Introduction

Coronary heart disease (CHD) is a well-known risk factor of non-cardiac surgery, and nearly half of postoperative mortality is caused by cardiac complications [1,2]. β-blockers, traditionally prescribed for hypertension, are the primary choice of treatment after myocardial infarction (MI) or chronic angina [3,4]. In addition, β-blockers have shown improved clinical outcome in patients with chronic heart failure (HF) [5,6]. In this regard, they have not only been recommended as first line therapy for patients with CHD, but also been proposed to reduce cardiac complications by moderating hemodynamic response in the perioperative period [2,7–9]. However, evidence for these recommendations has been questioned and there remains debate on the cardio-protective effects of perioperative β-blocker in non-cardiac surgery [10]. Recent studies suggest that perioperative β-blocker use may not be associated with postoperative clinical outcome in CHD patients, especially when left ventricular function is preserved [11–13].

We therefore conducted this study to investigate whether perioperative use of β-blocker is associated with postoperative clinical outcome of non-cardiac surgery in coronary revascularized patients without severe left ventricular systolic dysfunction (LVSD) or HF.

Methods

Result

A total of 537 patients were initially enrolled. Twenty-two patients with ejection fraction under 30% and 12 patients with heart failure were excluded. As a result, 503 patients remained for analysis. Types of surgery are summarized in S1 Table.

Baseline characteristics

Patients were divided into two groups: 271 (53.9%) in the β-blocker group and 232 (46.1%) in the no β-blocker group. Preoperative variables are summarized in Table 1. The incidence of hypertension, current smoking, and dyslipidemia was higher in the β-blocker group. After performing propensity score-matching, matched data set of 197 pairs was generated by 1:1 individual matching without replacement. There was no significant imbalance between the two groups in the propensity-matched population (Table 1).

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Table 1. Baseline characteristics.

https://doi.org/10.1371/journal.pone.0201311.t001

Clinical outcomes

On multivariate analysis, the incidence of MACCE on 1-year follow-up was not different between the two groups (HR, 1.01; CI 95%, 0.56–1.82; P = 0.963). The clinical outcomes in entire population are listed in Table 2. The propensity-matched population showed the same results on 1-year follow-up (HR, 1.25; CI, 0.65–2.38; P = 0.34). The results of the analysis in the propensity-matched population are summarized in Table 3. Clinical outcome during 30-days follow-up also showed no significant difference both in the entire and propensity-matched populations. Intraoperative events such as hypotension, bradycardia, and adrenergic drug requirement also showed no significant difference. The incidence of intraoperative events is summarized in S2 Table. Kaplan-Meier Curves for the primary outcome in the entire and propensity-matched populations are shown in Fig 1.

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Table 2. Clinical outcomes in entire population.

https://doi.org/10.1371/journal.pone.0201311.t002

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Table 3. Clinical outcomes in the propensity-matched population.

https://doi.org/10.1371/journal.pone.0201311.t003

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Fig 1. Kaplan-Meier Curves for major adverse cardiovascular and cerebral events during 1-year follow-up in the entire (A) and propensity-matched (B) populations.

https://doi.org/10.1371/journal.pone.0201311.g001

The result of subgroup analysis is shown in the hazard-ratio plots in Fig 2. There were no significant interactions between perioperative β-blocker use and preoperative variables of interest such as myocardial infarction, surgical risk, preserved left ventricular systolic function, revascularization type, multivessel disease, and chronic kidney disease with respect to the primary outcome.

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Fig 2. Subgroup analysis of history of myocardial infarction, high-risk surgery, ejection fraction over 50%, coronary arterial bypass grafting as revascularization type, multivessel disease and chronic kidney disease for major adverse cardiovascular and cerebral events on 1-year follow-up.

https://doi.org/10.1371/journal.pone.0201311.g002

Discussion

The present study shows that perioperative β-blocker use may not be associated with postoperative clinical outcomes of non-cardiac surgery in coronary revascularized patients without severe LVSD or HF. This finding suggests that routine use of β-blocker in every coronary revascularized patient during the perioperative period may not be reasonable.

β-blockers reduce key determinants of myocardial oxygen demand—heart rate, blood pressure, and stroke volume. Extrapolation of these benefits is especially valuable during the perioperative period, because surgical stress may cause type II MI. In this respect, current guidelines suggest continued treatment of β-blockers during the perioperative period in patients with previous β-blocker use. The 2002 ACC/AHA guideline was the first to strongly recommend perioperative β-blocker therapy in non-cardiac surgery, and they were mainly based on two randomized clinical trials [16,17]. After few modifications with conflicting evidence, the final recommendation of the 2009 ACC/AHA update was that it is reasonable to initiate β-blocker therapy before intermediate or high-risk surgery only in patients with established CHD [18–20]. The DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) study has been the main evidence for mortality benefit [8]. However, with questions on the reliability of this study, the efficacy and safety of perioperative β-blocker therapy are still controversial [10]. Recent meta-analyses showed that perioperative β-blocker therapy may not be associated with improved clinical outcome [10,13]. The result of this study corresponds well with these recent results.

