PJ Devereaux, MD, PhD McMaster University, Hamilton, Ontario, Canada

on behalf of POISE-2 Investigators

PeriOperative ISchemic Evaluation-2 Trial

POISE-2POISE-2

Disclosure• Member of research group with policy

– of not accepting honorariums or other payments from industry • for own personal financial gain

• Accept honorariums/payments from industry to support – research endeavors and reimbursement of costs to participate

in meetings

• Based on study questions I originated and grants I wrote– I have received grants from

• Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Philips, Roche Diagnostics, Stryker

• I have participated in – advisory boarding meeting GlaxoSmithKline – expert panel meeting AstraZeneca

Goals of presentation

• Background– magnitude of the problem– potential for perioperative aspirin and clonidine

• POISE-2 Trial– methods– aspirin results– clonidine results

• POISE-3• Take away messages

Background•Worldwide 200 million noncardiac surgeries annually

– 10 million suffer major vascular complication • MI is most common

Despite magnitude of problem– no known safe and effective prophylactic interventions

Aspirin background

•Surgery – associated with platelet activation• thrombosis may be mechanism of periop MI

•Strong evidence aspirin prevents periop VTE • but physicians more commonly use anticoagulants

•Substantial variability in periop usage of aspirin for prevention of arterial events

• aspirin-naive patients and

• patients taking aspirin chronically

Clonidine background• Surgery – activation of sympathetic system

– can lead to myocardial O2 supply-demand mismatch• may result in MI

• POISE – demonstrated periop beta-blocker– prevented MI but – increased risk of death, stroke, and hypotension

• Clonidine – α2-adrenergic agonist– blunts central sympathetic outflow and has

analgesic and anti-inflammatory effects– data suggest less hypotension than beta-blocker

POISE-2 methods

•Design – blinded 2 X 2 factorial RCT • aspirin vs placebo• clonidine vs placebo

•Eligiblity criteria – undergoing noncardiac surgery, ≥45 yrs, at risk of vascular complication •Excluded patients

• BMS <6 weeks before surgery • DES <1 year before surgery• took aspirin within 72 hrs before surgery

POISE-2 methods•2 aspirin strata

• Initiation Stratum (n=5628)• Continuation Stratum (n=4382)

•Intervention • aspirin/placebo (200 mg) just before surgery;

• continued daily (100 mg) 30 days in Initiation Stratum and 7 days in Continuation Stratum

• clonidine/placebo (0.2 mg/day)• started before surgery and continued until 72 hrs after Sx

•Primary outcome• death or nonfatal MI at 30 days

Outcome definitions• MI – universal definition of MI• Life threatening bleed – bleeding event with

– emergent surgery, intracranial hemorrhage, – hypotension required inotrope or vasopressor, or fatal

• Major bleed – bleeding with – Hb ≤70 g/L and ≥2 units RBCs; – Hb drop ≥50 g/L and ≥2 units of RBCs; – ≥4 units of RBCs within 24 hr period; – intervention (e.g., embolization); or – retroperitoneal, intraspinal, or intraocular bleed

• Hypotension: systolic <90 mmHg requiring treatment• Bradycardia: HR <55 beats/min requiring treatment

Recruitment by region

Follow-up complete on 99.9% of patients

Preoperative characteristics

Characteristics (N=10,010)

Age – (mean yrs) 69

Male (%) 53

Known vascular disease (%)

33

History of PCI (%) 5

Type of surgery and periop anticoagulant prophylaxis

Surgery (N=10,010)

Orthopedic

General

Urologic or gynecologic

Vascular

Other

39

27

17

6

11

65% of patients received prophylactic anticoagulant

Aspirin 1O and 2O outcome resultsOutcome Aspirin

(4998)Placebo(5012)

HR (95% CI)

P

1O outcome:death or nonfatal MI

351 (7.0) 355 (7.1) 0.99 (0.86-1.15) 0.92

Aspirin 1O and 2O outcome resultsOutcome Aspirin

(4998)Placebo(5012)

HR (95% CI)

