Journal of Vascular Surgery
Volume 51, Issue 2 , Pages 515-519, February 2010

Perioperative β-blockers for vascular surgery patients

  • Benjamin S. Brooke, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Benjamin S. Brooke, MD, Johns Hopkins Hospital, Tower 110, 600 N Wolfe St, Baltimore, MD 21287

Department of Surgery, Johns Hopkins Hospital, Baltimore, Md

Received 27 September 2009; accepted 30 September 2009. published online 18 December 2009.

Jan D. Blankensteijn, MD, PhD, Section Editor

Article Outline

Perioperative β-blocker therapy has been a heavily investigated and controversial topic during the past decade. Prior national consensus statements that recommended the routine use of these medications in patients undergoing high-risk surgical procedures have been called into question because of the results of recent clinical trials that involved heterogeneous groups of surgical patients. This article reviews the evidence for perioperative β-blocker usage as it pertains to patients undergoing vascular surgery procedures. The weight of evidence suggests that β-blockers lower the perioperative risk of myocardial ischemia or infarction and cardiovascular death among patients with clinical risk factors undergoing major vascular surgery. However, there appears to be a concurrent risk of adverse events associated with these medications if patients are not monitored properly during the perioperative period. Perioperative β-blockers should continue to occupy a prominent role in the therapeutic armamentarium for improving outcomes among high-risk patients undergoing major vascular surgery.

 

The use of β-blocker medications during the perioperative period has been a topic of intense research during the past decade. After the publication of several high-profile clinical trials in the 1990s that showed significant improvements in perioperative outcomes associated with these agents, consensus statements released from national organizations recommended routine β-blocker usage in patients undergoing vascular surgery and other major operations. Specifically, the American Heart Association (AHA) and the American College of Cardiology (ACC) recommended the use of β-blockers in patients undergoing vascular surgery at high cardiac risk due to preoperative testing (level I evidence) and patients undergoing major operations with known risk factors for cardiovascular disease (level IIa evidence).1 Routine perioperative β-blocker usage during vascular surgery was also endorsed by nationwide hospital quality improvement initiatives, including the Leapfrog Group, the American Medical Association (AMA) Physician Consortium for Performance Improvement, and the Joint Commission's Surgical Care Improvement Project (SCIP).2, 3

The emergence of new evidence in the past several years has raised questions about the routine use of perioperative β-blockers. The results from at least one recent large clinical trial evaluating β-blockers among a heterogeneous group of surgical patients suggest that these medications might actually be harmful during the perioperative period.4 This has led to the revision of some national consensus recommendations and caused many clinicians to change their clinical practice. It is important to evaluate the evidence surrounding perioperative β-blocker usage as it pertains specifically to patients undergoing vascular surgery.

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Methods 

A systematic literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases was performed to identify all studies that evaluated the perioperative use of β-blocker medications between January 1980 and September 2009. The studies considered for review were randomized controlled trials (RCTs), observational studies, and meta-analyses. Studies were excluded that did not evaluate the effect of β-blocker therapy on defined clinical outcomes, that did not include a non-β-blocker control group, or that did not include patients undergoing defined noncardiac vascular surgery procedures.

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Results 

A total of 13 RCTs, six meta-analyses, and four observational studies were identified that met inclusion criteria for review. Ten studies focused exclusively on patients undergoing vascular surgery procedures, including seven RCTs and three observational studies (Table I).5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Two of the earliest randomized trials evaluated patients undergoing carotid endarterectomy, both demonstrating significant reductions among hemodynamic variables in response to β-blocker therapy.5, 6 Raby et al7 showed that decreases in hemodynamic stress from using β-blockers led to a significant reduction in myocardial ischemia among high-risk vascular surgery patients. This was supported by data from Suttner et al,14 who found significant reductions in serum levels of troponin-T and B-type natriuretic peptide among high-risk vascular surgery patients randomized to esmolol. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) trial was the first RCT to find a significant reduction in both nonfatal myocardial infarction (MI) and cardiac mortality associated with perioperative β-blockade among high-risk patients undergoing major vascular surgery procedures.8 These results, however, were not replicated among lower-risk patients undergoing major vascular surgery who were randomized to receive metoprolol or placebo in both the Perioperative β-Blockade (POBBLE) and Metoprolol after Vascular Surgery (MaVS) trials.11, 12

