How Should Beta-Blockers Be Used Perioperatively?

Early Studies

The first randomized trial of perioperative beta-blockers came from the Multicenter Study of Perioperative Ischemia (McSPI) study group in 1996. The study consisted of 200 Veterans Affairs patients with or at risk for coronary artery disease (CAD) undergoing noncardiac surgery ( Table 14.1 ). Patients were randomly assigned to receive either placebo or atenolol (50 or 100 mg) 30 minutes before surgery and continued for 7 days afterwards. A 50% reduction in postoperative ischemia (from 34%–17% in days 0–2, p = .008) based on Holter monitoring was detected. Although beta-blockers did not affect perioperative MACE, during follow-up, the incidence of postoperative cardiac events and overall mortality were both shown to be significantly lower in the atenolol group at 6 months (0% versus 8%; p < .001) and remained significant throughout the 2-year study period (10% versus 21%; p = .019).

There were several important limitations to this trial. Patients were not excluded if they were already taking a beta-blocker; thus some patients randomly assigned into the placebo arm could have had effects from abrupt cessation of therapy. Beta-blocker withdrawal can lead to increases in heart rate and myocardial oxygen demand and predispose to myocardial ischemia. Additionally, only patients who survived to hospital discharge were examined because it was not an intention-to-treat analysis. If all in-hospital mortalities were included, the actual 2-year mortality rate would not have been significantly different ( p = .1).

In contrast to the McSPI study in which patients just at “risk” for CAD were included, the first DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography, 1999) trial enrolled only patients with positive results on preoperative dobutamine stress echocardiography before major vascular surgery. Patients were randomly assigned to either titrated bisoprolol therapy or standard perioperative care. Patients taking preoperative beta-blockers or those with extensive wall motion abnormalities were excluded. Bisoprolol (5–10 mg) was started at least 1 week before surgery (average, 37 days prior) and then continued for 30 days postoperatively; the target heart rate was 51 to 79 beats/min.

The results showed a significant reduction in the primary endpoint of composite death from cardiac causes or nonfatal MI within 30 days postoperatively (34% vs. 3.4%, p < .001). The trial was stopped early despite only enrolling 112 patients (20 cardiac events). This study was not double-blind, the degree of risk reduction was larger than many authors deemed reasonable, and the event rate in the placebo arm was also greater than expected. ^,

The Perioperative Beta-Blockade (POBBLE) study, published in 2005, found no difference in CV outcome in 97 vascular surgical patients randomly assigned to perioperative metoprolol versus placebo who underwent screening to ensure that CAD was not present. Similarly, both the Diabetic Postoperative Mortality and Morbidity (DIPOM; 921 patients) and Metoprolol after Vascular Surgery (MaVS; 496 patients) studies found no benefit in short- and long-term (6- to 18-month) cardiac outcomes with the administration of perioperative metoprolol initiated immediately before or very close to surgery. ^, A statistically significant increase in perioperative bradycardia and hypotension in the treatment arm was also shown.

It is important to note that the study populations in POBBLE, DIPOM, and MaVS represented a lower risk cohort than the DECREASE I trial did. Although DIPOM studied diabetic patients undergoing major surgery, major was defined as any procedure lasting longer than 1 hour and had somewhat vague exclusion criteria for patients with significant cardiac disease. The MaVS study specifically studied major vascular surgical patients but also had a low incidence of patients with known CAD and excluded those with significant comorbidities.

A large retrospective database cohort study of PBB by Lindenauer and colleagues used propensity score matching to adjust for differences in patients. They found that the administration of any beta-blocker perioperatively to patients not already taking them was associated with no benefit and possible harm in patients with a Revised Cardiac Risk Index (RCRI) of 0 to 1 (1 point each for the following: high-risk surgery, serum creatinine >2 mg/dL, with diabetes and taking insulin, or history of CAD, CHF, or cerebrovascular disease; Box 14.1 ). In patients with an RCRI of 2 or greater, however, perioperative beta-blockade was associated with a decreased risk for death.

Although the results of the POBBLE, DIPOM, and MaVS studies question the utility of PBB in mostly intermediate-risk patients, the DECREASE IV study showed more positive results for a similar cohort. The study enrolled 1066 patients considered to have a 1% to 6% perioperative CV risk who were randomly assigned to receive bisoprolol or placebo as well as fluvastatin or placebo. The study design for bisoprolol administration was identical to that of the DECREASE I trial. A significant reduction in MACE within 30 days was shown for the 533 patients who received bisoprolol (2.1% vs. 6.0%, p = .002). Similar to the original DECREASE trial, this trial also was not double-blind and was terminated early.

In considering these early trials, although the principal evidence for mortality benefit of perioperative beta-blockade come from the DECREASE family of studies, these studies were largely discredited in 2011 and subsequently underwent lengthy internal investigation for scientific misconduct for data fabrication and fictitious methodology. DECREASE I, published in 1999, escaped investigation because the terms of the investigation only reached back 10 years. ^, These studies are included in this analysis because it is important to understand their impact on paradigms surrounding PBB.