Association of β-Blocker Therapy at Discharge with Clinical Outcomes after Acute Coronary Syndrome in Patients without Heart Failure

Aim To evaluate the clinical impact of β-blocker in patients with adequate left ventricular ejection function (LVEF) who underwent percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Methods A total of 10,724 consecutive patients who underwent PCI throughout 2013 were prospectively enrolled in the study. Among these, we analyzed 5,631 ACS patients who were discharged with LVEF ≥ 40%. Patients were then compared according to the β-blocker prescription at discharge. Results During a 2-year follow-up, no significant association was observed of β-blocker use with all-cause mortality (with β-blockers 47/5,043 (0.9%) vs. without β-blocker use 8/588 (1.4%); hazard ratio (HR) 0.762, 95% confidence interval 0.36 to 1.64; P = 0.485), cardiac death, myocardial infarction (MI), or major adverse cardiovascular and cerebrovascular events. Subgroup analysis demonstrated that the β-blocker use at discharge reduced the 2-year mortality in patients with unstable angina (UA) (HR 0.42, 95% CI 0.19 to 0.94, P = 0.034). Landmark analysis at 1 year showed that patients with UA who were discharged with β-blockers had lower mortality (HR 0.17, 95% CI 0.04-0.65, P = 0.010) and cardiac death (HR 0.12, 95% CI 0.01-0.99, P = 0.049) than those discharged without β-blockers. However, the benefit was lost beyond 1 year. No differences in outcomes were recorded in the AMI or overall population. Conclusions We present that β-blocker significantly lowers the rate of all-cause death up to 1 year, in UA patients who have undergone PCI and have adequate LVEF. Its role in patients with AMI also deserves further exploration.


Introduction
The wide application of β-blockers in coronary artery disease patients is partially supported by the general belief that they can reduce cardiac events. American guidelines recommend oral treatment with β-blockers during the hospital stay in acute coronary syndrome (ACS) patients without contraindications; the oral treatment should continue even after hospital discharge regardless of the presence of left ventricular (LV) dysfunction (class I, level of evidence B). However, European guidelines have a class IIa indication for patients with adequate LV function [1][2][3][4][5]. These recommendations are mainly drawn from studies conducted in the prereperfusion era [6] or studies of heart failure (HF) [7] patients. Besides, mixed results have been reported on the clinical benefit of β-blocker in patients without HF and ACS patients who have undergone percutaneous coronary intervention (PCI) [8][9][10][11]. In as much as the use of β-blocker reduced mortality before the reperfusion era, a recent meta-analysis in an ACS population revealed that it was no longer the case in the modern era [11]. Furthermore, studies showing that Asians are more susceptible to the adverse effects of β-blockers thereby offsetting its clinical benefits in the Asian population have been published [12]. There is scant data on β-blocker therapy among the Asian population who underwent PCI for ACS and had mild recessive or normal LV function.
In this study, we sought to examine the association between β-blocker therapy at discharge and long-term clinical outcomes in ACS patients who underwent PCI with adequate LV function, from a single center of China.

Materials and Methods
2.1. Study Population. We consecutively enrolled 10,724 patients treated with stent implantation in Fuwai Hospital for coronary artery disease, between January and December 2013, and obtained their baseline data from the medical records.
Patients with a diagnosis of ACS at admission and underwent PCI and those above 18 years formed the inclusion criteria. However, exclusion criteria included (1) patients with a history of heart failure (HF) or left ventricular ejection fraction ðLVEFÞ < 40%, (2) in-hospital death or unstable in the hospital, (3) patients missing β-blocker information, and (4) patients with contraindication to β-blocker therapy such as hypotension (systolic blood pressure < 90 mmHg), significant bradycardia, or active asthma. Eventually, we included 5,631 patients in the study (Figure 1), and they were divided into two groups based on whether they used βblockers at discharge or not.
We complied with the Declaration of Helsinki and obtained approval from the Institutional Review Board of Fuwai Hospital. In addition, all participants submitted written informed consent before the intervention.

Treatment and Intervention. Coronary interventions
were performed by experienced cardiologists according to standard guidelines [13], and the treatment strategy, i.e., PCI and stent type, was left to the discretion of the operators. Patients received a loading dose of aspirin (300 mg) and clopidogrel (300 mg) orally and continued the dual antiplatelet therapy (aspirin (100 mg/day) and clopidogrel (75 mg/day)) for at least 12 months. Although unfractionated heparin (100 U/kg) was applied in all patients for anticoagulation during the procedure, glycoprotein IIb/IIIa antagonists were also administrated on a necessity basis. Standard secondary prevention for CAD was prescribed according to established guidelines [14].

