Steven L. Cohn, MD, MS, FACP, SFHM

Perioperative medicine is an evolving field with a rapidly growing body of literature. Because physicians and patients are often concerned about cardiac risk, we focus this review on perioperative cardiology.

The information we present here is derived from presentations at the Perioperative Medicine Summit and the annual meetings of the Society of Hospital Medicine and Society of General Internal Medicine in 2016. We surveyed perioperative literature from January 2015 through March 2016 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

We have divided this review into four sections:

• Preoperative cardiac risk assessment
• Medical therapy to reduce postoperative cardiac complications (beta-blockers, statins, and angiotensin II receptor blockers [ARBs])
• Perioperative management of patients with a coronary stent on antiplatelet therapy
• Perioperative bridging anticoagulation.

PREOPERATIVE ASSESSMENT OF CARDIAC RISK

Functionally independent patients do better

Visnjevac O, Davari-Farid S, Lee J, et al. The effect of adding functional classification to ASA status for predicting 30-day mortality. Anesth Analg 2015; 121:110–116.

Functional capacity is an independent predictor of perioperative death and is included in the algorithm of the current joint American College of Cardiology/American Heart Association (ACC/AHA) guidelines,¹ but it is not in the Revised Cardiac Risk Index² or the American Society of Anesthesiologists (ASA) classification.³

The study. Visnjevac et al⁴ performed a retrospective, observational cohort study of 12,324 patients who underwent noncardiac surgery, stratifying rates of all-cause mortality and 30-day postoperative complications based on ASA class and functional capacity.

The ASA physical status classification is defined as:

• 1—Normal healthy patient
• 2—Patient with mild systemic disease
• 3—Patient with severe systemic disease
• 4—Patient with severe systemic disease that is a constant threat to life
• 5—Moribund patient not expected to survive without surgery.

Functional capacity was defined as the ability to perform all activities of daily living. It was prospectively assessed during the patient interview by pre-anesthesia personnel and entered into the database of the Veterans Affairs Surgical Quality Improvement Program.

Results. Within each ASA class, the mortality rate was significantly lower for functionally independent patients than for partially or fully dependent patients:

• In class 2—odds ratio (OR) 0.14 for functionally independent patients
• In class 3—OR 0.29 for functionally independent patients
• In class 4—OR 0.5 for functionally independent patients.

The mortality rate was higher for dependent patients than for independent patients who were one ASA class higher, despite the higher class having greater rates of comorbidity.

Adding functional capacity to the ASA classification improved the area under the receiver operating curve from 0.811 to 0.848 (a perfect test would have a value of 1.0), suggesting that physicians should incorporate functional capacity into their preoperative evaluation, perhaps by increasing a patient’s ASA class to the next higher class if he or she is functionally dependent.

Angina portends poor outcomes

Pandey A, Sood A, Sammon JD, et al. Effect of preoperative angina pectoris on cardiac outcomes in patients with previous myocardial infarction undergoing major noncardiac surgery (data from ACS-NSQIP). Am J Cardiol 2015; 115:1080–1084.

Coronary artery disease is a risk factor for adverse perioperative outcomes, but the risk varies depending on whether the patient has had a myocardial infarction (and how long ago) and whether he or she has anginal symptoms (and how severe they are).

The study. Pandey et al⁵ used data from the American College of Surgeons National Surgical Quality Improvement Program to evaluate the impact of stable angina in 1,568 patients who underwent noncardiac surgery after a myocardial infarction.

Results. Postoperative myocardial infarction or cardiac arrest occurred in 5.5% of patients. The incidence was significantly greater in those who had anginal symptoms before surgery than in those without symptoms (8.4% vs 5%, P = .035); reintervention rates and length of stay were also higher in this group. In multivariate analysis, preoperative angina remained a significant predictor of postoperative myocardial infarction (OR 2.49, 95% confidence interval [CI] 1.20–5.81) and re­intervention (OR 2.4, 95% CI 1.44–3.82.

The authors cautioned against relying on predictive tools such as the Revised Cardiac Risk Index that do not consider stable angina and previous myocardial infarction as separate independent risk factors.

Implications for clinical practice. While functional capacity is an integral part of the ACC/AHA guideline algorithm,¹ the findings of these two studies suggest that other current tools to calculate perioperative risk (ASA class and Revised Cardiac Risk Index) could be improved by including functional capacity and stable angina.

PERIOPERATIVE MEDICAL THERAPY

Beta-blockers help only those at high risk and may harm others

Friedell ML, Van Way CW 3rd, Freyberg RW, Almenoff PL. ß-blockade and operative mortality in noncardiac surgery: harmful or helpful? JAMA Surg 2015; 150:658–663.

Beta-blockers have been used perioperatively for nearly 2 decades to try to reduce rates of postoperative major adverse cardiovascular events. However, in view of recent trials, fewer patients are likely to benefit from this intervention than has been thought.

The study. Friedell et al⁶ retrospectively analyzed data from 343,645 patients in Veterans Affairs hospitals to determine the effect of beta-blockers on major adverse cardiac event rates after major noncardiac surgery. Beta-blockers were considered to have been used perioperatively if given any time between 8 hours before and 24 hours after surgery. The outcome studied was the mortality rate at 30 days.

The authors derived a novel risk score and used multivariate analysis to attempt to adjust for confounding factors. The risk score was based on four risk factors identified a priori:

• Serum creatinine level > 2.0 mg/dL
• Coronary artery disease
• Diabetes
• Surgery in a major body cavity (abdomen or chest).

Results. In this cohort, 43.2% of patients had received a beta-blocker. The unadjusted mortality rates by risk category for patients receiving or not receiving a beta-blocker were:

• No risk factors: 1.0% with a beta-blocker vs 0.6% without
• One or two risk factors: 1.7% vs 1.5%
• Three or four risk factors: 2.3% vs 4.5%.

After adjustment for confounding factors, the 30-day mortality rate was higher in low-risk patients and lower in high-risk patients who received beta-blockers. Odds ratios for death in beta-blocker users (entire cohort) by risk category were:

• No risk factors: 1.19
• One or two risk factors 0.97
• Three or four risk factors 0.76.

In the 3.8% of the total cohort who underwent cardiac surgery, beta-blockers had no significant effect—beneficial or harmful—in any risk group.

Jørgensen ME, Hlatky MA, Køber L, et al. ß-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med 2015; 175:1923–1931.

The study. Jørgensen et al⁷ investigated the association between chronic beta-blocker use for the treatment of hypertension and 30-day rates of mortality and major adverse cardiac events. Eligible patients (N = 55,320) were at least 20 years old and were undergoing any type of noncardiac surgery. The authors established that hypertension was present through use of an algorithm based on the International Classification of Diseases (10th edition). Patients with existing cardiovascular disease and renal disease were excluded. The authors used multivariate analysis to adjust for confounding factors.

Results. Twenty-six percent of the patients were on chronic beta-blocker therapy for hypertension. The mortality rate at 30 days was 1.93% in patients treated with a beta-blocker alone or in combination with other antihypertensive drugs; the rate was 1.32% for patients receiving any combination of renin-angiotensin system inhibitor, calcium antagonist, or thiazide, but no beta-blocker. Similarly, the 30-day major adverse cardiac event rates were 1.32% with beta-blockers and 0.84% without beta-blockers.

In subgroup analysis, each medication combination that included a beta-blocker was associated with higher rates of death and major adverse cardiac events than the same combination without a beta-blocker. Odds ratios for major adverse cardiac events with beta-blocker combinations ranged from 1.22 to 2.16 compared with regimens with no beta-blocker.

Implications for clinical practice. These two studies added to a growing chorus of concerns about the value and safety of beta-blockers in surgical patients. Friedell et al⁶ made an observation that was remarkably similar to one reported by Lindenauer et al⁸ in 2005: when patients were stratified by baseline risk of death, only those with the highest baseline risk benefited from beta-blocker therapy. Those in the lowest risk group actually were harmed by beta-blocker use, ie, the mortality rate was higher.

More interesting is the novel observation by Jørgensen et al⁷ that even in patients with no known cardiovascular disease who are on chronic beta-blocker therapy—presumably on stable doses and not solely for perioperative risk reduction—rates of mortality and major adverse cardiac events were higher than for patients not on chronic beta-blocker therapy.

The current studies support a cautious, selective approach to the perioperative use of beta-blockers—they should be used only in high-risk patients undergoing high-risk surgery, as has been proposed by the ACC/AHA.¹

Statins protect

Antoniou GA, Hajibandeh S, Hajibandeh S, Vallabhaneni SR, Brennan JA, Torella F. Meta-analysis of the effects of statins on perioperative outcomes in vascular and endovascular surgery. J Vasc Surg 2015; 61:519–532.

The study⁹ was a comprehensive meta-analysis of randomized controlled trials and observational studies of the effects of HMG-CoA reductase inhibitors (statins) on perioperative outcomes in patients undergoing vascular surgery (but not for intracranial or coronary artery disease). Twenty-four studies were included, 4 randomized controlled trials and 20 observational studies (including 16 cohort and 4 case-controlled studies), with a total of 22,536 patients, 8,052 receiving statins and 15,484 not receiving statins.

Results. Although there was no significant difference in cardiovascular mortality rates, patients receiving statins had significantly lower rates of all-cause mortality, myocardial infarction, stroke, and a composite of myocardial infarction, stroke, and death at 30 days postoperatively than patients not receiving statins. Additionally, there was no difference in the incidence of kidney injury between groups. The possibility of publication bias was thought to be low for all of these outcomes.

Berwanger O, Le Manach Y, Suzumura EA, et al. Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study. Eur Heart J 2016; 37:177–185.

The study. The Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation (VISION) study^10,11 was an international prospective cohort study of more than 40,000 patients age 45 and older undergoing major noncardiac surgery with either general or regional anesthesia. Postoperative troponin measurements were obtained in all patients 6 to 12 hours after surgery and for the first 3 postoperative days. The authors evaluated the effect of preoperative statin use on cardiovascular outcomes at 30 days after surgery using a multivariate logistic model and propensity score analysis to correct for confounding factors. Statin use was defined as exposure within 7 days before surgery or 3 days after.

Results. In the 15,478 patients included in the analysis, statin use conferred a significant reduction in the primary outcome (composite of all-cause mortality, myocardial injury after noncardiac surgery, or stroke); the absolute risk reduction was 2.0%. Statin users also had a significantly lower risk of all-cause mortality, cardiovascular mortality, and myocardial injury after noncardiac surgery, but not of postoperative myocardial infarction or stroke. This analysis did not address the type of statin, dosing, or safety markers such as liver and muscle function.

Implications for clinical practice. With largely observational data and a few small randomized trials, these meta-analyses provide important information with respect to perioperative cardiovascular protection by statins. Starting a statin before surgery and continuing it perioperatively seems appropriate in patients at high risk (as recommended by the ACC/AHA guidelines¹). Based on other data, the benefit may be evident in as little as 5 days, as this is when statins appear to reach their plateau with regard to their vascular pleiotropic effects.¹² The incidence of adverse effects of statins, including muscle and liver injury, appears to be low in the perioperative setting.¹³

Given the inconsistent data regarding perioperative beta-blocker therapy, statins may very well be the most important perioperative medication with respect to cardiovascular risk reduction. However, a large randomized trial would help to confirm this belief.

Restart angiotensin II receptor blockers soon after surgery

Lee SM, Takemoto S, Wallace AW. Association between withholding angiotensin receptor blockers in the early postoperative period and 30-day mortality: a cohort study of the Veterans Affairs Healthcare System. Anesthesiology 2015; 123:288–306.

A concern about perioperative use of ARBs is that they impair the renin-angiotensin-aldosterone system, which maintains blood pressure under general anesthesia. ARB-induced intraoperative hypotension is particularly difficult to control, as it is often refractory to treatment with conventional adrenergic vasopressors.

The study. Lee et al¹⁴ conducted a retrospective cohort trial to evaluate the effects of continuing to withhold ARBs postoperatively. Of the 30,173 patients admitted for surgery in the Veterans Affairs system from 1999 through 2011 who were taking an ARB before surgery and who met the inclusion criteria, 10,205 (33.8%) were not restarted on their medication by postoperative day 2.

Results. The mortality rate at 30 days was higher in those whose ARBs were withheld than in those in whom it was resumed, with a multivariable-adjusted hazard ratio of 1.74 (95% CI 1.47–2.06; P < .001). The risk of withholding ARBs was more pronounced in younger patients (hazard ratio 2.52; 95% CI 1.69–3.76 in those under age 60) than in older patients (hazard ratio 1.42, 95% CI 1.09–1.85 in those over age 75).

Implications for clinical practice. While not addressing whether to continue or withhold ARBs preoperatively, this retrospective study presented evidence that delay in resuming chronic ARB therapy after surgery was common and appeared to be associated with a higher 30-day mortality rate. The ACC/AHA guidelines¹ state:

• Continuing angiotensin-converting enzyme (ACE) inhibitors or ARBs perioperatively is reasonable (class IIa recommendation, level of evidence B) (Table 1).
• If an ACE inhibitor or ARB is withheld before surgery, it is reasonable to restart it postoperatively as soon as clinically feasible (class IIa recommendation, level of evidence C).

Close attention to medication reconciliation in the postoperative period is necessary to facilitate early resumption of ARBs.

CORONARY STENTS AND ANTIPLATELET THERAPY IN NONCARDIAC SURGERY PATIENTS

Considerations in the management of noncardiac surgery patients with stents include risks of stent thrombosis, bleeding, and potentially delaying procedures to continue uninterrupted dual antiplatelet therapy. Evidence is evolving regarding the risks of perioperative complications in patients with bare-metal stents and drug-eluting stents, as well as the optimal timing before noncardiac surgery.

Bare-metal vs drug-eluting stents

Bangalore S, Silbaugh TS, Normand SL, Lovett AF, Welt FG, Resnic FS. Drug-eluting stents versus bare metal stents prior to noncardiac surgery. Catheter Cardiovasc Interv 2015; 85:533–541.

The study. Bangalore et al¹⁵ compared the safety of drug-eluting vs bare-metal stents in noncardiac surgery patients and investigated adverse events stratified by time since stent placement. This was a retrospective observational study of 8,415 patients in the Massachusetts claims database who underwent noncardiac surgery 1 year or less after percutaneous coronary intervention.

Results. There was no significant difference in the incidence of the primary outcome (composite of death, myocardial infarction, and bleeding) between the two groups.

With drug-eluting stents, patients had lower 30-day postoperative mortality rates, and their rate of the primary outcome decreased with time from percutaneous coronary intervention to surgery, being lowest beyond 90 days:

• 8.6% in days 1–30
• 7.5% in days 31–90
• 5.2% in days 91–180
• 5.8% in days 181–365 (P = .02).

With bare-metal stents, the event rate remained high over time:

• 8.2% in days 1–30
• 6.6% in days 31–90
• 8.1% in days 91–180
• 8.8% in days 181–365 (P = .60).

This study did not report information about perioperative antiplatelet management and was limited to first-generation drug-eluting stents. 

Saia F, Belotti LM, Guastaroba P, et al. Risk of adverse cardiac and bleeding events following cardiac and noncardiac surgery in patients with coronary stents: how important is the interplay between stent type and time from stenting to surgery? Circ Cardiovasc Qual Outcomes 2015; 9:39–47.

The study. Saia et al¹⁶ retrospectively examined predictors of periprocedural ischemic and bleeding events among cardiac and noncardiac surgical patients who had previously undergone percutaneous coronary intervention. They also assessed the risks associated with stent type and time from percutaneous coronary intervention to surgery.

Of 39,362 patients, 13,128 underwent procedures during the 5-year study period. The cumulative incidence of surgery was 3.6% at 30 days, 14% at 1 year, and 40% at 5 years after percutaneous coronary intervention. Almost 30% of the procedures were done urgently.

