By reducing adrenergic stimulation, P-blockers have the potential to ameliorate cardiac stress in the perioperative setting, thereby reducing the likelihood of clinical cardiac events.12 Potential cardioprotective effects of P-blockers include (1) reduction in myocar-dial oxygen demand via the negative inotropic and chronotropic effects of these agents; (2) increase in myocardial oxygen supply, brought about by prolongation of coronary diastolic filling time; (3) reduced arrhythmic potential despite perioperative increases in sympathetic tone; (4) decreased coronary shear stress, lowering the likelihood of coronary plaque rupture; and (5) anti-inflammatory effects, also possibly reducing the potential for plaque disruption. With respect to patients undergoing vascular surgery, although the presence of severe peripheral arterial disease previously was viewed as a contraindication to P-blocker therapy, recent studies have shown that

Study Drug N Follow-up ß-Blocker Placebo ß-Blocker Placebo ß-Blocker Placebo

McSPI Atenolol 200 2 yr 17* 32 10* 21 NR NR

DECREASE Bisoprolol 1 12 30 days 3* 34 3* 1 7 0* 1 7

DIPOM Metoprolol XL 921 18 mo 21 20 16 16 NR NR

MaVS Metoprolol 497 30 days 10 12 0.4 2.8 7.7 8.4

Table 7-3. Results of Randomized Trials of P-Blocker Therapy during Noncardiac Surgery

Composite Cardiac All-Cause Nonfatal Myocardial

NR, not reported.

these agents are well tolerated and are associated with a substantial survival benefit in patients with vascular disease.13

Based primarily on the results of two small randomized trials, the ACC/AHA guidelines for perioperative evaluation and management recommend (class I or Ila) the routine use of P-blocker therapy for patients with either established coronary disease, ischemia on preoperative stress testing, or multiple clinical risk factors who are scheduled to undergo an intermediate- or high-risk surgical procedure.14 In the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) trial, 112 patients with evidence of ischemia on stress echocardiography before vascular surgery were randomized to oral bisoprolol or placebo starting at least

7 days before surgery and continuing for 30 days postoperatively.15 Although the study was limited by its small sample size, nonblinded design, and low number of adverse events, bisoprolol therapy was associated with dramatic reductions in 30-day cardiac death (3.4% vs. 17%) and nonfatal MI (0% vs. 17%). The Multicenter Study of Perioperative Ischemia (McSPI) randomized 200 patients undergoing a variety of noncardiac surgical procedures to either a combination of oral and intravenous atenolol or placebo, initiated before the induction of anesthesia and continued for up to 7 days postoperatively.16 Although P-blocker therapy was not associated with a reduction in perioperative MI or death, it was associated with a 50% reduction in the number of ische-mic episodes on continuous ECG monitoring during the index hospitalization, as well as a 65% relative reduction in cardiac mortality (and a 55% reduction in all-cause mortality) at 2-year follow-up. The reason that a short course of P-blocker therapy during the perioperative period was associated with such a dramatic reduction in late mortality in this cohort is not clear.

Interestingly, two larger and more recently completed randomized studies failed to demonstrate benefit from perioperative P-blocker therapy (Table 7-3).17,18 In the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial, 921 patients with type 2 diabetes mellitus who were scheduled for noncardiac surgery and not already using P-blocker therapy were randomized to receive either metoprolol or placebo, initiated 2 hours before surgery and continued up to

8 days postoperatively. At 18-month follow-up, there were no differences based on treatment assignment in the incidence of either the primary composite end point of death, MI, unstable angina, or heart failure (21% vs. 20% for metoprolol vs. placebo) or all-cause mortality (16% vs. 16%). Similarly, in the Metoprolol after Vascular Surgery (MaVS) trial of 497 patients undergoing elective vascular surgery, metoprolol begun 2 hours before the operation and continued for 6 days afterward was not associated with a significant reduction in 30-day cardiac death (0% vs. 0.4% for metoprolol vs. placebo) or nonfatal MI (7.7% vs. 8.4%), although a trend toward reduced all-cause mortality was apparent with P-blocker therapy (0.4% vs. 2.8%).

A large observational study that examined outcomes of more than 100,000 patients who received P-blocker therapy during admission for noncardiac surgery suggests a relationship between a patient's degree of cardiac risk and the likelihood of benefit from perioperative P-blockers.19 Among individuals at the highest risk for perioperative cardiac events, P-blocker therapy was associated with a 43% relative reduction in the risk of in-hospital death after surgery; however, among patients with the lowest preopera-tive cardiac risk index, use of P-blockers was associated with a surprising 10% to 43% increased rate of in-hospital mortality (Fig. 7-4).

Based on current data, several important unanswered questions exist regarding the use of P-blockers in the perioperative setting, including (1) the optimal timing of therapy, including the issues of how long before surgery P-blockers should be initiated, and for what duration they should be continued postopera-tively; (2) whether a class-effect exists, or whether certain P-blocker agents are superior for preventing perioperative events; (3) whether the P-blocker dose should be individually titrated to effect (e.g., target heart rate), or whether a standard dose is sufficient; and (4) which patients are most likely to derive benefit from perioperative P-blocker therapy.20

Two large ongoing trials should help to further clarify the role of P-blockers. Until then, physicians should adhere to the current ACC/AHA guidelines, which advocate the use of P-blockers for higher-risk patients undergoing intermediate- or high-risk surgical procedures. Recent surveys have demonstrated that appropriate perioperative P-blocker therapy remains widely underused in clinical practice.21 It should also be recognized that potential adverse

Figure 7-4. Odds ratios for in-hospital death among patients receiving P-blocker therapy during hospitalization for noncardiac surgery, based on the patient's Revised Cardiac Risk Index score. Patients with lower scores (0,1) demonstrated increased mortality rates relative to patients not taking P-blockers at the time of surgery. Among patients at higher cardiac risk, however, use of P-blockers was associated with lower perioperative mortality rates. (From Lindenauer PK, Pekow P, Wang K, et al: Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med 2005;353:349-361.)

Revised cardiac risk index score 0

1.36 (1.27-1.45)


1.09 (1.01-1.19)


0.88 (0.80-0.98)


0.71 (0.63-0.80)


0.58 (0.50-0.67)

Odds ratio for in-hospital death (95% confidence interval)

Odds ratio for in-hospital death (95% confidence interval)

effects of P-blocker administration can occur. In the MaVS trial, for example, patients randomized to pre-treatment with P-blockers were significantly more likely to develop intraoperative hypotension or bra-dycardia requiring treatment. p-Blocker therapy likewise should be used with caution in low-risk individuals until further data emerge, given the paradoxical increase in mortality among lower-risk patients in the retrospective analysis discussed earlier. In summary, although P-blocker therapy most likely will continue to play an important role in perioperative management, because the antiadrenergic actions of P-blockers counter only one of several possible pathophysiologic mechanisms of perioperative MI, determination of other approaches to MI prevention will remain essential.22 As evidenced in clinical trials, perioperative cardiac events can still occur in more than 10% of patients receiving P-blocker therapy.

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