The evidence conclusively shows that BBs reduce the risk of death in patients with HFrEF. Their use is widely recognized in the recent clinical practice guidelines of the European Society of Cardiology (ESC).3Table 1 shows data from the main randomized trials4-10 supporting the use of BBs, as well as their ability to reduce the most important endpoints. Although metoprolol, bisoprolol, and carvedilol are associated with significant beneficial effects, the association is not as consistent for bucindolol and nebivolol. In the SENIORS trial (age > 70 years, 64% with rEF), nebivolol was associated with a lower risk of the composite endpoint of death and cardiovascular hospitalization, but not of death alone or the other endpoints.4 Bucindolol failed to reduce mortality in the BEST study, although it did reduce hospitalizations for HF.5 The 3 BBs with the strongest evidence in this population (metoprolol, bisoprolol, and carvedilol) are associated with reduced disease progression, as shown by the lower rates of directly related death (sudden and HF) and HF hospitalizations in the various trials.6–8

The COMET study, the only trial to directly compare 2 BBs—carvedilol vs metoprolol tartrate—, found lower mortality with carvedilol; however, the use of short-acting metoprolol, contrasting with the formulation used in the MERIT-HF trial,7 might somewhat explain these differences.9 In a large meta-analysis based mainly on BBs with proven survival benefit, no differences were found among the different BBs, which together reduced 12-month mortality by 31% without treatment–subgroup interactions.11Figure 1 shows the relative risk reduction and the number of patients needed to treat at 1 year to reduce the different events, based on the meta-analysis results.11

Figure 1.

Benefits of beta-blockers in patients with heart failure and reduced LVEF. A: Relative risk reduction and 95% confidence interval. B: NNT at 1 year. LVEF, left ventricular ejection fraction; NNT, number needed to treat.

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In recent years, different meta-analyses have addressed the relationship between the benefits of BBs and heart rate in patients with rEF. The connection between a higher heart rate and worse prognosis is well established. Nonetheless, a subanalysis of the HF-ACTION study showed that the benefit is greater in the presence of high BB doses, regardless of heart rate.12 On the other hand, other recent meta-analyses have indicated that the heart rate reduction-related benefit of BBs is only achieved in patients with sinus rhythm or is at least lower in patients with atrial fibrillation (AF).13 However, a subanalysis of the AF-CHF study showed that BBs also improved mortality rates in patients with AF and rEF.14

A particular issue is patients with asymptomatic rEF. In these patients, BBs theoretically prevent the adverse ventricular remodeling processes that promote the progression to symptomatic HF. The REVERT trial, the only study to randomize asymptomatic patients in New York Heart Association (NYHA) stage I and with rEF (stage B of the ACC/AHA),1 showed that metoprolol succinate was associated with reduced volumes and increased LVEF at 1 year.15 The CAPRICORN study (postinfarction LVEF <40%) identified less progression to symptomatic stages and improved remodeling and ventricular function.16 In an observational study, BB use reduced episodes of symptomatic HF by 60%.17

Prospective clinical trials are scarce and typically have indirect endpoints such as echocardiographic parameters or small sample sizes that merely allow estimation of the effect on clinical endpoints. An observational study, based on propensity score adjustment with a large population of hospitalized patients, and several meta-analyses indicate that BBs can reduce mortality in patients with a LVEF > 40%.18 Recently, a substudy of the TOPCAT trial (LVEF> 45%) showed that BBs, particularly in patients without previous infarction, were associated with increased adverse cardiovascular events.19 However, after the recommendation in the latest European guidelines to consider patients with midrange LVEF (40%-49%) as a separate subgroup, an individual meta-analysis that included the LVEF of each patient in the pivotal clinical trials showed that patients in sinus rhythm could indeed benefit from BB therapy in terms of mortality.20