Results. The 30-day rate of postoperative cardiac death was 2.5%, nonfatal myocardial infarction 1.5%, and serious bleeding events 6.5%. Older drug-eluting stents were associated with higher risks of adverse events than newer drug-eluting stents at any time point (odds ratio 2.1 at 0–180 days, 1.9 at 6–12 months, and 1.45 after 12 months). Surgery performed 6 to 12 months after percutaneous coronary intervention had lower rates of adverse outcomes than surgery performed within 6 months. Beyond 6 months from percutaneous coronary intervention, bare-metal stents and newer drug-eluting stents did not have significantly different adverse event rates; however, newer drug-eluting stents appeared safer than bare-metal stents from 0 to 180 days.

Limitations of this study included lack of information regarding periprocedural antiplatelet management and a relatively small subset of newer drug-eluting stent patients.

Implications for clinical practice. These studies added to earlier work that demonstrated that the risk of perioperative adverse events differs by both the stent type and the time from percutaneous coronary intervention to noncardiac surgery. In patients with a drug-eluting stent, the risk levels off 90 days after percutaneous coronary intervention, suggesting that the previously recommended 12 months of uninterrupted dual antiplatelet therapy (per the 2014 ACC/AHA guidelines¹) may not be needed, particularly with newer-generation drug-eluting stents. Based on new evidence, the ACC/AHA guidelines regarding perioperative management of dual antiplatelet therapy in noncardiac surgery patients were updated,¹⁷ as noted below.

An update to the ACC/AHA guidelines on dual antiplatelet therapy

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation 2016 Mar 29. DOI: 10.1161/CIR.0000000000000404. [Epub ahead of print]

The 2016 update¹⁷ provides the following recommendations for patients with coronary stents who undergo noncardiac surgery:

• Delay elective surgery for 30 days after placement of a bare-metal stent (class I recommendation, level of evidence B).
• It is optimal to delay elective surgery 6 months after drug-eluting stent placement (class I recommendation, level of evidence B).
• If dual antiplatelet therapy must be discontinued, then continue aspirin if possible and restart the P2Y₁₂ inhibitor as soon as possible postoperatively (class I recommendation, level of evidence C ).
• A consensus decision among treating clinicians is useful regarding the risks of surgery and discontinuation or continuation of antiplatelet therapy (class IIa recommendation, level of evidence C).
• If dual antiplatelet therapy must be discontinued, then elective surgery should not be performed less than 30 days after bare-metal stent placement, or less than 3 months after drug-eluting stent placement (class III recommendation, level of evidence B).
• Elective surgery after drug-eluting stent placement when the P2Y₁₂ inhibitor must be discontinued may be considered 3 months after drug-eluting stent placement if the risk of surgical delay is greater than the risk of stent thrombosis (class IIb recommendation, level of evidence C).

The basic differences are the new recommendations for a minimum of 6 months of dual antiplatelet therapy as opposed to 12 months after drug-eluting stent placement before elective noncardiac surgery, and to allow surgery after 3 months (as opposed to 6 months) if the risk of delaying surgery outweighs the risk of stent thrombosis or myocardial infarction.

PERIOPERATIVE ANTICOAGULATION

The optimal perioperative management of patients with atrial fibrillation who are on warfarin is uncertain. The American College of Chest Physicians guidelines¹⁸ categorized patients with atrial fibrillation into low, moderate, and high thromboembolic risk. Based primarily on observational data, these guidelines recommended perioperative bridging anticoagulation for those at high risk but not for those at low risk. For intermediate-risk patients, there were insufficient data to make any recommendation.

Bridging may not benefit those at intermediate risk

Douketis JD, Spyropoulos AC, Kaatz S, et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015; 373:823–833.

The study. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) trial¹⁹ was the first randomized controlled trial to examine the effects of perioperative bridging anticoagulation in patients with atrial fibrillation without mechanical heart valves.

Results. In 1,884 patients undergoing elective surgery, the incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (95% CI −0.6 to 0.8; P = .01 for noninferiority). Major bleeding occurred in 1.3% of patients in the no-bridging group and 3.2% in the bridging group (95% CI 0.20–0.78; P = .005 for superiority).

These results suggest that the risks of bridging therapy are greater than the benefits. Of note, the mean CHADS₂ score (1 point each for congestive heart failure, hypertension, age ≥ 75 years, and diabetes mellitus; 2 points for previous stroke or transient ischemic attack; a total score > 2 indicates significant risk of stroke) for patients enrolled in this trial was 2.3, and it may be difficult to extrapolate these results to the limited number of patients at highest risk, ie, who have a CHADS₂ score of 5 or 6. Also, this study did not address patients with arterial or venous thromboembolism.

Implications for clinical practice. Despite the limitations noted above, this study does provide guidance for management of the intermediate-risk group with atrial fibrillation as defined by the American College of Chest Physicians: a no-bridging strategy is the best option.

Perioperative medicine is an evolving field with a rapidly growing body of literature. Because physicians and patients are often concerned about cardiac risk, we focus this review on perioperative cardiology.

The information we present here is derived from presentations at the Perioperative Medicine Summit and the annual meetings of the Society of Hospital Medicine and Society of General Internal Medicine in 2016. We surveyed perioperative literature from January 2015 through March 2016 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

We have divided this review into four sections:

• Preoperative cardiac risk assessment
• Medical therapy to reduce postoperative cardiac complications (beta-blockers, statins, and angiotensin II receptor blockers [ARBs])
• Perioperative management of patients with a coronary stent on antiplatelet therapy
• Perioperative bridging anticoagulation.

PREOPERATIVE ASSESSMENT OF CARDIAC RISK

Functionally independent patients do better

Visnjevac O, Davari-Farid S, Lee J, et al. The effect of adding functional classification to ASA status for predicting 30-day mortality. Anesth Analg 2015; 121:110–116.

Functional capacity is an independent predictor of perioperative death and is included in the algorithm of the current joint American College of Cardiology/American Heart Association (ACC/AHA) guidelines,¹ but it is not in the Revised Cardiac Risk Index² or the American Society of Anesthesiologists (ASA) classification.³

The study. Visnjevac et al⁴ performed a retrospective, observational cohort study of 12,324 patients who underwent noncardiac surgery, stratifying rates of all-cause mortality and 30-day postoperative complications based on ASA class and functional capacity.

The ASA physical status classification is defined as:

• 1—Normal healthy patient
• 2—Patient with mild systemic disease
• 3—Patient with severe systemic disease
• 4—Patient with severe systemic disease that is a constant threat to life
• 5—Moribund patient not expected to survive without surgery.

Functional capacity was defined as the ability to perform all activities of daily living. It was prospectively assessed during the patient interview by pre-anesthesia personnel and entered into the database of the Veterans Affairs Surgical Quality Improvement Program.

Results. Within each ASA class, the mortality rate was significantly lower for functionally independent patients than for partially or fully dependent patients:

• In class 2—odds ratio (OR) 0.14 for functionally independent patients
• In class 3—OR 0.29 for functionally independent patients
• In class 4—OR 0.5 for functionally independent patients.

The mortality rate was higher for dependent patients than for independent patients who were one ASA class higher, despite the higher class having greater rates of comorbidity.

Adding functional capacity to the ASA classification improved the area under the receiver operating curve from 0.811 to 0.848 (a perfect test would have a value of 1.0), suggesting that physicians should incorporate functional capacity into their preoperative evaluation, perhaps by increasing a patient’s ASA class to the next higher class if he or she is functionally dependent.

Angina portends poor outcomes

Pandey A, Sood A, Sammon JD, et al. Effect of preoperative angina pectoris on cardiac outcomes in patients with previous myocardial infarction undergoing major noncardiac surgery (data from ACS-NSQIP). Am J Cardiol 2015; 115:1080–1084.

Coronary artery disease is a risk factor for adverse perioperative outcomes, but the risk varies depending on whether the patient has had a myocardial infarction (and how long ago) and whether he or she has anginal symptoms (and how severe they are).

The study. Pandey et al⁵ used data from the American College of Surgeons National Surgical Quality Improvement Program to evaluate the impact of stable angina in 1,568 patients who underwent noncardiac surgery after a myocardial infarction.

Results. Postoperative myocardial infarction or cardiac arrest occurred in 5.5% of patients. The incidence was significantly greater in those who had anginal symptoms before surgery than in those without symptoms (8.4% vs 5%, P = .035); reintervention rates and length of stay were also higher in this group. In multivariate analysis, preoperative angina remained a significant predictor of postoperative myocardial infarction (OR 2.49, 95% confidence interval [CI] 1.20–5.81) and re­intervention (OR 2.4, 95% CI 1.44–3.82.

The authors cautioned against relying on predictive tools such as the Revised Cardiac Risk Index that do not consider stable angina and previous myocardial infarction as separate independent risk factors.

Implications for clinical practice. While functional capacity is an integral part of the ACC/AHA guideline algorithm,¹ the findings of these two studies suggest that other current tools to calculate perioperative risk (ASA class and Revised Cardiac Risk Index) could be improved by including functional capacity and stable angina.

PERIOPERATIVE MEDICAL THERAPY

Beta-blockers help only those at high risk and may harm others

Friedell ML, Van Way CW 3rd, Freyberg RW, Almenoff PL. ß-blockade and operative mortality in noncardiac surgery: harmful or helpful? JAMA Surg 2015; 150:658–663.

Beta-blockers have been used perioperatively for nearly 2 decades to try to reduce rates of postoperative major adverse cardiovascular events. However, in view of recent trials, fewer patients are likely to benefit from this intervention than has been thought.

The study. Friedell et al⁶ retrospectively analyzed data from 343,645 patients in Veterans Affairs hospitals to determine the effect of beta-blockers on major adverse cardiac event rates after major noncardiac surgery. Beta-blockers were considered to have been used perioperatively if given any time between 8 hours before and 24 hours after surgery. The outcome studied was the mortality rate at 30 days.

The authors derived a novel risk score and used multivariate analysis to attempt to adjust for confounding factors. The risk score was based on four risk factors identified a priori:

• Serum creatinine level > 2.0 mg/dL
• Coronary artery disease
• Diabetes
• Surgery in a major body cavity (abdomen or chest).

Results. In this cohort, 43.2% of patients had received a beta-blocker. The unadjusted mortality rates by risk category for patients receiving or not receiving a beta-blocker were:

• No risk factors: 1.0% with a beta-blocker vs 0.6% without
• One or two risk factors: 1.7% vs 1.5%
• Three or four risk factors: 2.3% vs 4.5%.

After adjustment for confounding factors, the 30-day mortality rate was higher in low-risk patients and lower in high-risk patients who received beta-blockers. Odds ratios for death in beta-blocker users (entire cohort) by risk category were:

• No risk factors: 1.19
• One or two risk factors 0.97
• Three or four risk factors 0.76.

In the 3.8% of the total cohort who underwent cardiac surgery, beta-blockers had no significant effect—beneficial or harmful—in any risk group.

Jørgensen ME, Hlatky MA, Køber L, et al. ß-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med 2015; 175:1923–1931.

The study. Jørgensen et al⁷ investigated the association between chronic beta-blocker use for the treatment of hypertension and 30-day rates of mortality and major adverse cardiac events. Eligible patients (N = 55,320) were at least 20 years old and were undergoing any type of noncardiac surgery. The authors established that hypertension was present through use of an algorithm based on the International Classification of Diseases (10th edition). Patients with existing cardiovascular disease and renal disease were excluded. The authors used multivariate analysis to adjust for confounding factors.

Results. Twenty-six percent of the patients were on chronic beta-blocker therapy for hypertension. The mortality rate at 30 days was 1.93% in patients treated with a beta-blocker alone or in combination with other antihypertensive drugs; the rate was 1.32% for patients receiving any combination of renin-angiotensin system inhibitor, calcium antagonist, or thiazide, but no beta-blocker. Similarly, the 30-day major adverse cardiac event rates were 1.32% with beta-blockers and 0.84% without beta-blockers.

In subgroup analysis, each medication combination that included a beta-blocker was associated with higher rates of death and major adverse cardiac events than the same combination without a beta-blocker. Odds ratios for major adverse cardiac events with beta-blocker combinations ranged from 1.22 to 2.16 compared with regimens with no beta-blocker.

Implications for clinical practice. These two studies added to a growing chorus of concerns about the value and safety of beta-blockers in surgical patients. Friedell et al⁶ made an observation that was remarkably similar to one reported by Lindenauer et al⁸ in 2005: when patients were stratified by baseline risk of death, only those with the highest baseline risk benefited from beta-blocker therapy. Those in the lowest risk group actually were harmed by beta-blocker use, ie, the mortality rate was higher.

More interesting is the novel observation by Jørgensen et al⁷ that even in patients with no known cardiovascular disease who are on chronic beta-blocker therapy—presumably on stable doses and not solely for perioperative risk reduction—rates of mortality and major adverse cardiac events were higher than for patients not on chronic beta-blocker therapy.

The current studies support a cautious, selective approach to the perioperative use of beta-blockers—they should be used only in high-risk patients undergoing high-risk surgery, as has been proposed by the ACC/AHA.¹

Statins protect

Antoniou GA, Hajibandeh S, Hajibandeh S, Vallabhaneni SR, Brennan JA, Torella F. Meta-analysis of the effects of statins on perioperative outcomes in vascular and endovascular surgery. J Vasc Surg 2015; 61:519–532.

The study⁹ was a comprehensive meta-analysis of randomized controlled trials and observational studies of the effects of HMG-CoA reductase inhibitors (statins) on perioperative outcomes in patients undergoing vascular surgery (but not for intracranial or coronary artery disease). Twenty-four studies were included, 4 randomized controlled trials and 20 observational studies (including 16 cohort and 4 case-controlled studies), with a total of 22,536 patients, 8,052 receiving statins and 15,484 not receiving statins.

Results. Although there was no significant difference in cardiovascular mortality rates, patients receiving statins had significantly lower rates of all-cause mortality, myocardial infarction, stroke, and a composite of myocardial infarction, stroke, and death at 30 days postoperatively than patients not receiving statins. Additionally, there was no difference in the incidence of kidney injury between groups. The possibility of publication bias was thought to be low for all of these outcomes.

Berwanger O, Le Manach Y, Suzumura EA, et al. Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study. Eur Heart J 2016; 37:177–185.

The study. The Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation (VISION) study^10,11 was an international prospective cohort study of more than 40,000 patients age 45 and older undergoing major noncardiac surgery with either general or regional anesthesia. Postoperative troponin measurements were obtained in all patients 6 to 12 hours after surgery and for the first 3 postoperative days. The authors evaluated the effect of preoperative statin use on cardiovascular outcomes at 30 days after surgery using a multivariate logistic model and propensity score analysis to correct for confounding factors. Statin use was defined as exposure within 7 days before surgery or 3 days after.

Results. In the 15,478 patients included in the analysis, statin use conferred a significant reduction in the primary outcome (composite of all-cause mortality, myocardial injury after noncardiac surgery, or stroke); the absolute risk reduction was 2.0%. Statin users also had a significantly lower risk of all-cause mortality, cardiovascular mortality, and myocardial injury after noncardiac surgery, but not of postoperative myocardial infarction or stroke. This analysis did not address the type of statin, dosing, or safety markers such as liver and muscle function.

Implications for clinical practice. With largely observational data and a few small randomized trials, these meta-analyses provide important information with respect to perioperative cardiovascular protection by statins. Starting a statin before surgery and continuing it perioperatively seems appropriate in patients at high risk (as recommended by the ACC/AHA guidelines¹). Based on other data, the benefit may be evident in as little as 5 days, as this is when statins appear to reach their plateau with regard to their vascular pleiotropic effects.¹² The incidence of adverse effects of statins, including muscle and liver injury, appears to be low in the perioperative setting.¹³

Given the inconsistent data regarding perioperative beta-blocker therapy, statins may very well be the most important perioperative medication with respect to cardiovascular risk reduction. However, a large randomized trial would help to confirm this belief.