Definitions and
Outcomes. The follow-up was prespecified to occur after 1, 6, 12, and 24 months. The primary outcome was all-cause death, defined as all incident death that could be attributed to a cardiac or noncardiac etiology, while secondary outcomes included cardiac death, recurrent MI, and major adverse cardiovascular and cerebrovascular events (MACCE). Death that could not be attributed to a noncardiac etiology was considered a cardiac death. MI was defined by the third universal definition of myocardial infarction [15], while MACCE was defined as the composite of allcause death, nonfatal MI, unplanned target vessel revascularization, stent thrombosis, and stroke during the follow-up. Unplanned target vessel revascularization was defined as repeat percutaneous intervention or surgical bypass of any segment of the target vessel for ischemic symptoms and event-driven. Stent thrombosis was defined according to the Academic Research Consortium, including definite and probable in the analysis.
All endpoints were adjudicated centrally by 2 independent cardiologists, and disagreement was resolved by consensus.
2.4. Statistical Analysis. Continuous variables are presented as the mean ± SD or median (25th and 75th percentiles) when appropriate and were compared by Student's t-test or the Mann-Whitney U test. Categorical variables are presented as frequency (percentage) and were compared using the chi-squared test or Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. To estimate the hazard ratio (HR) and the 95% confidence interval (CI) of β-blocker therapy and adverse event risk, we performed Cox proportional regression analysis. Variables with a P value < 0.05 in the univariate Cox proportional hazard model were included for further multivariate analysis (details in Table 1). Subgroup analysis was conducted with the covariates of clinical presentation (AMI vs. unstable angina (UA)). Additionally, we conducted the landmark analysis to assess outcomes at 1 year and between 1 and 2 years in overall and subgroups.
Significance was set at P < 0:05, and all analyses were performed using SPSS 22.0 (IBM Corp., USA).

Results
3.1. Baseline and Procedure Characteristics. Out of the 5,631 patients discharged alive with LVEF ≥ 40% and without HF, 5,043 (89.56%) received β-blocker treatment at discharge. The baseline characteristics of patients are presented in Table 2. In particular, patients with β-blocker treatment at discharge were mainly younger, females, and nonsmokers.

Cardiovascular Therapeutics
In addition, a larger proportion of those discharged with βblocker had diabetes and dyslipidemia, presenting with AMI. Patients with β-blocker therapy at discharge had more complicated lesions and a higher SYNTAX score (SS). However, they recorded significantly lower residual SS (rSS) after the intervention, compared with those without β-blockers at discharge.

Two-Year Clinical
Outcomes in the Overall Population. 5,603 (99.5%) patients had complete two-year follow-up   Cardiovascular Therapeutics information as summarized in Table 3. Table 1 presents the landmark analysis of events occurring within and after 1 year, while Kaplan-Meier curves of the overall population for time to all-cause death, cardiac death, MI, and MACCE are shown in Figure 2. At the 2-year follow-up, the incidences of allcause death (HR 0.69, 95% CI 0.32 to 1.47, P = 0:336), cardiac death (P = 0:925), MI (P = 0:338), or MACCE (P = 0:614) did not differ significantly between the two groups. Multivariate Cox proportional regression analysis revealed that age was an independent risk factor, while clopidogrel use was a protective factor for 2-year all-cause death. Moreover, age, prior PCI, and rSS > 8 were independent risk factors for 2year cardiac death, while LVEF was a protective factor. Prior coronary artery bypass grafting and rSS > 8 were however independent risk factors for 2-year nonfatal MI. Additionally, left ascending artery lesion, GPIIb/IIIa use, and rSS > 8 were independent risk factors for 2-year MACCE. Rates of clinical outcomes within and after 1 year were similar between the two groups as revealed by the landmark analysis. Table 2 shows the baseline and procedure characteristics of subgroups, while Tables 1 and 3  Together with β-blocker use, clopidogrel use served as a protective factor for allcause death. Besides, landmark analysis showed that the use of a β-blocker was effective on all-cause death after the first year of follow-up ( Figure 3). However, the risk of all-cause death beyond 1 year was similar between the two groups.

Subgroup Analysis.
Although not statistically significant (HR 0.36, 95% CI 0.10-1.32, P = 0:123), we observed a decline in 2-year cardiac deaths among patients discharged with β-blockers. Landmark analysis also revealed a protective effect of β-blocker use on 1-year cardiac death, but not beyond 1 year (Table 1). There was no impact of β-blocker use at discharge on 2-year MI or MACCE. In the UA subpopulation, clopidogrel use was a protective factor for 2-year cardiac death. In addition, the prior coronary artery bypass graft and rSS > 8 were independent risk factors for 2-year nonfatal MI, while left ascending artery lesion and rSS > 8 were independent risk factors for 2-year MACCE.
In the AMI subpopulation, we did not observe any association of β-blocker use at discharge, with clinical outcomes, shown either within or after a 1-year follow-up. However, in patients with AMI, stroke and left main lesion were significantly related to 2-year all-cause death; hence, we considered prior MI and left main lesion to be independent risk factors for 2-year cardiac death. Peripheral vascular disease, left main lesion, and rSS > 8 were independent risk factors for 2-year nonfatal MI, while left ascending artery lesion and rSS > 8 were independent risk factors for 2-year MACCE.

