β-Blockade in Noncardiac Surgery:  Outcome at All Levels of Cardiac Risk FREE

Patients with coronary artery disease or with risk factors for coronary artery disease who undergo noncardiac surgery are at significant risk for perioperative cardiac events such as death, stroke, and myocardial infarction (MI). Prevention of these perioperative cardiac complications continues to be the goal of intense research and investigations.

Multiple mechanisms for postoperative MI have been suggested, many of which involve a hyperadrenergic state with sustained sinus tachycardia and increased myocardial oxygen demand. Landesberg et al¹ noted that perioperative ischemic events in patients undergoing vascular surgery were consistently preceded by a significant rise in heart rate, usually during the immediate postoperative period. In addition, plasma catecholamine concentrations rise during the first 48 hours after surgery and are believed to be associated with increased perioperative thrombotic events such as MI.² The combination of increased catecholamines and tachycardia subjects coronary plaque to higher intravascular shear stress, eventually leading to its rupture and the initiation of a thrombotic event.³ The potential role of tachycardia and catecholamines in the pathogenesis of perioperative myocardial events, in addition to clinical reports⁴ of improved outcome in patients taking β-blockers for hypertension, triggered a significant interest in perioperative β-blockade.

Results of 2 landmark clinical studies by Pasternack et al⁵ and by Stone et al⁴ in the 1980s suggested a beneficial cardioprotective role for β-blockade in noncardiac surgery. These findings were later confirmed by Mangano et al⁶ in a randomized, double-blinded, placebo-controlled trial that showed a 67% reduction in postdischarge cardiac death in patients receiving perioperative β-blockers. In contrast to previous studies^4- 6 that failed to detect any cardioprotective effect in the immediate perioperative period, Poldermans et al⁷ reported a greater than 90% decrease in perioperative mortality and nonfatal MI with the use of β-blockers in high-risk patients undergoing vascular surgery. Despite some methodological flaws, these landmark studies paved the way for extensive research about the use of perioperative β-blockade in the past 8 to 10 years. Most recently, the Canadian Metoprolol After Vascular Surgery study⁸ found no difference in postoperative cardiac morbidity and mortality at 1 month vs at 6 months with the use of β-blockers. Other evidence suggests that tight perioperative heart rate control is essential to decrease the incidence of perioperative cardiac morbidity and mortality.⁹ The most recent American College of Cardiology and American Heart Association (ACC/AHA) guidelines reviewed the available evidence and suggested a benefit to perioperative β-blockade in high-risk patients undergoing noncardiac surgery, particularly vascular surgery.¹⁰ Despite the absence of definitive evidence, the ACC/AHA guidelines recommended initiation of β-blocker therapy before surgery and titration of the resting heart rate to a target at between 50 and 60 beats/min “to assure the patient is indeed receiving the benefit of β-blockade.”^10(p2667) With the recent release of preliminary results from the Perioperative Ischemic Evaluation (POISE) trial¹¹ showing a higher incidence of total deaths and stroke in patients receiving perioperative β-blockade compared with placebo, these guidelines are now in question.

The present study was undertaken among patients at all levels of cardiac risk. We sought to determine the effect of β-blockers on perioperative heart rate and on perioperative cardiac morbidity and mortality in noncardiac surgery.

Between January 1, 2000, and December 31, 2000, patients undergoing general anesthesia for various noncardiac surgical procedures at Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, were screened and classified before surgery by the operating surgeon as at high, intermediate, low, or negligible cardiac risk based on ACC/AHA guidelines. Because the patients were evaluated in 2000, they were classified according to the ACC/AHA guidelines published in 1996.¹² These were slightly modified in subsequent ACC/AHA guidelines.¹⁰

Patients included in the study underwent a noncardiac surgical procedure using general anesthesia within 6 months of the preoperative risk classification. If a patient underwent more than 1 noncardiac surgery using general anesthesia, only the first procedure was included in the analysis. The surgical procedures performed included plastic, vascular, urologic, abdominal, orthopedic, head and neck, ophthalmologic, skin and soft-tissue, and hernia repair surgery. Each procedure was also classified as high, intermediate, or low in risk as defined by the ACC/AHA guidelines.¹²

Patients' medical records were reviewed for the use of β-blockers at the time of surgery. Note was made of patients for whom β-blockers were started in the perioperative phase and of patients who were already receiving β-blockers before the operation for various reasons such as hypertension, congestive heart failure, or coronary artery disease. Specific β-blockers were recorded such as metoprolol succinate or metoprolol tartrate, atenolol, and propranolol hydrochloride.