Restart angiotensin II receptor blockers soon after surgery

Lee SM, Takemoto S, Wallace AW. Association between withholding angiotensin receptor blockers in the early postoperative period and 30-day mortality: a cohort study of the Veterans Affairs Healthcare System. Anesthesiology 2015; 123:288–306.

A concern about perioperative use of ARBs is that they impair the renin-angiotensin-aldosterone system, which maintains blood pressure under general anesthesia. ARB-induced intraoperative hypotension is particularly difficult to control, as it is often refractory to treatment with conventional adrenergic vasopressors.

The study. Lee et al¹⁴ conducted a retrospective cohort trial to evaluate the effects of continuing to withhold ARBs postoperatively. Of the 30,173 patients admitted for surgery in the Veterans Affairs system from 1999 through 2011 who were taking an ARB before surgery and who met the inclusion criteria, 10,205 (33.8%) were not restarted on their medication by postoperative day 2.

Results. The mortality rate at 30 days was higher in those whose ARBs were withheld than in those in whom it was resumed, with a multivariable-adjusted hazard ratio of 1.74 (95% CI 1.47–2.06; P < .001). The risk of withholding ARBs was more pronounced in younger patients (hazard ratio 2.52; 95% CI 1.69–3.76 in those under age 60) than in older patients (hazard ratio 1.42, 95% CI 1.09–1.85 in those over age 75).

Implications for clinical practice. While not addressing whether to continue or withhold ARBs preoperatively, this retrospective study presented evidence that delay in resuming chronic ARB therapy after surgery was common and appeared to be associated with a higher 30-day mortality rate. The ACC/AHA guidelines¹ state:

• Continuing angiotensin-converting enzyme (ACE) inhibitors or ARBs perioperatively is reasonable (class IIa recommendation, level of evidence B) (Table 1).
• If an ACE inhibitor or ARB is withheld before surgery, it is reasonable to restart it postoperatively as soon as clinically feasible (class IIa recommendation, level of evidence C).

Close attention to medication reconciliation in the postoperative period is necessary to facilitate early resumption of ARBs.

CORONARY STENTS AND ANTIPLATELET THERAPY IN NONCARDIAC SURGERY PATIENTS

Considerations in the management of noncardiac surgery patients with stents include risks of stent thrombosis, bleeding, and potentially delaying procedures to continue uninterrupted dual antiplatelet therapy. Evidence is evolving regarding the risks of perioperative complications in patients with bare-metal stents and drug-eluting stents, as well as the optimal timing before noncardiac surgery.

Bare-metal vs drug-eluting stents

Bangalore S, Silbaugh TS, Normand SL, Lovett AF, Welt FG, Resnic FS. Drug-eluting stents versus bare metal stents prior to noncardiac surgery. Catheter Cardiovasc Interv 2015; 85:533–541.

The study. Bangalore et al¹⁵ compared the safety of drug-eluting vs bare-metal stents in noncardiac surgery patients and investigated adverse events stratified by time since stent placement. This was a retrospective observational study of 8,415 patients in the Massachusetts claims database who underwent noncardiac surgery 1 year or less after percutaneous coronary intervention.

Results. There was no significant difference in the incidence of the primary outcome (composite of death, myocardial infarction, and bleeding) between the two groups.

With drug-eluting stents, patients had lower 30-day postoperative mortality rates, and their rate of the primary outcome decreased with time from percutaneous coronary intervention to surgery, being lowest beyond 90 days:

• 8.6% in days 1–30
• 7.5% in days 31–90
• 5.2% in days 91–180
• 5.8% in days 181–365 (P = .02).

With bare-metal stents, the event rate remained high over time:

• 8.2% in days 1–30
• 6.6% in days 31–90
• 8.1% in days 91–180
• 8.8% in days 181–365 (P = .60).

This study did not report information about perioperative antiplatelet management and was limited to first-generation drug-eluting stents. 

Saia F, Belotti LM, Guastaroba P, et al. Risk of adverse cardiac and bleeding events following cardiac and noncardiac surgery in patients with coronary stents: how important is the interplay between stent type and time from stenting to surgery? Circ Cardiovasc Qual Outcomes 2015; 9:39–47.

The study. Saia et al¹⁶ retrospectively examined predictors of periprocedural ischemic and bleeding events among cardiac and noncardiac surgical patients who had previously undergone percutaneous coronary intervention. They also assessed the risks associated with stent type and time from percutaneous coronary intervention to surgery.

Of 39,362 patients, 13,128 underwent procedures during the 5-year study period. The cumulative incidence of surgery was 3.6% at 30 days, 14% at 1 year, and 40% at 5 years after percutaneous coronary intervention. Almost 30% of the procedures were done urgently.

Results. The 30-day rate of postoperative cardiac death was 2.5%, nonfatal myocardial infarction 1.5%, and serious bleeding events 6.5%. Older drug-eluting stents were associated with higher risks of adverse events than newer drug-eluting stents at any time point (odds ratio 2.1 at 0–180 days, 1.9 at 6–12 months, and 1.45 after 12 months). Surgery performed 6 to 12 months after percutaneous coronary intervention had lower rates of adverse outcomes than surgery performed within 6 months. Beyond 6 months from percutaneous coronary intervention, bare-metal stents and newer drug-eluting stents did not have significantly different adverse event rates; however, newer drug-eluting stents appeared safer than bare-metal stents from 0 to 180 days.

Limitations of this study included lack of information regarding periprocedural antiplatelet management and a relatively small subset of newer drug-eluting stent patients.

Implications for clinical practice. These studies added to earlier work that demonstrated that the risk of perioperative adverse events differs by both the stent type and the time from percutaneous coronary intervention to noncardiac surgery. In patients with a drug-eluting stent, the risk levels off 90 days after percutaneous coronary intervention, suggesting that the previously recommended 12 months of uninterrupted dual antiplatelet therapy (per the 2014 ACC/AHA guidelines¹) may not be needed, particularly with newer-generation drug-eluting stents. Based on new evidence, the ACC/AHA guidelines regarding perioperative management of dual antiplatelet therapy in noncardiac surgery patients were updated,¹⁷ as noted below.

An update to the ACC/AHA guidelines on dual antiplatelet therapy

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation 2016 Mar 29. DOI: 10.1161/CIR.0000000000000404. [Epub ahead of print]

The 2016 update¹⁷ provides the following recommendations for patients with coronary stents who undergo noncardiac surgery:

• Delay elective surgery for 30 days after placement of a bare-metal stent (class I recommendation, level of evidence B).
• It is optimal to delay elective surgery 6 months after drug-eluting stent placement (class I recommendation, level of evidence B).
• If dual antiplatelet therapy must be discontinued, then continue aspirin if possible and restart the P2Y₁₂ inhibitor as soon as possible postoperatively (class I recommendation, level of evidence C ).
• A consensus decision among treating clinicians is useful regarding the risks of surgery and discontinuation or continuation of antiplatelet therapy (class IIa recommendation, level of evidence C).
• If dual antiplatelet therapy must be discontinued, then elective surgery should not be performed less than 30 days after bare-metal stent placement, or less than 3 months after drug-eluting stent placement (class III recommendation, level of evidence B).
• Elective surgery after drug-eluting stent placement when the P2Y₁₂ inhibitor must be discontinued may be considered 3 months after drug-eluting stent placement if the risk of surgical delay is greater than the risk of stent thrombosis (class IIb recommendation, level of evidence C).

The basic differences are the new recommendations for a minimum of 6 months of dual antiplatelet therapy as opposed to 12 months after drug-eluting stent placement before elective noncardiac surgery, and to allow surgery after 3 months (as opposed to 6 months) if the risk of delaying surgery outweighs the risk of stent thrombosis or myocardial infarction.

PERIOPERATIVE ANTICOAGULATION

The optimal perioperative management of patients with atrial fibrillation who are on warfarin is uncertain. The American College of Chest Physicians guidelines¹⁸ categorized patients with atrial fibrillation into low, moderate, and high thromboembolic risk. Based primarily on observational data, these guidelines recommended perioperative bridging anticoagulation for those at high risk but not for those at low risk. For intermediate-risk patients, there were insufficient data to make any recommendation.

Bridging may not benefit those at intermediate risk

Douketis JD, Spyropoulos AC, Kaatz S, et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015; 373:823–833.

The study. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) trial¹⁹ was the first randomized controlled trial to examine the effects of perioperative bridging anticoagulation in patients with atrial fibrillation without mechanical heart valves.

Results. In 1,884 patients undergoing elective surgery, the incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (95% CI −0.6 to 0.8; P = .01 for noninferiority). Major bleeding occurred in 1.3% of patients in the no-bridging group and 3.2% in the bridging group (95% CI 0.20–0.78; P = .005 for superiority).

These results suggest that the risks of bridging therapy are greater than the benefits. Of note, the mean CHADS₂ score (1 point each for congestive heart failure, hypertension, age ≥ 75 years, and diabetes mellitus; 2 points for previous stroke or transient ischemic attack; a total score > 2 indicates significant risk of stroke) for patients enrolled in this trial was 2.3, and it may be difficult to extrapolate these results to the limited number of patients at highest risk, ie, who have a CHADS₂ score of 5 or 6. Also, this study did not address patients with arterial or venous thromboembolism.

Implications for clinical practice. Despite the limitations noted above, this study does provide guidance for management of the intermediate-risk group with atrial fibrillation as defined by the American College of Chest Physicians: a no-bridging strategy is the best option.

Perioperative medicine is an evolving field with a rapidly growing body of literature. Because physicians and patients are often concerned about cardiac risk, we focus this review on perioperative cardiology.

The information we present here is derived from presentations at the Perioperative Medicine Summit and the annual meetings of the Society of Hospital Medicine and Society of General Internal Medicine in 2016. We surveyed perioperative literature from January 2015 through March 2016 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

We have divided this review into four sections:

• Preoperative cardiac risk assessment
• Medical therapy to reduce postoperative cardiac complications (beta-blockers, statins, and angiotensin II receptor blockers [ARBs])
• Perioperative management of patients with a coronary stent on antiplatelet therapy
• Perioperative bridging anticoagulation.

PREOPERATIVE ASSESSMENT OF CARDIAC RISK

Functionally independent patients do better

Visnjevac O, Davari-Farid S, Lee J, et al. The effect of adding functional classification to ASA status for predicting 30-day mortality. Anesth Analg 2015; 121:110–116.

Functional capacity is an independent predictor of perioperative death and is included in the algorithm of the current joint American College of Cardiology/American Heart Association (ACC/AHA) guidelines,¹ but it is not in the Revised Cardiac Risk Index² or the American Society of Anesthesiologists (ASA) classification.³

The study. Visnjevac et al⁴ performed a retrospective, observational cohort study of 12,324 patients who underwent noncardiac surgery, stratifying rates of all-cause mortality and 30-day postoperative complications based on ASA class and functional capacity.

The ASA physical status classification is defined as:

• 1—Normal healthy patient
• 2—Patient with mild systemic disease
• 3—Patient with severe systemic disease
• 4—Patient with severe systemic disease that is a constant threat to life
• 5—Moribund patient not expected to survive without surgery.

Functional capacity was defined as the ability to perform all activities of daily living. It was prospectively assessed during the patient interview by pre-anesthesia personnel and entered into the database of the Veterans Affairs Surgical Quality Improvement Program.

Results. Within each ASA class, the mortality rate was significantly lower for functionally independent patients than for partially or fully dependent patients:

• In class 2—odds ratio (OR) 0.14 for functionally independent patients
• In class 3—OR 0.29 for functionally independent patients
• In class 4—OR 0.5 for functionally independent patients.

The mortality rate was higher for dependent patients than for independent patients who were one ASA class higher, despite the higher class having greater rates of comorbidity.

Adding functional capacity to the ASA classification improved the area under the receiver operating curve from 0.811 to 0.848 (a perfect test would have a value of 1.0), suggesting that physicians should incorporate functional capacity into their preoperative evaluation, perhaps by increasing a patient’s ASA class to the next higher class if he or she is functionally dependent.

Angina portends poor outcomes

Pandey A, Sood A, Sammon JD, et al. Effect of preoperative angina pectoris on cardiac outcomes in patients with previous myocardial infarction undergoing major noncardiac surgery (data from ACS-NSQIP). Am J Cardiol 2015; 115:1080–1084.

Coronary artery disease is a risk factor for adverse perioperative outcomes, but the risk varies depending on whether the patient has had a myocardial infarction (and how long ago) and whether he or she has anginal symptoms (and how severe they are).

The study. Pandey et al⁵ used data from the American College of Surgeons National Surgical Quality Improvement Program to evaluate the impact of stable angina in 1,568 patients who underwent noncardiac surgery after a myocardial infarction.

Results. Postoperative myocardial infarction or cardiac arrest occurred in 5.5% of patients. The incidence was significantly greater in those who had anginal symptoms before surgery than in those without symptoms (8.4% vs 5%, P = .035); reintervention rates and length of stay were also higher in this group. In multivariate analysis, preoperative angina remained a significant predictor of postoperative myocardial infarction (OR 2.49, 95% confidence interval [CI] 1.20–5.81) and re­intervention (OR 2.4, 95% CI 1.44–3.82.

The authors cautioned against relying on predictive tools such as the Revised Cardiac Risk Index that do not consider stable angina and previous myocardial infarction as separate independent risk factors.

Implications for clinical practice. While functional capacity is an integral part of the ACC/AHA guideline algorithm,¹ the findings of these two studies suggest that other current tools to calculate perioperative risk (ASA class and Revised Cardiac Risk Index) could be improved by including functional capacity and stable angina.

PERIOPERATIVE MEDICAL THERAPY

Beta-blockers help only those at high risk and may harm others

Friedell ML, Van Way CW 3rd, Freyberg RW, Almenoff PL. ß-blockade and operative mortality in noncardiac surgery: harmful or helpful? JAMA Surg 2015; 150:658–663.

Beta-blockers have been used perioperatively for nearly 2 decades to try to reduce rates of postoperative major adverse cardiovascular events. However, in view of recent trials, fewer patients are likely to benefit from this intervention than has been thought.

The study. Friedell et al⁶ retrospectively analyzed data from 343,645 patients in Veterans Affairs hospitals to determine the effect of beta-blockers on major adverse cardiac event rates after major noncardiac surgery. Beta-blockers were considered to have been used perioperatively if given any time between 8 hours before and 24 hours after surgery. The outcome studied was the mortality rate at 30 days.

The authors derived a novel risk score and used multivariate analysis to attempt to adjust for confounding factors. The risk score was based on four risk factors identified a priori:

• Serum creatinine level > 2.0 mg/dL
• Coronary artery disease
• Diabetes
• Surgery in a major body cavity (abdomen or chest).

Results. In this cohort, 43.2% of patients had received a beta-blocker. The unadjusted mortality rates by risk category for patients receiving or not receiving a beta-blocker were:

• No risk factors: 1.0% with a beta-blocker vs 0.6% without
• One or two risk factors: 1.7% vs 1.5%
• Three or four risk factors: 2.3% vs 4.5%.

After adjustment for confounding factors, the 30-day mortality rate was higher in low-risk patients and lower in high-risk patients who received beta-blockers. Odds ratios for death in beta-blocker users (entire cohort) by risk category were:

• No risk factors: 1.19
• One or two risk factors 0.97
• Three or four risk factors 0.76.

In the 3.8% of the total cohort who underwent cardiac surgery, beta-blockers had no significant effect—beneficial or harmful—in any risk group.

Jørgensen ME, Hlatky MA, Køber L, et al. ß-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med 2015; 175:1923–1931.