Discussion
In the present study, we investigated the association of βblocker therapy with clinical outcomes in real-life patients using data from a large, prospective, single-center series in China. Moreover, among ACS patients who underwent PCI with normal or mildly reduced LVEF, the use of β-blockers at discharge did not correlate with a lower risk of clinical outcomes up to 2 years. However, in the subgroup analysis of the UA population, a reduction of mortality with βblocker therapy at discharge was observed, though the superiority was only significant within the first year, but not after a 2-year follow-up.
β-Blockers are accepted as the standard care for coronary heart disease, especially in MI patients. As mentioned before, there is a divergence between international guidelines in their recommendations for the use of β-blockers in ACS patients without HF, or LV dysfunction [1][2][3][4]16]. Besides, all the recommendations relying on evidence from the prerevascularization era [6] and expert opinion (level C) only in patients with normal LV function with NSTE-ACS [7]. Despite its benefits on hard clinical outcomes in ACS patients with HF and reduced LV function being evident in the pre-and revascularization eras [9], the use of β-blockers remains controversial in patients undergoing PCI with adequate LV function [9,17,18]. Studies on the Asian population have reported inconsistent results [8,[19][20][21], with scant data focused on the relatively low-risk patients with normal or mild recessive LVEF. In Li et al.'s Chinese population data, β-blocker use significantly lowered the risk of all-cause death in ACS patients who underwent PCI. However, the relatively low-risk population without HF or LV dysfunction was not explored [19]. In Nakatani et al.'s analysis in Japanese, βblocker therapy at discharge had beneficial effects for highrisk patients only [21].
This study, therefore, sought to clarify this controversy. After full adjustment of potential confounding factors, we demonstrated that β-blocker therapy at discharge was associated with a significant reduction in 2-year mortality in patients who underwent PCI for UA and had adequate LVEF. Landmark analysis demonstrated the benefit of β-blocker use on all-cause death and cardiac death at a 1-year follow-up, but not beyond that period. Since we were uncertain of the duration of β-blocker use after discharge, our results should be interpreted with some caution.
In the era of PCI and modern medical therapy, it is true that the clinical outcomes of relatively low-risk patients, with normal or mild recessive LV function after ACS, would be improved. However, recurrent myocardial ischemia, tachyarrhythmia, and adrenergic activation remain serious problems for these patients. Since there is no other optimal substitute for β-blockers in controlling these problems effectively [22], our results supported the β-blocker use in relatively low-risk patients who underwent PCI for UA and had adequate LVEF.
Patients with myocardial damage from AMI may have higher levels of sympathetic tone and circulating catecholamine than those with UA, hence more likely to benefit from β-blocker therapy. However, in the present study, we did not observe any significant impact of β-blocker use on clinical outcomes in the AMI population. This could be attributed to the sample size and relatively low event rates encountered in the AMI subpopulation. It is therefore not accurate to conclude from this study alone that the drug is ineffective in patients with AMI.
Beyond the medicine, the present study also revealed the importance of interventional therapy for the prognosis of the ACS population. Besides, incomplete revascularization (rSS > 8) was shown to be an independent risk factor for MI and MACCE. This was true for the overall AMI and UA populations, respectively.
This study, however, has the following limitations. First, it is an observational study; hence, conventional limitations for such apply. Secondly, the present study was conducted in a Chinese population with relatively low incidences of cardiac events. Despite the total population of 5,631 cases, only 588 of the patients did not use β-blockers, which is a small sample size. Thirdly, unmeasured confounders may have led to biased results. Finally, the study lacks data on specific β-blockers and doses, and as mentioned before, we are uncertain of the duration that β-blockers were administered after discharge. Large-scale, prospective, randomized controlled trials should be conducted to clarify the effects of long-term β-blocker therapy in ACS patients who have undergone PCI with adequate LVEF.

Conclusion
Our findings are in agreement that β-blocker significantly lowers the rate of all-cause death up to 1 year, in UA patients 8 Cardiovascular Therapeutics who have undergone PCI and have adequate LVEF. Its role in patients with AMI also deserves further exploration.

Data Availability
The data used to support the findings of this study are restricted by the ethical review board at Fuwai Hospital in order to protect patient's privacy. Data are available from Jin-qing Yuan for researchers who meet the criteria for access to confidential data.