Therapy with beta-blockers is recommended for patients after an acute coronary syndrome, but the most commonly prescribed doses are less than half those evaluated in the randomized clinical trials that demonstrated efficacy, and optimum doses have not been validated. The data of our study do not demonstrate increased survival in patients treated with beta-blocker doses approximating those used in previous randomized clinical trials compared with lower doses. These findings provide the rationale to investigate the appropriate beta-blocker dosage after acute coronary syndrome to derive optimal benefit from this therapy.

Beta-blocker treatment is part of the therapeutic arsenal commonly used after an acute coronary syndrome (ACS). The prognostic benefit of these drugs after an ACS was established by studies carried out in the era prior to percutaneous revascularization1,2 as well as by studies on patients with left ventricular systolic dysfunction.3 However, based on data from multiple contemporary non-randomized studies,4–6 clinical practice guidelines consider it reasonable to extrapolate their prognostic benefit to the full spectrum of ACS patients, unless there is an established contraindication.7–10

While the recommendation for beta-blockers after an ACS is based on solid scientific evidence, the type and dosage are not consensual. Clinical trials used high doses of beta-blockers to establish the efficacy of this medication,1,2,11 however such high doses are often not tolerated and are not used in daily clinical practice.12 Based on available clinical trials and extrapolation of existing evidence in the field of heart failure,13 it seems reasonable to prescribe the beta-blocker doses used in these studies, or at least titrate to the highest dose tolerated by the patient. However, there is little evidence on this question, and the available data are controversial.14,15

This study aims to analyze whether there are prognostic differences between high and low doses of beta-blockers in terms of long-term survival after an ACS.

Of the 2702 discharged ACS patients, 1685 were treated with beta-blockers (80.5%). Table 1 shows the characteristics of patients stratified by use of beta-blockers. The most commonly used beta-blocker was bisoprolol (n=1435, 85.2%), followed by carvedilol (n=210, 12.5%), atenolol (n=20, 1.2%), nebivolol (n=16, 0.9%) and metoprolol (n=4, 0.2%). Of the patients discharged with beta-blockers, 190 were treated with <25% of the optimal target dose (11.3%), 967 with doses between 25 and 49.9% of target dose (57.4%), 453 with doses between 50 and 74.9% (26.9%), and only 75 with doses ≥75% of target dose (4.5%). Thus, only 31.4% of patients (n=528) were discharged with beta-blocker doses ≥50% of the optimal target dose. Patients who were prescribed high doses were younger, with a higher rate of hypertension and previous myocardial infarction (MI) and a lower rate of COPD, more frequently with ventricular dysfunction and multivessel disease, and a lower rate of complete revascularization (Table 2).

During follow-up (18.6±9.7 months), 114 patients died (6.8%). Patients who received beta-blockers had lower mortality than those who did not (unadjusted HR: 0.599, 95% CI 0.423-0.848, p=0.004). Compared with patients who were not prescribed beta-blockers, unadjusted HR was similar for high doses (HR: 0.574, 95% CI 0.368-0.895, p=0.014) and low doses (HR: 0.611, 95% CI 0.422-0.883, p=0.009), with no difference between the two doses (Figure 1).

Figure 1.

Kaplan-Meier survival curves before propensity score matching comparing high-dose and low-dose beta-blockers with no beta-blocker therapy. CI: confidence interval; HR: hazard ratio.

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After propensity score matching (Table 3), there were no statistically significant differences in post-discharge mortality between the two groups (Figure 2). Analysis by subgroups (Table 4) also did not reveal a prognostic benefit of high beta-blocker doses. Even in patients with STEMI, high-dose beta-blockers were associated with higher mortality than low-dose beta-blockers (HR: 2.998, 95% CI 1.190-7.557, p=0.020).

Figure 2.

Kaplan-Meier survival curves after propensity score matching comparing high-dose to low-dose beta-blockers. CI: confidence interval; HR: hazard ratio.

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The present study was designed to assess whether there is a prognostic benefit in terms of survival of high doses (≥50% of the target dose previously used in randomized controlled trials) vs. low doses of beta-blockers in patients discharged after an ACS. The results were contrary to the initial hypothesis, demonstrating an absence of reduction in mortality with high compared to low doses of beta-blockers. Although there were differences in baseline characteristics, mode of presentation of ACS and angiographic characteristics that could have influenced the prescription of high vs. low beta-blocker doses, the absence of a prognostic benefit of high doses remained after adjustment by propensity score matching.