The study. Jørgensen et al⁷ investigated the association between chronic beta-blocker use for the treatment of hypertension and 30-day rates of mortality and major adverse cardiac events. Eligible patients (N = 55,320) were at least 20 years old and were undergoing any type of noncardiac surgery. The authors established that hypertension was present through use of an algorithm based on the International Classification of Diseases (10th edition). Patients with existing cardiovascular disease and renal disease were excluded. The authors used multivariate analysis to adjust for confounding factors.

Results. Twenty-six percent of the patients were on chronic beta-blocker therapy for hypertension. The mortality rate at 30 days was 1.93% in patients treated with a beta-blocker alone or in combination with other antihypertensive drugs; the rate was 1.32% for patients receiving any combination of renin-angiotensin system inhibitor, calcium antagonist, or thiazide, but no beta-blocker. Similarly, the 30-day major adverse cardiac event rates were 1.32% with beta-blockers and 0.84% without beta-blockers.

In subgroup analysis, each medication combination that included a beta-blocker was associated with higher rates of death and major adverse cardiac events than the same combination without a beta-blocker. Odds ratios for major adverse cardiac events with beta-blocker combinations ranged from 1.22 to 2.16 compared with regimens with no beta-blocker.

Implications for clinical practice. These two studies added to a growing chorus of concerns about the value and safety of beta-blockers in surgical patients. Friedell et al⁶ made an observation that was remarkably similar to one reported by Lindenauer et al⁸ in 2005: when patients were stratified by baseline risk of death, only those with the highest baseline risk benefited from beta-blocker therapy. Those in the lowest risk group actually were harmed by beta-blocker use, ie, the mortality rate was higher.

More interesting is the novel observation by Jørgensen et al⁷ that even in patients with no known cardiovascular disease who are on chronic beta-blocker therapy—presumably on stable doses and not solely for perioperative risk reduction—rates of mortality and major adverse cardiac events were higher than for patients not on chronic beta-blocker therapy.

The current studies support a cautious, selective approach to the perioperative use of beta-blockers—they should be used only in high-risk patients undergoing high-risk surgery, as has been proposed by the ACC/AHA.¹

Statins protect

Antoniou GA, Hajibandeh S, Hajibandeh S, Vallabhaneni SR, Brennan JA, Torella F. Meta-analysis of the effects of statins on perioperative outcomes in vascular and endovascular surgery. J Vasc Surg 2015; 61:519–532.

The study⁹ was a comprehensive meta-analysis of randomized controlled trials and observational studies of the effects of HMG-CoA reductase inhibitors (statins) on perioperative outcomes in patients undergoing vascular surgery (but not for intracranial or coronary artery disease). Twenty-four studies were included, 4 randomized controlled trials and 20 observational studies (including 16 cohort and 4 case-controlled studies), with a total of 22,536 patients, 8,052 receiving statins and 15,484 not receiving statins.

Results. Although there was no significant difference in cardiovascular mortality rates, patients receiving statins had significantly lower rates of all-cause mortality, myocardial infarction, stroke, and a composite of myocardial infarction, stroke, and death at 30 days postoperatively than patients not receiving statins. Additionally, there was no difference in the incidence of kidney injury between groups. The possibility of publication bias was thought to be low for all of these outcomes.

Berwanger O, Le Manach Y, Suzumura EA, et al. Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study. Eur Heart J 2016; 37:177–185.

The study. The Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation (VISION) study^10,11 was an international prospective cohort study of more than 40,000 patients age 45 and older undergoing major noncardiac surgery with either general or regional anesthesia. Postoperative troponin measurements were obtained in all patients 6 to 12 hours after surgery and for the first 3 postoperative days. The authors evaluated the effect of preoperative statin use on cardiovascular outcomes at 30 days after surgery using a multivariate logistic model and propensity score analysis to correct for confounding factors. Statin use was defined as exposure within 7 days before surgery or 3 days after.

Results. In the 15,478 patients included in the analysis, statin use conferred a significant reduction in the primary outcome (composite of all-cause mortality, myocardial injury after noncardiac surgery, or stroke); the absolute risk reduction was 2.0%. Statin users also had a significantly lower risk of all-cause mortality, cardiovascular mortality, and myocardial injury after noncardiac surgery, but not of postoperative myocardial infarction or stroke. This analysis did not address the type of statin, dosing, or safety markers such as liver and muscle function.

Implications for clinical practice. With largely observational data and a few small randomized trials, these meta-analyses provide important information with respect to perioperative cardiovascular protection by statins. Starting a statin before surgery and continuing it perioperatively seems appropriate in patients at high risk (as recommended by the ACC/AHA guidelines¹). Based on other data, the benefit may be evident in as little as 5 days, as this is when statins appear to reach their plateau with regard to their vascular pleiotropic effects.¹² The incidence of adverse effects of statins, including muscle and liver injury, appears to be low in the perioperative setting.¹³

Given the inconsistent data regarding perioperative beta-blocker therapy, statins may very well be the most important perioperative medication with respect to cardiovascular risk reduction. However, a large randomized trial would help to confirm this belief.

Restart angiotensin II receptor blockers soon after surgery

Lee SM, Takemoto S, Wallace AW. Association between withholding angiotensin receptor blockers in the early postoperative period and 30-day mortality: a cohort study of the Veterans Affairs Healthcare System. Anesthesiology 2015; 123:288–306.

A concern about perioperative use of ARBs is that they impair the renin-angiotensin-aldosterone system, which maintains blood pressure under general anesthesia. ARB-induced intraoperative hypotension is particularly difficult to control, as it is often refractory to treatment with conventional adrenergic vasopressors.

The study. Lee et al¹⁴ conducted a retrospective cohort trial to evaluate the effects of continuing to withhold ARBs postoperatively. Of the 30,173 patients admitted for surgery in the Veterans Affairs system from 1999 through 2011 who were taking an ARB before surgery and who met the inclusion criteria, 10,205 (33.8%) were not restarted on their medication by postoperative day 2.

Results. The mortality rate at 30 days was higher in those whose ARBs were withheld than in those in whom it was resumed, with a multivariable-adjusted hazard ratio of 1.74 (95% CI 1.47–2.06; P < .001). The risk of withholding ARBs was more pronounced in younger patients (hazard ratio 2.52; 95% CI 1.69–3.76 in those under age 60) than in older patients (hazard ratio 1.42, 95% CI 1.09–1.85 in those over age 75).

Implications for clinical practice. While not addressing whether to continue or withhold ARBs preoperatively, this retrospective study presented evidence that delay in resuming chronic ARB therapy after surgery was common and appeared to be associated with a higher 30-day mortality rate. The ACC/AHA guidelines¹ state:

• Continuing angiotensin-converting enzyme (ACE) inhibitors or ARBs perioperatively is reasonable (class IIa recommendation, level of evidence B) (Table 1).
• If an ACE inhibitor or ARB is withheld before surgery, it is reasonable to restart it postoperatively as soon as clinically feasible (class IIa recommendation, level of evidence C).

Close attention to medication reconciliation in the postoperative period is necessary to facilitate early resumption of ARBs.

CORONARY STENTS AND ANTIPLATELET THERAPY IN NONCARDIAC SURGERY PATIENTS

Considerations in the management of noncardiac surgery patients with stents include risks of stent thrombosis, bleeding, and potentially delaying procedures to continue uninterrupted dual antiplatelet therapy. Evidence is evolving regarding the risks of perioperative complications in patients with bare-metal stents and drug-eluting stents, as well as the optimal timing before noncardiac surgery.

Bare-metal vs drug-eluting stents

Bangalore S, Silbaugh TS, Normand SL, Lovett AF, Welt FG, Resnic FS. Drug-eluting stents versus bare metal stents prior to noncardiac surgery. Catheter Cardiovasc Interv 2015; 85:533–541.

The study. Bangalore et al¹⁵ compared the safety of drug-eluting vs bare-metal stents in noncardiac surgery patients and investigated adverse events stratified by time since stent placement. This was a retrospective observational study of 8,415 patients in the Massachusetts claims database who underwent noncardiac surgery 1 year or less after percutaneous coronary intervention.

Results. There was no significant difference in the incidence of the primary outcome (composite of death, myocardial infarction, and bleeding) between the two groups.

With drug-eluting stents, patients had lower 30-day postoperative mortality rates, and their rate of the primary outcome decreased with time from percutaneous coronary intervention to surgery, being lowest beyond 90 days:

• 8.6% in days 1–30
• 7.5% in days 31–90
• 5.2% in days 91–180
• 5.8% in days 181–365 (P = .02).

With bare-metal stents, the event rate remained high over time:

• 8.2% in days 1–30
• 6.6% in days 31–90
• 8.1% in days 91–180
• 8.8% in days 181–365 (P = .60).

This study did not report information about perioperative antiplatelet management and was limited to first-generation drug-eluting stents. 

Saia F, Belotti LM, Guastaroba P, et al. Risk of adverse cardiac and bleeding events following cardiac and noncardiac surgery in patients with coronary stents: how important is the interplay between stent type and time from stenting to surgery? Circ Cardiovasc Qual Outcomes 2015; 9:39–47.

The study. Saia et al¹⁶ retrospectively examined predictors of periprocedural ischemic and bleeding events among cardiac and noncardiac surgical patients who had previously undergone percutaneous coronary intervention. They also assessed the risks associated with stent type and time from percutaneous coronary intervention to surgery.

Of 39,362 patients, 13,128 underwent procedures during the 5-year study period. The cumulative incidence of surgery was 3.6% at 30 days, 14% at 1 year, and 40% at 5 years after percutaneous coronary intervention. Almost 30% of the procedures were done urgently.

Results. The 30-day rate of postoperative cardiac death was 2.5%, nonfatal myocardial infarction 1.5%, and serious bleeding events 6.5%. Older drug-eluting stents were associated with higher risks of adverse events than newer drug-eluting stents at any time point (odds ratio 2.1 at 0–180 days, 1.9 at 6–12 months, and 1.45 after 12 months). Surgery performed 6 to 12 months after percutaneous coronary intervention had lower rates of adverse outcomes than surgery performed within 6 months. Beyond 6 months from percutaneous coronary intervention, bare-metal stents and newer drug-eluting stents did not have significantly different adverse event rates; however, newer drug-eluting stents appeared safer than bare-metal stents from 0 to 180 days.

Limitations of this study included lack of information regarding periprocedural antiplatelet management and a relatively small subset of newer drug-eluting stent patients.

Implications for clinical practice. These studies added to earlier work that demonstrated that the risk of perioperative adverse events differs by both the stent type and the time from percutaneous coronary intervention to noncardiac surgery. In patients with a drug-eluting stent, the risk levels off 90 days after percutaneous coronary intervention, suggesting that the previously recommended 12 months of uninterrupted dual antiplatelet therapy (per the 2014 ACC/AHA guidelines¹) may not be needed, particularly with newer-generation drug-eluting stents. Based on new evidence, the ACC/AHA guidelines regarding perioperative management of dual antiplatelet therapy in noncardiac surgery patients were updated,¹⁷ as noted below.

An update to the ACC/AHA guidelines on dual antiplatelet therapy

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation 2016 Mar 29. DOI: 10.1161/CIR.0000000000000404. [Epub ahead of print]

The 2016 update¹⁷ provides the following recommendations for patients with coronary stents who undergo noncardiac surgery:

• Delay elective surgery for 30 days after placement of a bare-metal stent (class I recommendation, level of evidence B).
• It is optimal to delay elective surgery 6 months after drug-eluting stent placement (class I recommendation, level of evidence B).
• If dual antiplatelet therapy must be discontinued, then continue aspirin if possible and restart the P2Y₁₂ inhibitor as soon as possible postoperatively (class I recommendation, level of evidence C ).
• A consensus decision among treating clinicians is useful regarding the risks of surgery and discontinuation or continuation of antiplatelet therapy (class IIa recommendation, level of evidence C).
• If dual antiplatelet therapy must be discontinued, then elective surgery should not be performed less than 30 days after bare-metal stent placement, or less than 3 months after drug-eluting stent placement (class III recommendation, level of evidence B).
• Elective surgery after drug-eluting stent placement when the P2Y₁₂ inhibitor must be discontinued may be considered 3 months after drug-eluting stent placement if the risk of surgical delay is greater than the risk of stent thrombosis (class IIb recommendation, level of evidence C).

The basic differences are the new recommendations for a minimum of 6 months of dual antiplatelet therapy as opposed to 12 months after drug-eluting stent placement before elective noncardiac surgery, and to allow surgery after 3 months (as opposed to 6 months) if the risk of delaying surgery outweighs the risk of stent thrombosis or myocardial infarction.

PERIOPERATIVE ANTICOAGULATION

The optimal perioperative management of patients with atrial fibrillation who are on warfarin is uncertain. The American College of Chest Physicians guidelines¹⁸ categorized patients with atrial fibrillation into low, moderate, and high thromboembolic risk. Based primarily on observational data, these guidelines recommended perioperative bridging anticoagulation for those at high risk but not for those at low risk. For intermediate-risk patients, there were insufficient data to make any recommendation.

Bridging may not benefit those at intermediate risk

Douketis JD, Spyropoulos AC, Kaatz S, et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015; 373:823–833.

The study. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) trial¹⁹ was the first randomized controlled trial to examine the effects of perioperative bridging anticoagulation in patients with atrial fibrillation without mechanical heart valves.

Results. In 1,884 patients undergoing elective surgery, the incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (95% CI −0.6 to 0.8; P = .01 for noninferiority). Major bleeding occurred in 1.3% of patients in the no-bridging group and 3.2% in the bridging group (95% CI 0.20–0.78; P = .005 for superiority).

These results suggest that the risks of bridging therapy are greater than the benefits. Of note, the mean CHADS₂ score (1 point each for congestive heart failure, hypertension, age ≥ 75 years, and diabetes mellitus; 2 points for previous stroke or transient ischemic attack; a total score > 2 indicates significant risk of stroke) for patients enrolled in this trial was 2.3, and it may be difficult to extrapolate these results to the limited number of patients at highest risk, ie, who have a CHADS₂ score of 5 or 6. Also, this study did not address patients with arterial or venous thromboembolism.

Implications for clinical practice. Despite the limitations noted above, this study does provide guidance for management of the intermediate-risk group with atrial fibrillation as defined by the American College of Chest Physicians: a no-bridging strategy is the best option.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

Prophylactic use of beta-blockers in the perioperative period is highly controversial. Initial studies in the 1990s were favorable, but evidence has been conflicting since then.

The pendulum swung away from routinely recommending beta-blockers after the publication of negative results from several studies, including the Perioperative Ischemic Evaluation (POISE) trial in 2008.¹ Highlighting this change in practice, a Canadian study² found that the use of perioperative beta-blockade increased between 1999 and 2005 but subsequently declined from 2005 to 2010. However, there was no appreciable change in this pattern after the POISE trial or after changes in the American College of Cardiology guidelines in 2002 and 2006.³

In 2008, Harte and Jaffer reviewed the perioperative use of beta-blockers in noncardiac surgery in this journal.⁴ Since then, a number of meta-analyses and retrospective observational studies have reported variable findings related to specific beta-blockers and specific complications.

In this paper, we review the rationale and recent evidence for and against the perioperative use of beta-blockers as guidance for internists and hospitalists.

