Pre-op and Post-op Beta Blockers
Alla Kotlyanskaya, Pharm.D.
Clinical Pharmacist – Critical Care
Woodhull Medical Center, Brooklyn, New York
Adjunct Professor of Pharmacology
College of Nursing Graduate Programs
SUNY Downstate College of Nursing
And
Adjunct Professor of Pharmacotherapy
Physician Assistant Program
Objectives
 Discuss the protective effects of β-blockers in
setting of perioperative beta blockade
 Present standards of care for use of perioperative β-blocker therapy
 Describe the benefits & limitations of β-blockers
in surgical population
 Deliver final recommendations on when to use
and why to avoid β-blockers in select patients
Magnitude of Risks of Non-Cardiac Surgery
 NON-cardiac surgery  risk of CARDIAC
mortality
 Adverse outcomes of post-op myocardial infarction
(MI)
  LOS & healthcare costs
 Results in 15 - 25% of all in-hospital mortality
  Cardiac death or non-fatal MI in next 6 months
Why is Non-Cardiac Surgery Associated
with Cardiac Complications
 100 million have non-cardiac surgery each year
 Huge at-risk population
 1 million suffer perioperative cardiac event
 huge burden of disease
 Frequently silent
 Few interventions proven to lower risk
Barriers Surrounding a Silent Myocardial
Infarction
 Frequency of silent MI
 Chest pain (14%)
 Single symptom or sign (50%)
 Numerous explanations for under-diagnosis
 Opioids administration for surgical pain
 Residual effect of anesthesia
 Other reasons for BP, HR, SOB, N&V
 Different pathophysiology of perioperative MI?
Pathophysiology
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
Rupture
Stress state
Plaque
Rupture
Coronary
thrombosis
Hypoxic state
O2
demand
O2
delivery
Myocardial
ischemia
PMI
Initial Risk Assessment
 In 1977 Goldman et al
developed a preoperative
cardiac risk index
 9 Individual risk factors and their
scores
 Risk Index:
 Class I = 0-5 points (low)
 Class II = 6-12 points
(intermediate)
 Class III = 13-25 pts (high)
 Class IV  25 pts (very high)
N Engl J Med 1977;297:845-850
Risk Factor
Score
3rd Heart sound (S3)
11
Elevated JV pressure
11
MI in past 6 months
10
ECG: premature atrial
contractions or any rhythm
other than sinus
7
ECG shows >5 premature
ventricular contractions per
minute
7
Age >70 years
5
Emergency Procedure
4
Intra-thoracic, intraabdominal or aortic surgery
3
Poor general status,
metabolic or bedridden
3
Goldman Cardiac Risk Index
Risk of Death and Major
Cardiac Complications
Based on the Goldman Index Class
CLASS I
1.3%
CLASS II
4.7%
CLASS III
15.3%
CLASS IV
56%
N Engl J Med 1977;297:845-850
Cardiac Risk Stratification Proposals
 Goldman: 1977
 Detsky: 1986
 Eagle: 1989
 Lee:1999
ACC/AHA Guidelines
Risk stratification according to major, intermediate or minor
clinical predictors
Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.
ACC/AHA Guideline Summary:
Major Clinical Predictors
High Risk:
•Acute or recent MI (7-30 d)
•Unstable coronary syndrome
•Decompensated CHF
•Significant Arrhythmias
•Severe Valvular Disease
Surgery
Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.
ACC/AHA Guideline Summary:
Clinical Risk Factors
Proceed Cautiously With:
•History of heart disease
•Compensated or prior CHF
•Cerebrovascular disease
•Diabetes Mellitus
•Renal Insufficiency
3 or more risk factors
& Vascular surgery
1 – 2 risk factors
Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.
Consider testing
Proceed with surgery
or consider testing
ACC/AHA Guideline Summary:
Minor Clinical Predictors
Low Risk:
•Low risk surgery
•Good functional capacity
•No cardiac symptoms
•No “active cardiac conditions”
•No clinical risk factors
Reasonable to proceed with surgery
Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.
