Propranolol entered clinical use for angina and myocardial infarction in the 1960s [23]. At that time, the existing therapies for chronic heart failure were digitalis, diuretics, and bed rest [24]. Early work into the pathophysiology of heart failure suggested that the heart was functionally deinnervated in heart failure [25] and that the elevated heart rate seen in patients with advanced cardiomyopathy was required to maintain cardiac output [26]. Therefore, it is not surprising that there was a long delay before the first clinical use of β-blockers for HFREF.

Then in the early 1970s, Waagstein and colleagues made the observation that treatment with propranolol improved pulmonary edema in patients with acute heart failure due to ischemia [27]. The mechanism of this benefit was thought to be reduction of tachycardia and decreased myocardial oxygen utilization [28]. Waagstein reasoned that patients with cardiomyopathy and resting tachycardia might derive a similar benefit from treatment with β-blockers. They treated seven patients with dilated cardiomyopathy for 2–12 months and found that β-blocker treatment decreased heart failure symptoms, improved exercise tolerance, and increased ejection time; they even noted an increased ejection fraction (EF) in three patients [27]. The next demonstration of the clinical utility of β-blocker therapy was by Swedberg and colleagues [29]. They initiated 24 patients with dilated cardiomyopathy already being treated with diuretics and digoxin on metoprolol, practolol, or alprenolol, and slowly increased the dose over 1–4 weeks. Treatment duration was at least six months. Survival was markedly improved in the group treated with β-blocker therapy in addition to diuretics and digoxin, as compared to historical controls treated with diuretics and digoxin alone (survival at 2 years 66 % versus 19 %).

β-blocker therapy for HFREF was initially met with skepticism [30], perhaps due to the small sample size and lack of control use in these early studies. This skepticism was further sustained by two small clinical trials that failed to show clinical benefit of β-blocker treatment in a total of 25 patients with dilated cardiomyopathy [31, 32].

The first randomized, placebo-controlled, multicenter clinical trial of β-blocker therapy in HFREF was the Metoprolol in Dilated Cardiomyopathy (MDC) trial [33]. In this trial, 383 patients with symptomatic dilated cardiomyopathy with a left ventricular EF less than 40 %, already on background treatment with an angiotensin converting enzyme inhibitor (ACEI), were treated with metoprolol tartrate or placebo, and followed for 12–18 months. Metoprolol tartrate was initiated at 10 mg twice daily and the dose titrated up to a target of 100–150 mg daily (mean dose 108 mg daily). Metoprolol treatment was associated with a 34 % reduction in the combined endpoint of death or need for heart transplantation, but this trend was not statistically significant. Treatment with metoprolol also lead to improvements in both exercise capacity and New York Heart Association (NYHA) class.

The Cardiac Insufficiency Bisoprolol Study (CIBIS) was initiated to determine the effect of β-blocker therapy on mortality in patients with dilated as well as ischemic cardiomyopathy, and to assess the tolerability of β-blocker therapy [34]. In the study, 641 patients with advanced symptomatic heart failure (NYHA classes III and IV) with an EF less than 40 % were treated with bisoprolol or placebo and followed for a mean of 1.9 years. Bisoprolol treatment was associated with a 20 % reduction in all-cause mortality, but once again this was not statistically significant (confidence interval 0.56–1.15). However, there was a statistically significant decrease in hospitalization for heart failure and improvement in NYHA class with bisoprolol treatment. Two possible explanations for the failure of both the MDC and CIBIS trials to show a statistically significant effect of β-blocker therapy on mortality are either insufficient power in both trials, and/or the relatively low drug doses used in the studies (mean metoprolol dose in MDC of 108 mg, mean bisoprolol dose in CIBIS of 3.8 mg).

By 1994, β-blocker therapy had been shown to improve quality of life and decrease hospitalization for heart failure, but had not proven to affect mortality. Several large-scale clinical trials were initiated to determine if β-blocker therapy would indeed improve survival: (1) US Carvedilol Trials Program, (2) Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and (3) Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). The US Carvedilol Trials Program was actually four clinical trials that were performed as part of phase III evaluation of carvedilol and were analyzed together [20]. In that trials program, 1094 patients with symptomatic heart failure were treated with carvedilol or placebo [35]. The program was ended early due to the significantly lower number of deaths in patients receiving carvedilol. The annual mortality rate was 3.2 % in the carvedilol group as compared to 7.8 % in the placebo group (relative risk reduction of 65 %). In May 1997, carvedilol became the first β-blocker to be approved by the FDA for the treatment of HFREF.

