Update on the Perioperative Cardiovascular Evaluation and Care Guidelines: Perioperative Beta Blockade Todd W. Gress, MD, MPH Associate Professor Marshall University Joan C. Edwards School of Medicine Department of Internal Medicine
ACCF/AHA Perioperative Guideline • Published in 2002 • Update published in 2007 • New focused update added in 2009 regarding perioperative beta antagonist therapy
Perioperative Beta Blockade 2007 • Addressed in the 2007 guideline • Indicated in active cardiac conditions and with clinical risk factors • Limited evidence on perioperative beta blocker use
Perioperative Beta Blockade: Specific Clinical Trial Limitations • • • • • •
Power Few examined MACE Limited high risk patients Intermediate and low risk populations lacking How to prescribe? Which beta blocker?
Objectives • Review the evidence behind the guideline recommendations for beta blockade • Explain the rationale for the current recommendations regarding perioperative use of beta blockers
Perioperative Beta Blocker: Abdominal Aortic Aneurysm Repair (1987)
Pasternack PF, Imparato AM, Baumann FG et al. Circulation 1987; 76(3 Pt 2):IIII-III7.
Perioperative Beta Blocker: Vascular Surgery (1989) • Pasternack, et. al. • 48 vascular surgery patients treated with oral metoprolol preoperatively • 152 ‘similar’ patients not treated • Silent intraoperative ischemic episdes: – 0.8 (sd 1.6) metoprolol vs 1.8 (sd 3.2) control
Pasternack PF, Grossi EA, Baumann FG et al. Am J Surg 1989; 158(2):113-116.
Perioperative Beta Blocker: Noncardiac Surgery (1988) • Stone et al. • 128 ‘mildly’ hypertensive surgical patients • Nonblinded but randomized to atenolol, labetalol, or oxprenolol • Groups ‘similar’ but not compared statistically • Surgical type not reported • Myocardial ischemia 2/89 (2%) treated and 11/39 (28%) controls (p<0.001) Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Anesthesiology 1988; 68(4):495-500.
Perioperative Beta Blocker: Vascular Surgery (1999) • Raby et al. • 26 patients with preoperative ischemia by holter monitor • Randomized to preoperative IV esmolol • 5/15 (33%) treated vs. 8/11 (72.7%) control had postoperative ischemia by 48 hour holter • 1 myocardial infarction in each group
Perioperative Beta Blocker: Bisoprolol and Vascular Surgery (1999) • 112 high risk patient undergoing vascular surgery identified by dobutamine echo • Randomized (nonblinded) to bisoprolol or placebo an average of 37 days prior to surgery • Prior use of beta blockers not excluded • Dose titration performed based on heart rate and blood pressure • 30 day cardiac death and nonfatal MI
Base-Line Characteristics of the Patients
Poldermans D et al. N Engl J Med 1999;341:1789-1794
Results of Dobutamine Echocardiography
Poldermans D et al. N Engl J Med 1999;341:1789-1794
Characteristics of Surgical Procedures
Poldermans D et al. N Engl J Med 1999;341:1789-1794
Mean Heart Rates of Randomized Patients at Base Line and One, Three, and Seven Days Postoperatively
Poldermans D et al. N Engl J Med 1999;341:1789-1794
Kaplan-Meier Estimates of the Cumulative Percentages of Patients Who Died of Cardiac Causes or Had a Nonfatal Myocardial Infarction during the Perioperative Period
Poldermans D et al. N Engl J Med 1999;341:1789-1794
Perioperative Beta Blocker: Atenolol and Noncardiac Surgery (1996) • 200 patients with CAD or 2 risk factors for CAD • Randomized the day of surgery to atenolol or placebo (intravenous followed by oral) • Prior beta blocker use not excluded • Double blind design
Characteristics of the Patients, According to Study Group
Mangano D et al. N Engl J Med 1996;335:1713-1721
Overall Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol and Placebo Groups Who Survived to Hospital Discharge
Mangano D et al. N Engl J Med 1996;335:1713-1721
Use of Cardiovascular Medications before and after Surgery, According to Study Group
Mangano D et al. N Engl J Med 1996;335:1713-1721
Daily Dose and Side Effects of Atenolol
Mangano D et al. N Engl J Med 1996;335:1713-1721
Perioperative Beta Blocker: Noncardiac Surgery (2000) • Urban et al. • 107 patients randomized preoperatively to iv esmolol then metoprolol orally for 48 hours vs. placebo • Postoperative ECG ischemia 0/52 treated vs. 4/55 control, p=0.04 • Significantly more ischemic time and ischemic events, but overall cardiac events did not differ between the two groups
Perioperative Beta Blocker: POBBLE (2005) • 103 patients without prior MI undergoing infrarenal vascular surgery • Double blind, randomized, placebo controlled • Oral metoprolol (and iv if necessary) from admit to 7 days after surgery • Excluded patients on beta blocker • Beta blocker not titrated to heart rate • MI, unstable angina, ventricular tachycardia, stroke, and death at 30 days
POBBLE: Baseline Characteristics
Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. J Vasc Surg 2005; 41(4):602-609.
