Pro- Beta Bloqueador

Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery
[Cardiovascular Anesthesia: Cardiovascular and Thoracic Education: Editorial]
Schouten, Olaf MD; Bax, Jeroen J. MD, FESC; Dunkelgrun, Martin MD; Feringa, Harm H.H. MD; Poldermans, Don MD, FESC

Section Editor(s): Hogue, Charles W. Jr; London, Martin J.

From the Department of Vascular Surgery, Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Accepted for publication May 26, 2006.
Dr. O. Schouten is supported by an unrestricted research grant from The Netherlands Organization for Health Research and Development (ZonMw), The Hague, the Netherlands and an unrestricted research grant from “Lijf & Leven” Foundation, Rotterdam, the Netherlands. Dr. M. Dunkelgrun is supported by an unrestricted research grant (#2003B143) from the Netherland Heart Foundation, The Hague, the Netherlands.
Address correspondence and reprint requests to Prof. Dr. Don Poldermans, Department of Anesthesiology, Room H 921, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Address e-mail to d.poldermans@erasmusmc.nl.
Of the estimated 100 million adults undergoing noncardiac surgery annually, approximately 500,000 patients (0.5%) will experience cardiac death perioperatively (1). Lee et al. (2) reported an overall risk for myocardial infarction (MI) after noncardiac surgery to be 1.1%, translating into about 1.1 million MIs annually worldwide. Although the pathophysiology of perioperative MI is not entirely clear, coronary plaque rupture, leading to thrombus formation and subsequent vessel occlusion, is implicated, similar to MI in the nonoperative setting (3). The incidence of plaque rupture is possibly increased by the stress response to major surgery. This response includes sympathetic activation promoting sheer stress on arterial plaques, enhanced vascular reactivity conducive to the development of vasospasm, reduced fibrinolytic activity, platelet activation, and hypercoagulability (4). Heightened sympathetic tone further increases myocardial oxygen demand (e.g., tachycardia and increased contractility), leading to myocardial oxygen supply/demand mismatch that, when sustained, might lead to MI (4,5). At least two studies evaluating the pathophysiology of perioperative MI using noninvasive tests, coronary angiography, and autopsy have shown that coronary plaque rupture and thrombus formation occurred in 50% of all fatal MIs, whereas a sustained oxygen supply/demand mismatch was responsible for the remaining 50% (3,6).

MECHANISM OF THE PROTECTIVE EFFECT OF BETA-BLOCKERS
Because of the role of sympathetic activation in adverse perioperative cardiac outcomes, [beta]-adrenergic receptor blocking drugs have been proposed as a means for providing cardioprotection. Potential cardioprotective mechanisms of [beta]-blockers include a) reduced heart rate and contractility and subsequently lower myocardial oxygen demand; b) a shift in energy metabolism from free fatty acids to the more energy efficient glucose; c) antiarrhythmic effects; d) anti-renin/angiotensin properties; and e) antiinflammatory effects possibly promoting plaque stability (7–9). The effects on heart rate, contractility, and energy substrate shift occur almost instantly, whereas the antiinflammatory effects may be observed only after prolonged use of [beta]-blockers.

CLINICAL EVIDENCE FOR THE EFFECTIVENESS OF PERIOPERATIVE BETA-BLOCKER THERAPY
Although widely prescribed as a means for reducing perioperative cardiac events, the evidence supporting this indication for [beta]-blockers is based mainly on two small, prospectively randomized clinical trials and several observational studies. In the first study, Mangano et al. (10) randomized 200 patients with either known or suspected coronary artery disease undergoing high-risk noncardiac surgery to receive atenolol (50 mg or 100 mg) or placebo. Atenolol therapy was not associated with an improved in-hospital outcome (cardiac death or MI); however, it was associated with a 50% reduction in electrocardiogram evidence of myocardial ischemia detected with continuous 3-lead Holter monitoring during the first 48 h after surgery. Interestingly, patients receiving perioperative atenolol had a reduced rate of cardiac events 6 to 8 mo after surgery compared with the placebo group, suggesting a delayed beneficial response. In the second trial, the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study)-I trial (11), of 112 vascular surgery patients with evidence of myocardial ischemia on preoperative dobutamine stress-echocardiography, Poldermans et al. showed a 10-fold reduction in the incidence of perioperative cardiac death and MI with perioperative bisoprolol use compared with placebo (3.4% versus 34%; P < 0.001). The high incidence of perioperative cardiac events was explained by the selection of high-risk patients for study. From a population of 1351 patients, only 112 met entrance criteria of inducible myocardial ischemia.

These promising results supporting perioperative [beta]-blocker use as a means for improving cardiac outcomes are not supported by two more recent trials. In the POBBLE (PeriOperative Beta-BLockadE) trial (12), only low-risk patients (history of ischemic heart disease was an exclusion) scheduled for vascular surgery were studied. This low-risk population was randomized to receive either metoprolol 25 mg or 50 mg (n = 55) or placebo (n = 48) starting the day before surgery and continued during the first 7 days after surgery. There was no difference in the incidence of perioperative cardiovascular events between the placebo and metoprolol groups (34% versus 32%). The duration of hospitalization though was shorter for those patients receiving metoprolol versus placebo (10 days versus 12 days).

In the DIPOM (Diabetic Postoperative Mortality and Morbidity) study (20) the cardioprotective effect of 100 mg metoprolol started the evening before major noncardiac surgery was compared with placebo in 921 diabetic patients. In that study, there were no difference in 30-day morbidity and mortality (21% versus 20%; P = 0.66). A limitation of the DIPOM study was that it was only powered to detect a 10% difference in mortality after 1 yr of follow-up.