The US Carvedilol Trials Program was followed by publication of the CIBIS-II trial and the MERIT-HF trial. In CIBIS-II, treatment with bisoprolol as compared to placebo conveyed a strong mortality benefit in patients with advanced heart failure (83 % of patients were NYHA class III and 17 % were NYHA class IV) and an EF of less than 35 % [36]. In MERIT-HF, 3991 patients with symptomatic heart failure (mostly NYHA classes II and III) and an EF of less than 40 % were randomized to metoprolol succinate or placebo [37]. It showed statistically significant improvement in multiple outcomes: a 34 % reduction in mortality, a 49 % reduction in death from heart failure, and a 41 % reduction in sudden cardiac death with metoprolol treatment. Table 6.2 is a summary of the five β-blocker trials that have shown statistically significant decreases in mortality.

Despite the results of CIBIS-II, there was not widespread adoption of β-blocker therapy for patients with advanced heart failure [38]. In addition, there was concern whether certain racial minorities and women, who had both been underrepresented in previous trials, would also derive benefit from β-blocker therapy. To address these issues, the Beta-Blocker Evaluation of Survival Trial (BEST) was performed. In BEST, 2708 patients with advanced symptomatic heart failure (NYHA classes III and IV) and an EF less than 35 % were treated with bucindolol or placebo and followed for a mean of 24 months [39]. The BEST study population was 30 % minorities and 23 % women. The trial was ended early due to the absence of a significant difference in mortality between the treatment and placebo groups (hazard ratio of 0.9). It is worth noting that there were statistically significant decreases in the secondary outcomes of death from cardiovascular causes and hospitalization for heart failure.

Subgroup analysis of the BEST study showed that patients with non-black race received a mortality benefit from bucindolol, whereas black patients had no benefit. Given this, possible explanations for the failure of the trial to show a mortality benefit included that bucindolol had different pharmacologic properties as compared to the other β-blocking drugs, or that the population under study had pharmacogenetic differences that led to non-response. A subsequent study by Bristow and colleagues has suggested that the lack of efficacy in African-American patients may be due to a specific deletion within the α_2c-AR gene [40]. Additional work has confirmed that β-blockers do improve outcomes in African-American patients with heart failure, although to a lesser extent than in white patients [41].

Given that the BEST trial showed no survival benefit of bucindolol in patients with advanced cardiomyopathy, there was continuing concern that β-blocker therapy would worsen heart failure in patients with advanced cardiomyopathy. This led in part to the design and execution of the Carvedilol Prospective Randomized Cumulative Survival Study Group trial (COPERNICUS) [35]. In this trial, 2289 patients with advanced symptomatic heart failure (NYHA classes III and IV) and an EF less than 25 % were treated with carvedilol or placebo and followed for a mean duration of 10.4 months. The trial was stopped early due to a statistically significant 35 % decrease in the risk of death in the treatment group. Importantly, therapy with carvedilol was well tolerated in this population, with a higher withdrawal rate at 1 year in the placebo group (18.5 % vs. 14.8 %).

Packer and colleagues published a meta-analysis in 2001 that showed that treatment with carvedilol led to a greater increase in EF as compared to metoprolol [42]. To assess whether this difference in EF led to a difference in outcome, the Carvedilol Or Metoprolol European Trial (COMET) was performed. In this trial, 3029 patients with symptomatic heart failure and an admission for heart failure within the last 2 years were randomized to carvedilol or metoprolol tartrate [43]. The mean doses achieved were 41.6 mg daily for carvedilol and 85 mg daily for metoprolol. After a mean of 58 months, patients treated with carvedilol had a 17 % lower risk of death, but there was no difference in the risk of hospital admission between the two groups. The results of the COMET trial are controversial because metoprolol tartrate is not FDA-approved for heart failure and the dose achieved in the metoprolol arm was relatively low [44]. Post-hoc analysis of the data from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) showed that carvedilol was superior to metoprolol [45]. Over a follow up of 3.4 years in 1515 patients with mild heart failure (NYHA class I and II, EF ≤ 30 %), carvedilol treatment was associated with a 28 % lower risk of death or hospitalization for heart failure as compared to metoprolol.