For each patient, a preoperative heart rate (PreopHR) reading was documented before the induction of general anesthesia and the start of the operation. Intraoperative heart rate was recorded every 5 minutes. From these tracings, the mean heart rate (MeanHR), maximum heart rate (MaxHR), and minimum heart rate (MinHR) values were extracted for each patient.

Patients who received perioperative β-blockers or were already taking (and had received) β-blockers at the time of surgery constituted the β-blocker group. This group was matched to a control group from the same patient population that did not receive β-blockers at the time of surgery. The 2 groups were matched for age, sex, smoking status, cardiac risk (as per the ACC/AHA classification¹²), procedure risk (as per the ACC/AHA classification), and renal insufficiency (defined as a preoperative creatinine value >2.0 mg/dL [to convert creatinine level to micromoles per liter, multiply by 88.4]).

Thirty-day postoperative cardiovascular morbidity was measured for both groups. These included stroke, nonfatal MI, and cardiac arrest with successful resuscitation. Mortality at 30 days and mortality at 1 year were documented as well. To determine the occurrence of these outcomes, a review of all medical records was performed by one of us (H.M.A.K., P.V.A., and K.M.F.I.). In particular, the diagnosis of MI involved a combination of clinical symptoms, electrocardiographic changes, elevation of troponin or creatine kinase MB level, and medical records documentation by surgeons, internists, or cardiologists.

After adequate matching was ensured, PreopHR, MeanHR, MaxHR, and MinHR were compared between the β-blocker group and the control group. The incidences of postoperative cardiovascular events and of all-cause mortality at 30 days and at 1 year were compared between the 2 groups. Finally, within each group, the PreopHR, MeanHR, MaxHR, and MinHR were compared between those patients who had a postoperative event (including mortality) and those who did not. t, Fisher exact, and χ² tests were used as appropriate. Confidence intervals were set at the 95th percentile, and statistical significance was set at P ≤ .05. Institutional review board approval was obtained for the conduct of this study.

A total of 1238 patients underwent noncardiac surgery and were classified before surgery into high, intermediate, low, or negligible cardiac risk categories based on the ACC/AHA classification.¹² Two hundred thirty-eight patients received β-blockers perioperatively. These patients constituted the β-blocker group and were matched to a control group of 408 patients who underwent noncardiac surgery at the same medical center during the same year but who did not receive perioperative β-blockade. The matching criteria used were age, sex, cardiac risk, procedure risk, smoking status, and renal insufficiency.

Table 1 gives the baseline characteristics in the β-blocker and control groups. The 2 groups were comparable for sex, smoking status, renal insufficiency, cardiac risk classification, and procedure risk classification. In addition, no statistical difference was noted between the ages of the 2 groups (mean [SD], 61.7 [9.8] years for the β-blocker group and 60.9 [12.0] years for the control group; P =.34).

The mean values for the PreopHR, MeanHR, MinHR, and MaxHR were calculated for both groups. Table 2 summarizes the results. The β-blocker group, having received perioperative β-blockers, had lower PreopHR (70 vs 74 beats/min, P =.001), MeanHR (71 vs 78 beats/min, P < .001), MinHR (60 vs 63 beats/min, P =.02), and MaxHR (86 vs 91 beats/min, P < .001).

When outcomes in the 30-day postoperative period were evaluated and compared, patients in the β-blocker group had statistically higher incidences of nonfatal MI (2.94% vs 0.74%, P =.03), total cardiovascular morbidity (5.04% vs 1.47%, P =.003), and all-cause mortality (2.52% vs 0.25%, P =.007) (Table 3). All-cause mortality rates at 1 year were similar between the 2 groups.

In the β-blocker group only, the mean PreopHR of the patients who died within 30 days of their surgery was significantly higher than that of the patients who survived (86 vs 70 beats/min, P =.03). In addition, the patient who died within 30 postoperative days in the control group had a PreopHR of 110 beats/min compared with a mean PreopHR of 74 beats/min in the rest of the control group. There were no statistical differences in the MeanHR, MinHR, or MaxHR when the patients who died were compared with the patients who survived the 30-day postoperative phase in both the β-blocker and the control groups.

None of the patients who died within 30 days of surgery in the β-blocker group were classified as at high risk; 3 were at intermediate risk; and 3 were at low or negligible risk. All of them underwent intermediate-risk to high-risk procedures.