P

1O outcome:death or nonfatal MI

351 (7.0) 355 (7.1) 0.99 (0.86-1.15) 0.92

2O outcomes:death, MI, or stroke

362 (7.2) 370 (7.4) 0.98 (0.85-1.13) 0.80

death, MI, revasc, PE, DVT

402 (8.0) 407 (8.1) 0.99 (0.86-1.14) 0.90

No interaction with clonidine study drug

Aspirin tertiary outcome results

Outcome Aspirin(4998)

Placebo(5012)

HR (95% CI)

P

Mortality 65 (1.3) 62 (1.2) 1.05 (0.74-1.49) 0.78

MI 309 (6.2) 315 (6.3) 0.98 (0.84-1.15) 0.85

Periph arterial thrombosis

13 (0.3) 15 (0.3) 0.87 (0.41-1.83) 0.71

Aspirin tertiary outcome resultsOutcome Aspirin

(4998)Placebo(5012)

HR (95% CI)

P

Mortality 65 (1.3) 62 (1.2) 1.05 (0.74-1.49) 0.78

MI 309 (6.2) 315 (6.3) 0.98 (0.84-1.15) 0.85

Periph arterial thrombosis

13 (0.3) 15 (0.3) 0.87 (0.41-1.83) 0.71

PE 33 (0.7) 31 (0.6) 1.07 (0.65-1.74) 0.79

DVT 25 (0.5) 35 (0.7) 0.72 (0.43-1.20) 0.20

acute kidney injury, dialysis

33 (0.7) 19 (0.4) 1.75 (1.00-3.09) 0.05

Aspirin safety outcome results

Outcome Aspirin(4998)

Placebo(5012)

HR (95% CI)

P

Major bleed 230 (4.6) 188 (3.8) 1.23 (1.01-1.49) 0.04

Life-threat bleed

87 (1.7) 73 (1.5) 1.19 (0.88-1.63) 0.26

Stroke 16 (0.3) 19 (0.4) 0.84 (0.43-1.64) 0.62

Strata and bleeding results

• 1O and 2nd outcome results similar in both aspirin strata• Multivariable regression – life-threatening or major

bleed independent predictor of periop MI– HR, 1.82; (95% CI, 1.40-2.36); P<0.001

Absolute risk increase in life-threatening or major bleeding on each day until day 30

From this day to 30 day f-up

Aspirin%

Placebo%

Abs. risk increase (%)

P

Day of Sx 6.3 5.1 1.2 0.01

Day 1 > Sx 4.0 2.7 1.3 <0.001

Day 2 > Sx 2.9 1.9 1.0 0.002

Day 3 > Sx 2.2 1.2 1.0 <0.001

Day 4 > Sx 1.6 0.7 0.9 <0.001

From this day to 30 day f-up

Aspirin%

Placebo%

Abs. risk increase (%)

P

Day 5 > Sx 1.3 0.6 0.7 <0.001

Day 6 > Sx 0.9 0.5 0.4 0.03

Day 7 > Sx 0.8 0.5 0.3 0.03

Day 8 > Sx 0.8 0.5 0.3 0.29

Day 9 > Sx 0.6 0.5 0.1 0.82

Day 10 > Sx 0.5 0.5 0.0 0.67

Absolute risk increase in life-threatening or major bleeding on each day until day 30

Aspirin conclusions• Periop aspirin did not prevent death or MI

• but increased risk of major bleeding• findings apply to both patients naive to aspirin and

patients taking aspirin chronically

• Life-threatening and major bleeding • independent predictor of MI

• may explain difference b/w non-operative & periop aspirin results

• Among patients taking aspirin chronically• no increase in thrombotic events due to periop

withholding of aspirin• optimal time to restart aspirin

• 8 – 10 days after surgery

Clonidine 1O and 2O outcome results

Outcome Clonidine(5009)

Placebo(5001)

HR (95% CI)

P

1O outcome:death or MI 367 (7.3) 339 (6.8)

1.08 (0.93-1.26) 0.29

Clonidine 1O and 2O outcome results

Outcome Clonidine(5009)

Placebo(5001)

HR (95% CI)

P

1O outcome:death or MI 367 (7.3) 339 (6.8)

1.08 (0.93-1.26) 0.29

2O outcome:death, MI, or stroke

380 (7.6) 352 (7.0) 1.08 (0.93-1.25) 0.30

No interaction with aspirin study drug

Clonidine tertiary outcomesOutcome Clonidine

(5009)Placebo(5001)

