Pre-op and Post-op Beta Blockers

Pre-op and Post-op Beta Blockers

Alla Kotlyanskaya, Pharm.D. Clinical Pharmacist – Critical Care

Woodhull Medical Center, Brooklyn, New YorkAdjunct Professor of Pharmacology

College of Nursing Graduate ProgramsSUNY Downstate College of Nursing

AndAdjunct 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 peri-

operative 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

PMI

TRIGGERS: surgery, anaesthesia, analgesia, intubation,extubation, pain, hypothermia, bleeding, anaemia, fasting

Inflammation Hypercoagulability Stress state Hypoxic state

PlaqueRupture

PlaqueRupture

Coronarythrombosis

O2demand

O2delivery

Myocardialischemia

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)

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, intra-abdominal or aortic surgery

3

Poor general status, metabolic or bedridden

3

N Engl J Med 1977;297:845-850

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

Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.

Risk stratification according to major, intermediate or minor clinical predictors

Surgery

ACC/AHA Guideline Summary: Major Clinical Predictors

•Acute or recent MI (7-30 d)•Unstable coronary syndrome•Decompensated CHF•Significant Arrhythmias•Severe Valvular Disease

High Risk:


ACC/AHA Guideline Summary: Clinical Risk Factors

3 or more risk factors& Vascular surgery

•History of heart disease•Compensated or prior CHF•Cerebrovascular disease•Diabetes Mellitus•Renal Insufficiency

Proceed Cautiously With:

Consider testing

1 – 2 risk factorsProceed with surgery or consider testing


ACC/AHA Guideline Summary: Minor Clinical Predictors

Reasonable to proceed with surgery

•Low risk surgery•Good functional capacity•No cardiac symptoms•No “active cardiac conditions”•No clinical risk factors

Low Risk:


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

How to stratify it How to modify it

ß Blocker Other New Agents

Perioperative MI

The Evolution of ß-Blockers

1960s 1970s 1980s-1990s 2007

Non-Non-SelectiveSelective

Non-Non-SelectiveSelective

VasodilatingVasodilatingVasodilating Vasodilating

Non-Selective

Non-Selective

Selective Selective

Propranolol Atenolol

Metroprolol

Carvedilol

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*

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.

*With long-term use

Protective Effect of -blockers Against Cardiac Events During and After Surgery


Inflammation Hypercoagulability Stress state Hypoxic state

PlaqueRupture

PlaqueRupture

Coronarythrombosis

O2demand

O2delivery

Myocardialischemia

PMI

Protective Effect of -blockers Against Cardiac Events During and After Surgery


Stress state

PlaqueRupture

Coronarythrombosis

O2demand

Myocardialischemia

PMI

Catechols/cortisol

Coronary arteryshear stress

HR, BP, FFAs

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 trialPerioperative β -blockers 2005–2008 Yang et al. at 20064

MaVS study Juul et al. at 20065

DiPoM trial

Effect of Atenolol on Mortality andCardiovascular 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

Surgery

PO Atenolol 50 mg

Patients werefollowed over the subsequent two years

IV Atenolol 5 mg

Placebo

Before After

Placebo

For the Duration of Hospitalization

N Engl J Med. 1996; 335: 1713-1720

Mangano Trial: Postoperative Mortality Reduction

8

14

21

0

3

10

0

5

10

15

20

25

Placebo Atenolol

6 Months 1 Year 2 Years

Num

ber o

f dea

th d

urin

g Fo

llow

up

N Engl J Med. 1996; 335: 1713-1720

The Effect of Bisoprolol on PerioperativeMortality and Myocardial Infarction in High-risk

Patients Undergoing Vascular SurgeryDutch 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

17 17

3.40

0

5

10

15

20

25

%

Placebo Bisoprolol

Beta-Blockade

Cardiac Death 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 … -blockers reduce perioperative ischaemia, and may reduce the risk of MI and death in high-risk

patients”RECOMMENDATIONSClass I1. Beta-blockers required in the recent past to control symptoms of angina or patients with symptomatic arrhythmias or hypertension2. 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 ResultsRelative 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 – 2007Study Patients and Protocol Findings

Yang et al2006(MaVS study)

496 vascular surgery patientsMetoprolol begun immediately before surgery, continued through to discharge

No impact on in-hospital cardiac events or deathsCardiac 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 al2006(DiPoM trial)

921 patients with diabetes who were undergoing major noncardiac surgery100 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

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])

POBBLE Trial Overview


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

POBBLE Trial Results and ConclusionOR (CV event or death) = 0.93 (95% CI: 0.53-1.64)

This trial indicates that in lower-risk patients, perioperative β-blockade does not reduce cardiovascular mortality BUT may have adverse intraoperative effects


RECOMMENDATIONSClass I1. 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

3548

1506

406

886191 sites23 countries

2005

Trial Flow Diagram

8351 randomized

4174 allocated to metoprolol CR

8 lost to follow-up

4177 allocated to matching placebo

12 lost to follow-up

99.8% complete 30 day follow-up and include in intention-to-treat analysis

Criteria (%) Metoprolol (n = 4174)

Placebo(n = 4177)

Coronary artery disease 43.3 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

82% of participants had atherosclerotic disease

Risk Criteria

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

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

Outcome Metoprolol(n = 4174)

Placebo(n = 4177)

HR(95% CI)

Pvalue

Total mortality 129 (3.1%)

97 (2.3%)

1.33 (1.02-1.74)

0.03

Significanthypotension

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

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

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

After the POISE Study

… Cont’d

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

After the POISE Study

… 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

Pre-op and Post-op Beta Blockers

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