This article highlights the major studies of perioperative beta-blockade to prevent cardiac complications and identify which patients may benefit most from this therapy.
Cardiac complications (cardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest) significantly contribute to the morbidity and mortality that can occur during the perioperative period in patients undergoing major noncardiac surgeries. In-hospital mortality approaches 17% for patients that experience a perioperative myocardial infarction,1 whereas those who survive to hospital discharge are at increased risk of cardiovascular death and nonfatal myocardial infarction 6 months postoperatively.2 Mortality associated with perioperative cardiac arrest is 65%. Those that experience nonfatal cardiac arrest are at increased risk of cardiac death 5 years postoperatively.3
Pathophysiology of Perioperative Myocardial Infarction
Major surgery can be likened to an extreme stress test. In the setting of surgical trauma, general anesthesia, intubation and extubation, fasting, hypothermia, and pain, the body produces excess levels of catecholamines and cortisol. This in turn results in increases in heart rate, blood pressure, and coronary artery shear stress, which can trigger plaque fissuring, acute coronary thrombosis, and significantly increased cardiac oxygen demand.4 Increased oxygen demand can precipitate perioperative myocardial ischemia, which has been strongly linked with the occurrence of perioperative myocardial infarction.5 Ongoing research in this area aims to identify which underlying mechanism (plaque fissure/coronary thrombosis vs myocardial ischemia) may be the greatest contributor to the development of perioperative myocardial infarction in the hopes that prevention or attenuation can significantly reduce the incidence of these perioperative cardiac complications.
Pioneering work from the 1970s and 1980s6,7 identified various risk factors associated with the development of cardiac complications and allowed the clinician to stratify patients according to risk for developing cardiac complications after noncardiac surgery. Given advancements in the modern practice of surgery, anesthesia, and postoperative care, Lee et al8 developed a revised index referred to as the Revised Cardiac Risk Index for prediction of risk of cardiac complications following major noncardiac surgery. They observed 2893 patients undergoing elective major noncardiac procedures—the majority of which (66%) were orthopedic or high-risk vascular procedures—to identify 6 independent predictors of major cardiac complications, which were then validated among a cohort of 1422 patients. The risk of cardiac complications increased as the number of risk factors present increased (Table 1).
In addition to identifying risk factors present for any given patient, it is also important to take into account the risk associated with the surgical procedure to be performed (Table 2). For example, although a patient undergoing cataract surgery with 1 risk factor according to the Revised Cardiac Risk Index (low risk procedure) requires no further workup, a patient with 5 risk factors scheduled to undergo orthopedic surgery (intermediate risk procedure) likely requires an in-depth discussion on the cardiac risk and complications that can occur during or after the procedure, as well as the possible need for revascularization or pharmacological therapy to prevent it.
Numerous perioperative pharmacological therapies have been studied to prevent the occurrence of cardiac complications in patients undergoing noncardiac surgery. The most extensively studied agents have been cardioselective (β1) beta adrenergic receptor antagonists. Because one of the underlying contributors to cardiac complications is the high stress state and corresponding increase in sympathetic activity that occurs during and following surgery, investigators postulated that attenuating this high sympathetic output would result in a significant decrease in the mortality and morbidity associated with perioperative cardiac complications.
Initial studies produced promising results that supported the administration of β1-antagonists in high-risk patients undergoing major noncardiac surgery. The first of these trials was a double-blinded, randomized controlled trial comparing the effects of atenolol vs placebo in 200 patients with or at risk for coronary artery disease undergoing elective major noncardiac surgery.11 Overall mortality was significantly lower in the atenolol group at all points of follow up; 6 months (0% vs 8%, P<.001), 1 year (3% vs 14%, P=.005), 2 years (10% vs 21%, P=.019). Limitations of this study include its small sample size and definition of primary end point. Mortality was defined as post-discharge mortality. When in-hospital deaths are included in the analysis, the results become insignificant. The DECREASE trial evaluated bisoprolol vs placebo in 112 high-risk patients undergoing major vascular surgery.12 The overall rate of the combined endpoint of death from cardiac causes or nonfatal myocardial infarction was significantly reduced in the bisoprolol arm (3.4% vs 34%; P<.001). However, significant limitations of this trial include small sample size, lack of blinding, and the unexpected and almost unbelievable 90% reduction in events (2 vs 18).