30 Day Primary Outcome Events
Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. J Vasc Surg 2005; 41(4):602-609.
Perioperative Beta Blockers: DIPOM (2006) • 921 patients with diabetes for major noncardiac surgery • Randomized, blinded, and placebo controlled • Metoprolol immediately before surgery and for 8 days postoperative • Prior beta blocker use exluded • Composite all cause mortality, acute MI, unstable angina, or CHF
Fig 1 Flow of patients through study (*includes five patients who refused to take part after randomisation but before any medication and surgery; includes two patients who had previously been randomised in the DIPOM trial)
Juul, A. B. et al. BMJ 2006;332:1482
Copyright Š2006 BMJ Publishing Group Ltd.
Entry Characteristics of Study Participants
Juul AB, Wetterslev J, Gluud C et al. BMJ 2006; 332(7556):1482.
Fig 2 Kaplan-Meier plot of time to primary outcome measure during maximum follow-up and during first 30 days (with 95% confidence intervals)
Juul, A. B. et al. BMJ 2006;332:1482
Copyright Š2006 BMJ Publishing Group Ltd.
Outcomes from DIPOM Hazard ratio (95% CI)
P value
All cause mortality
1.03 (0.74 to 1.42)
0.88
Cardiac events
1.02 (0.67 to 1.57)
0.91
Cardiac death
0.85 (0.45 to 1.60)
0.61
1.24 (0.70 to 2.17)
0.46
1.10 (0.75 to 1.61)
0.63
All cause mortality
1.01 (0.72 to 1.41)
0.79
Cardiac events
1.03 (0.69 to 1.54)
0.87
Cardiac death
0.84 (0.46 to 1.52)
0.56
1.23 (0.68 to 2.23)
0.44
Univariate analyses
Non-fatal cardiac events Non-cardiac death Multivariate analyses
Non-fatal cardiac events
Perioperative Beta Blockers: MaVS (2006) • 496 patients for vascular surgery • Randomized to metoprolol immediately before surgery and until discharge but no longer than 5 postoperative days • Excluded prior beta blocker use • 30 day composite outcome
Revised Cardiac Risk Index by Treatment Group Risk score
Placebo (n = 250)
Metoprolol (n = 246)
1
159 (63.6%)
138 (56.1%)
2
63 (25.2%)
89 (36.2%)
3
25 (10.0%)
15 (6.1%)
â&#x2030;Ľ4
3 (1.2%)
4 (1.6%)
Yang H, Raymer K, Butler R, Parlow J, Roberts R. Am Heart J 2006; 152(5):983-990.
MaVS Intraoperative Data Placebo (n = 250)
Metoprolol (n = 246)
General
103 (41.2%)
113 (46.3%)
Regional
37 (14.8%)
31 (12.7%)
Combined
110 (44.0%)
100 (41.0%)
Sedation
0 (0%)
0 (0%)
55.0 ± 19.1 (n = 135)
54.6 ± 20.6 (n = 135)
2.7 ± 0.9
2.7 ± 0.9
350 (100-700)
400 (200-800)
Systolic
138.8 ± 25.2
131.7 ± 24.8
Diastolic
71.2 ± 15.1
69.5 ± 13.1
Postoperative heart rate (beat/min)
79.1 ± 15.7
69.4 ± 12.9†
Types of anesthesia
X-clamp duration (min) Surgery Time (h) Estimated blood loss (mL) (median IQR) Postoperative BP (mm Hg)
Yang H, Raymer K, Butler R, Parlow J, Roberts R. Am Heart J 2006; 152(5):983-990.
MaVS Composite Event Rate
Yang H, Raymer K, Butler R, Parlow J, Roberts R. Am Heart J 2006; 152(5):983-990.
MaVS Outcomes Placebo (n = 250) 30 (12.0%)
Metoprolol (n = 246) 25 (10.2%)
P .57
Cardiac death
1 (0.4%)
0 (0.0%)
1.00
MI CHF Unstable angina
21 (8.4%) 3 (1.2%) 0 (0.0%)
19 (7.7%) 5 (2.0%) 1 (0.4%)
.87 .50 1.00
Dysrhythmia Noncardiac death
10 (4.1%) 3 (1.2%)
7 (2.9%) 0 (0.0%)
.62
7 4
8 5
5
7
28
24
Primary outcome
Secondary outcomes Reoperation Postoperative CVA New or worsened renal insufficiency Any rehospitalization
MaVS Complications Placebo (n = 250)
Metoprolol (n = 246)
P
Intraoperative hypotension
102 (40.8%)
131 (53.7%)
.0069
Treatment required
84 (33.6%)
114 (46.3%)
.0045
Intraoperative bradycardia
26 (10.4%)
84 (34.6%)
<.000005
Treatment required
19 (7.6%)
53 (21.5%)
.00001
Perioperative Beta Blockers: POISE (2008)
Devereaux PJ, Yang H, Yusuf S et al. Lancet 2008; 371(9627):1839-1847.