Table I. Clinical studies evaluating β-blocker therapy vs control among patients undergoing vascular surgery procedures
Author (year)Study designProcedure types(s)Surgical risk class# Pts (β-block/control)β-Blocker titratedResults, main conclusions
Cucchiara5 (1986)RCTCEAIntermed74(37/37)NoSignificantly reduction in HR and BP (P < .01) during intubation/induction.
Davies6 (1992)RCTCEAIntermed40(20/20)NoSignificant reduction in peri-op tachycardia (10% vs 65%; P < .01).
Raby7 (1999)RCTCEA, AAA, infrainguinalIntermed-high26(15/11)YesSignificant reduction in post-op ischemia (33% vs 73%; P < .05).
Poldermans8 (1999), DECREASERCTAAA, infrainguinalHigh112(59/53)YesSignificant reduction in 30-day CV death or MI (3.4% vs 34%; P < .001).
Boersma9 (2001)Prospect cohortAAA, infrainguinalHigh1292(360/932)NoSignificant reduction in 30-day risk of CV death or MI (adjusted OR, 0.3; P < .05).
Kertai10 (2004)Retrosp cohortAAAHigh570(256/314)NoSignificant reduction in 30-day risk of death or MI (adjusted OR, 0.24; P < .001).
Brady11 (2005), POBBLERCTAAA, EVAR, infrainguinalIntermed-high97(50/43)NoNo significant reduction in 30-day CV events or death (34% vs 34%).
Yang12 (2006), MaVSRCTAAA, EA, infrainguinalHigh496(246/250)NoNo significant reduction in 30-day CV events or death (10% vs 12%).
Brooke13 (2007)Retrosp cohortAAAHigh8570(2167/6403)NoSignificant reduction in risk of in-hospital all-cause mortality (adjusted OR, 0.49; P < .05).
Suttner14 (2009)RCTAAA, infrainguinalHigh50(25/25)YesSignificant reduction in myocardial ischemia markers, including ST-segment changes, cardiac troponin, & BNP levels (all P < .05) ≤48 hours post-op.

AAA, Abdominal aortic aneurysm; BNP, brain natriuretic peptide; BP, blood pressure; CEA, carotid endarterectomy; CV, cardiovascular DECREASE, Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography trial; EA, extra-anatomic; EVAR, endovascular aneurysm repair; HR, heart rate; MaVS, Metoprolol after Vascular Surgery; MI, myocardial infarction; OR, odds ratio; POBBLE, Perioperative β-Blockade; RCT, randomized controlled trial.

Several large observational studies have evaluated β-blocker therapy among patients undergoing high-risk vascular surgery (Table I). Similar results were obtained from a large prospective cohort as well as a retrospective cohort study that both demonstrated a >70% relative reduction (both P < .05) in the adjusted risk of cardiovascular events or death, or both, among patients undergoing open abdominal aortic aneurysm (AAA) repair and other major vascular procedures.9, 10 Furthermore, Brooke et al13 found an estimated 50% reduction (P < .05) in adjusted all-cause mortality among patients undergoing open AAA repair in hospitals compliant with routine β-blocker usage compared with patients undergoing this procedure in hospitals without this policy.

The benefit of perioperative β-blockade among heterogeneous groups of surgical patients, including those undergoing vascular procedures, has been evaluated by five RCTs and one large retrospective cohort study (Table II).4, 15, 16, 17, 18, 19 The proportion of vascular surgery patients represented by these studies has varied from 7% to 42% of surgical procedures. These studies consistently demonstrated a reduction in perioperative myocardial ischemia associated with β-blocker usage.4, 15, 17

Table II. Clinical trials evaluating perioperative β-blockers among heterogeneous surgical populations that included vascular surgery procedures
Author (year)Study designPopulation/procedure %# Pts (β-blocker/control)Results of primary outcome analysisAdverse events
Stone15 (1988)RCT
Vascular, 15%

Abdominal, 47%

Other, 38%

128(89/39)Reduced cardiac ischemia (2% vs 28%; P < .001) during day of surgery.No difference in risk of bradycardia or hypotensive episodes.
Mangano16 (1996)RCT
Vascular, 41%

Abdominal, 21%

Orthopedic, 14%

Neurosurgical, 9%

Other, 15%

200(99/101)Reduced all-cause mortality (9% vs 21%; P = .02) & CV death (4% vs 12%; P = .03) at 2-years follow-up.Increased risk of intra-op bradycardia (38% vs 15%; P < .001).
Wallace17 (1998)RCT
Vascular, 41%

