Perioperative Use of β-Adrenergic Antagonists and Anemia

Abstract

I N seminal publications, Mangano et al. demonstrated an association of postoperative tachycardia and myocardial ischemia in patients with or at risk for coronary artery disease , after surgery other than cardiac surgery, 1 after having previously shown an association between postoperative isch-emia and adverse cardiac outcomes. 2 Thus, a link was established for postoperative tachycardia, myocardial ischemia, and adverse outcomes. That group followed with a logical extension of their work, showing in a prospective, random-ized, double-blinded, but relatively small trial of 200 patients , with or at risk for arteriosclerotic coronary artery disease , undergoing surgery other than cardiac surgery, that administration of a-adrenergic antagonist begun immediately before surgery and continued for the first of 7 days or hospital discharge decreased postoperative myocardial isch-emia, 3 and long-term (2-yr) mortality. 4 The former publication was accompanied by an editorial by Warltier, 5 decrying the underutilization of-adrenergic antagonists. These results were confirmed by another small (112 patients) prospective, randomized, but not blinded, trial in patients with dobutamine echo-confirmed coronary arterio-sclerotic heart disease in which another-adrenergic antagonist, bisoprolol, initiated at least 1 week before surgery , and continued until postoperative day 30, decreased cardiac and all-cause mortality and nonfatal myocardial in-farction. 6 The results of these trials and several endorsements and recommendations led to widespread acceptance and use of this class of drugs in patients at high risk for myocardial ischemia and by some clinicians for patients with lesser risk, as well. Perhaps, acceptance and use were facilitated by the sound physiologic and pathophysiologic basis for these findings: that-adrenergic antagonism (even if partial) decreases myocardial oxygen consumption by decreasing heart rate (and, thus, work) and myocardial contractility, while at the same time increasing diastolic time and coronary artery flow, thus improving the balance of myocardial oxygen delivery and oxygen consumption. Also, it has been speculated that at least some of the-adrenergic blockade-induced reduction of myocardial infarction may be due to plaque stabilization, 7 because of hemodynamic-induced plaque stress reduction. More recently, a flawed retrospective analysis using propensity score, but with unsuccessful matching, of more than half a million surgical patients in 329 U.S. hospitals noted a decreased mortality for high-risk patients but no improvement of mortality for low-risk patients given-adrenergic antagonists during the first 2 days of hospitalization. Notably, the date of surgery was unknown. 8 Subsequently, some clinical trials have failed to reproduce these previous results. However, one was underpow-ered to detect a decrease of even 50% of cardiac events, 9 and another 10 was halted early because of poor patient recruitment and, thus, also was underpowered. Complicating the issue further, a randomized prospective trial of 8,351 patients with or at risk for arteriosclerotic disease undergoing noncardiac surgery (41.5% had vascular surgery) in 190 hospitals in 23 countries, taking 5 yr to complete (The PeriOperative ISchemic Evaluation trial) and using a high dose of extended release metoprolol found a benefit of-adrenergic antagonist administration for a composite cardiac endpoint (cardiovascular death, nonfatal myo-cardial infarction, and nonfatal cardiac arrest) and all myo-cardial infarctions, but a greater incidence of death (3.1% vs. 2.3%) and stroke (1.0% vs. 0.5%); nearly all of the latter was ischemic in origin. 11 This trial, too, was stopped early for the unusual reason, "mainly because the remaining study drug expired" the following month. 11 A more recent case-controlled examination of a single-center database of 186,779 patients with a much smaller incidence of postoperative stroke (0.02% when excluding patients who had intracerebral or carotid surgery) failed to find an increased association of computed tomography-confirmed postoperative stroke with chronic-adrenergic antagonist therapy. 12 It is difficult to compare these studies as they involved different-adrenergic antagonists, initiated and administered over varying durations relative to surgery, with popu