These five clinical trials form the evidence-basis for the utilization of β-blockers in HFREF (summarized in Table 6.2). Use of β-blockers has been shown to decrease mortality, hospitalization and death from heart failure, and sudden cardiac death; therefore all patients with a left ventricular EF of 40 % and below should be treated with a β-blocker in the absence of a significant contraindication [46]. Because MERIT-HF used metoprolol succinate, BEST showed no benefit with bucindolol, and carvedilol was found to be superior to metoprolol tartrate in COMET, guidelines from the American College of Cardiology [47] and the Heart Failure Society of America [46] recommend that only carvedilol, bisoprolol, or metoprolol succinate be used to treat patients with HFREF.

In practice, clinicians caring for patients with newly diagnosed HFREF need to decide whether to initiate medical therapy for heart failure with an ACEI or a β-blocker. This dilemma is especially pertinent for patients whose initial BP is not sufficient to allow treatment with evidence-based doses of both agents. It is important to note that in the five β-blocker trials showing a decrease in mortality, nearly all patients (>90 %) in each trial were already being treated with an ACEI or angiotensin receptor blocker (ARB). Given this, current guidelines recommend initiation of an ACEI or ARB prior to the initiation of a β-blocker [46]. However, there is a small body of data that suggests that upfront initiation of a β-blocker is safe and effective. Sliwa and colleagues performed a single-center randomized trial of carvedilol or perindopril (an ACEI) as initial therapy for 78 patients with idiopathic dilated cardiomyopathy [48]. Treatment with the first agent was continued for 6 months and then the second agent added. Endpoints were reviewed after 1 year. They found that patients in the carvedilol-first group experienced a greater improvement in NYHA class, EF, B-type natriuretic peptide levels, with a higher carvedilol dose achieved. These positive findings led to the CIBIS-III trial, in which 1010 patients with symptomatic heart failure and an EF less than 35 % were randomized to monotherapy with bisoprolol or enalapril for 6 months [49]. After this time, the complimentary drug was initiated and maintained through the end of the trial. Treatment with bisoprolol-first was noninferior to enalapril-first in the intention-to-treat sample with regards to the primary endpoint of mortality or hospitalization for HF. There was no statistical difference in the frequency of adverse events between the groups. Further analysis of CIBIS-III has shown that 60 % of the adverse events occurred during the monotherapy period [50], suggesting that both guideline-based therapies should be implemented and uptitrated without delay.

In addition to a mortality benefit, β-blocker therapy has been shown to have other significant clinical benefits in patients with HFREF. Treatment with carvedilol and metoprolol succinate have been shown to lead to reverse remodeling of the left ventricle, characterized by an increase in the EF and a decrease in the end-systolic and end-diastolic volumes [51]. β-blocker therapy improves heart failure symptoms, with a net effect of lowering NYHA class by one grade and improving exercise time [52]. Only one meta-analysis of ten trials showed no significant improvement in quality of life with β-blocker therapy [53].

Peak oxygen consumption (VO₂) and natriuretic peptides are commonly used markers of heart failure severity that are affected by treatment with β-blockers. In 1991 Mancini and colleagues followed a group of ambulatory heart failure patients with a VO₂ > 14 mL/kg/min who had similar one- and two-year survival rates with or without heart transplantation [54]. Subsequently, this VO₂ value has served as a useful threshold to inform the timing of heart transplantation. This study was completed before the widespread use of β-blockers in HFREF. While β-blocker treatment does not change peak VO₂, long-term mortality is improved with a hazard ratio of 0.6 [55]. Because of this improved mortality while on treatment, Peterson and colleagues showed that advanced cardiomyopathy patients receiving β-blockers do not benefit from heart transplantation until VO₂ < 12 mL/kg/min [56].

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-BNP) are used as both diagnostic and prognostic markers for heart failure [57]. Stanek and colleagues were among the first to examine the effect of β-blocker treatment on BNP and NT-BNP levels [58]. They found that treatment with atenolol for 6 months reduced NT-BNP but not BNP levels. In a substudy of the COPERNICUS trial, treatment with carvedilol did not decrease the median level of NT-BNP as compared to placebo, but did strongly decrease NT-BNP when analyzed as a change from baseline level for each patient (25 % decrease with carvedilol as compared to 5 % decrease with placebo at 6 months) [59]. Treatment with a β-blocker does not affect the utility of these prognostic markers, as BNP and NT-BNP levels remain strongly predictive of mortality [58, 60].

