Journal ClubJournal ClubJournal ClubJournal ClubLei Zhang PGY 3Lei Zhang PGY 3

7/16/097/16/09

Case• 55 y.o. F, PMH HTN, DM, TIA, and

diverticulosis• Had multitple diverticulitis, lower GIB in

the past • Scheduled to have elective colon

resection in 2 wks• Presented to the office for pre-op

clearance• Denied CP, SOB, swelling

Case• HTN well controlled with Lisinopril and

HCTZ• DM well controlled with Glipizide and

Metformin• Also taking ASA and Zocor• Good functional status, able to climb 2

flight of stairs carrying grocery• Recent EKG/CXR within normal limits • Recent CBC, Chem 7 within normal limits

Anything Else Needed Anything Else Needed Pre-operatively? Pre-operatively?

Anything Else Needed Anything Else Needed Pre-operatively? Pre-operatively?

Add Beta-blocker? Add Beta-blocker?

Perioperative Beta Blocker use

• Circulation, 2006• Feringa and colleagues performed an

observational cohort study of 272 vascular surgery patients

• Higher doses of -blockers and tight heart rate (< 70 bpm) control associated with reduced perioperative myocardial ischemia and troponin release and improved long-term outcome

Perioperative Beta Blocker use

• J AM Coll Cardio, 2006• Poldermans and colleagues randomly

assigned 770 intermediate-risk patients to cardiac stress testing (n386) or no testing (n384) preoperatively

• Concluded that cardiac testing can safely be omitted in intermediate-risk patients if beta blockers aimed at tight heart rate control are prescribed

Perioperative Beta Blocker use

• BMJ, 2005• Donald Redelmeier & colleague

performed retrospective cohort study in Canada in 37,151 asymptomatic patients older than 65 admitted for elective surgery (mainly abd & ortho procedure)

• Patients receiving long-acting beta-blockers have lower perioperative cardiac risk than short-acting agent

ACC/AHA Guideline for Pre-op Beta-blocker

Use

Perioperative Beta Blocker use

• Am Heart J. 2006• Yang & colleague performed a double-blind

randomized controlled trial of perioperative metoprolol versus placebo in 496 patients undergoing vascular surgery

• Metoprolol was not effective in reducing the 30-day & 6-month postop cardiac event rates.

• Concluded that prophylactic use of perioperative beta-blockers in all vascular patients is not indicated

Perioperative Beta Blocker use

• BMJ, 2006• Anne Benedicte Juul & colleague designed a

randomized, controlled and blinded multicentre trial in 921 diabetic patients, age > 39, scheduled for major non-cardiac surgery

• 100 mg metoprolol extended release or placebo given from the day before surgery to a max of 8 perioperative days

• Conclusions: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity

Perioperative Beta Blocker use

• BMJ, 2006• Devereaux & colleague published a

meta-analysis of randomized controlled trials in non-cardiac surgery pts

• β blockers might prevent major cardiovascular events but increase the risk of hypotension & bradycardia

Peri-operative Use of Peri-operative Use of Beta-blockerBeta-blocker

Peri-operative Use of Peri-operative Use of Beta-blockerBeta-blocker

Yes or NOYes or NO

POISE TRIAL• PeriOperative ISchemic

Evaluation• Purpose of the trial:

– Comparing the effect of extended-release metoprolol with that of placebo on 30-day risk of major cardiovascular events in patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery.

POISE TRIAL• Research question

– Does peri-operative β-blocker regimen benefit noncardiac surgery pts without substantial harm?

• Double-blinded, randomized, controlled, multi-center trial

POISE TRIAL• Involved 8,351 pts and 190

hospitals in 23 countries• Study period 10/2002 – 7/2007

• Ethical approval for all participating sites obtained

• Written informed consent obtained from all pts

POISE TRIAL• Inclusion criteria

– undergoing non-cardiac surgery– aged 45 years or older– expected length of hospital stay > 24 h– any one of the following criteria

• hx of CAD • hx of PVD• Stroke

POISE TRIAL• hospitalization for CHF within past 3 years • undergoing major vascular surgery

– Or, any three of seven risk criteria• undergoing intrathoracic or intraperitoneal

surgery• hx of CHF• hx of TIA• hx of diabetes• creatinine >175 μmol/L ( >2.0 mg/dL)• age >70 years• undergoing emergent or urgent surgery

POISE TRIAL• Exclusion criteria

– HR < 50 bpm– 2nd or 3rd AVB– Asthma– Receiving β blocker or planned to start one

perioperatively– Prior adverse reaction to β blocker– CABG in the preceding 5 years with no

ischemia– Low-risk surgical procedure– On verapamil

POISE TRIAL• Patients were randomly assigned to

two groups via a 24-h computerized randomization phone service

• Participants, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation

Trial Profile…

Figure 1

Table 2

Method• 1st dose of the study drug (ie, oral

extended-release metoprolol 100 mg or matching placebo) given 2–4 h before surgery

