Beta-Blockers Reduce Surgical Risk

Sources: Mangano DT, et al. N Engl J Med 1996;335:1713-1720; Eagle KA, Froehlich JB. N Engl J Med 1996;335:1761-1762..

Morbidity and mortality in individuals undergoing major noncardiac surgery is substantial, particularly in those with or at risk for coronary artery disease (CAD). Prior studies have suggested a many-fold increased risk of serious cardiovascular complications over a 1-2 year period following such surgery. Much of the early perioperative risk is presumed to be due to increased sympathetic tone and resulting tachycardia. A number of small trials have suggested that perioperative use of beta blockers may decrease myocardial ischemia. The present study asked whether intensive beta-blocker therapy begun immediately prior to surgery and continuing for seven days decreases short- and long-term cardiovascular morbidity and mortality.

The trial was organized out of the San Francisco VA Medical Center and enrolled 200 male veterans who were undergoing elective noncardiac surgery and had definite CAD or had two or more major CAD risk factors (age > 65, hypertension, smoking, elevated cholesterol, or diabetes). The patients were randomized to atenolol 100 mg daily or placebo, with an intravenous dose starting one hour prior to surgery. Subjects were followed for two years, and postoperative nonstudy medications were determined by the patient’s physicians. The randomization schedule provided a reasonably good balance between the 100 patients in each group, although the placebo patients had slightly greater history of prior cardiac events. Atenolol-treated patients had a greater likelihood of postoperative therapy with active cardiovascular medication, including nonstudy beta blockers, and had a higher use of ACE inhibitors. More placebo patients used calcium blockers.

The dosing schedule was modified by baseline and post-drug heart rate and blood pressure responses. During treatment, the average and maximal heart rates were lower in the atenolol cohort. The majority of the patients were able to tolerate 100 mg of atenolol for seven days. There were few adverse effects. Over two-thirds of the surgical procedures were "major vascular" and one-fifth were "intra-abdominal." The rest were divided between orthopedic, neurosurgical, and miscellaneous procedures. The results demonstrated an impressive reduction in risk in the atenolol patients, with a decrease in total mortality and cardiovascular death as well as a reduction in combined cardiac event outcomes (non-fatal MI, heart failure, unstable angina, revascularization). The primary outcome was all-cause mortality during the two years after discharge. The benefits of the beta blocker were seen very quickly, with early separation of Kaplan-Meier curves. The majority of this benefit was achieved within 6-8 months, and, thereafter, the curves for survival and event-free survival were parallel. Overall, post-discharge mortality was 16% (there was a 55% risk reduction in the atenolol patients and a 65% decrease in cardiovascular mortality). Combined cardiac outcomes were also favorably affected by atenolol, with no events in the first six months in these patients compared to 12 events in the placebo group, a 67% decrease in any event within one year, and a 48% decrease at two years. Again, the principal effect was seen within the first eight months.

Analysis of risk factors for death showed that atenolol demonstrated a robust decrease in mortality, whereas diabetes increased the hazard ratio by three-fold and postoperative ischemia by two-fold. However, in a multivariant model, only diabetes and atenolol affected long-term survival.

The authors stress that "a large treatment effect" was demonstrated, with an absolute increase of 15% in event-free survival after hospital discharge (83% atenolol, 68% placebo). Long-term survival was 90% at two years in the beta blocker patients vs. 79% in the placebo patients, and event free survival of two years was 83% vs. 68%. The authors believe that the benefits of the beta blocker were achieved through sympatholytic mechanisms, with lower heart rates leading to less acute cardiac events. The safety record of the atenolol was reassuring, in diabetic patients as well as nondiabetics. In fact, atenolol literally eliminated the adverse risk carried by the presence of diabetes. An unsophisticated cost analysis was favorable. The authors estimate that, of the 3,000,000 similar patients in the United States at risk for a major cardiovascular event, the atenolol would cost approximately $2,500 per life-year saved, an extremely cost-effective figure.

The article is accompanied by an editorial by Eagle and Froehlich who review the appropriate workup for patients undergoing noncardiac surgery and current therapeutic strategies that should be used in such individuals. The editorialists point out that beta blocker use in individuals with documented CAD who entered into the study was only 13%. The low use of beta blockers in patients with CAD has been shown in many studies and is particularly true in America. Eagle and Froehlich emphasize the very low overall perioperative mortality in the VA cohort, indicating that excellent surgical results can be achieved in a contemporary setting. These authors appear less impressed with the event-rate reduction and suggest that there may be baseline differences between the atenolol and placebo patients that could inadvertently favor the beta-blocker cohort over the two years of the study. They propose that beta blockers be used in individuals with definite CAD or hypertension, but do not commit to routine beta-blocker policy in individuals undergoing noncardiac surgery who appear not to have any clinical evidence of coronary disease risk (history of CAD, poor functional capacity).

Comment by Jonathan Abrams, MD

These results should be interpreted in light of a variety of concordant beta-blocker data that date back 15-20 years and demonstrate that beta-adrenergic blockade is truly cardio-protective. This is opposed to the calcium-channel antagonists and nitrates for which there are no data that cardiovascular morbidity, and mortality can be favorably influenced. Post-myocardial infarction trials in the pre-thrombolytic era, as well as in recent studies, continue to show a beneficial effect for beta blockers, even though mortality of acute myocardial infarction has been substantially reduced. Furthermore, beta blockers are our best drugs for suppressing silent myocardial ischemia, and recent trials would suggest that beta-blocker therapy may decrease events in such individuals. Beta blockers have a modest antiarrhythmic effect and are often used for ventricular arrhythmias in high-risk patients. These drugs, when used carefully, also appear to be beneficial in heart failure and may prevent adverse remodeling of the left ventricle as well as improve survival. Thus, it is not surprising that atenolol appeared to substantially decrease cardiovascular morbidity and mortality within the first year following discharge.

The mechanisms for a favorable effect are not completely clear. Suppression of ischemia leading to protection of vulnerable plaque is an attractive hypothesis. Both the heart-rate and blood-pressure lowering effects of these drugs should be beneficial in individuals with underlying obstructive vascular disease, with and without rupture-prone plaque. While it is true that one cannot be certain that the two cohorts were truly equal with respect to cardiovascular risk, the robust risk reduction in the atenolol arm, particularly within the first 6-8 months, is quite impressive and is in keeping with previous data. Thus, it would appear reasonable to strongly consider atenolol therapy in high-risk patients undergoing major non-surgical procedures. It is ironic that some years ago beta blockers were deliberately discontinued in patients undergoing bypass surgery, which in retrospect appears to have been an inappropriate therapeutic strategy. Not only should these drugs be used in the operating suite for days after (atenolol was used only for seven days in this study), it would be beneficial for physicians to use these drugs far more frequently in patients who have documented CAD who are not undergoing surgery. Recent surveys continue to document underutilization of these proven pharmacologic agents.

Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.