Despite many studies in the past 3 decades, controversy continues regarding the indications and proper use of β-blockers in noncardiac surgery. According to the ACC/AHA 2006 update on perioperative β-blockade,¹⁰ class I recommendations (ie, conditions in which there is evidence or general agreement that the treatment is beneficial, useful, and effective) exist only for the following 2 patient populations: (1) patients who are already taking β-blockers before surgery for other indications such as angina, dysrhythmias, or hypertension and (2) patients undergoing vascular surgery with high cardiac risk as evidenced by ischemia on preoperative cardiac testing.¹⁰ Most studies have not evaluated the effect of β-blockers in patients at intermediate or low cardiac risk. In addition, few studies of perioperative β-blocker use have evaluated the optimal type, dose, regimen, or duration of therapy required.¹⁰ No definite consensus has been reached regarding the population at intermediate cardiac risk and the target heart rate needed for effect. The ACC/AHA recommendation for a resting heart rate at between 50 and 60 beats/min along with maintenance of a heart rate below 80 beats/min through the intraoperative and postoperative periods is the only guideline that is available.

In our study of patients at all levels of cardiac risk, including higher proportions of low-risk and intermediate-risk patients, β-blockers failed to provide perioperative cardioprotection. Unexpectedly, patients receiving β-blockers were at higher risk of 30-day cardiovascular events and overall mortality. This mortality difference disappeared at 1 year. A recent observational study by Lindenauer et al¹³ found that β-blockade decreases in-hospital mortality only in the surgical population with the highest cardiovascular risk and “might be harmful” in the subset of patients with the lowest risk. More recently, the controversy about the use of perioperative β-blockade was further fueled by results of the POISE trial.¹¹ Similar to our study, this large, double-blinded, placebo-controlled trial showed an increase in overall 30-day mortality with the use of metoprolol, despite a lower incidence of postoperative MI, raising new concerns about the safety of perioperative β-blockade in noncardiac surgery.¹¹

Our study analysis demonstrates that the patients who died within 30 days of their operation were not classified as high-risk patients and raises questions about the safety of β-blockers in low-risk or intermediate-risk patients. In addition, the patients who died within 30 days had a clinically and statistically higher PreopHR than that of their counterparts. As subtle as it may be, this finding suggests that a low target preoperative rather than intraoperative heart rate is essential for the protective effect of β-blockers. The relationship between preoperative (rather than intraoperative or postoperative) heart rate and perioperative mortality stresses the importance of not only initiating but also titrating the effect of β-blockers to an acceptable target heart rate before surgery. The biologic basis for such a finding is intriguing and could be explained by evidence in animal investigations showing that treating aged hearts with metoprolol improves the β-adrenergic receptor density and its signaling pathways.¹⁴

Our study has some limitations. First, it is a retrospective study, and some additional confounding variables might exist, despite our meticulous attempt at matching the β-blocker and control groups. Second, our population is a predominantly male veteran population, and one might argue whether our findings are applicable to the general population undergoing noncardiac surgery. Third, there was no uniform regimen for β-blockade used in our population with regard to the type, dose, or duration of therapy, and data regarding the concomitant use of statins, α-blockers, or antiplatelet therapy were unavailable.

In summary, our study adds to the controversy regarding the optimal use of perioperative β-blockers in patient populations at various levels of cardiac risk. Overall, our data found worse perioperative cardiovascular outcome and worse overall mortality associated with the use of β-blockers. Patients who died were at less than high cardiac risk and had worse PreopHR control. Further investigations in this field with standardizing of β-blockade regimen and with monitoring of heart rate in populations at various levels of cardiac risk should be pursued.

Accepted for Publication: January 5, 2008.

Correspondence: Kamal M. F. Itani, MD, Department of Surgery, Veterans Affairs Boston Healthcare System (112), 1400 VFW Pkwy, West Roxbury, MA 02132 (kitani@med.va.gov).

Author Contributions:Study concept and design: Kaafarani and Itani. Acquisition of data: Kaafarani, Atluri, and Itani. Analysis and interpretation of data: Kaafarani, Thornby, and Itani. Drafting of the manuscript: Kaafarani and Itani. Critical revision of the manuscript for important intellectual content: Kaafarani, Atluri, Thornby, and Itani. Statistical analysis: Thornby. Administrative, technical, and material support: Kaafarani and Itani.

Financial Disclosure: None reported.