For patients hospitalized with rEF, continuation of BBs during admission reduces the risk of death by 40%, whereas initiation of BB therapy in BB-naïve patients reduces the risk by almost 60%.21 In contrast, withdrawal of BBs during hospitalization doubles mortality.22 The COPERNICUS study evaluated patients with severe HF (NYHA class III-IV and LVEF <25%), including hospitalized or decompensated patients taking intravenous diuretics. The use of carvedilol reduced the overall risk of death by 35%.7 In addition, BB initiation during hospitalization facilitated adherence to BB therapy during follow-up.23 In another subanalysis of the MERIT-HF trial that included patients with worse clinical deterioration (NYHA class III-IV and LVEF <25%), the benefit of metoprolol was clear and even greater.24

BBs are first-line drugs for the control of heart rate in the context of AF in patients without contraindications.48 Although rate control therapy plays a fundamental role in AF management, sympathetic activity is related to both AF initiation and maintenance.49 Nonetheless, the role of BBs in rhythm control is secondary, although it is true that, in a randomized study vs placebo, metoprolol reduced AF recurrence by 11%.50 In addition, in patients with HF or acute myocardial infarction (AMI), BBs can reduce the incidence of AF.51

BBs are particularly useful for the control of ventricular arrhythmias related to sympathetic activity, such as perioperative arrhythmias and those associated with stress, AMI, and HF.52 They prevent sudden cardiac death by reducing malignant ventricular arrhythmias in different contexts, mainly under acute ischemic, systolic dysfunction, and channelopathy conditions. In the setting of AMI, BBs increase the threshold for ventricular fibrillation during acute ischemia.53,54 In a more stable phase, they are especially useful for preventing scar-related ventricular arrhythmias after a confirmed AMI, which generally present as sustained monomorphic ventricular tachycardia. In patients with rEF, an absolute reduction in sudden cardiac death rates of about 2% to 3% has been demonstrated (∼40% relative reduction vs placebo).55 In patients with channelopathies, particularly those with long QT syndrome and catecholaminergic ventricular tachycardia, BBs are the drug of choice. In this context, a retrospective study of 233 patients with long QT syndrome and a history of syncope showed a marked reduction in mortality with BBs vs placebo.56 For patients with catecholaminergic polymorphic ventricular tachycardia, BBs are the drug of choice, particularly nadolol.57 The clinical situations with proven benefit of BBs for the prevention of sudden cardiac death due to ventricular arrhythmias are shown in Figure 3.

Figure 3.

Clinical situations with proven benefits of beta-blockers for the prevention of sudden death due to ventricular arrhythmias. AMI, acute myocardial infarction; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia.

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During the course of AMI, catecholamine-mediated sympathetic activity occurs in response to pain, anxiety, and decreased cardiac output. This increase in sympathetic tone has negative consequences, such as an elevated myocardial oxygen demand that accelerates myocardial necrosis and a decreased ventricular fibrillation threshold that increases the risk of sudden cardiac death. The increased sympathetic activity also activates various types of circulating cells, such as platelets and neutrophils. The latter significantly contribute to the phenomenon known as reperfusion injury.59

Most trials conducted in the prereperfusion era compared the use of intravenous BBs immediately after AMI diagnosis followed by oral BBs vs placebo.58 The early initiation of intravenous BB was explored as an intervention capable of limiting the extent of necrosis, but the results were inconclusive. In the absence of reperfusion, it is difficult to find a benefit in limiting the extent of the necrosis. In the pharmacological reperfusion (fibrinolysis) era, intravenous atenolol was ineffective in reducing infarct size in a randomized trial.60 However, another nonrandomized study showed that intravenous metoprolol was associated with a smaller infarct size.61 The first clinical study of this issue in patients reperfused by primary angioplasty was the METOCARD-CNIC trial, performed in Spain.62 In this trial, metoprolol administration was associated with smaller infarct size53 and higher long-term LVEF.63 Another subsequent trial, the EARLY-BAMI study, failed to corroborate the cardioprotective effects of early metoprolol administration in patients with AMI undergoing primary angioplasty.64 The discrepancy between the 2 trials seems to be due to the time of metoprolol administration (much earlier in METOCARD-CNIC) because the longer the time between the intravenous administration of metoprolol and reperfusion, the greater its cardioprotective effect.65 The mechanism underlying the ability of metoprolol to reduce infarct size when it is intravenously administered early before reperfusion appears to involve a direct effect on circulating neutrophils and their aggregation with platelets, which results in reduced reperfusion injury and reduced microvascular obstruction.66