Functional Capacity



Determined by how much physical
activity a patient can tolerate without
severe exertion
Provides valuable prognostic
information
Patients with good functional status
have a lower risk of complications
Perioperative MI
How to stratify it
How to modify it
ß Blocker
Other New Agents
The Evolution of ß-Blockers
1960s
NonNonSelective
Selective
Propranolol
1970s
Selective
1980s-1990s
2007
NonNonSelective
Selective
Selective
Vasodilating
Vasodilating
Vasodilating
Atenolol
Carvedilol
Metroprolol
Labetalol
Nebivolol
Protective Effect of β-Blockers
 Decrease sympathetic CNS outflow
 ↓ Heart rate and ↓ contractility
 ↓ Myocardial oxygen demand
 Membrane stabilizing effect
 Antiarrhythmic property
 Anti-renin/antgiotensin properties
 Inhibit renin release
 Anti-inflammatory effect
 Possible ↑ plaque stability*
*With long-term use
Schouten O et al. Cardiovascular Anesthesia 2007; 104(1):8-10.
Cruickshank JM. European Heart Journal 2000; 21:354-364.
Ohtsuka T et al. J Am Coll Cardiol 2001; 37(2):412-417.
Protective Effect of b-blockers
Against Cardiac Events During and After Surgery
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
Rupture
Stress state
Plaque
Rupture
Coronary
thrombosis
Hypoxic state
O2
demand
O2
delivery
Myocardial
ischemia
PMI
Protective Effect of b-blockers
Against Cardiac Events During and After Surgery
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
 Catechols/cortisol
Coronary artery
shear stress
Plaque
Rupture
Stress state
HR, BP, FFAs
Coronary
thrombosis
O2
demand
Myocardial
ischemia
PMI
Reducing Myocardial Ischemia






Avoid tachycardia & hypertension
Avoid hypotension
Avoid pain
Avoid hypercoagulation
Avoid vasospasm
Avoid tissue injury
Does Perioperative Beta Blockade Work?
Perioperative β-Blockers 1995 to 2005
 Mangano et al. at 19961
 Atenolol study
 Poldermans et al. at 19992
 DECREASE trial
Perioperative β -blockers 2005–2008
 Yang et al. at 20064
 MaVS study
 Juul et al. at 20065
 DiPoM trial
Effect of Atenolol on Mortality and
Cardiovascular Morbidity After
Noncardiac Surgery
Mangano DT, Layug EL, Wallace A, et al.
N Engl J Med. 1996; 335: 1713-1720
Mangano Trial: Overview
 Randomized, double-blind, placebo-controlled trial
 200 patients included VA (Veterans’ Admin) patients with >= 2
risk factors for CAD





Age >65 y/o
Total cholesterol >240 mg/dL
Hypertension
Diabetes mellitus
Current smoking
 Surgeries were:
 Major vascular (~40%)
 “Intraabdominal” (~20%)
 Neurosurgery, general, plastic surgery and head and neck surgery
Mangano Trial: Study Design
PO Atenolol 50 mg
IV Atenolol 5 mg
Before
Surgery
Placebo
After
For the Duration of
Hospitalization
Placebo
Patients were
followed over the subsequent two years
N Engl J Med. 1996; 335: 1713-1720
Number of death during Follow up
Mangano Trial:
Postoperative Mortality Reduction
25
21
20
14
15
10
10
8
3
5
0
0
Placebo
6 Months
Atenolol
1 Year
2 Years
N Engl J Med. 1996; 335: 1713-1720
The Effect of Bisoprolol on Perioperative
Mortality and Myocardial Infarction in High-risk
Patients Undergoing Vascular Surgery
Dutch Echocardiographic Cardiac Risk Evaluation
Applying Stress Echocardiography Study Group
Poldermans D, Boersma E, Bax JJ, et al.
N Engl J Med 1999; 341:1789–1794
The DECREASE Trial : Overview
 European, multicentered, unblinded RCT
 112 high risk patients undergoing major vascular
surgery were randomized to
 Bisoprolol 5mg orally (min. of 7 days before surgery)
(n = 59)
 Standard care (n = 53)
 The study was stopped early
The DECREASE Trial:
Postoperative Cardiac Events
Beta-Blockade
25
20
%
17
17
15
10
3.4
5
0
0
Placebo
Cardiac Death
Bisoprolol
Non-fatal MI
Poldermans et al. NEJM 1999;341:1789.
