provides strong evidence in a prospective, randomized trial that patients with advanced HF, treated aggressively to reduce congestion and improve symptoms, benefit substantially from the introduction of beta blockade.43

The beta blockers studied in clinical trials are now established as routine therapy in patients with reduced LVEF. This therapy is well tolerated by a large majority of patients with HF, even those with comorbid conditions like diabetes mellitus,44,45 chronic obstructive lung disease46 and peripheral vascular disease.47

Clinical trials of beta blockers in HF have been conducted by uptitrating beta blockers to a maximum tolerated dose rather than titrating to a reduction in heart rate. Recent meta-analyses of previous trials suggest that the magnitude of benefit of beta blockers may be related to the reduction in heart rate rather than the dose of beta blocker.48-51 However, until further data are available the current recommendation to uptitrate to doses of beta blockers used in randomized clinical trials will remain unchanged. In trials of chronic HF with reduced LVEF, beta blockers were initiated at low doses and uptitrated gradually, typically at 2-week intervals.24-27 In patients with reduced LVEF following newly diagnosed MI, beta blockers were initiated at low disease and uptitrated after 3-10 day intervals.34 Doses found to be effective in HF trials are generally achieved in 8 to 12 weeks. Patients developing worsening HF symptoms or other side effects during titration may require a dosage adjustment of diuretic or concomitant vasoactive medications. If side effects resolve with medication adjustment, patients can subsequently be titrated to target or maximally tolerated doses. Some patients may require a more prolonged interval during uptitration, a temporary reduction in beta blocker dose, or, in rare cases, withdrawal of therapy. If switching from a non-evidence based beta blocker to an evidence-based beta blocker, wait 24 hours from the last dose of a once-daily agent or wait 12 hours from the last dose of a twice-daily agent before beginning an evidence-based beta blocker.52 The dose of the evidence-based beta blocker should be the equivalent of one-half the non evidence-based dose for most patients, although lower initial doses may be clinically appropriate for some patients; then uptitrate to target dose at 2-week intervals.52

Clinical deterioration during stable maintenance therapy with beta blockers rarely is related to administration of these agents. Nonadherence to medications, progression of underlying LV dysfunction and the adverse influence of a number of comorbid factors, including the occurrence of ischemia, hemodynamic instability from arrhythmia, and pulmonary complications such as pneumonia, are much more likely to be responsible for clinical deterioration. The best course is to use standard therapy to relieve congestion and treat exacerbating factors, rather than reduce or discontinue beta blockade. A retrospective review of patients enrolled in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial of patients hospitalized with ADHF, found that continuation of beta blockade did not interfere with symptomatic improvement during admission,53 supporting the continuation of beta blockade in patients hospitalized with an episode of decompensation. This same observation was made in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial.54 In the Carvedilol or Metoprolol European Trial (COMET), patients whose beta blocker was discontinued or the dose reduced during a HF hospitalization had a higher mortality at 1 and 2 years as compared to patients whose therapy was continued.55 Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry also demonstrated an association between lower post-discharge mortality risk and continuation of beta blocker therapy during a HF hospitalization, even after adjustment for other prognostic factors.56

The Beta-blocker Continuation Versus Interruption in Patients with Congestive Heart Failure Hospitalized for a Decompensation Episode (B-CONVINCED) study was a randomized, controlled, open label trial of beta-blockade continuation versus discontinuation in 169 patients with acutely decompensated HF and LVEF <40%.57 There was no difference between groups in general well-being or dyspnea at either day 3 or day 8 after randomization. Length of hospital stay was not different between groups, and there was no difference in in-hospital mortality or death or rehospitalization at 3 months. The proportion of patients receiving beta blockade at 3 months was higher for patients who were maintained on beta blockade during the hospitalization (90% vs. 76%, P=0.04).57

Abrupt withdrawal of beta blockade should be avoided, especially in patients with coronary artery disease. Studies of the withdrawal of beta blockade in patients with reduced LVEF, but improved and stable clinical HF, have revealed a substantial risk of worsening HF and early death after beta blocker discontinuation.58,59

In certain patients, frequent return visits for dose titration may be difficult to accommodate in a busy clinical practice. Trained personnel, including nurse practitioners, physician assistants, and pharmacists, with physician supervision, may more efficiently perform patient education and reevaluation during uptitration. HF specialty programs are more likely to have the resources to provide this follow-up and education.60 Patients should be aware that symptomatic deterioration is possible early in therapy and that symptomatic improvement may be delayed weeks to months.

Referral to clinicians with HF expertise may be helpful for patients who do not have contraindications to beta blockade (such as symptomatic bradycardia), but who have difficulty initiating, uptitrating or maintaining beta blocker therapy. Several factors may contribute to difficulty in using beta blocker therapy, including recent or multiple HF hospitalizations; HF associated with ischemia, uncontrolled hypertension, moderate -severe valvular disease, syncope, or renal dysfunction; other multiple, active comorbidities, including asthma and chronic obstructive pulmonary disease; intolerance to other recommended HF drug therapies; persistent poor adherence to the HF plan of care; low output state; and persistent NYHA class III or IV symptoms.