A number of trials have investigated the possible benefit of beta-blockade in various other patient populations that have produced discordant results as compared to the 2 trials mentioned above. The first of these is the POBBLE trial, which compared metoprolol to placebo in 103 “lower-risk” patients undergoing infrarenal vascular surgery.13 The investigators found no difference in the rates of 30-day cardiovascular events with metoprolol (34% vs 32%, adjusted relative risk 0.87) but noted a significant reduction in the time from operation to discharge in the metoprolol arm (10 vs 12 days, P<.02).
The DiPoM trial compared extended release metoprolol to placebo in type II diabetics scheduled to undergo major noncardiac surgery.14 No significant differences were noted in any of the primary or secondary endpoints. Short duration of beta-blocking therapy (average of 4.6 days) as well as the administration of a fixed dose of extended release metoprolol (ie lack of titration to heart rate) were both significant methodological flaws of the trial.
The MaVS trial randomized 496 patients undergoing elective vascular surgery to metoprolol or placebo.15 No significant difference was noted in the rates of primary outcome events (nonfatal myocardial infarction, unstable angina, new congestive heart failure, new atrial/ventricular dysrhythmia requiring treatment, or cardiac death) between groups at 30 days (10.2% vs 12.0%; P=.57) or 6 months (P=.81). However, significantly more patients in the metoprolol arm experienced intraoperative hypotension and bradycardia requiring treatment.
The largest trial to date addressing the question of beta-blockade to reduce the incidence of cardiac complications in at-risk patients undergoing noncardiac surgery is the POISE trial. In this trial, 8351 patients with or at risk for coronary artery disease undergoing major noncardiac surgery (~40% vascular) were randomly assigned to treatment with either extended release metoprolol at 100 mg once daily vs placebo.16 Fewer patients in the metoprolol group than the placebo group reached the primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal cardiac arrest) at 30 days (5.8% vs 6.9%, P=.04). The reduction in the rate of myocardial infarction (4.2% vs 5.7%, P=.0017) was responsible for the overall benefit noted with metoprolol treatment. However, significantly more deaths occurred in the metoprolol group (3.1% vs 2.3%; P=.0317) due to a higher incidence of stroke (1.0% vs 0.5%; P=.0053). A major flaw in trial design is the administration of extended release metoprolol, which cannot be titrated to heart rate given its significantly long half-life. It should be noted that a greater proportion of patients in the metoprolol group experienced significant hypotension (15% vs 9.7%) and bradycardia (6.6% vs 2.4%). It is plausible that the excess episodes of hypotension are responsible for the increased rates of stroke noted in POISE.
DECREASE-IV is the most recently conducted trial. It used a 2×2 factorial design that randomized 1066 intermediate-risk patients undergoing vascular surgery to receive bisoprolol (titrated to perioperative heart rate 50-70 beats per minute), fluvastatin, a combination of the 2, or double placebo.17 Patients randomized to bisoprolol had a significantly lower incidence of 30-day cardiac death and nonfatal myocardial infarction (2.1% vs 6.0%; P=.002). No difference was noted between bisoprolol and placebo in the incidence of beta-blocker related safety endpoint (stroke, heart failure, clinically significant bradycardia, or hypotension). Lack of blinding and early termination due to slow enrollment are noteworthy limitations of this trial.
Since the publication of POISE and DECREASE-IV, the American College of Cardiology (ACC) and the American Heart Association (AHA) issued a focused update on beta blockade18 to the guidelines on perioperative care for noncardiac surgery. The guidelines recommend beta blocker therapy titrated to heart rate and blood pressure as reasonable in patients undergoing vascular or intermediate risk surgery who are identified as high risk defined by the presence of >1 clinical risk factor. Given the relationship between bradycardia or hypotension and morbidity or mortality found in POISE, a new recommendation is that routine administration of high-dose beta blockers in the absence of dose titration is not useful and may be harmful and the committee advises that any beta-blocker protocol should be designed to avoid hemodynamic instability.
Given the conflicting results of the available evidence, which patients should receive beta-blockers and how should they be administered? As noted above, the ACC and AHA recommend beta-blockers for patients who carry a high cardiac risk. The data are less clear when choosing which beta-blocker to use; the clinician should take into account the differences in pharmacology of the various drugs. A cardioselective agent (metoprolol, atenolol, or bisoprolol) titrated to a heart rate between 60 and 80 beats per minute is recommended. Given the current data, it is possible that beta-blockers with a longer half-life (atenolol and bisoprolol) may be more effective than shorter acting agents (metoprolol). The POISE trial emphasizes the deleterious effects of sustained perioperative hypotension; therefore the use of extended release formulations of beta-blockers should be avoided in this patient population.