Patients with chronic heart failure are a heterogeneous group with a wide spectrum of cardiovascular diseases and underlying comorbidities. Despite this heterogeneity, multiple subgroups of patients with HFREF are able to be safety treated with β-blocker therapy and there are few absolute contraindications to their use.

There are important considerations and cautions for the use of β-blockers in the treatment of HFREF. Table 6.3 contains a list of the comorbidities and conditions in which β-blocker therapy for HFREF is generally tolerated or in which therapy should be used with caution or avoided.

Concerns that treating HFREF with β-blockers would worsen heart failure symptoms and precipitate decompensation shortly after drug initiation have been prevalent [61]. Hemodynamic data confirm that left ventricular systolic pressure and cardiac index acutely decrease [62]. β-blocker administration may decrease sodium excretion and thereby increase volume overload [63]. Consistent with this, both BNP and NT-BNP levels are increased compared to baseline when measured 6 weeks after β-blocker initiation, and then decline by 3 months [59, 64]. These data underscore the point that β-blocker initiation may cause a transient worsening of clinical status.

By following three principles during initiation of β-blocker therapy, clinicians can help ensure tolerability and patient acceptance. First, β-blockers should not be initiated in patients in acute hemodynamic instability. Second, β-blockers should not be initiated in patients with worsening symptoms and signs of volume overload. In all of the large clinical trials discussed above, patients were clinically euvolemic at the time of drug initiation. Third, β-blockers should be initiated at a low dose, and then titrated upwards at regular intervals over several weeks. Before each dose increase, the clinician should ensure the patient has maintained clinical stability in terms of symptoms, volume status, heart rate, and BP. The frequency of dose increase in clinical trials has varied between 1 week (as in CIBIS-II and BEST) and 2 weeks (as in MERIT-HF, COPERNICUS, and COMET), with current guidelines recommending dose increases at 2 week intervals [46]. In our practice, we individualize both the starting dose and the speed of uptitration according to multiple clinical characteristics of the patient, including NYHA class, EF, BP, heart rate, and diuretic requirements. Specialized programs for uptitration of β-blocker dose by nurse clinicians may be helpful, as they have been shown to achieve higher rates of target β-blocker dose utilization as compared to standard of care [65].

The above three principles have been followed by all of the above-mentioned clinical trials of β-blockers and have contributed to the remarkable tolerability of therapy in these studies. Analysis of data from the MERIT-HF trial showed that as early as 90 days after initiation of metoprolol succinate there was a decrease in the risk of mortality or hospitalization, no change in symptoms, and a decrease in the daily dose of furosemide [66]. Even in patients at very high risk of decompensation, there was no increase in death or hospitalization at 8 weeks in the COPERNICUS trial [67].

Overall tolerability of β-blocker therapy in clinical trials has been excellent, with more patients discontinuing therapy in the placebo group than in the active treatment group [68]. Side effects of bradycardia, dizziness, and hypotension do occur more frequently with β-blocker treatment as compared to placebo, but have been shown to be infrequent causes of discontinuation of therapy. Table 6.4 lists the incidence of these side effects as determined in a meta-analysis by Ko and colleagues [68]. It is important to note that β-blockers will decrease the sinus rate and prolong conduction through the atrioventricular node, and so use is contraindicated in patients with bradycardia (HR < 55 BPM) or second- and third-degree AVB [69]. The role of pacemaker placement to facilitate β-blocker therapy, in the absence of indications for an implantable cardiac defibrillator or cardiac resynchronization therapy (CRT) is unclear. The Dual Chamber and VVI Implantable Defibrillator II Trial (DAVID-II) showed that atrial pacing at a rate of 70 BPM was safe, although it provided no clinical benefit over backup ventricular pacing at 40 BPM, in patients with HFREF (mean EF 26 %) and an implanted defibrillator [70]. Notably, the percentage of patients receiving target dose β-blocker therapy was similar between the two groups, suggesting that pacemaker mode did not significantly affect β-blocker dose titration.