• VS checked each time before medication to ensure HR > 50 bpm & SBP > 100 mm Hg

Method• Within 6 h postop, pt received 1st post-

op dose• 12 h after 1st post-op dose, start

Metoprolol extended-release 200mg or placebo p.o. daily for 30 days

• If HR <45bpm or SBP < 100, study drug withheld until recovered

• Study drug was then restarted at 100mg daily

Method• If HR consistently 45–49 bpm, SBP

>100 mm Hg, delayed taking the study drug for 12 h

• If unable to take p.o., study drug given by slow or rapid IV infusion q6h

• Investigators were allowed to select either the slow or rapid IV infusion

Method• Slow infusion

– 15 mg of study drug in 25 mL NS over 60 min

– HR & BP checked at 10, 30, and 60 min into the infusion

• If HR/BP drop, study drug reduce to 10mg

Method• Rapid infusion

– 5 mg of the study drug IV over 2 min and repeated every 5 min for a total of 15 mg

• ECG recorded 6–12 h postoperatively and on the 1st, 2nd , and 30th days

• Troponin or CK-MB at 6–12 h postoperatively & on the 1st , 2nd , and 3rd days

POISE TRIAL• Primary outcome

– cardiovascular death– non-fatal MI – non-fatal cardiac arrest at 30 days

Statistical Analysis• Study has 85% power to detect a

relative risk reduction of 25%• All analyses used Cox proportional

hazards models

Table 3

Results• Fewer in the metoprolol group reached

the primary endpoint (hazard ratio 0·84, 95% CI 0·70–0·99, p=0·039)

• Fewer patients in the metoprolol group had a non-fatal MI (hazard ratio 0·70, 95% CI 0·57–0·86; p=0·0008)

• Fewer in the metoprolol group had cardiac revascularisation or developed new A fib

Result• More in the Metoprolol group had a

stroke (hazard ratio 2·17, 95% CI 1·26–3·74, p=0·0053)

• More people receiving metoprolol died (1·33, 1·03–1·74, p=0·0317)

• More pts receiving Metoprolol had significant hypotension and bradycardia

Primary MIs

Strokes Death

Figure 2

Results• Median length of hospital stay was

8 (IQR 4–14) days in the Metoprolol group and 8 (4–15) days in the placebo group (p=0·4046)

• The number of nights spent in ICU/CCU was much the same in the two groups

Results• At discharge, Metoprolol group

had – a lower mean HR(71·6 [SD 12·0]vs

78·6 [11·8]; p<0·0001)– lower mean SBP & DBP (129

[18·9]/72 [11·1] vs 131 [18·2]/74 [11·1]mm Hg; p<0·0001)

Discussion• Why extended-release Metoprolol

have increased risk of death and stroke?

• Clinically significant hypotension, bradycardia and stroke contribute to the increasing risk of death

Table 5

Discussion• Sepsis or infection was the only

cause of death that was significantly more common in Metoprolol group

• Hypotension caused by β blockers could have predisposed pts to developing nosocomial infection

Discussion• β blockers suppress tachycardia

could delay the recognition of sepsis and infection, therefore delaying treatment, which might increase the risk of death

Discussion• Pts receiving β-blocker who

develop sepsis or infection might not have the capacity to mount enough response to sustain life or allow adequate delivery of antibiotics to tissue

Discussion• POISE researchers also performed

several meta-analysis of trials of periop Beta-blocker use– Decrease risk of non-fatal MI– Increase risk of death– Increase risk of non-fatal stroke

Figure 4

Conclusion

Summary• Are the results valid?

– Yes• Are the results important?

– Yes• Can you apply the results to your

patient?– Yes

Validity• This is a large, multi-center,

randomized, double-blind, controlled clinical trial

• Both groups were comparable in terms of back ground information, type of surgery, anesthesia, and medications

• Both groups were treated equally

Validity• Confounding criteria were well-

accounted between the two groups• Clear inclusion and exclusion criteria• Study has detailed medication

administration and side-effect monitoring protocol

• Follow-up was complete for majority of pts

Validity

• Although involving large of amount of pts and study personnel from 190 hospitals in 23 countries, the study was well regulated by central and on-site monitoring system

• Problems found in Iran and Colombia were caught immediately and data excluded from the study

Applicability• This is a large multi-country study,

involving different racial, ethnic & economic population; it is safe to generalized the study results to our practice patients

Significance• The study have enormous

influence on current medicine practice

• It challenged the currently popular concept of perioperative Beta-blocker use

Significance• For every 15 patients in POISE

trial, one had a cardiovascular death, non-fatal myocardial infarction, non-fatal cardiac arrest, or non-fatal stroke at 30-day follow-up

Significance• Suggest that the addition of

perioperative Beta-blocker potentially has serious risks

• Lead to the further question of who will benefit from Beta-blocker and who will not?

Thank YouThank YouThank YouThank You

ACC/AHA Guideline for Preop Eval for

Noncardiac Surgery• Pts with active cardiac conditions,

indicate major clinical risk– unstable coronary syndromes,

• acute MI < 7 days• recent MI > 7 days but </= 1 month with

evidence of ischemia• unstable or severe angina

– decompensated heart failure,– significant arrhythmias– severe valvular disease

ACC/AHA Guideline for Preop Eval for

Noncardiac Surgery• Pts with clinical risk factors

– history of heart disease,• hx MI or Q waves by ECG

– history of compensated or prior CHF– history of cerebrovascular disease, TIA,

stroke– diabetes mellitus, preop use of insulin– renal insufficiency, preop Cr >2.0