POTENTIAL CARDIOPROTECTIVE EFFECTS OF BETA-BLOCKERS

Myocardial infarction and unstable angina are the leading cardiovascular causes of death after surgery.⁵ These events are multifactorial. Some are caused by the stress of surgery, which precipitates physiologic changes related to inflammatory mediators, sympathetic tone, and oxygen supply and demand; others are caused by acute plaque rupture, thrombosis, and occlusion.⁶ Most perioperative infarcts are non-Q-wave events⁷ and occur within the first 2 days after the procedure, when the effects of anesthetics, pain, fluid shifts, and physiologic changes are greatest. Because multiple causes may contribute to perioperative myocardial infarction, a single preventive strategy may not be sufficient.^8,9

Beta-blockers do several things that may be beneficial in the perioperative setting. They reduce myocardial oxygen demand by decreasing the force of contraction and by slowing the heart rate, and slowing the heart rate increases diastolic perfusion time.¹⁰ They suppress arrhythmias; they limit leukocyte recruitment, the production of free radicals, metalloproteinase activity, monocyte activation, release of growth factors, and inflammatory cytokine response; and they stabilize plaque.¹¹ Their long-term use may also alter intracellular signaling processes, thus improving cell survival by decreasing the expression of receptors for substances that induce apoptosis.¹²

INITIAL POSITIVE TRIALS

Mangano et al¹³ began the beta-blocker trend in 1996 with a study in 200 patients known to have coronary artery disease or risk factors for it who were undergoing noncardiac surgery. Patients were randomized to receive either atenolol orally and intravenously, titrated to control the heart rate, or placebo in the immediate perioperative period.

The atenolol group had less perioperative ischemia but no difference in short-term rates of myocardial infarction and death. However, the death rate was lower in the atenolol group at 6 months after discharge and at 2 years, although patients who died in the immediate postoperative period were excluded from the analysis.

Although this finding did not appear to make sense physiologically, we now know that patients may experience myocardial injury without infarction after noncardiac surgery, a phenomenon associated with an increased risk of death in the short term and the long term.¹⁴ Preventing these episodes may be the explanation for the improved outcome.

The DECREASE trial¹⁵ (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) provided additional support for beta-blocker use. The patients were at high risk, had abnormal dobutamine stress echocardiograms, and were undergoing vascular surgery; 112 patients were randomized to receive either oral bisoprolol (started 1 month before surgery, titrated to control the heart rate, and continued for 1 month after surgery) or placebo.

The study was stopped early because the bisoprolol group reportedly had a 90% lower rate of myocardial infarction and cardiac death 1 month after surgery. However, the study was criticized because the total number of patients enrolled was small and the benefit was much greater than usual for any pharmacologic intervention, thus calling the results into question.

In a follow-up study,¹⁶ survivors continued to be followed while receiving bisoprolol or usual care. The incidence of myocardial infarction or cardiac death at 2 years was significantly lower in the group receiving bisoprolol (12% vs 32%, odds ratio [OR] 0.30, P = .025).

Boersma et al,¹⁷ in an observational study, analyzed data from all 1,351 patients scheduled for major vascular surgery being considered for enrollment in the DECREASE trial. The DECREASE protocol required patients to undergo dobutamine stress echocardiography if they had one or more risk factors (age 70 or older, angina, prior myocardial infarction, congestive heart failure, treatment for ventricular arrhythmia, treatment for diabetes mellitus, or limited exercise capacity) or if their physician requested it. Twenty-seven percent received beta-blockers.

In multivariate analysis, clinical predictors of adverse outcome were age 70 or older; current or prior history of angina; and prior myocardial infarction, heart failure, or cerebrovascular accident.

In patients who had fewer than three clinical risk factors, beta-blocker use was associated with a lower rate of complications (0.8% vs 2.3%). Dobutamine stress echocardiography had minimal predictive value in this lower-risk group, suggesting that stress testing may not be necessary in this group if beta-blockers are used appropriately. However, in patients who had three or more risk factors, this test did provide additional prognostic information; those without stress-induced ischemia had lower event rates than those with ischemia, and beta-blocker use further reduced those rates, except in patients with extensive ischemia (more than five left ventricular segments involved).

The Revised Cardiac Risk Index. Lee et al¹⁸ devised an index to assist in preoperative cardiac risk stratification that was subsequently incorporated into the 2007 American College of Cardiology/American Heart Association preoperative risk guidelines. (It does not, however, address the beta-blocker issue.) It consists of six independent risk-predictors of major cardiac complications derived from 4,315 patients over age 50 undergoing non-cardiac surgery. The risk factors, each of which is given 1 point, are:

• Congestive heart failure based on history or examination
• Renal insufficiency (serum creatinine level > 2 mg/dL)
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• History of transient ischemic attack or stroke
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with 3 or more points are considered to be at high risk, and those with 1 or 2 points are considered to be at intermediate risk. The American College of Cardiology/American Heart Association preoperative cardiac risk algorithm subsequently included five of these six risk factors (the type of surgery was considered separately) and made recommendations concerning noninvasive stress testing and heart rate control.

On the basis of these studies, specialty societies, guideline committees, and hospitals enthusiastically recommended the prophylactic use of beta-blockers to decrease postoperative cardiac complications.

THREE NEGATIVE TRIALS OF METOPROLOL

In 2005 and 2006, two studies in vascular surgery patients and another in patients with diabetes cast doubt on the role of beta-blockers when the results failed to show a benefit. The trials used metoprolol, started shortly before surgery, and with no titration to control the heart rate.

The MaVS study¹⁹ (Metoprolol After Vascular Surgery) randomized 496 patients to receive metoprolol or placebo 2 hours before surgery and until hospital discharge or a maximum of 5 days after surgery. The metoprolol dose varied by weight: patients weighing 75 kg or more got 100 mg, those weighing between 40 and 75 kg got 50 mg, and those weighing less than 40 kg got 25 mg. Overall effects at 6 months were not significantly different, but intraoperative bradycardia and hypotension requiring intervention were more frequent in the metoprolol group.

The POBBLE study²⁰ (Perioperative Beta Blockade) randomized 103 patients who had no history of myocardial infarction to receive either metoprolol 50 mg twice daily or placebo from admission to 7 days after surgery. Myocardial ischemia was present in one-third of the patients after surgery. Metoprolol did not reduce the 30-day cardiac mortality rate, but it was associated with a shorter length of stay.

The DIPOM trial²¹ (Diabetic Postoperative Mortality and Morbidity) randomized 921 diabetic patients to receive long-acting metoprolol succinate controlled-release/extended release (CR/XL) or placebo. Patients in the metoprolol group received a test dose of 50 mg the evening before surgery, another dose 2 hours before surgery (100 mg if the heart rate was more than 65 bpm, or 50 mg if between 55 and 65 bpm), and daily thereafter until discharge or a maximum of 8 days. The dose was not titrated to heart-rate control.

Metoprolol had no statistically significant effect on the composite primary outcome measures of time to death from any cause, acute myocardial infarction, unstable angina, or congestive heart failure or on the secondary outcome measures of time to death from any cause, death from a cardiac cause, and nonfatal cardiac morbidity.

ADDITIONAL POSITIVE STUDIES

Lindenauer et al²² retrospectively evaluated the use of beta-blockers in the first 2 days after surgery in 782,969 patients undergoing non-cardiac surgery. Using propensity score matching and Revised Cardiac Risk Index scores, they found a lower rate of postoperative mortality in patients with three or more risk factors who received a beta-blocker. There was no significant difference in the group with two risk factors, but in the lowest-risk group (with a score of 0 to 1), beta-blockers were not beneficial and may have been associated with harm as evidenced by a higher odds ratio for death, although this was probably artifactual and reflecting database limitations.

Feringa et al,²³ in an observational cohort study of 272 patients undergoing vascular surgery, reported that higher doses of beta-blockers and tight heart-rate control were associated with less perioperative myocardial ischemia, lower troponin T levels, and better long-term outcome.

THE POISE TRIAL: MIXED RESULTS

The randomized POISE trial,¹ published in 2008, compared the effects of extended-release metoprolol succinate vs placebo on the 30-day risk of major cardiovascular events in 8,351 patients with or at risk of atherosclerotic disease who were undergoing noncardiac surgery. The metoprolol regimen was 100 mg 2 to 4 hours before surgery, another 100 mg by 6 hours after surgery, and then 200 mg 12 hours later and once daily for 30 days.

The incidence of the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days was lower in the metoprolol group than in the placebo group (5.8% vs 6.9%; P = .04), primarily because of fewer nonfatal myocardial infarctions. However, more patients in the metoprolol group died of any cause (3.1% vs 2.3% P = .03) or had a stroke (1.0% vs 0.5% P = .005) than in the placebo group.

The metoprolol group had a higher incidence of clinically significant hypotension, bradycardia, and stroke, which could account for much of the increase in the mortality rate. Sepsis was the major cause of death in this group; hypotension may have increased the risk of infection, and beta-blockers may have potentiated hypotension in patients who were already septic. Also, the bradycardic and negative inotropic effects of the beta-blocker could have masked the physiologic response to systemic infection, thereby delaying recognition and treatment or impeding the normal immune response.

One of the major criticisms of the POISE trial was its aggressive dosing regimen (200 to 400 mg within a 36-hour period) in patients who had not been on beta-blockers before then. Also, the drug was started only a few hours before surgery. In addition, these patients were at higher risk of death and stroke than those in other trials based on a high baseline rate of cerebrovascular disease, and inclusion of urgent and emergency surgical procedures.

STUDIES SINCE POISE

The POISE trial results¹ prompted further questioning of the prophylactic perioperative use of beta-blockers. However, proponents of beta-blockers voiced serious criticisms of the trial, particularly the dosing regimen, and continued to believe that these drugs were beneficial if used appropriately.

The DECREASE IV trial. Dunkelgrun et al,²⁴ in a study using bisoprolol started approximately 1 month before surgery and titrated to control the heart rate, reported beneficial results in intermediate-risk patients. In their randomized open-label study with a 2 × 2 factorial design, 1,066 patients at intermediate cardiac risk were assigned to receive bisoprolol, fluvastatin, combination treatment, or control therapy at least 34 days before surgery. Bisoprolol was started at 2.5 mg orally daily and slowly titrated up to a maximum dose of 10 mg to keep the heart rate between 50 and 70 beats per minute. The group of 533 patients randomized to receive bisoprolol had a lower incidence rate of cardiac death and nonfatal myocardial infarction than the control group (2.1% vs 6.0%, HR 0.34, P = .002). A potential limitation of this study was its open-label design, which might have led to treatment bias.

Updated guidelines. Based on the results from POISE and DECREASE IV, the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines²⁵ published a focused update on beta-blockers in 2009 as an amendment to their 2007 guidelines on perioperative evaluation and care for noncardiac surgery. The European Society of Cardiology²⁶ released similar but somewhat more liberal guidelines (Table 1).

London et al,²⁷ in an observational study published in 2013, found a lower 30-day overall mortality rate with beta-blockers (relative risk [RR] 0.73, 95% confidence interval [CI] 0.65–0.83, P < .001, number needed to treat [NNT] 241), as well as a lower rate of cardiac morbidity (nonfatal myocardial infarction and cardiac death), but only in nonvascular surgery patients who were on beta-blockers within 7 days of scheduled surgery. Moreover, similar to the findings of Lindenauer et al,²² only patients with a Revised Cardiac Risk Index score of 2 or more benefited from beta-blocker use in terms of a lower risk of death, whereas the lower-risk patients did not:

• Risk score of 0 or 1—no association
• Score of 2—RR 0.63, 95% CI 0.50–0.80, P < .001, NNT 105
• Score of 3—RR 0.54, 95% CI 0.39–0.73, P < .001, NNT 41
• Score of 4 or more—RR 0.40, 95% CI 0.24–0.73, P < .001, NNT 18).

Beta-blocker exposure was associated with a significantly lower rate of cardiac complications (RR 0.67, 95% CI 0.57–0.79, P < .001, NNT 339), also limited to nonvascular surgery patients with a risk score of 2 or 3.

The Danish Nationwide Cohort Study²⁸ examined the effect of beta-blockers on major adverse cardiac events (MACE, ie, myocardial infarction, cerebrovascular accident, and death) in 28,263 patients with ischemic heart disease undergoing noncardiac surgery; 7,990 with heart failure and 20,273 without. Beta-blockers were used in 53% of patients with heart failure and 36% of those without heart failure. Outcomes for all of the beta-blocker recipients:

• MACE—HR 0.90, 95% CI 0.79–1.02
• All-cause mortality—HR 0.95, 95% CI 0.85–1.06.

Outcomes for patients with heart failure if they received beta-blockers:

• MACE—HR 0.75, 95% CI 0.70–0.87
• All-cause mortality—HR 0.80, 95% CI 0.70–0.92.

There was no significant benefit from beta-blockers in patients without heart failure. Outcomes for those patients if they received beta-blockers:

• MACE—HR 1.11, 95% CI 0.92–1.33
• All-cause mortality—HR 1.15, 95% CI 0.98–1.35.

However, in patients without heart failure but with a history of myocardial infarction within the past 2 years, beta-blockers were associated with a lower risk of MACE and all-cause mortality. In patients with neither heart failure nor a recent myocardial infarction, beta-blockers were associated with an increased risk of MACE and all-cause mortality.

This difference in efficacy depending on the presence and timing of a prior myocardial infarction is consistent with the 2012 American College of Cardiology/American Heart Association guidelines for secondary prevention, in which beta-blockers are given a class I recommendation only for patients with a myocardial infarction within the past 3 years.

Meta-analyses and outcomes

A number of meta-analyses have been published over the past 10 years, with conflicting results (Table 2). The divergent findings are primarily due to the different studies included in the analyses as well as the strong influence of the POISE trial.¹ The studies varied in terms of the specific beta-blocker used, dose titration and heart rate control, time of initiation of beta-blocker use before surgery, type of surgery, patient characteristics, comorbidities, biomarkers and diagnosis of myocardial infarction, and clinical end points.

In general, these meta-analyses have found that prophylactic perioperative use of beta-blockers decreases ischemia and tends to reduce the risk of nonfatal myocardial infarction. They vary on whether the overall mortality risk is decreased. The meta-analyses that included POISE¹ found an increased incidence of stroke, whereas those that excluded POISE found no significant difference, although there appeared to be slightly more strokes in the beta-blocker groups.

The beta-blocker controversy increased even further when Dr. Don Poldermans was fired by Erasmus Medical Center in November 2011 for violations of academic integrity involving his research, including the DECREASE trials. The most recent meta-analysis, by Bouri et al,²⁹ included nine “secure trials” and excluded the DECREASE trials in view of the controversy about their authenticity. The analysis showed an increase in overall mortality as well as stroke, primarily because it was heavily influenced by POISE.¹ In contrast, the DECREASE trials had reported a decreased risk of myocardial infarction and death, with no significant increase in stroke. The authors concluded that guideline bodies should “retract their recommendations based on the fictitious data without further delay.”²⁹

Although the design of the DECREASE trials (in which beta-blockers were started well in advance of surgery and doses were titrated to achieve heart rate control) is physiologically more compelling than those of the negative trials, the results have been questioned in light of the integrity issue. However, to date, none of the published DECREASE trials have been retracted.

Two other meta-analyses,^30,31 published in 2013, also found a decreased risk of myocardial infarction and increased risk of stroke but no significant difference in short-term all-cause mortality.

ARE ALL BETA-BLOCKERS EQUIVALENT?

In various studies evaluating specific beta-blockers, the more cardioselective agents bisoprolol and atenolol were associated with better outcomes than metoprolol. The affinity ratios for beta-1/beta-2 receptors range from 13.5 for bisoprolol to 4.7 for atenolol and 2.3 for metoprolol.³² Blocking beta-1 receptors blunts tachycardia, whereas blocking beta-2 receptors may block systemic or cerebral vasodilation.