Physicians should follow the systemic BP closely during titration of medical therapy for HFREF. Indeed, BP is linked to outcome in heart failure with lower BP associated with more advanced cardiomyopathy and consequently higher mortality [71]. Patients with hypotension (BP < 100 mmHg) were excluded from all the major β-blocker trials except COPERNICUS and COMET. Analysis of outcomes data by baseline BP in the COPERNICUS trial showed that patients with the lowest BP, ranging from 85–95 mmHg, had an equal benefit of β-blocker therapy [72]. However, these patients did experience a higher frequency of side effects and were more likely to stop treatment. In practice, β-blocker therapy can be initiated cautiously in asymptomatic patients (i.e., without orthostatic symptoms) and chronic BP 85–95 mmHg. These patients require careful monitoring to ensure stability of their clinical status during treatment.

Diabetes mellitus (DM) is present in about 25 % of patients with HFREF [73]. Patients with DM and HFREF are at an increased risk of mortality and derive a survival benefit from treatment with β-blockers [74]. However, because β-blockers can blunt the autonomic response that alerts patients to the presence of hypoglycemia, there are long-standing concerns that β-blocker use may be dangerous in patients with DM. In contrast to these concerns, Shorr and colleagues found a decreased risk of serious hypoglycemia with cardioselective β-blocker use (relative risk 0.73) and a small, non-significant increased risk with nonselective β-blocker use (relative risk 1.26) in 13,559 patients being treated with antihypertensive medications [75].

Peripheral arterial disease with claudication was initially a contraindication to β-blocker therapy because of case reports describing a worsening of symptoms with therapy [76]. A subsequent meta-analysis of six small trials has shown no significant effect of β-blocker therapy on time to claudication or walking distance [77]. Thus, β-blocker therapy can be used cautiously in patients with advanced peripheral arterial disease.

Pulmonary disease has been another comorbidity affecting the utilization of β-blocker therapy. The lung contains β₂-AR that mediates bronchial smooth muscle cell relaxation and are the pharmacologic target of agonist drugs used in both reactive airway disease (RAD) and chronic obstructive pulmonary disease (COPD) [78]. Early on, the nonselective β-blocker propranolol was shown to precipitate bronchospasm in asthmatic patients [79]. Salpeter and colleagues showed that in patients with RAD, treatment with a cardioselective β-blocker led to a 7.5 % decrease in forced expiratory volume in 1 second (FEV1) after the first dose without causing respiratory symptoms. Continued treatment was not associated with a further decline in FEV1 and was well tolerated in the short-range trials analyzed in this meta-analysis [80]. By comparison, the nonselective β-blocker carvedilol was tolerated in only six of 12 patients with asthma [81]. The use of cardioselective β-blockers in patients with stable RAD is acceptable but treatment of patients with severe disease should be avoided. The use of selective β-blockers should be considered.

Patients with COPD are able to tolerate β-blocker therapy more readily than those with RAD, and newer data suggests that COPD patients without heart failure may have decreased mortality with β-blocker treatment [82]. Salpeter and colleagues have examined the use of cardioselective β-blockers in patients with COPD and found that they are well tolerated [83]. Two studies have evaluated the use of nonselective β-blockers in patients with COPD and HFREF. Jabbour and colleagues performed a trial with 35 patients with COPD and HFREF and found that FEV1 was lower with carvedilol as compared to metoprolol or bisoprolol, but all three agents were well-tolerated [84]. Furthermore, an analysis of data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) showed that there was no difference in survival between patients treated with selective versus nonselective β-blockers in HFREF patients with COPD [85].

Hospitalization for acute decompensated heart failure is common with over one million hospitalizations occurring in 2009 [86]. In 1999, due to studies indicating that antagonism of the adrenergic system could lead to volume overload [87] as well as an absence of data showing benefit of β-blocker use in patients with NYHA class IV symptoms, the Advisory Council To Improve Outcomes Nationwide in Heart Failure (ACTION HF) guidelines recommended that patients with decompensation requiring hospitalization or the use of intravenous agents have their β-blocker dose reduced or discontinued [61]. Furthermore, de novo initiation or re-initiation of therapy was recommended to be performed exclusively in the outpatient setting after discharge [88]. However, over the last 10 years, several clinical studies have shown that outcomes are improved by continuing β-blocker therapy during hospitalization and initiating therapy before hospital discharge. In the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial, 363 patients were randomized to initiation of carvedilol before discharge or at least 2 weeks after discharge [89]. The number of patients treated with any β-blocker at 60 days after discharge was significantly higher in the before discharge group (91 % vs. 73 %), without a significant difference in outcome between the groups. Fonarow and colleagues extended these findings in an analysis of patients with HFREF hospitalized in the OPTIMIZE-HF registry [90]. They found that patients continued on β-blocker therapy at hospital admission or started de novo had a lower risk of mortality at 60–90 days after discharge, even after adjusting for clinical variables predictive of post-discharge mortality. Thus, continuation of β-blocker therapy in patients with HFREF that are hospitalized for an acute decompensation is recommended, unless other contraindications to continued therapy, such as bradycardia or shock, are present [46]. Data from OPTIMIZE-HF showed that patients who are initiated on β-blocker therapy while hospitalized for heart failure are three times more likely to be treated with a β-blocker at 60–90 day follow-up [91]. Thus, we conclude that therapy should be initiated before discharge for most patients with HFREF.