The use of β-blocker, as the cornerstone of pharmacotherapy in patients with CHD, is another issue. Other than reducing myocardial oxygen demand, β-blocker increases coronary blood flow with prolongation of diastole, and reduces the burden of angina in patients with obstructive coronary lesion [6,21]. International guidelines recommend use of β-blockers in all patients with acute MI regardless of LVSD or HF [22,23]. However, unlike patients with unstable symptoms in which β-blocker effects are well established, β-blocker effects in stable CHD has been questioned and these guidelines face an enormous challenge, especially in terms of long-term therapy in patients without LVSD or HF [24]. Indeed, most of the evidence of these guidelines predates the era of coronary revascularization. Coronary intervention may make a difference because it potentially preserves more viable and less arrhythmogenic myocardium compared to non-invasive treatment. Moreover, the beneficial effects of β-blocker given early after acute MI in hemodynamically stable patients, is largely driven by a reduction in ventricular arrhythmias and re-infarction, and the mortality advantage after 1 month of use in acute MI patients without LVSD is not known [25]. A meta-analysis on 10 observational studies among more than 40,000 patients showed that the beneficial effects of β-blocker after percutaneous coronary intervention is limited to those with reduced ejection fraction [26]. The most recent study also showed that among survivors after hospitalization due to acute MI without LVSD or HF, β-blocker therapy was not associated with lower all-cause mortality within 1-year follow-up [12].

β-blockers are not completely free from potential harms during the perioperative period. Many patients actually report side effects and many medications show decreased drug adherence [27]. In patients with lowest cardiac risk, perioperative β-blocker use was not associated with any benefit but even with harm [28]. It is also reported that perioperative β-blockers started within one day or less before non-cardiac surgery may be associated with increased risk of bradycardia, hypotension, stroke and even death [1]. We acknowledge that the circumstances of patients in this study are different, in that they pose a certain cardiac risk and showed no side effects of β-blocker from previous use. None of these intraoperative events were increased in this study. However, avoidance of hypotension is still critical in the postoperative period, and β-blocker is no longer recommended as a first line therapy of hypertension [29]. Therefore, in coronary revascularized patients, routine use of perioperative β-blockers may be preserved for ptients who are tolerated by previous use, but not in every patient.

The strength of this study is that it is conducted in patients from coronary revascularization era. The results of our study showing neutral effect of perioperative β-blocker among coronary revascularized patients without severe LVSD, correspond with previous studies on patients with stable CHD and share a potential explanation for the inconsistent effect of β-blocker therapy [11,12]. β-blockers also showed neutral effects in patients undergoing coronary arterial bypass grafts [30]. This study has an adequate setting, which can easily translate the results into everyday clinical practice in the coronary revascularization era. Patients with stable symptoms after coronary revascularization, are commonly scheduled for non-cardiac surgery because prolonged life expectancy leads to higher chances of other pathological conditions requiring surgical treatment [31]. Results of this study showing a neutral effect of perioperative β-blocker in both short-term and long-term follow-up suggest that the addition of β-blocker for coronary revascularized patients during the perioperative period might not be necessary.

Although β-blocker use did not improve overall postoperative clinical outcome, perioperative β-blocker use, according to current guidelines, may have selectively affected those with a history of MI undergoing high-risk surgery. Therfore, we also performed a subgroup analysis to further evaluate interactions with cofactors including history of MI, preserved left ventricular systolic function, and high-risk surgery. In subgroup analysis, no significant interaction was found.

The result of this study must be appraised in the light of following limitations. First, as a nature of retrospective studies, confounding factors may have influenced the results. Even with a propensity score-matched analysis to adjust potential confounding factors, unmeasured factors could not be corrected. Duration of time interval between coronary revascularization and start of β-blocker use might have affected the results, because the benefit of β-blocker is known to be maximal in the early post-MI period. Total duration of β-blocker use could also have affected the results. However, accurate durations were not available in all patients and therefore were not analyzed. Second, the effects of β-blocker initiated immediately before surgery could not be evaluated because this study was only in patients who had been on β-blockers therapy. Third, patients on previous β-blocker might have higher risk, and this might not have been fully adjusted even after propensity matching. Despite these limitations, this is the first study to evaluate the effect of perioperative β-blockers in coronary revascularized patients.

Conclusion

In coronary revascularized patients without severe LVSD or HF, perioperative β-blocker use may not be associated with postoperative clinical outcome. Large registry data or randomized controlled trials are needed to support this finding.

Supporting information