HR (95% CI)

P

Total mortality 64 (1.3) 63 (1.3) 1.01 (0.72-1.44) 0.94

Vascular mortality

38 (0.8) 32 (0.6) 1.19 (0.74-1.90) 0.48

Myocardial infarction

329 (6.6) 295 (5.9) 1.11 (0.95-1.30) 0.18

Cardiac revascularisation

19 (0.4) 11 (0.2) 1.73 (0.82-3.63) 0.15

Pulmonary embolus

32 (0.6) 32 (0.6) 1.00 (0.61-1.63) 0.99

Nonfatal cardiac arrest

16 (0.3) 5 (0.1) 3.20 (1.17-8.73) 0.02

Clonidine safety outcomesOutcome Clonidine

(5009)Placebo(5001)

HR (95% CI)

P

Clinically important hypotension

2385 (48) 1854 (37) 1.32 (1.24-1.40) <0.001

Clinically important bradycardia

600 (12) 403 (8) 1.49 (1.32-1.69) <0.001

Stroke 18 (0.4) 17 (0.3) 1.06 (0.54-2.05) 0.87

Independent predictor of MI

Predictor Adjusted HR (95% CI)

P

Clinically important hypotension

1.37 (1.16-1.62)

<0.001

POISE vs POISE-2

• Discordant results– POISE metoprolol MI HR: 0.73 (0.60-0.89)– POISE-2 clonidine MI HR: 1.11 (0.95-1.30)

• Clinically important hypotension increased by• metoprolol HR: 1.55 (1.38-1.74) • clonidine HR: 1.32 (1.24-1.40)

• More clinically important bradycardia with metoprolol• metoprolol HR: 2.74 (2.19-3.43) • clonidine HR: 1.49 (1.32-1.69)

• Preventing MIs may be balance between• decreasing HR (minimizing oxygen demand)• avoiding hypotension (ensuring oxygen supply)

Clonidine conclusions

• Clonidine does not reduce postop MI or death• increases clinically important hypotension

• Clinically important hypotension • independent predictor of MI

POISE-3

• Design – blinded factorial RCT• Eligibility – age ≥45 yrs, undergoing

noncardiac surgery, NT-proBNP ≥100• Intervention

– Ivabradine versus placebo– Tranexamic acid versus placebo

Take away messages

• Sometimes in research discovered unintended ways to help patients– any discovery that help patients is positive

• By not giving clonidine and aspirin to patients having noncardiac surgery in an effort to reduce perioperative mortality or MI– we can help patients

• POISE-3 will inform 2 promising interventions

Risk and duration of hypotensionPeriod Clonidine

(%)Placebo

(%)P Placebo

duration minutes

Clonidineduration minutes

P

Surgery 39 32 <0.001 15 15 0.12

PACU 8 4 <0.001 30 30 0.30

Post-op Day 1

8 5 <0.001 150 180 0.13

Post-op Day 2

3 2 <0.001 110 160 0.03

Post-op Day 3

1.1 0.6 0.004 109 214 0.07

32

Aspirin 1O outcome subgroup analyses

0.16

0.89

0.92

Independent predictors of MIPredictor Adj HR

(95% CI)P

Hx of CAD 1.49 (1.25-1.78) <0.001

Hx of PVD 2.10 (1.69-2.60) <0.001

Hx of CHF 1.60 (1.15-2.22) 0.005

eGFR <60 ml/min/ 1.73m2 1.52 (1.28-1.79) <0.001

Age ≥ 75 1.89 (1.60-2.23) <0.001

Clin. Imp. hypotension 1.37 (1.16-1.62) <0.001

Life threatening & major bleed 1.82 (1.40-2.36) <0.001

Strata subgroup analysis for stroke

OutcomeAspirinn/N (%)

Placebon/N (%)

HR(95%)

PInter-action

P

Overall 16/4998 (0.3)

19/5012 (0.4)

0.84 (0.43-1.64)

0.62

ASA Starting

3/2807 (0.1)

12/2821 (0.4)

0.25 (0.07-0.89)

0.03 0.01

ASA Continuation

13/2191 (0.6)

7/2191 (0.3)

1.86 (0.74-4.66)

0.19