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Apresentação do estudo poise 2
1. PJ Devereaux, MD, PhD
McMaster University, Hamilton, Ontario, Canada
on behalf of POISE-2 Investigators
PeriOperative ISchemic Evaluation-2 Trial
POISE-2POISE-2
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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
12. 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
13. Aspirin 1O
and 2O
outcome results
Outcome 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
14. Aspirin 1O
and 2O
outcome results
Outcome 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
26. Independent predictor of MI
Predictor Adjusted HR
(95% CI)
P
Clinically important
hypotension
1.37
(1.16-1.62)
<0.001
27. 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)
28. Clonidine conclusions
• Clonidine does not reduce postop MI or death
• increases clinically important hypotension
• Clinically important hypotension
• independent predictor of MI
29. POISE-3
• Design – blinded factorial RCT
• Eligibility – age ≥45 yrs, undergoing
noncardiac surgery, NT-proBNP ≥100
• Intervention
– Ivabradine versus placebo
– Tranexamic acid versus placebo
30. 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
31. Risk and duration of hypotension
Period Clonidine
(%)
Placebo
(%)
P Placebo
duration
minutes
Clonidine
duration
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