Patients hospitalized with acute decompensated heart failure who are placed on inotropic therapy for hemodynamic support represent a special category of patients with advanced cardiomyopathy [92]. The inotropes approved for use in the United States are the β₁-agonist, dobutamine and the phosphodiesterase III inhibitor, milrinone. Inotropic therapy has long been used to improve hemodynamics in NYHA class IV patients with depressed cardiac output. However, given the improvement in clinical outcomes seen in patients with NYHA class IV heart failure in COPERNICUS, it might be beneficial to treat patients with advanced disease with both an inotrope and a β-blocker [93]. Mehtra and colleagues were the first to carefully study this issue by measuring the hemodynamic response to dobutamine and enoximone (an oral phosphodiesterase III inhibitor) before and after treatment with a β-blocker in 34 patients with HFREF [94]. They found that the hemodynamic effects of dobutamine infusion were blunted by treatment with metoprolol and carvedilol, but the effects of enoximone were not blunted by treatment with either agent. This trial showed that β-blockers should not be used in conjunction with dobutamine, but can be used with phosphodiesterase III inhibitors. A review of four studies examining combination treatment with milrinone and β-blockers showed that co-treatment is well-tolerated and has a neutral or beneficial effect on mortality [95]. Combination treatment has also been investigated as a method to help improve cardiac function sufficiently to allow inotrope weaning [96]. We have concluded that β-blockers should not be used with dobutamine because of their blunting effect on the hemodynamic response, but appear to be safe to be used with milrinone, and may improve outcomes.

There are patient-related and system-based barriers for the optimal utilization of β-blocker therapy in patients with HFREF. Given that β-blockers decrease heart rate and BP, a small number of patients may not tolerate even low-dose therapy or be able to reach target doses of therapy. In the OPTIMIZE-HF registry, 9.4 % of patients with HFREF were not discharged on a β-blocker due to a documented contraindication (Fig. 6.2) [91]. Patient characteristics associated with the inability to tolerate the initiation of carvedilol in the outpatient setting include higher NYHA class, older age, lower diastolic blood pressure, and higher blood urea nitrogen concentration [97]. In a cohort of 340 patients with HFREF, 10 % of patients discontinued therapy over a 2 year period. The most common reason for discontinuation was a failure to restart a β-blocker after hospitalization [98].

Based on the dosing strategy utilized in the major clinical trials, β-blockers should be generally initiated at a low dose and uptitrated until dose-limiting side effects occur or until the target dose is reached. Analysis of the clinical trial data supports this “target dose” strategy, with dose-related improvements in outcomes seen in the MOCHA [99], CIBS-II [100], and COMET trials [101]. This benefit has not been uniformly shown however, as patients in MERIT-HF receiving low-dose metoprolol (≤ 100 mg daily) or high-dose metoprolol (> 100 mg daily) had a similar benefit of therapy [102]. In practice, only a minority of patients treated with β-blockers reach target doses. In the Carvedilol Heart Failure Registry (COHERE), 55 % of patients were receiving less than the target dose of carvedilol [103].

Another potential strategy is to uptitrate the β-blocker dose based on the heart rate, as analyses of the CIBIS-II and COMET trials showed that the benefit of therapy was related to the magnitude of heart rate reduction [101, 104]. McAllister and colleagues performed a meta-analysis of 17 β-blocker clinical trials and found that the magnitude of survival benefit was related to the heart rate reduction, with a relative risk reduction for death of 18 % for each decrease in heart rate by five beats/minute [105]. In this meta-analysis there was no relationship between the β-blocker dose achieved and the survival benefit. At this time the optimal dosing strategy is unclear, but guidelines recommend titration to target the doses used in the clinical trials of β-blockers [47].