Of note, the thresholds for withholding treatment in POISE were a systolic blood pressure <100 mm Hg or heart rate <45 beats per minute. Protocols should use more conservative parameters with clear guidelines that define when to reduce the dose or hold therapy altogether to avoid significant hypotension or bradycardia.
Given the considerable variability between beta-blockade protocols, the current literature does not elucidate the optimal timing of initiation of these agents nor does it delineate an appropriate duration of therapy. If possible, earlier initiation (ie, weeks vs days or hours) would be of greater benefit, as it will allow the clinician adequate time to stabilize the patient’s heart rate and blood pressure preoperatively.
Duration of therapy is up for debate. The majority of protocols have continued beta-blockade for 7 days after surgery, but more recent trials have continued therapy for 30 days postoperatively. Given that sympathetic tone increases postoperatively and returns to baseline within 4 to 5 days, perioperative beta-blockade should be continued for at least 7 days in hemodynamically stable patients.
| The Bottom Line |
- Cardiac complications-such as perioperative myocaridal infarction, new onset congestive heart failure and cardiac arrest-occurring after noncardiac surgery greatly influence patient morbidity and mortality.
- The most recent ACC/AHA guidelines recommend that patients scheduled to undergo vascular or intermediate-risk surgery (eg, orthopedic surgery) with >1 clinical risk factor be treated with cardioselective beta-blocker therapy with the dose titrated to a heart rate between 60 and 80 beats per minute.
- Beta-blockers that have been prospectively studied include atenolol, bisoprolol, and metoprolol but there are currently no comparative trials of these agents. Extended release beta-blockers should be avoided in this patient population as they may increase the risk of sustained significant perioperative hypotension.
- Perioperative beta-blockade should be initiated weeks prior to surgery to stabilize the patient's resting heart rate and blood pressure. Therapy should be continued for at least 7 days unless the patient develops significant hypotension or bradycardia.
- Badner NH, Knill RL, Brown JE, Novick TV, Gelb AW. Myocardial infarction after noncardiac surgery. Anesthesiology. 1998; 88(3):572-578.
- Mangano DT, Browner WS, Hollenberg M, Li J, Tateo IM. Long-term cardiac prognosis following noncardiac surgery. The Study of Perioperative Ischemia Research Group. JAMA. 1992; 268(2):233-239.
- Sprung J, Warner ME, Contreras MG, et al. Predictors of survival following cardiac arrest in patients undergoing noncardiac surgery: a study of 518,294 patients at a tertiary referral center. Anesthesiology. 2003; 99(2):259-269.
- Priebe HJ. Triggers of perioperative myocardial ischaemia and infarction. Br J Anaesth. 2004; 93(1):9-20.
- Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group. N Engl J Med. 1990; 323(26):1782-1788.
- Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977; 297(16):845-850.
- Detsky AS, Abrams HB, McLaughlin JR, et al. Predicting cardiac complications in patients undergoing non-cardiac surgery. J Gen Intern Med. 1986; 1(3):211-219.
- Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999; 100(10):1043-1049.
- Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMAJ. 2005; 173(6):627-634.
- Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. J Am Coll Cardiol. 2007; 50(17):159-241.
- Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996; 335(23):1713-1720.
- Poldermans D, Boersma E, Bax JJ, Thomson IR, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999; 341(24):1789-1794.
- Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR; POBBLE trial investigators. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. 2005; 41(4):602-609.
- Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomized placebo controlled, blinded multicentre trial. BMJ. 2006; 332(7556):1482.
- Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: Results of the metoprolol after vascular surgery (MaVS) study, a randomized controlled trial. Am Heart J. 2006; 152(5):983-990.
- POISE Study Group, Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008; 371(9627):1839-1847.
- Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AW, van Poorten F, Bax JJ, Thomson IR, et al. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV). Ann Surg. 2009; 249(6):921-926.
- American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; American Society of Nuclear Cardiology; et al. 2009 ACCF/AHA focused update on perioperative beta blockade. J Am Coll Cardiol. 2009; 54(22):2102-2128.
Drs Ashton and Flynn are from Pharmacy Services, UKHealthCare, Dr Hatton is from the Department of Anesthesiology, University of Kentucky College of Medicine, and Dr Flynn is also from the Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky.
Drs Ashton, Hatton, and Flynn have no relevant financial relationships to disclose.
Correspondence should be addressed to: Jennifer N. Ashton, PharmD, 1600 SW Archer Rd, Box 100316, Gainesville, FL 32610-0316 (firstname.lastname@example.org).