Abdominal, 21%

Orthopedic, 14%

Neurosurgical, 9%

Other, 15%

200(99/101)Reduced cardiac ischemia (24% vs 39%; P < .05) in the first post-op week but no difference among in-hospital death rates.Increased risk of intra-op bradycardia (38% vs 15%; P < .001).
Lindenauer18 (2005)Retro cohort
Vascular, 8%

Abdominal, 33%

Orthopedic, 37%

Thoracic, 7%

Other, 15%

663,635(122,338/541,297)Reduced risk of in-hospital death for RCRI scores of 2(OR, 0.88 [0.80-0.98]; 3(OR, 0.71 [0.63-0.80]) & ≥4(OR, 0.58 [0.50-0.67]).Increased risk of death for RCRI scores of 0 (OR, 1.36 [1.27-1.45]) & 1 (OR, 1.09 [1.01-1.19]).
Juul19 (2006), DIPOMRCT
Vascular, 7%

Abdominal, 27%

Orthopedic, 32%

Neurosurgery, 8%

Gynecologic, 5%

Thoracic, 4%

921(462/459)No difference in all cause mortality or CV events (21% vs 20%) at 30 days.Increased risk of bradycardia/hypotension (32% vs 17%).
Devereaux4 (2008), POISERCT
Vascular, 42%

Abdominal, 23%

Orthopedic, 19%

8351(4174/4177)Reduced MI rate (4.2% vs 5.7% P < .01) & combined CV events (5.8% vs 6.9%; P < .05) at 30 days.Increased total mortality (3.1% vs 2.3%; P < .05) and stroke rate (1.0% vs 0.5%; P < .05).

CI, Confidence interval; CV, cardiovascular; DIPOM, Diabetic Postoperative Mortality and Morbidity; MI, myocardial infarction; OR, odds ratio; POISE, PeriOperative Ischemic Evaluation; RCRI, Revised Cardiac Risk Index; RCT, randomized controlled trial.

In one study with a high percentage of vascular surgery patients, Mangano et al16 found a significant reduction in both all-cause and cardiovascular mortality among patients randomized to atenolol vs placebo. The PeriOperative Ischemic Evaluation (POISE) trial has been the largest single RCT of perioperative blockade completed to date and contained the highest proportion of vascular surgery patients.4 POISE found a significant reduction in the primary composite end point of cardiovascular death, nonfatal MI, and nonfatal cardiac arrest associated with β-blocker use, although subgroup analysis indicated that this therapy was also associated with a higher overall risk of all-cause mortality and stroke.

Adverse events reported in other RCTs include a significantly increased risk of intraoperative bradycardia and hypotension associated with perioperative β-blocker usage.16, 17, 19 Data from a large prospective cohort containing >663,000 patients suggests that the risk vs benefit attributed to perioperative β-blocker therapy is directly correlated with each patient's level of cardiac risk, with an increased risk of death for low-risk patients but a reduced risk of in-hospital death for patients at moderate to high-risk.18

Six meta-analyses were identified that pooled data from randomized trials on perioperative β-blockers in noncardiac surgery (Table III).20, 21, 22, 23, 24, 25 None of these studies, however, focused exclusively on vascular surgery. Results obtained from these meta-analyses consistently show a significant reduction in myocardial ischemia and nonfatal MI during the perioperative period associated with β-blocker therapy.20, 21, 22, 23, 24, 25 In comparison, the results obtained for cardiovascular and all-cause mortality are heavily influenced by the large POISE trial. Four meta-analyses before POISE suggested that a mortality benefit was associated with perioperative β-blocker usage, whereas the two studies that included this trial found a higher risk of cardiovascular and all-cause death attributed to these agents.