In patients with anemia, beta-blockade in general may be harmful, but beta-2 blockade may be even worse. Beta-blockers were associated with an increased risk of MACE (6.5% vs 3.0%)³³ in patients with acute surgical anemia if the hemoglobin concentration decreased to less than 35% of baseline, and increased risks of hospital death (OR 6.65) and multiorgan dysfunction syndrome (OR 4.18) with severe bleeding during aortic surgery.³⁴

In addition, the pathway by which the beta-blocker is metabolized may also affect outcome, with less benefit from beta-blockers metabolized by the CYP2D6 isoenzyme of the cytochrome P450 system. Individual variations in CYP2D6 activity related to genetics or drug interactions may result in insufficient or excessive beta-blockade. Because metoprolol is the most dependent on this system, patients using it may be more susceptible to bradycardia.³⁵

Studies comparing atenolol and metoprolol found that the atenolol groups had fewer myocardial infarctions and deaths³⁶ and lower 30-day and 1-year mortality rates³⁷ than the groups on metoprolol. Studies comparing the three beta-blockers found better outcomes with atenolol and bisoprolol than with metoprolol—fewer strokes,^38,39 a lower mortality rate,³¹ and a better composite outcome³⁹ (Table 3 and Table 4).

START THE BETA-BLOCKER EARLY, TITRATE TO CONTROL THE HEART RATE

A number of studies suggest that how long the beta-blocker is given before surgery may influence the outcome (Table 5). The best results were achieved when beta-blockers were started approximately 1 month before surgery and titrated to control the heart rate.

Because this long lead-in time is not always practical, it is important to determine the shortest time before surgery in which starting beta-blockers may be beneficial and yet safe. Some evidence suggests that results are better when the beta-blocker is started more than 1 week preoperatively compared with less than 1 week, but it is unknown what the minimum or optimal time period should be.

If a beta-blocker is started well in advance of the scheduled surgery, there is adequate time for dose titration and tighter heart rate control. Most of the studies demonstrating beneficial effects of perioperative beta-blockers used dose titration and achieved lower heart rates in the treatment group than in the control group. A criticism of the MaVs,¹⁹ POBBLE,²⁰ and DIPOM²¹ trials was that the patients did not receive adequate beta-blockade. The POISE trial¹ used a much higher dose of metoprolol in an attempt to assure beta-blockade without dose titration, and although the regimen decreased nonfatal myocardial infarctions, it increased strokes and the overall mortality rate, probably related to excess bradycardia and hypotension. The target heart rate should probably be between 55 and 70 beats per minute.

RISK OF STROKE

POISE¹ was the first trial to note a clinically and statistically significant increase in strokes with perioperative beta-blocker use. Although no other study has shown a similar increased risk, almost all reported a higher number of strokes in the beta-blocker groups, although the absolute numbers and differences were small and not statistically significant. This risk may also vary from one beta-blocker to another (Table 4).

The usual incidence rate of postoperative stroke after noncardiac, noncarotid surgery is well under 1% in patients with no prior history of stroke but increases to approximately 3% in patients with a previous stroke.⁴⁰ An observational study from the Dutch group reported a very low incidence of stroke overall (0.02%) in 186,779 patients undergoing noncardiac surgery with no significant difference in those on chronic beta-blocker therapy.⁴¹ The DECREASE trials, with a total of 3,884 patients, also found no statistically significant increase in stroke with beta-blocker use (0.46% overall vs 0.5% with a beta-blocker),⁴² which in this case was bisoprolol started well in advance of surgery and titrated to control the heart rate. Although the DECREASE data are under suspicion, they seem reasonable and consistent with those of observational studies.

Proposed mechanisms by which beta-blockers may increase stroke risk include the side effects of hypotension and bradycardia, particularly in the setting of anemia. They may also cause cerebral ischemia by blocking cerebral vasodilation. This effect on cerebral blood flow may be more pronounced with the less cardioselective beta-blockers, which may explain the apparent increased stroke risk associated with metoprolol.

WHAT SHOULD WE DO NOW?

The evidence for the safety and efficacy of beta-blockers in the perioperative setting continues to evolve, and new clinical trials are needed to clarify the ongoing controversy, particularly regarding the risk of stroke.

If patients have other indications for beta-blocker therapy, such as history of heart failure, myocardial infarction in the past 3 years, or atrial fibrillation for rate control, they should be receiving them if time permits.

If prophylactic beta-blockers are to be effective in minimizing perioperative complications, it appears that they may need to be more cardioselective, started at least 1 week before surgery, titrated to control heart rate, and used in high-risk patients (Revised Cardiac Risk Index score > 2 or 3) undergoing high-risk surgery.

Ideally, a large randomized controlled trial using a cardioselective beta-blocker started in advance of surgery in patients with a Revised Cardiac Risk Index score greater than 2, undergoing intermediate or high-risk procedures, is needed to fully answer the questions raised by the current data.

Prophylactic use of beta-blockers in the perioperative period is highly controversial. Initial studies in the 1990s were favorable, but evidence has been conflicting since then.

The pendulum swung away from routinely recommending beta-blockers after the publication of negative results from several studies, including the Perioperative Ischemic Evaluation (POISE) trial in 2008.¹ Highlighting this change in practice, a Canadian study² found that the use of perioperative beta-blockade increased between 1999 and 2005 but subsequently declined from 2005 to 2010. However, there was no appreciable change in this pattern after the POISE trial or after changes in the American College of Cardiology guidelines in 2002 and 2006.³

In 2008, Harte and Jaffer reviewed the perioperative use of beta-blockers in noncardiac surgery in this journal.⁴ Since then, a number of meta-analyses and retrospective observational studies have reported variable findings related to specific beta-blockers and specific complications.

In this paper, we review the rationale and recent evidence for and against the perioperative use of beta-blockers as guidance for internists and hospitalists.

POTENTIAL CARDIOPROTECTIVE EFFECTS OF BETA-BLOCKERS

Myocardial infarction and unstable angina are the leading cardiovascular causes of death after surgery.⁵ These events are multifactorial. Some are caused by the stress of surgery, which precipitates physiologic changes related to inflammatory mediators, sympathetic tone, and oxygen supply and demand; others are caused by acute plaque rupture, thrombosis, and occlusion.⁶ Most perioperative infarcts are non-Q-wave events⁷ and occur within the first 2 days after the procedure, when the effects of anesthetics, pain, fluid shifts, and physiologic changes are greatest. Because multiple causes may contribute to perioperative myocardial infarction, a single preventive strategy may not be sufficient.^8,9

Beta-blockers do several things that may be beneficial in the perioperative setting. They reduce myocardial oxygen demand by decreasing the force of contraction and by slowing the heart rate, and slowing the heart rate increases diastolic perfusion time.¹⁰ They suppress arrhythmias; they limit leukocyte recruitment, the production of free radicals, metalloproteinase activity, monocyte activation, release of growth factors, and inflammatory cytokine response; and they stabilize plaque.¹¹ Their long-term use may also alter intracellular signaling processes, thus improving cell survival by decreasing the expression of receptors for substances that induce apoptosis.¹²

INITIAL POSITIVE TRIALS

Mangano et al¹³ began the beta-blocker trend in 1996 with a study in 200 patients known to have coronary artery disease or risk factors for it who were undergoing noncardiac surgery. Patients were randomized to receive either atenolol orally and intravenously, titrated to control the heart rate, or placebo in the immediate perioperative period.

The atenolol group had less perioperative ischemia but no difference in short-term rates of myocardial infarction and death. However, the death rate was lower in the atenolol group at 6 months after discharge and at 2 years, although patients who died in the immediate postoperative period were excluded from the analysis.

Although this finding did not appear to make sense physiologically, we now know that patients may experience myocardial injury without infarction after noncardiac surgery, a phenomenon associated with an increased risk of death in the short term and the long term.¹⁴ Preventing these episodes may be the explanation for the improved outcome.

The DECREASE trial¹⁵ (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) provided additional support for beta-blocker use. The patients were at high risk, had abnormal dobutamine stress echocardiograms, and were undergoing vascular surgery; 112 patients were randomized to receive either oral bisoprolol (started 1 month before surgery, titrated to control the heart rate, and continued for 1 month after surgery) or placebo.

The study was stopped early because the bisoprolol group reportedly had a 90% lower rate of myocardial infarction and cardiac death 1 month after surgery. However, the study was criticized because the total number of patients enrolled was small and the benefit was much greater than usual for any pharmacologic intervention, thus calling the results into question.

In a follow-up study,¹⁶ survivors continued to be followed while receiving bisoprolol or usual care. The incidence of myocardial infarction or cardiac death at 2 years was significantly lower in the group receiving bisoprolol (12% vs 32%, odds ratio [OR] 0.30, P = .025).

Boersma et al,¹⁷ in an observational study, analyzed data from all 1,351 patients scheduled for major vascular surgery being considered for enrollment in the DECREASE trial. The DECREASE protocol required patients to undergo dobutamine stress echocardiography if they had one or more risk factors (age 70 or older, angina, prior myocardial infarction, congestive heart failure, treatment for ventricular arrhythmia, treatment for diabetes mellitus, or limited exercise capacity) or if their physician requested it. Twenty-seven percent received beta-blockers.

In multivariate analysis, clinical predictors of adverse outcome were age 70 or older; current or prior history of angina; and prior myocardial infarction, heart failure, or cerebrovascular accident.

In patients who had fewer than three clinical risk factors, beta-blocker use was associated with a lower rate of complications (0.8% vs 2.3%). Dobutamine stress echocardiography had minimal predictive value in this lower-risk group, suggesting that stress testing may not be necessary in this group if beta-blockers are used appropriately. However, in patients who had three or more risk factors, this test did provide additional prognostic information; those without stress-induced ischemia had lower event rates than those with ischemia, and beta-blocker use further reduced those rates, except in patients with extensive ischemia (more than five left ventricular segments involved).

The Revised Cardiac Risk Index. Lee et al¹⁸ devised an index to assist in preoperative cardiac risk stratification that was subsequently incorporated into the 2007 American College of Cardiology/American Heart Association preoperative risk guidelines. (It does not, however, address the beta-blocker issue.) It consists of six independent risk-predictors of major cardiac complications derived from 4,315 patients over age 50 undergoing non-cardiac surgery. The risk factors, each of which is given 1 point, are:

• Congestive heart failure based on history or examination
• Renal insufficiency (serum creatinine level > 2 mg/dL)
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• History of transient ischemic attack or stroke
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with 3 or more points are considered to be at high risk, and those with 1 or 2 points are considered to be at intermediate risk. The American College of Cardiology/American Heart Association preoperative cardiac risk algorithm subsequently included five of these six risk factors (the type of surgery was considered separately) and made recommendations concerning noninvasive stress testing and heart rate control.

On the basis of these studies, specialty societies, guideline committees, and hospitals enthusiastically recommended the prophylactic use of beta-blockers to decrease postoperative cardiac complications.

THREE NEGATIVE TRIALS OF METOPROLOL

In 2005 and 2006, two studies in vascular surgery patients and another in patients with diabetes cast doubt on the role of beta-blockers when the results failed to show a benefit. The trials used metoprolol, started shortly before surgery, and with no titration to control the heart rate.

The MaVS study¹⁹ (Metoprolol After Vascular Surgery) randomized 496 patients to receive metoprolol or placebo 2 hours before surgery and until hospital discharge or a maximum of 5 days after surgery. The metoprolol dose varied by weight: patients weighing 75 kg or more got 100 mg, those weighing between 40 and 75 kg got 50 mg, and those weighing less than 40 kg got 25 mg. Overall effects at 6 months were not significantly different, but intraoperative bradycardia and hypotension requiring intervention were more frequent in the metoprolol group.

The POBBLE study²⁰ (Perioperative Beta Blockade) randomized 103 patients who had no history of myocardial infarction to receive either metoprolol 50 mg twice daily or placebo from admission to 7 days after surgery. Myocardial ischemia was present in one-third of the patients after surgery. Metoprolol did not reduce the 30-day cardiac mortality rate, but it was associated with a shorter length of stay.

The DIPOM trial²¹ (Diabetic Postoperative Mortality and Morbidity) randomized 921 diabetic patients to receive long-acting metoprolol succinate controlled-release/extended release (CR/XL) or placebo. Patients in the metoprolol group received a test dose of 50 mg the evening before surgery, another dose 2 hours before surgery (100 mg if the heart rate was more than 65 bpm, or 50 mg if between 55 and 65 bpm), and daily thereafter until discharge or a maximum of 8 days. The dose was not titrated to heart-rate control.

Metoprolol had no statistically significant effect on the composite primary outcome measures of time to death from any cause, acute myocardial infarction, unstable angina, or congestive heart failure or on the secondary outcome measures of time to death from any cause, death from a cardiac cause, and nonfatal cardiac morbidity.

ADDITIONAL POSITIVE STUDIES

Lindenauer et al²² retrospectively evaluated the use of beta-blockers in the first 2 days after surgery in 782,969 patients undergoing non-cardiac surgery. Using propensity score matching and Revised Cardiac Risk Index scores, they found a lower rate of postoperative mortality in patients with three or more risk factors who received a beta-blocker. There was no significant difference in the group with two risk factors, but in the lowest-risk group (with a score of 0 to 1), beta-blockers were not beneficial and may have been associated with harm as evidenced by a higher odds ratio for death, although this was probably artifactual and reflecting database limitations.

Feringa et al,²³ in an observational cohort study of 272 patients undergoing vascular surgery, reported that higher doses of beta-blockers and tight heart-rate control were associated with less perioperative myocardial ischemia, lower troponin T levels, and better long-term outcome.

THE POISE TRIAL: MIXED RESULTS

The randomized POISE trial,¹ published in 2008, compared the effects of extended-release metoprolol succinate vs placebo on the 30-day risk of major cardiovascular events in 8,351 patients with or at risk of atherosclerotic disease who were undergoing noncardiac surgery. The metoprolol regimen was 100 mg 2 to 4 hours before surgery, another 100 mg by 6 hours after surgery, and then 200 mg 12 hours later and once daily for 30 days.

The incidence of the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days was lower in the metoprolol group than in the placebo group (5.8% vs 6.9%; P = .04), primarily because of fewer nonfatal myocardial infarctions. However, more patients in the metoprolol group died of any cause (3.1% vs 2.3% P = .03) or had a stroke (1.0% vs 0.5% P = .005) than in the placebo group.

The metoprolol group had a higher incidence of clinically significant hypotension, bradycardia, and stroke, which could account for much of the increase in the mortality rate. Sepsis was the major cause of death in this group; hypotension may have increased the risk of infection, and beta-blockers may have potentiated hypotension in patients who were already septic. Also, the bradycardic and negative inotropic effects of the beta-blocker could have masked the physiologic response to systemic infection, thereby delaying recognition and treatment or impeding the normal immune response.

One of the major criticisms of the POISE trial was its aggressive dosing regimen (200 to 400 mg within a 36-hour period) in patients who had not been on beta-blockers before then. Also, the drug was started only a few hours before surgery. In addition, these patients were at higher risk of death and stroke than those in other trials based on a high baseline rate of cerebrovascular disease, and inclusion of urgent and emergency surgical procedures.

STUDIES SINCE POISE

The POISE trial results¹ prompted further questioning of the prophylactic perioperative use of beta-blockers. However, proponents of beta-blockers voiced serious criticisms of the trial, particularly the dosing regimen, and continued to believe that these drugs were beneficial if used appropriately.

The DECREASE IV trial. Dunkelgrun et al,²⁴ in a study using bisoprolol started approximately 1 month before surgery and titrated to control the heart rate, reported beneficial results in intermediate-risk patients. In their randomized open-label study with a 2 × 2 factorial design, 1,066 patients at intermediate cardiac risk were assigned to receive bisoprolol, fluvastatin, combination treatment, or control therapy at least 34 days before surgery. Bisoprolol was started at 2.5 mg orally daily and slowly titrated up to a maximum dose of 10 mg to keep the heart rate between 50 and 70 beats per minute. The group of 533 patients randomized to receive bisoprolol had a lower incidence rate of cardiac death and nonfatal myocardial infarction than the control group (2.1% vs 6.0%, HR 0.34, P = .002). A potential limitation of this study was its open-label design, which might have led to treatment bias.