EXPLAINING THE CONFLICTING RESULTS OF PERIOPERATIVE BETA-BLOCKER TRIALS
There are several explanations for the divergent findings from randomized trials of perioperative [beta]-blockers, including the use of a fixed versus individualized dose titrated to the patients heart rate.

In a study of 150 patients, Raby et al. (13) assessed the heart rate threshold for myocardial ischemia before surgery using Holter monitoring. Patients with myocardial ischemia (n = 26) were then randomized to receive a) IV esmolol titrated to aiming at tight heart rate 20% less than the ischemic threshold but >60 bpm or b) placebo. Of the 15 patients receiving esmolol, 9 had mean heart rates below the ischemic threshold and none experienced postoperative ischemia. Four of 11 patients receiving placebo had a mean heart rate below the ischemic threshold, and 3 of the 4 had no postoperative ischemia. Together, of the 13 patients with heart rates below the ischemic threshold, 1 (7.7%) had postoperative electrocardiogram myocardial ischemia versus 12 of 13 (92%) patients with heart rates exceeding the ischemic threshold. Feringa et al. (14) found similar results in a study of 272 patients receiving [beta]-blocker therapy and undergoing vascular surgery. In that study it was shown that higher doses of [beta]-blockers and lower heart rate (HR) were associated with reduced Holter monitoring-detected perioperative myocardial ischemia (HR, 2.49; 95% confidence interval [CI], 1.79-3.48) and troponin T release (HR, 1.53; 95% CI, 1.16-2.03) increased. These data suggest that monitoring of the heart rate and consequent [beta]-blocker dose adjustment is of critical importance.

The conflicting results of perioperative [beta]-blocker trials might be further explained by varying durations of therapy. As mentioned, although the sympathico-inhibitory effects of [beta]-blockers occur almost instantly, the antiinflammatory effects may be observed only after prolonged treatment. As mentioned, in the Mangano et al. study (10), the major benefits of atenolol were observed in the months after surgery. In both the DIPOM and POBBLE trials, [beta]-blocker therapy was initiated on the day before surgery. The DECREASE-I trial showed the largest effect of perioperative [beta]-blocker therapy. The time between [beta]-blocker therapy initiation and surgery was 37 days in this trial (11). Further, withdrawal of [beta]-blocker therapy shortly before surgery, or in the immediate postoperative period, might contribute to adverse myocardial effects resulting from a “rebound” effect resulting in increased arterial blood pressure, HR, and plasma noradrenalin concentrations (15). Redelmeier et al. (16) have recently shown that the long-acting agent atenolol was superior to the short-acting drug, metoprolol, when given perioperatively, probably as the result of acute withdrawal effects from missed doses of short-acting [beta]-blockers.

Finally, recent data from Lanfear et al. (17) suggest that gene polymorphisms might modulate the response to [beta]-blockers. They found that survival for patients receiving [beta]-blocker therapy after an acute coronary syndrome was lower for patients with the 70C and 46A ADRB2 genotypes. In the future, perhaps, identifying patients most likely to benefit from perioperative [beta]-blocker therapy might be possible by genotyping patients before surgery.

SHOULD ALL PATIENTS AT INCREASED CARDIAC RISK RECEIVE PERIOPERATIVE BETA-BLOCKER THERAPY?
The central question asked in these editorials is whether, based on existing evidence, all high-risk patients should receive a [beta]-blocker perioperatively. A simple answer would be “yes.” Perhaps a more critical question involves identifying which patients are at increased risk for perioperative cardiac complications. In a recent cohort study of 663,635 patients, Lindenauer et al. (18) reported that, in patients at intermediate or high risk (i.e., >=2 risk factors according to the Revised Cardiac Risk Index (2), undergoing major noncardiac surgery, [beta]-blocker use was associated with a reduced incidence of in-hospital mortality. On the other hand, patients at low risk for cardiac complications were found to have no benefit from perioperative [beta]-blocker therapy and in fact experienced a higher incidence of in-hospital mortality. This finding indicates that perioperative [beta]-blocker therapy is effective for selected patients, based on their risk for cardiac complications.

CONCLUSION
In high-risk patients, the existing data suggest that perioperative [beta]-blocker use is effective for reducing the frequency of adverse cardiac events when administered in a dose titrated to a heart rate below the ischemic threshold typically between 60 and 65 bpm. Beta-blocker therapy should be started before surgery to achieve the optimal protective effect and most likely it should be continued after surgery, and possibly the treatment should be life-long. For patients at intermediate risk and for diabetics, the benefits of [beta]-blockers are less clear. The results of randomized trials in patients at intermediate risk conducted so far (i.e., DIPOM and POBBLE) cannot be considered conclusive because poor heart rate control and the short interval between initiation and surgery may have seriously influenced the outcome of these two studies. The results of two large ongoing trials might help better define [beta]-blocker use in these populations. In the POISE (PeriOperative ISchemic Evaluation) trial, a fixed dose of [beta]-blockers is compared with placebo in patients at low or intermediate risk for cardiac complications. The DECREASE IV trial will evaluate the effect of [beta]-blockers (aiming at a heart rate between 60 and 65 bpm), statins, or a combination of both in patients at intermediate cardiac risk undergoing major noncardiac surgery (19). These trials may help to determine the effectiveness of perioperative [beta]-blocker use in patients at intermediate risk.