“There are still very few RCTs … and they do not provide enough data
from which to draw firm conclusions. Current studies, however, suggest
that … b-blockers reduce perioperative ischaemia, and may reduce the
risk of MI and death in high-risk patients”
RECOMMENDATIONS
Class I
1. Beta-blockers required in the recent past to control symptoms of angina or patients
with symptomatic arrhythmias or hypertension
2. Beta-blockers: patients at high cardiac risk owing to the finding of ischemia on
preoperative testing who are undergoing vascular surgery
Eagle KA, et.al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery:
executive summary. J Am Coll Cardiol. 2002;39:542–553
 22 RCTs published between 1980 and 2004




Median sample size: 61patients (total = 2437)
Variety of patients and surgeries
Treatment duration: 1 dose  30 days
Length of follow-up: PACU discharge  30 days
 Overall quality of trials was acceptable
 4 trials inadequate blinding
 2 trials stopped early
 1 trial inadequate randomization concealment
Devereaux et al.: Metaanalysis Results
Relative risks for major perioperative cardiovascular events (cardiovascular
death, non-fatal myocardial infarction, or non-fatal cardiac arrest)
Devereaux et al.: Metaanalysis Results
Relative risks for bradycardia needing treatment
Devereaux et al.:
Metaanalysis Conclusion
 Growing evidence suggests BB may reduce the
risk of major perioperative cardiovascular events
 However, increases the risk of bradycardia and
hypotension requiring treatment
 Evidence indicates that more further studies are
needed
Perioperative β -blockers 2005 – 2007
Study
Patients and Protocol
Findings
Yang et al
2006
(MaVS
study)
496 vascular surgery patients
Metoprolol begun immediately
before surgery, continued through to
discharge
No impact on in-hospital cardiac
events or deaths
Cardiac events in patients given
β-blockers vs patients given
placebo: at 6 months, 0% vs 8%,
P< 0.001; at 2 years, 10% vs
21%, P< 0.019
Juul et al
2006
(DiPoM
trial)
921 patients with diabetes who
were undergoing major noncardiac
surgery
100 mg metoprolol controlled and
ER or placebo administered from the
day before surgery to a maximum of 8
perioperative days
All-cause deaths, cardiac deaths,
and major cardiac events at 30
days in patients given –blockers
vs patients given placebo:
21% vs 20%, P = NS
Does Perioperative Beta Blockade
Increase Risk ?
Perioperative -blockade (POBBLE) for patients
undergoing infrarenal vascular surgery: Results of
a randomized double-blind controlled trial.
POBBLE Trial Investigators, London, United Kingdom
Brady AR, et.al. J Vasc Surg 2005; 41:602–609
POBBLE Trial Overview
 Double-blind randomized placebo-controlled trial
 Included low risk patients
 Treatment
 Metoprolol 50 mg PO BID or placebo ( from
admission until 7 days after surgery)
 Primary endpoint
 30 day cumulative risk of cardiac death, non-fatal MI,
unstable angina, VT or stroke
 Patient group (n = 103 [stopped early])
Brady AR, et.al. J Vasc Surg 2005; 41:602–609
POBBLE Trial Results and Conclusion
OR (CV event or death) = 0.93 (95% CI: 0.53-1.64)
Control
(n = 48)
Treatment
(n = 55)
P value
Cardiac Events
15 (34%)
17 (32%)
0.57
Heart rate (4 hr after)
77 ± 15
65 ± 10
0.0001
Bradycardia
7 (14%)
31 (57%)
0.0001
Hypotension
34 (77%)
49 (92%)
0.0001
This trial indicates that in lower-risk patients, perioperative β-blockade does not
reduce cardiovascular mortality BUT may have adverse intraoperative effects
Brady AR, et.al. J Vasc Surg 2005; 41:602–609
RECOMMENDATIONS
Class I
1. Beta blockers should be continued in patients undergoing surgery who are previously
receiving beta blockers to treat angina, symptomatic arrhythmias, hypertension, or
other ACC/AHA class I guideline indications. (Level of Evidence: C)
2. Beta blockers should be given to patients undergoing vascular surgery who are at
high cardiac risk owing to the finding of ischemia on preoperative testing.