Updated guidelines. Based on the results from POISE and DECREASE IV, the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines²⁵ published a focused update on beta-blockers in 2009 as an amendment to their 2007 guidelines on perioperative evaluation and care for noncardiac surgery. The European Society of Cardiology²⁶ released similar but somewhat more liberal guidelines (Table 1).

London et al,²⁷ in an observational study published in 2013, found a lower 30-day overall mortality rate with beta-blockers (relative risk [RR] 0.73, 95% confidence interval [CI] 0.65–0.83, P < .001, number needed to treat [NNT] 241), as well as a lower rate of cardiac morbidity (nonfatal myocardial infarction and cardiac death), but only in nonvascular surgery patients who were on beta-blockers within 7 days of scheduled surgery. Moreover, similar to the findings of Lindenauer et al,²² only patients with a Revised Cardiac Risk Index score of 2 or more benefited from beta-blocker use in terms of a lower risk of death, whereas the lower-risk patients did not:

• Risk score of 0 or 1—no association
• Score of 2—RR 0.63, 95% CI 0.50–0.80, P < .001, NNT 105
• Score of 3—RR 0.54, 95% CI 0.39–0.73, P < .001, NNT 41
• Score of 4 or more—RR 0.40, 95% CI 0.24–0.73, P < .001, NNT 18).

Beta-blocker exposure was associated with a significantly lower rate of cardiac complications (RR 0.67, 95% CI 0.57–0.79, P < .001, NNT 339), also limited to nonvascular surgery patients with a risk score of 2 or 3.

The Danish Nationwide Cohort Study²⁸ examined the effect of beta-blockers on major adverse cardiac events (MACE, ie, myocardial infarction, cerebrovascular accident, and death) in 28,263 patients with ischemic heart disease undergoing noncardiac surgery; 7,990 with heart failure and 20,273 without. Beta-blockers were used in 53% of patients with heart failure and 36% of those without heart failure. Outcomes for all of the beta-blocker recipients:

• MACE—HR 0.90, 95% CI 0.79–1.02
• All-cause mortality—HR 0.95, 95% CI 0.85–1.06.

Outcomes for patients with heart failure if they received beta-blockers:

• MACE—HR 0.75, 95% CI 0.70–0.87
• All-cause mortality—HR 0.80, 95% CI 0.70–0.92.

There was no significant benefit from beta-blockers in patients without heart failure. Outcomes for those patients if they received beta-blockers:

• MACE—HR 1.11, 95% CI 0.92–1.33
• All-cause mortality—HR 1.15, 95% CI 0.98–1.35.

However, in patients without heart failure but with a history of myocardial infarction within the past 2 years, beta-blockers were associated with a lower risk of MACE and all-cause mortality. In patients with neither heart failure nor a recent myocardial infarction, beta-blockers were associated with an increased risk of MACE and all-cause mortality.

This difference in efficacy depending on the presence and timing of a prior myocardial infarction is consistent with the 2012 American College of Cardiology/American Heart Association guidelines for secondary prevention, in which beta-blockers are given a class I recommendation only for patients with a myocardial infarction within the past 3 years.

Meta-analyses and outcomes

A number of meta-analyses have been published over the past 10 years, with conflicting results (Table 2). The divergent findings are primarily due to the different studies included in the analyses as well as the strong influence of the POISE trial.¹ The studies varied in terms of the specific beta-blocker used, dose titration and heart rate control, time of initiation of beta-blocker use before surgery, type of surgery, patient characteristics, comorbidities, biomarkers and diagnosis of myocardial infarction, and clinical end points.

In general, these meta-analyses have found that prophylactic perioperative use of beta-blockers decreases ischemia and tends to reduce the risk of nonfatal myocardial infarction. They vary on whether the overall mortality risk is decreased. The meta-analyses that included POISE¹ found an increased incidence of stroke, whereas those that excluded POISE found no significant difference, although there appeared to be slightly more strokes in the beta-blocker groups.

The beta-blocker controversy increased even further when Dr. Don Poldermans was fired by Erasmus Medical Center in November 2011 for violations of academic integrity involving his research, including the DECREASE trials. The most recent meta-analysis, by Bouri et al,²⁹ included nine “secure trials” and excluded the DECREASE trials in view of the controversy about their authenticity. The analysis showed an increase in overall mortality as well as stroke, primarily because it was heavily influenced by POISE.¹ In contrast, the DECREASE trials had reported a decreased risk of myocardial infarction and death, with no significant increase in stroke. The authors concluded that guideline bodies should “retract their recommendations based on the fictitious data without further delay.”²⁹

Although the design of the DECREASE trials (in which beta-blockers were started well in advance of surgery and doses were titrated to achieve heart rate control) is physiologically more compelling than those of the negative trials, the results have been questioned in light of the integrity issue. However, to date, none of the published DECREASE trials have been retracted.

Two other meta-analyses,^30,31 published in 2013, also found a decreased risk of myocardial infarction and increased risk of stroke but no significant difference in short-term all-cause mortality.

ARE ALL BETA-BLOCKERS EQUIVALENT?

In various studies evaluating specific beta-blockers, the more cardioselective agents bisoprolol and atenolol were associated with better outcomes than metoprolol. The affinity ratios for beta-1/beta-2 receptors range from 13.5 for bisoprolol to 4.7 for atenolol and 2.3 for metoprolol.³² Blocking beta-1 receptors blunts tachycardia, whereas blocking beta-2 receptors may block systemic or cerebral vasodilation.

In patients with anemia, beta-blockade in general may be harmful, but beta-2 blockade may be even worse. Beta-blockers were associated with an increased risk of MACE (6.5% vs 3.0%)³³ in patients with acute surgical anemia if the hemoglobin concentration decreased to less than 35% of baseline, and increased risks of hospital death (OR 6.65) and multiorgan dysfunction syndrome (OR 4.18) with severe bleeding during aortic surgery.³⁴

In addition, the pathway by which the beta-blocker is metabolized may also affect outcome, with less benefit from beta-blockers metabolized by the CYP2D6 isoenzyme of the cytochrome P450 system. Individual variations in CYP2D6 activity related to genetics or drug interactions may result in insufficient or excessive beta-blockade. Because metoprolol is the most dependent on this system, patients using it may be more susceptible to bradycardia.³⁵

Studies comparing atenolol and metoprolol found that the atenolol groups had fewer myocardial infarctions and deaths³⁶ and lower 30-day and 1-year mortality rates³⁷ than the groups on metoprolol. Studies comparing the three beta-blockers found better outcomes with atenolol and bisoprolol than with metoprolol—fewer strokes,^38,39 a lower mortality rate,³¹ and a better composite outcome³⁹ (Table 3 and Table 4).

START THE BETA-BLOCKER EARLY, TITRATE TO CONTROL THE HEART RATE

A number of studies suggest that how long the beta-blocker is given before surgery may influence the outcome (Table 5). The best results were achieved when beta-blockers were started approximately 1 month before surgery and titrated to control the heart rate.

Because this long lead-in time is not always practical, it is important to determine the shortest time before surgery in which starting beta-blockers may be beneficial and yet safe. Some evidence suggests that results are better when the beta-blocker is started more than 1 week preoperatively compared with less than 1 week, but it is unknown what the minimum or optimal time period should be.

If a beta-blocker is started well in advance of the scheduled surgery, there is adequate time for dose titration and tighter heart rate control. Most of the studies demonstrating beneficial effects of perioperative beta-blockers used dose titration and achieved lower heart rates in the treatment group than in the control group. A criticism of the MaVs,¹⁹ POBBLE,²⁰ and DIPOM²¹ trials was that the patients did not receive adequate beta-blockade. The POISE trial¹ used a much higher dose of metoprolol in an attempt to assure beta-blockade without dose titration, and although the regimen decreased nonfatal myocardial infarctions, it increased strokes and the overall mortality rate, probably related to excess bradycardia and hypotension. The target heart rate should probably be between 55 and 70 beats per minute.

RISK OF STROKE

POISE¹ was the first trial to note a clinically and statistically significant increase in strokes with perioperative beta-blocker use. Although no other study has shown a similar increased risk, almost all reported a higher number of strokes in the beta-blocker groups, although the absolute numbers and differences were small and not statistically significant. This risk may also vary from one beta-blocker to another (Table 4).

The usual incidence rate of postoperative stroke after noncardiac, noncarotid surgery is well under 1% in patients with no prior history of stroke but increases to approximately 3% in patients with a previous stroke.⁴⁰ An observational study from the Dutch group reported a very low incidence of stroke overall (0.02%) in 186,779 patients undergoing noncardiac surgery with no significant difference in those on chronic beta-blocker therapy.⁴¹ The DECREASE trials, with a total of 3,884 patients, also found no statistically significant increase in stroke with beta-blocker use (0.46% overall vs 0.5% with a beta-blocker),⁴² which in this case was bisoprolol started well in advance of surgery and titrated to control the heart rate. Although the DECREASE data are under suspicion, they seem reasonable and consistent with those of observational studies.

Proposed mechanisms by which beta-blockers may increase stroke risk include the side effects of hypotension and bradycardia, particularly in the setting of anemia. They may also cause cerebral ischemia by blocking cerebral vasodilation. This effect on cerebral blood flow may be more pronounced with the less cardioselective beta-blockers, which may explain the apparent increased stroke risk associated with metoprolol.

WHAT SHOULD WE DO NOW?

The evidence for the safety and efficacy of beta-blockers in the perioperative setting continues to evolve, and new clinical trials are needed to clarify the ongoing controversy, particularly regarding the risk of stroke.

If patients have other indications for beta-blocker therapy, such as history of heart failure, myocardial infarction in the past 3 years, or atrial fibrillation for rate control, they should be receiving them if time permits.

If prophylactic beta-blockers are to be effective in minimizing perioperative complications, it appears that they may need to be more cardioselective, started at least 1 week before surgery, titrated to control heart rate, and used in high-risk patients (Revised Cardiac Risk Index score > 2 or 3) undergoing high-risk surgery.

Ideally, a large randomized controlled trial using a cardioselective beta-blocker started in advance of surgery in patients with a Revised Cardiac Risk Index score greater than 2, undergoing intermediate or high-risk procedures, is needed to fully answer the questions raised by the current data.

Prophylactic use of beta-blockers in the perioperative period is highly controversial. Initial studies in the 1990s were favorable, but evidence has been conflicting since then.

The pendulum swung away from routinely recommending beta-blockers after the publication of negative results from several studies, including the Perioperative Ischemic Evaluation (POISE) trial in 2008.¹ Highlighting this change in practice, a Canadian study² found that the use of perioperative beta-blockade increased between 1999 and 2005 but subsequently declined from 2005 to 2010. However, there was no appreciable change in this pattern after the POISE trial or after changes in the American College of Cardiology guidelines in 2002 and 2006.³

In 2008, Harte and Jaffer reviewed the perioperative use of beta-blockers in noncardiac surgery in this journal.⁴ Since then, a number of meta-analyses and retrospective observational studies have reported variable findings related to specific beta-blockers and specific complications.

In this paper, we review the rationale and recent evidence for and against the perioperative use of beta-blockers as guidance for internists and hospitalists.

POTENTIAL CARDIOPROTECTIVE EFFECTS OF BETA-BLOCKERS

Myocardial infarction and unstable angina are the leading cardiovascular causes of death after surgery.⁵ These events are multifactorial. Some are caused by the stress of surgery, which precipitates physiologic changes related to inflammatory mediators, sympathetic tone, and oxygen supply and demand; others are caused by acute plaque rupture, thrombosis, and occlusion.⁶ Most perioperative infarcts are non-Q-wave events⁷ and occur within the first 2 days after the procedure, when the effects of anesthetics, pain, fluid shifts, and physiologic changes are greatest. Because multiple causes may contribute to perioperative myocardial infarction, a single preventive strategy may not be sufficient.^8,9

Beta-blockers do several things that may be beneficial in the perioperative setting. They reduce myocardial oxygen demand by decreasing the force of contraction and by slowing the heart rate, and slowing the heart rate increases diastolic perfusion time.¹⁰ They suppress arrhythmias; they limit leukocyte recruitment, the production of free radicals, metalloproteinase activity, monocyte activation, release of growth factors, and inflammatory cytokine response; and they stabilize plaque.¹¹ Their long-term use may also alter intracellular signaling processes, thus improving cell survival by decreasing the expression of receptors for substances that induce apoptosis.¹²

INITIAL POSITIVE TRIALS

Mangano et al¹³ began the beta-blocker trend in 1996 with a study in 200 patients known to have coronary artery disease or risk factors for it who were undergoing noncardiac surgery. Patients were randomized to receive either atenolol orally and intravenously, titrated to control the heart rate, or placebo in the immediate perioperative period.

The atenolol group had less perioperative ischemia but no difference in short-term rates of myocardial infarction and death. However, the death rate was lower in the atenolol group at 6 months after discharge and at 2 years, although patients who died in the immediate postoperative period were excluded from the analysis.

Although this finding did not appear to make sense physiologically, we now know that patients may experience myocardial injury without infarction after noncardiac surgery, a phenomenon associated with an increased risk of death in the short term and the long term.¹⁴ Preventing these episodes may be the explanation for the improved outcome.

The DECREASE trial¹⁵ (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) provided additional support for beta-blocker use. The patients were at high risk, had abnormal dobutamine stress echocardiograms, and were undergoing vascular surgery; 112 patients were randomized to receive either oral bisoprolol (started 1 month before surgery, titrated to control the heart rate, and continued for 1 month after surgery) or placebo.

The study was stopped early because the bisoprolol group reportedly had a 90% lower rate of myocardial infarction and cardiac death 1 month after surgery. However, the study was criticized because the total number of patients enrolled was small and the benefit was much greater than usual for any pharmacologic intervention, thus calling the results into question.

In a follow-up study,¹⁶ survivors continued to be followed while receiving bisoprolol or usual care. The incidence of myocardial infarction or cardiac death at 2 years was significantly lower in the group receiving bisoprolol (12% vs 32%, odds ratio [OR] 0.30, P = .025).

Boersma et al,¹⁷ in an observational study, analyzed data from all 1,351 patients scheduled for major vascular surgery being considered for enrollment in the DECREASE trial. The DECREASE protocol required patients to undergo dobutamine stress echocardiography if they had one or more risk factors (age 70 or older, angina, prior myocardial infarction, congestive heart failure, treatment for ventricular arrhythmia, treatment for diabetes mellitus, or limited exercise capacity) or if their physician requested it. Twenty-seven percent received beta-blockers.

In multivariate analysis, clinical predictors of adverse outcome were age 70 or older; current or prior history of angina; and prior myocardial infarction, heart failure, or cerebrovascular accident.

In patients who had fewer than three clinical risk factors, beta-blocker use was associated with a lower rate of complications (0.8% vs 2.3%). Dobutamine stress echocardiography had minimal predictive value in this lower-risk group, suggesting that stress testing may not be necessary in this group if beta-blockers are used appropriately. However, in patients who had three or more risk factors, this test did provide additional prognostic information; those without stress-induced ischemia had lower event rates than those with ischemia, and beta-blocker use further reduced those rates, except in patients with extensive ischemia (more than five left ventricular segments involved).

The Revised Cardiac Risk Index. Lee et al¹⁸ devised an index to assist in preoperative cardiac risk stratification that was subsequently incorporated into the 2007 American College of Cardiology/American Heart Association preoperative risk guidelines. (It does not, however, address the beta-blocker issue.) It consists of six independent risk-predictors of major cardiac complications derived from 4,315 patients over age 50 undergoing non-cardiac surgery. The risk factors, each of which is given 1 point, are:

• Congestive heart failure based on history or examination
• Renal insufficiency (serum creatinine level > 2 mg/dL)
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• History of transient ischemic attack or stroke
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with 3 or more points are considered to be at high risk, and those with 1 or 2 points are considered to be at intermediate risk. The American College of Cardiology/American Heart Association preoperative cardiac risk algorithm subsequently included five of these six risk factors (the type of surgery was considered separately) and made recommendations concerning noninvasive stress testing and heart rate control.