Clinical trials of beta-blockers have used high target doses. However, this is not the usual prescription pattern in daily clinical practice.16 In our study, only 31.3% of patients received ≥50% of the target dose proposed in these studies. This is consistent with data from the Outcomes of Beta-blocker Therapy After Myocardial Infarction (OBTAIN) registry and the Intermountain Heart Collaborative Study (IHCS), in both of which fewer than 20% of patients received ≥50% of the target dose.14,15 Metoprolol was the most used beta-blocker in both studies, as opposed to bisoprolol in our study. It should be noted that clinical trials with beta-blockers in MI have not provided information on dose response, focusing only on the target dose, but this target dose is rarely tolerated in daily clinical practice with real-world patients.17,18 Hence the importance of the question posed in our work: are there prognostic differences between low-dose and high-dose beta-blockers?

Our study's findings show equivalence in terms of mortality, without finding a benefit of high vs. low beta-blocker doses. Although low doses were associated with advanced age, more COPD, and less use of angiotensin-converting enzyme inhibitors (ACEIs), after the analysis was adjusted by propensity score matching, no prognostic differences were found regarding the use of high doses of beta-blockers. Although these results are somewhat surprising, and contrary to the initial hypothesis, they are consistent with the results of recent studies by Goldberger et al.14 and Allen et al.15 It should be noted that as early as 1998, Barron et al. found in 1165 patients who had survived MI that those receiving low-dose beta-blockers (<50% of the optimal dose tested in clinical trials) had a greater reduction in mortality (HR 0.33 for low dose vs. no beta-blockers, p=0.009; HR 0.82 for high dose vs. no beta-blockers, p=0.510).12 More recently (2015), in the OBTAIN registry, patients treated with ≤25% of the target dose appeared to show better survival than those receiving ≥50%,14 and data from the ICHS registry, also contemporary (2016), were consistent with our findings, with no differences between the different beta-blocker doses.15

The marked prognostic benefit of beta-blockers in survival after an ACS, demonstrated in the 1980s and 1990s,19 based on the reduction of ischemia, reinfarction and ventricular tachyarrhythmias, has been mitigated in the current era by generalization of PCI and the extension of optimal medical therapy with dual antiplatelet therapy, statins and ACEIs to the majority of patients. This reduction in their prognostic impact may add to the potential negative prognostic impact of bradyarrhythmias, as demonstrated in the CHARISMA study, in which up to 17% of patients treated with beta-blockers at high doses after MI with LVEF <40% had sinus bradycardia or high-grade atrioventricular block.20 Furthermore, the adverse events associated with beta-blockers – depression, fatigue and sexual dysfunction – should also be taken into consideration.18 This has led in recent years to questioning of the clinical utility of beta-blockers after an ACS, with conflicting results generating some degree of confusion, although current evidence seems to favor beta-blocker therapy, even in patients with LVEF >40%.4–6 What is not clear is the dose to be used. There may not be a single optimal dose of beta-blockers for all patients; dosage should be individually adjusted, as some patients will benefit from low doses and others from high doses. Some studies suggest that beta-adrenergic receptor polymorphisms may play an important role in patients with ACS and heart failure.21 On the other hand, other studies have suggested that the reduction in post-MI mortality with beta-blockers is due to the degree of reduction in heart rate rather than to the dose or type of the beta-blocker itself.22,23 Thus, there are various individual factors that could affect the prognostic benefit of beta-blocker dose.

There are several limitations that should be considered when interpreting the results of our study. First, it was not randomized, and suffers from the usual limitations and biases inherent to retrospective analyses. It is worth noting that it was based on the principle of intention to treat, since it is not possible to assess adherence to or changes in treatment during follow-up. It should also be noted in this regard that, according to previous studies, only a minority of patients undergo changes in beta-blocker therapy in the first three years after MI. Another potential limitation is the use of different types of beta-blockers, although most patients were treated with bisoprolol. Moreover, although analysis by propensity score is more robust than classic regression, it suffers from certain weaknesses compared to a randomized clinical trial, such as the inability to correct for unmeasured confounding factors. Also, given the retrospective nature of the study, it was not possible to analyze other endpoints that might have been of interest, such as control of anginal symptoms, blood pressure, heart rate or arrhythmic events. Despite these limitations, our results showing the lack of benefit of high vs. low doses of beta-blockers are consistent with the two recently published studies discussed above. Thus, the combined findings of all these papers form a consistent basis for guiding future clinical trials that may have a clinical impact on daily medical practice.

No prognostic benefit was found for high doses of beta-blockers (≥50% of the maximum recommended dose) compared to low doses. Given this finding, we emphasize the need to re-evaluate the role of beta-blocker dose in the current era of coronary revascularization and optimal medical treatment.

The authors have no conflicts of interest to declare.