Table III. Summary of outcomes derived from meta-analyses that evaluated perioperative β-blocker treatment among patients undergoing noncardiac surgery
Author (year)StudiesPatientsCardiac ischemiaNonfatal MICV deathAll-cause death
RR (95% CI)RR (95% CI)RR (95% CI)RR (95% CI)
McGory20 (2005)66320.47(0.34-0.65)0.14(0.04-0.47)0.25(0.07-0.87)0.52(0.20-1.35)
Devereaux21 (2005)222437N/A0.38(0.11-1.29)0.40(0.14-1.15)0.56(0.14-2.31)
Schouten,22 (2006)1510770.35(0.23-0.54)0.44(0.20-0.97)0.55(0.25-1.22)0.79(0.36-1.76)
Wiesbauer,23 (2007)2720570.38(0.21-0.69)0.59(0.25-1.39)N/A0.78(0.33-1.87)
Bangalore24 (2008)3312,3060.36(0.26-0.50)0.65(0.54-0.79)1.15(0.85-1.56)1.20(0.95-1.51)
Talati25 (2009)610,183N/A0.74(0.61-0.89)N/A1.21(0.98-1.49)

CI, Confidence interval; CV, cardiovascular; MI, myocardial infarction; N/A, not applicable; RR, relative risk.

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Discussion 

The theoretic advantage of using β-blocker medications during the perioperative period is aimed at decreasing stress-induced myocardial ischemia in patients undergoing major operations, such as vascular surgery, who are at increased risk for adverse cardiac events. This is achieved through the reduction of heart rate and myocardial contractility, with a resulting balance of myocardial supply and demand. β-Blockers are also thought to exert a cardioprotective effect by stabilizing coronary plaques, inhibiting renin release, and increasing the threshold for unstable ventricular tachyarrhythmias.26

These cardiac benefits of β-blocker therapy in patients undergoing vascular surgery and other major operations have been confirmed by numerous RCTs and meta-analyses. Use of perioperative β-blockers among these patients consistently leads to significant reductions in myocardial ischemia and nonfatal MI (Table I, Table III). The debate lies, however, in whether these agents affect the risk of death after surgery. Although early RCTs, meta-analyses, and observational cohort studies all suggested that cardiovascular and all-cause mortality was reduced by perioperative β-blockade, the results of more contemporary studies suggest that patients may actually have a higher risk of death while taking these agents.4, 24 This may result from the increased risk of adverse perioperative events such as hypotension, bradycardia, and stroke associated with β-blocker overtreatment.

One of the main difficulties with evaluating the evidence for perioperative β-blockade is the heterogeneity of clinical studies, with results often obtained from combining surgical patient populations with disparate levels of procedure risk. When procedure risks are stratified, however, the mortality benefit of perioperative β-blockade in vascular surgery becomes more apparent. For example, when primary outcomes from the POISE trial were stratified by procedure type, patients undergoing vascular surgery were found to receive a far greater benefit from perioperative β-blockers than patients undergoing orthopedic and intraperitoneal procedures.4 Moreover, a recent meta-analysis that incorporated the results from the POISE trial as well as 32 other RCTs of perioperative β-blockade found that all-cause mortality was not significantly decreased in patients at low or intermediate surgical risk, but a 63% reduction was noted in all-cause mortality among high-risk cases such as major vascular surgery.24 Finally, another study showed that although perioperative β-blockade was associated with a significant reduction in death for patients undergoing open AAA repair, no mortality benefit was found for patients undergoing lower-risk endovascular AAA repair.13

The benefit of perioperative β-blockers in vascular surgery is also heavily dependent on each patient's individual cardiac risk profile. Evidence from multiple RCTs suggests that β-blockers effectively decrease perioperative death only in patients at high cardiac risk.8, 16 This is supported by data from a large cohort study in which patients undergoing major surgical procedures received a significant mortality benefit from perioperative β-blockers only if they had a Revised Cardiac Risk Index (RCRI) score ≥2.18 These findings may help explain why there was no treatment benefit associated with perioperative β-blockade in the MaVS and POBBLE trials, where most of the patients undergoing vascular surgery had RCRI scores <2 and were deemed to be at low-cardiac risk.11, 12

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Conclusions 

The weight of evidence suggests that perioperative β-blocker therapy effectively reduces cardiovascular morbidity and mortality among patients with clinical risk factors undergoing major vascular surgery. However, current data do not support the perioperative use of these agents among patients at low cardiac risk and those undergoing minor surgical procedures. Vascular surgery patients treated with β-blockers should be monitored carefully during the perioperative period to avoid adverse consequences of overtreatment.

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References 

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 Competition of interest: none.

 The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest.

PII: S0741-5214(09)02060-6

doi:10.1016/j.jvs.2009.09.057

Journal of Vascular Surgery
Volume 51, Issue 2 , Pages 515-519, February 2010

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