POISE UpToDate

Goals of presentation • beware trials stopped early for benefit • beware prestigious journal publication bias • stay skeptical of expert recommendations that are not rigorously evidence-based • beware composite endpoints • note the unbearable lightness of physiological reasoning • beware the limitations of sub-group analysis • beware limitations observational studies – comparative effectiveness

• challenges of recommendation that appropriately balance benefits and risk

Background •

100 Million adults worldwide undergo noncardiac surgery annually 1 million suffer major perioperative CV event

•

Noncardiac surgery increases catecholamines –

leads to increase in HR, BP, free fatty acid • • •

increases myocardial O2 demand increases arrhythmias beta-blockers attenuate both effects

Poldermans, NEJM, 1999 • elective vascular surgery

– positive dobutamine stress echo

• compared bisoprolol to placebo – unblinded

• primary endpoint death or nonfatal MI

Poldermans NEJM 1999 • planned sample size 266 • prior planned single look at 100 pts – stop if exceeded O’Brien-Fleming boundary • p < 0.001

• stopped after 112 patients • primary endpoint – 2 of 59 (3.4%) in bisoprolol group – 18 of 53 (34%) in placebo

• RR 0.09, 95% CI 0.02 to 0.37, P< 0.001

Composite – Random Effects Study ID

Year

RR (95% CI)

Jakobsen

1997

3 (0.13 to 69.09)

Wallace

1998

0.65 (0.17 to 2.41)

Bayliff

1999

0.73 (0.15 to 3.52)

Poldermans

1999

0.12 (0.03 to 0.43)

Raby

1999

0.25 (0.01 to 5.62)

Zaugg

1999

0.07 (0 to 1.26)

Urban

2000

0.43 (0.07 to 2.81)

MaVS

2006

0.88 (0.49 to 1.57)

Combined Estimate

0.48 (0.24 to 0.97)

p=0.1 for heterogeneity, I-squared=39% 0.001

0.01

0.1

1

10

RR (log scale)

Total events 83/1152

100

POISE - Methods • does metoprolol CR reduce 30 day risk of major CV events after noncardiac surgery • eligibility – > 45 yrs, undergoing noncardiac surgery and – CAD, PVD, stroke, CHF admission, major vascular surgery, or – 3 of 7 risk factors • high risk surgery, CHF, DM, renal insufficiency, age > 70 yrs, TIA, or urgent/emergent surgery

• intervention – metoprolol CR or placebo started 2-4 hrs preoperatively, continued for 30 days • primary outcome measure – 30 day composite of

Validity • randomization concealed • blinded – – – –

patients clinicians date collectors adjudicators

• follow-up 99.8%

Outcomes Outcome

Metoprolol (N=4174)

no.

Placebo (N=4177)

HR (95% CI)

P

0.04

Primary outcome (CV death, nonfatal MI, nonfatal CA)

243 (5.8%)

290 (6.9%)

0.83 (0.70-0.99)

nonfatal MI

151 (3.6%)

215 (5.1%)

0.70 0.0007 (0.56-0.86)

CV death

75 (1.8%)

58 (1.4%)

1.30 (0.92-1.83)

0.14

21 (0.5%)

19 (0.5%)

1.11 (0.60-2.06)

0.74

nonfatal CA

Primary Outcome

Non-fatal MI

Subgroups primary outcome Primary Subgroup

Cardiac Risk Index Risk 0 Risk 1 Risk 2 Risk 3 Risk 4+

INTERACTION P-VALUE

//2.74 0.126

//3.69

Secondary Subgroups Gender

Males Females

0.965

Surgery

Vascular Orthopedic Intraperitoneal

0.271

Secondary Outcomes Outcome

total mortality

Metoprolol (N=4174)

129 (3.1%)

Placebo (N=4177)

HR (95% CI)

P

97 (2.3%)

1.33 (1.02-1.74)

0.03

Causes of death as reported by centres Cause of death

CV death cardiogenic shock or CHF Non-CV death sepsis or infection

Metoprolol (N=129)

Placebo (N=97)

P

75 (1.8%) 7 (5.4%)

58 (1.4%) 9 (9.3%)

0.14

54 (1.3%) 36 (27.9%)

39 (0.9%) 18 (18.6%)

0.62 0.12 0.02

Total Mortality

0.02 0.01

Risk

0.03

HR(95%CI)=1.33(1.02-1.74), p=0.032

Metoprolol

0.0

Placebo

0

No. at Risk 4177 P 4174 M

10

20

30 Days

4116 4113

4091 4066

4069 4038

Total Mortality

0.02 0.01

Risk

0.03

HR(95%CI)=1.33(1.02-1.74), p=0.032

Metoprolol

0.0

Placebo

0

No. at Risk 4177 P 4174 M

10

20

30 Days

4116 4113

4091 4066

4069 4038

Secondary Outcomes Outcome

stroke

Metoprolol (N=4174)

41 (1.0%)

Placebo (N=4177)

19 (0.5%)

HR (95% CI)

P

2.17 0.005 (1.26-3.73)

Stroke

Nonfatal MI – Fixed Effects

Summary of Findings Quality Assessment Illustrative comparative risks

Outcome

Number of participants (studies)

Limitations

Consistency

Directness

Precision

Reporting Bias

Myocardial infarction

10,125 (9)

No

OK

OK

OK

No

Quality

Relative Effect Relative (95% CI) or WMD

High

0.71 (0.57 to 0.86)

5.1%

3.6% (2.9% to 4.4%)

Mortality – Fixed Effects

Summary of Findings Quality Assessment Illustrative comparative risks Quality

Relative Effect Relative (95% CI) or WMD

No

High

0.71 (0.57 to 0.86)

5.1%

3.6% (2.9% to 4.4%)

No

Moderate or low

1.23 (0.98 – 1.55)

2.3%

2.8% (2.2% to 3.6%)

Outcome

Number of participants (studies)

Limitations

Consistency

Directness

Precision

Reporting Bias

Myocardial infarction

10,125 (9)

No

OK

OK

OK

Mortality

10,205 (7)

No

Possible ↓

OK

Imprecise

Stroke – Fixed Effects

Summary of Findings Quality Assessment Illustrative comparative risks Quality

Relative Effect Relative (95% CI) or WMD

No

High

0.71 (0.57 to 0.86)

5.1%

Imprecise

No

Moderate or low

1.23 (0.98 – 1.55)

2.3%

OK

No

High

2.21 (1.37 – 3.55)

0.5%

Outcome

Number of participants (studies)

Limitations

Consistency

Directness

Precision

Reporting Bias

Myocardial infarction

10,125 (9)

No

OK

OK

OK

Mortality

10,205 (7)

No

Possible ↓

OK

Stroke

10,889 (5)

No

OK

OK

3.6% (2.9% to 4.4%) 2.8% (2.2% to 3.6%) 1.1 (0.69% to 1.8%)

Recommendations • beta blockers – for – against

• Strength of recommendation – strong – weak

Goals of presentation • beware trials stopped early for benefit • beware prestigious journal publication bias • stay skeptical of expert recommendations that are not rigorously evidence-based • beware composite endpoints • note the unbearable lightness of physiological reasoning • beware the limitations of sub-group analysis • beware the limitations of observational studies – comparative effectiveness

• challenges of recommendation that appropriately balance benefits and risk