The early use of intravenous BBs in AMI has been questioned because of its potential ability to increase the incidence of cardiogenic shock. This concern is based on the results of the COMMIT study.54 In this trial, the early administration of metoprolol to patients with AMI was associated with a significant reduction in ventricular fibrillation, but an increase in shock. However, the COMMIT population included patients with advanced disease. In addition, half did not undergo reperfusion. Moreover, patients who developed cardiogenic shock had clear signs of acute HF along with tachycardia and hypotension. In contrast, a meta-analysis that included all trials involving early administration of intravenous BBs, which amounted to more than 73 000 patients, demonstrated that this strategy is safe if applied to patients without signs of HF and also significantly reduces the frequency of ventricular fibrillation.67

Based on the new trials performed in patients undergoing primary angioplasty, the ESC guidelines for the treatment of patients with ST-segment elevation AMI recommend the early use of intravenous BBs (class IIa A) in the absence of HF signs or systolic hypotension (<120mmHg).68

The use of BBs after AMI was exhaustively investigated in the prereperfusion era.58 Apart from the COMMIT trial,54 with a follow-up of only 1 month, the only clinical trial to examine the role of oral maintenance BBs after AMI is the CAPRICORN study.16 In this trial, 1950 post-AMI patients with LVEF ≤ 40% were randomized to carvedilol or placebo. BB use was associated with a reduction in overall mortality.16 Because many of the trials focusing on HFrEF (Table 1) included post-AMI patients, it is considered established that all patients who have had an AMI with a LVEF ≤ 40% have an indication for BBs. However, there is a lack of evidence on the benefits of BBs for post-AMI patients with a LVEF> 40%. Numerous observational studies have attempted to shed light on this issue, but all have major limitations and thus do not provide definitive information (an aspect reviewed by Ibáñez et al.1).

Given all of the above, the ESC clinical practice guidelines on patients with AMI strongly (class IA) recommend BB use whenever LVEF is ≤ 40%, regardless of whether patients have ST-segment or non–ST-segment elevation AMI. However, the recommendation for patients who have had an AMI with a LVEF> 40% is weaker.1

Figure 4 shows the clinical situations with proven benefit of BBs in the context of AMI.

Figure 4.

Current status of beta-blockers in the different phases of acute coronary syndrome. AMI, acute myocardial infarction; IV, intravenous; LVEF, left ventricular ejection fraction.

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Due to this lack of evidence on such an important aspect of daily clinical care, 3 large pragmatic clinical trials are underway in Europe to explore the role of BBs in patients without reduced LVEF who have had an AMI. The REBOOT clinical trial (NCT03596385), directed from the National Center for Cardiovascular Research (CNIC) in Spain, involves the participation of more than 70 Spanish and Italian centers. About 8500 post-AMI patients with LVEF> 40% will be included in this large Spanish study. In addition, the REDUCE-SWEDEHEART (NCT03278509) and BETAMI (NCT03646357) trials are being conducted in Sweden and Norway, respectively; their designs are similar to that of REBOOT. These large clinical trials will have a clear impact on clinical practice in this setting.

Table 3 summarizes the results of the different clinical trials16,53,54,60,64,69–72 that have analyzed the role of BBs, either in the acute phase of AMI or in the maintenance period after the acute event.

The antianginal effects of BBs are well established and are included in the clinical practice guidelines.73 Compared with calcium channel blockers, BBs reduce anginal episodes and the time to ischemia onset in exercise testing.74 However, no clinical trial has studied in a randomized manner and with sufficient statistical power whether BBs improve the survival of patients with stable coronary disease but without AMI or rEF. In a systematic review and meta-analysis, their use did not reduce mortality.75 The REACH registry, which included more than 40 000 Swedish patients, found no benefit in patients with stable coronary disease but without previous AMI after propensity score adjustment. Several studies support the conclusion that, in the presence of stable coronary disease and without previous AMI, BB use does not have beneficial effects on mortality and adverse cardiovascular events.76