Fleisher LA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac
surgery: executive summary. Anesth Analg 2008;106:685–712.
Perioperative Beta Blockade After
Another heated debate about the pros and cons of using
beta blockers perioperatively in noncardiac surgery
 RCT of metoprolol versus placebo (30 d)
 Non-cardiac surgery
 With or at risk of IHD
 Sample size
 10,000 patients
 Primary outcome
 30 day cumulative risk of cardiac death, nonfatal MI and
non-fatal cardiac arrest
Devereaux PJ,et al. Am J Heart 2006; 152: 223-30
8,351 Patients Recruited
406
3548
2005
1506
191 sites
23 countries
886
Trial Flow Diagram
8351 randomized
4174 allocated to
metoprolol CR
4177 allocated to
matching placebo
8 lost to follow-up
12 lost to follow-up
99.8% complete 30 day follow-up and include in
intention-to-treat analysis
Risk Criteria
Criteria (%)
Metoprolol
(n = 4174)
43.3
Placebo
(n = 4177)
42.7
Peripheral vascular disease
41.5
40.3
Stroke
14.9
15.4
Chronic heart failure admission
2.7
2.6
Major vascular surgery
35.7
35.6
Three of 7 risk factors
18.3
18.8
Coronary artery disease
82% of participants had atherosclerotic disease
Primary Outcome
Metoprolol
(n = 4174)
Placebo
(n = 4177)
HR
(95% CI)
P
value
Primary outcome
243
(5.8%)
290
(6.9%)
0.83
(0.70-0.99)
0.04
Non-fatal MI*
151
(3.6%)
215
(5.1%)
0.70
(0.56-0.86)
0.0007
68% of MIs were asymptomatic
Secondary Outcomes
Outcome
Metoprolol
(n = 4174)
Placebo
(n = 4177)
HR
(95% CI)
P
value
Total mortality
129
(3.1%)
97
(2.3%)
1.33
(1.02-1.74)
0.03
Significant
hypotension
626
(15.0%)
404
(9.7%)
1.55
(1.38-1.74)
<0.0001
Significant
bradycardia
274
(6.6%)
101
(2.4%)
2.71
(2.17-3.39)
<0.0001
Stroke
41
(1.0%)
19
(0.5%)
2.17
(1.26-3.73)
0.005
 60 strokes reported
 49 ischemic, 3 hemorrhagic and 8 uncertain
 Of non-fatal strokes
 59 % patients in the metoprolol group required help to perform daily
activities
After the POISE Study
 For every 1,000 patients treated, metoprolol would
prevent
 15 MIs
 7 cases of new onset AF
 3 post-op CABGs
 …. And there would be
 8 excess deaths
 5 excess strokes
 53 patients with significant hypotension
 No effect on total mortality
After the POISE Study
 Continue β-blockers in patients who are on them already
 Start β -blockers perioperatively only in patients who need
lifelong β-blocker therapy
 Coronary ischemia who are undergoing vascular surgery
 Starting β-blockers immediately before surgery may be
harmful
 Start β-blockers as early before surgery as possible
 7 - 30 days before procedure
… Cont’d
After the POISE Study
 After surgery focus shifts to continuing β-blockers
appropriately
 Assess for infection, pain, hypovolemia, or bleeding
 If discontinuing β-blockers
 Titrate
 Restart as soon as unstable issues are resolved
… Cont’d
Conclusion
 The data suggests that Beta Blockers are beneficial in
patients with major cardiac risk
 Beta Blockers associated with severe bradycardia and
hypotension leading to stroke and death
 Patients with low cardiac risk may exhibit a higher
risk/benefit ratio
 Intermediate risk patient need to undergo for further
work up