POISE Outcomes Metoprolol group (n=4174)
Placebo group (n=4177)
Hazard ratio
p value
244 (5·8%)
290 (6·9%)
0·84 (0·70–0·99)
0·0399
75 (1·8%)
58 (1·4%)
1·30 (0·92–1·83)
0·1368
152 (3·6%)
215 (5·1%)
0·70 (0·57–0·86)
0·0008
21 (0·5%)
19 (0·5%)
1·11 (0·60–2·06)
0·7436
Total mortality Myocardial infarction
129 (3·1%) 176 (4·2%)
97 (2·3%) 239 (5·7%)
1·33 (1·03–1·74) 0·73 (0·60–0·89)
0·0317 0·0017
Cardiac revascularisation†
11 (0·3%)
27 (0·6%)
0·41 (0·20–0·82)
0·0123
Stroke Non-fatal stroke
41 (1·0%) 27 (0·6%)
19 (0·5%) 14 (0·3%)
2·17 (1·26–3·74) 1·94 (1·01–3·69)
0·0053 0·0450
Congestive heart failure†
132 (3·2%)
116 (2·8%)
1·14 (0·89–1·46)
0·3005
91 (2·2%)
120 (2·9%)
0·76 (0·58–0·99)
0·0435
625 (15·0%)
404 (9·7%)
1·55 (1·38–1·74)
<0·0001
277 (6·6%)
101 (2·4%)
2·74 (2·19–3·43)
<0·0001
54 (1·3%)
39 (0·9%)
1·39 (0·92–2·10)
0·1169
Cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest* Cardiovascular death Non-fatal myocardial infarction Non-fatal cardiac arrest
New clinically significant atrial fibrillation† Clinically significant hypotension† Clinically significant bradycardia† Non-cardiovascular death
Devereaux PJ, Yang H, Yusuf S et al. Lancet 2008; 371(9627):1839-1847.
Perioperative Beta Blockers: DECREASE IV (2009) • 1066 intermediate risk patients undergoing noncardiovascular surgery • Randomized to bisoprolol with a dose titration an average of 30 days before surgery • Prior beta blocker use excluded • Also looked at statin (fluvastatin) • Open design, 2 X 2 factorial design • 30 day cardiac death and nonfatal MI
DECREASE IV Primary Outcome by Treatment Group
Dunkelgrun M, Boersma E, Schouten O et al. Ann Surg 2009; 249(6):921-926.
DECREASE IV Primary Outcome by Individual Treatment
Dunkelgrun M, Boersma E, Schouten O et al. Ann Surg 2009; 249(6):921-926.
Class I Recommendation for Perioperative Beta Blockers â&#x20AC;˘ Beta blockers should be continued in patients undergoing surgery who are receiving beta blockers for treatment of conditions with ACCF/AHA Class I guideline indications for the drugs. (Level of Evidence: C)
Class IIa Recommendation for Perioperative Beta Blockers 1. Beta blockers titrated to heart rate and blood pressure are probably recommended for patients undergoing vascular surgery who are at high cardiac risk owing to coronary artery disease or the finding of cardiac ischemia on preoperative testing . (Level of Evidence: B) 2. Beta blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment for vascular surgery identifies high cardiac risk, as defined by the presence of more than 1 clinical risk factor.(Level of Evidence: C) 3. Beta blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment identifies coronary artery disease or high cardiac risk, as defined by the presence of more than 1 clinical risk factor, who are undergoing intermediate-risk surgery. (Level of Evidence: B)
CLASS III Recommendation for Perioperative Beta Blocker 1. Beta blockers should not be given to patients undergoing surgery who have absolute contraindications to beta blockade. (Level of Evidence: C) 2. Routine administration of high-dose beta blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery. (Level of Evidence: B)
Conclusion • Perioperative Beta Blockers should be initiated well before the planned procedure if possible • Titration of dose to heart rate/blood pressure goals appears more effective with less adverse effects • With the exception of POISE and a few other less rigorous studies, most intermediate to high risk patients either derive some benefit or at least no effect on mortality from perioperative beta blocker use • Unknown, but risk may outweigh benefit in low risk patients