On the basis of these studies, specialty societies, guideline committees, and hospitals enthusiastically recommended the prophylactic use of beta-blockers to decrease postoperative cardiac complications.

THREE NEGATIVE TRIALS OF METOPROLOL

In 2005 and 2006, two studies in vascular surgery patients and another in patients with diabetes cast doubt on the role of beta-blockers when the results failed to show a benefit. The trials used metoprolol, started shortly before surgery, and with no titration to control the heart rate.

The MaVS study¹⁹ (Metoprolol After Vascular Surgery) randomized 496 patients to receive metoprolol or placebo 2 hours before surgery and until hospital discharge or a maximum of 5 days after surgery. The metoprolol dose varied by weight: patients weighing 75 kg or more got 100 mg, those weighing between 40 and 75 kg got 50 mg, and those weighing less than 40 kg got 25 mg. Overall effects at 6 months were not significantly different, but intraoperative bradycardia and hypotension requiring intervention were more frequent in the metoprolol group.

The POBBLE study²⁰ (Perioperative Beta Blockade) randomized 103 patients who had no history of myocardial infarction to receive either metoprolol 50 mg twice daily or placebo from admission to 7 days after surgery. Myocardial ischemia was present in one-third of the patients after surgery. Metoprolol did not reduce the 30-day cardiac mortality rate, but it was associated with a shorter length of stay.

The DIPOM trial²¹ (Diabetic Postoperative Mortality and Morbidity) randomized 921 diabetic patients to receive long-acting metoprolol succinate controlled-release/extended release (CR/XL) or placebo. Patients in the metoprolol group received a test dose of 50 mg the evening before surgery, another dose 2 hours before surgery (100 mg if the heart rate was more than 65 bpm, or 50 mg if between 55 and 65 bpm), and daily thereafter until discharge or a maximum of 8 days. The dose was not titrated to heart-rate control.

Metoprolol had no statistically significant effect on the composite primary outcome measures of time to death from any cause, acute myocardial infarction, unstable angina, or congestive heart failure or on the secondary outcome measures of time to death from any cause, death from a cardiac cause, and nonfatal cardiac morbidity.

ADDITIONAL POSITIVE STUDIES

Lindenauer et al²² retrospectively evaluated the use of beta-blockers in the first 2 days after surgery in 782,969 patients undergoing non-cardiac surgery. Using propensity score matching and Revised Cardiac Risk Index scores, they found a lower rate of postoperative mortality in patients with three or more risk factors who received a beta-blocker. There was no significant difference in the group with two risk factors, but in the lowest-risk group (with a score of 0 to 1), beta-blockers were not beneficial and may have been associated with harm as evidenced by a higher odds ratio for death, although this was probably artifactual and reflecting database limitations.

Feringa et al,²³ in an observational cohort study of 272 patients undergoing vascular surgery, reported that higher doses of beta-blockers and tight heart-rate control were associated with less perioperative myocardial ischemia, lower troponin T levels, and better long-term outcome.

THE POISE TRIAL: MIXED RESULTS

The randomized POISE trial,¹ published in 2008, compared the effects of extended-release metoprolol succinate vs placebo on the 30-day risk of major cardiovascular events in 8,351 patients with or at risk of atherosclerotic disease who were undergoing noncardiac surgery. The metoprolol regimen was 100 mg 2 to 4 hours before surgery, another 100 mg by 6 hours after surgery, and then 200 mg 12 hours later and once daily for 30 days.

The incidence of the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days was lower in the metoprolol group than in the placebo group (5.8% vs 6.9%; P = .04), primarily because of fewer nonfatal myocardial infarctions. However, more patients in the metoprolol group died of any cause (3.1% vs 2.3% P = .03) or had a stroke (1.0% vs 0.5% P = .005) than in the placebo group.

The metoprolol group had a higher incidence of clinically significant hypotension, bradycardia, and stroke, which could account for much of the increase in the mortality rate. Sepsis was the major cause of death in this group; hypotension may have increased the risk of infection, and beta-blockers may have potentiated hypotension in patients who were already septic. Also, the bradycardic and negative inotropic effects of the beta-blocker could have masked the physiologic response to systemic infection, thereby delaying recognition and treatment or impeding the normal immune response.

One of the major criticisms of the POISE trial was its aggressive dosing regimen (200 to 400 mg within a 36-hour period) in patients who had not been on beta-blockers before then. Also, the drug was started only a few hours before surgery. In addition, these patients were at higher risk of death and stroke than those in other trials based on a high baseline rate of cerebrovascular disease, and inclusion of urgent and emergency surgical procedures.

STUDIES SINCE POISE

The POISE trial results¹ prompted further questioning of the prophylactic perioperative use of beta-blockers. However, proponents of beta-blockers voiced serious criticisms of the trial, particularly the dosing regimen, and continued to believe that these drugs were beneficial if used appropriately.

The DECREASE IV trial. Dunkelgrun et al,²⁴ in a study using bisoprolol started approximately 1 month before surgery and titrated to control the heart rate, reported beneficial results in intermediate-risk patients. In their randomized open-label study with a 2 × 2 factorial design, 1,066 patients at intermediate cardiac risk were assigned to receive bisoprolol, fluvastatin, combination treatment, or control therapy at least 34 days before surgery. Bisoprolol was started at 2.5 mg orally daily and slowly titrated up to a maximum dose of 10 mg to keep the heart rate between 50 and 70 beats per minute. The group of 533 patients randomized to receive bisoprolol had a lower incidence rate of cardiac death and nonfatal myocardial infarction than the control group (2.1% vs 6.0%, HR 0.34, P = .002). A potential limitation of this study was its open-label design, which might have led to treatment bias.

Updated guidelines. Based on the results from POISE and DECREASE IV, the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines²⁵ published a focused update on beta-blockers in 2009 as an amendment to their 2007 guidelines on perioperative evaluation and care for noncardiac surgery. The European Society of Cardiology²⁶ released similar but somewhat more liberal guidelines (Table 1).

London et al,²⁷ in an observational study published in 2013, found a lower 30-day overall mortality rate with beta-blockers (relative risk [RR] 0.73, 95% confidence interval [CI] 0.65–0.83, P < .001, number needed to treat [NNT] 241), as well as a lower rate of cardiac morbidity (nonfatal myocardial infarction and cardiac death), but only in nonvascular surgery patients who were on beta-blockers within 7 days of scheduled surgery. Moreover, similar to the findings of Lindenauer et al,²² only patients with a Revised Cardiac Risk Index score of 2 or more benefited from beta-blocker use in terms of a lower risk of death, whereas the lower-risk patients did not:

• Risk score of 0 or 1—no association
• Score of 2—RR 0.63, 95% CI 0.50–0.80, P < .001, NNT 105
• Score of 3—RR 0.54, 95% CI 0.39–0.73, P < .001, NNT 41
• Score of 4 or more—RR 0.40, 95% CI 0.24–0.73, P < .001, NNT 18).

Beta-blocker exposure was associated with a significantly lower rate of cardiac complications (RR 0.67, 95% CI 0.57–0.79, P < .001, NNT 339), also limited to nonvascular surgery patients with a risk score of 2 or 3.

The Danish Nationwide Cohort Study²⁸ examined the effect of beta-blockers on major adverse cardiac events (MACE, ie, myocardial infarction, cerebrovascular accident, and death) in 28,263 patients with ischemic heart disease undergoing noncardiac surgery; 7,990 with heart failure and 20,273 without. Beta-blockers were used in 53% of patients with heart failure and 36% of those without heart failure. Outcomes for all of the beta-blocker recipients:

• MACE—HR 0.90, 95% CI 0.79–1.02
• All-cause mortality—HR 0.95, 95% CI 0.85–1.06.

Outcomes for patients with heart failure if they received beta-blockers:

• MACE—HR 0.75, 95% CI 0.70–0.87
• All-cause mortality—HR 0.80, 95% CI 0.70–0.92.

There was no significant benefit from beta-blockers in patients without heart failure. Outcomes for those patients if they received beta-blockers:

• MACE—HR 1.11, 95% CI 0.92–1.33
• All-cause mortality—HR 1.15, 95% CI 0.98–1.35.

However, in patients without heart failure but with a history of myocardial infarction within the past 2 years, beta-blockers were associated with a lower risk of MACE and all-cause mortality. In patients with neither heart failure nor a recent myocardial infarction, beta-blockers were associated with an increased risk of MACE and all-cause mortality.

This difference in efficacy depending on the presence and timing of a prior myocardial infarction is consistent with the 2012 American College of Cardiology/American Heart Association guidelines for secondary prevention, in which beta-blockers are given a class I recommendation only for patients with a myocardial infarction within the past 3 years.

Meta-analyses and outcomes

A number of meta-analyses have been published over the past 10 years, with conflicting results (Table 2). The divergent findings are primarily due to the different studies included in the analyses as well as the strong influence of the POISE trial.¹ The studies varied in terms of the specific beta-blocker used, dose titration and heart rate control, time of initiation of beta-blocker use before surgery, type of surgery, patient characteristics, comorbidities, biomarkers and diagnosis of myocardial infarction, and clinical end points.

In general, these meta-analyses have found that prophylactic perioperative use of beta-blockers decreases ischemia and tends to reduce the risk of nonfatal myocardial infarction. They vary on whether the overall mortality risk is decreased. The meta-analyses that included POISE¹ found an increased incidence of stroke, whereas those that excluded POISE found no significant difference, although there appeared to be slightly more strokes in the beta-blocker groups.

The beta-blocker controversy increased even further when Dr. Don Poldermans was fired by Erasmus Medical Center in November 2011 for violations of academic integrity involving his research, including the DECREASE trials. The most recent meta-analysis, by Bouri et al,²⁹ included nine “secure trials” and excluded the DECREASE trials in view of the controversy about their authenticity. The analysis showed an increase in overall mortality as well as stroke, primarily because it was heavily influenced by POISE.¹ In contrast, the DECREASE trials had reported a decreased risk of myocardial infarction and death, with no significant increase in stroke. The authors concluded that guideline bodies should “retract their recommendations based on the fictitious data without further delay.”²⁹

Although the design of the DECREASE trials (in which beta-blockers were started well in advance of surgery and doses were titrated to achieve heart rate control) is physiologically more compelling than those of the negative trials, the results have been questioned in light of the integrity issue. However, to date, none of the published DECREASE trials have been retracted.

Two other meta-analyses,^30,31 published in 2013, also found a decreased risk of myocardial infarction and increased risk of stroke but no significant difference in short-term all-cause mortality.

ARE ALL BETA-BLOCKERS EQUIVALENT?

In various studies evaluating specific beta-blockers, the more cardioselective agents bisoprolol and atenolol were associated with better outcomes than metoprolol. The affinity ratios for beta-1/beta-2 receptors range from 13.5 for bisoprolol to 4.7 for atenolol and 2.3 for metoprolol.³² Blocking beta-1 receptors blunts tachycardia, whereas blocking beta-2 receptors may block systemic or cerebral vasodilation.

In patients with anemia, beta-blockade in general may be harmful, but beta-2 blockade may be even worse. Beta-blockers were associated with an increased risk of MACE (6.5% vs 3.0%)³³ in patients with acute surgical anemia if the hemoglobin concentration decreased to less than 35% of baseline, and increased risks of hospital death (OR 6.65) and multiorgan dysfunction syndrome (OR 4.18) with severe bleeding during aortic surgery.³⁴

In addition, the pathway by which the beta-blocker is metabolized may also affect outcome, with less benefit from beta-blockers metabolized by the CYP2D6 isoenzyme of the cytochrome P450 system. Individual variations in CYP2D6 activity related to genetics or drug interactions may result in insufficient or excessive beta-blockade. Because metoprolol is the most dependent on this system, patients using it may be more susceptible to bradycardia.³⁵

Studies comparing atenolol and metoprolol found that the atenolol groups had fewer myocardial infarctions and deaths³⁶ and lower 30-day and 1-year mortality rates³⁷ than the groups on metoprolol. Studies comparing the three beta-blockers found better outcomes with atenolol and bisoprolol than with metoprolol—fewer strokes,^38,39 a lower mortality rate,³¹ and a better composite outcome³⁹ (Table 3 and Table 4).

START THE BETA-BLOCKER EARLY, TITRATE TO CONTROL THE HEART RATE

A number of studies suggest that how long the beta-blocker is given before surgery may influence the outcome (Table 5). The best results were achieved when beta-blockers were started approximately 1 month before surgery and titrated to control the heart rate.

Because this long lead-in time is not always practical, it is important to determine the shortest time before surgery in which starting beta-blockers may be beneficial and yet safe. Some evidence suggests that results are better when the beta-blocker is started more than 1 week preoperatively compared with less than 1 week, but it is unknown what the minimum or optimal time period should be.

If a beta-blocker is started well in advance of the scheduled surgery, there is adequate time for dose titration and tighter heart rate control. Most of the studies demonstrating beneficial effects of perioperative beta-blockers used dose titration and achieved lower heart rates in the treatment group than in the control group. A criticism of the MaVs,¹⁹ POBBLE,²⁰ and DIPOM²¹ trials was that the patients did not receive adequate beta-blockade. The POISE trial¹ used a much higher dose of metoprolol in an attempt to assure beta-blockade without dose titration, and although the regimen decreased nonfatal myocardial infarctions, it increased strokes and the overall mortality rate, probably related to excess bradycardia and hypotension. The target heart rate should probably be between 55 and 70 beats per minute.

RISK OF STROKE

POISE¹ was the first trial to note a clinically and statistically significant increase in strokes with perioperative beta-blocker use. Although no other study has shown a similar increased risk, almost all reported a higher number of strokes in the beta-blocker groups, although the absolute numbers and differences were small and not statistically significant. This risk may also vary from one beta-blocker to another (Table 4).

The usual incidence rate of postoperative stroke after noncardiac, noncarotid surgery is well under 1% in patients with no prior history of stroke but increases to approximately 3% in patients with a previous stroke.⁴⁰ An observational study from the Dutch group reported a very low incidence of stroke overall (0.02%) in 186,779 patients undergoing noncardiac surgery with no significant difference in those on chronic beta-blocker therapy.⁴¹ The DECREASE trials, with a total of 3,884 patients, also found no statistically significant increase in stroke with beta-blocker use (0.46% overall vs 0.5% with a beta-blocker),⁴² which in this case was bisoprolol started well in advance of surgery and titrated to control the heart rate. Although the DECREASE data are under suspicion, they seem reasonable and consistent with those of observational studies.

Proposed mechanisms by which beta-blockers may increase stroke risk include the side effects of hypotension and bradycardia, particularly in the setting of anemia. They may also cause cerebral ischemia by blocking cerebral vasodilation. This effect on cerebral blood flow may be more pronounced with the less cardioselective beta-blockers, which may explain the apparent increased stroke risk associated with metoprolol.

WHAT SHOULD WE DO NOW?

The evidence for the safety and efficacy of beta-blockers in the perioperative setting continues to evolve, and new clinical trials are needed to clarify the ongoing controversy, particularly regarding the risk of stroke.

If patients have other indications for beta-blocker therapy, such as history of heart failure, myocardial infarction in the past 3 years, or atrial fibrillation for rate control, they should be receiving them if time permits.

If prophylactic beta-blockers are to be effective in minimizing perioperative complications, it appears that they may need to be more cardioselective, started at least 1 week before surgery, titrated to control heart rate, and used in high-risk patients (Revised Cardiac Risk Index score > 2 or 3) undergoing high-risk surgery.

Ideally, a large randomized controlled trial using a cardioselective beta-blocker started in advance of surgery in patients with a Revised Cardiac Risk Index score greater than 2, undergoing intermediate or high-risk procedures, is needed to fully answer the questions raised by the current data.