POISE-2: Aspirin and
Clonidine to Prevent
Perioperative MI
Kate Leslie, MBBS, MD, M Epi, FANZCA
Royal Melbourne Hospital
Scope of this Talk
Pathophysiology of perioperative MI
 Measures to prevent perioperative MI
 a2-agonists
 Aspirin
 The POISE-2 Trial

Magnitude of the Problem


Non-cardiac surgery is associated with significant
cardiac morbidity and mortality
Perioperative MI adversely affects outcomes
•  In-hospital mortality
•  Hospital stay and overall cost
•  Cardiac death or non-fatal MI in next 6 months

Huge at-risk population  huge burden of disease
• 200 million have non-cardiac surgery each year
• 5 million suffer perioperative cardiac event

Despite magnitude of problem no proven safe and
effective prophylactic interventions
Perioperative MI

MI is most common major perioperative
vascular event



5.7% of POISE-1 placebo group within 30 days
2/3 of perioperative MI silent
Perioperative MI carries poor prognosis


11.6% of POISE-1patients suffering perioperative MI
died within 30 days
Asymptomatic and symptomatic perioperative MIs
were independent predictors of death at 30 days
with similar hazard ratios in POISE-1
Pathophysiology
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI
Supply-Demand Mismatch

Increased demand



Surgery associated with high physiological stress and
increased oxygen extraction
In POISE-I, pre-randomization heart rate independently
associated with risk of perioperative MI
Decreased supply


Coronary artery with high grade stenosis or occlusion
has limited supply response
Small autopsy studies after fatal perioperative MI
• 2/3 of patients had significant left main or 3-vessel CAD
• 1/3 of patients had intracoronary thrombus
Coronary Thrombosis

Perioperative coronary thrombosis and
plaque fissuring facilitated by

Sympathetic hyperactivity
• Up-regulation of coagulation and platelets
• Down-regulation fibrinolysis
• Increased coronary shear stress

Systemic inflammation
• Increased TNF-a, IL-6, IL-8

CARP Trial

Coronary revascularization did not reduce
risk of perioperative MI
Scope of this Talk
Pathophysiology of perioperative MI
 Measures to prevent perioperative MI
 a2-agonists
 Aspirin
 The POISE-2 Trial

b-blockers
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI
Before POISE





Poldermans’ and others suggested
dramatic b-blocker effect
Beta-blockers recommended in
ACC/AHA guidelines
Devereaux meta-analysis suggested
cumulative evidence insufficient
DIPOM (n = 951) reported no
significant effect
Pooled OR = 0.89 (95% CI: 0.55-1.43)
Metoprolol
Placebo
HR
(n = 4174) (n = 4177) (95% CI)
Primary outcome
243
290
0.83
(5.8%)
(6.9%)
(0.70-0.99)
Cardiovascular
75
58
0.70
death
(1.8%)
(1.4%)
(0.57-0.86)
Non-fatal MI
Non-fatal cardiac
arrest
151
(3.6%)
21
(0.5%)
215
(5.1%)
19
(0.5%)
P
value
0.04
0.14
0.70
(0.56-0.86) 0.0008
1.11
(0.60-2.06) 0.74
Outcome
Death
Stroke
Hypotension
Bradycardia
Metoprolol
(n = 4174)
Placebo
(n = 4177)
HR
(95% CI)
P
value
129
(3.1%)
41
(1.0%)
97
(2.3%)
19
(0.5%)
1.33
(1.02-1.74)
2.17
(1.26-3.73)
626
(15.0%)
274
(6.6%)
404
(9.7%)
101
(2.4%)
1.55
(1.38-1.74) <0.0001
2.71
(2.17-3.39) <0.0001
0.03
0.005

Class I


Class II



Pre-existing b-blockade should be continued (level C)
Beta-blockers titrated to heart rate and blood pressure are
probably recommended for patients undergoing vascular surgery
who are at high cardiac risk (level B)
Beta-blockers titrated to heart rate and blood pressure are
reasonable for patients in whom preoperative assessment identifies
high cardiac risk (level B)
Class III

Routine administration of high-dose beta-blockers in the absence of
dose titration is not useful and may be harmful (level B)
Conclusions

POISE raises more questions than it answers






Is there a sub-group effect?
Was the dose in POISE too large?
Was treatment started too late?
Should the dose be titrated?
Was post-operative care inadequate?
Current role of b-blockers for prevention of
perioperative MI is unclear and widespread
use for primary prevention is not indicated
Statins
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI
The Action of Statins

HMG-CoA reductase inhibition


 LDL-cholesterol levels
Pleiotropic effects
•
•
•
•



Improved endothelial function
Anti-inflammatory
Vasodilatory
Anti-thrombogenic
4 weeks for effects to develop
1 year for survival benefit in CAD
Withdrawal leads to rapid return of
endothelial dysfunction
1000 intermediate-risk non-cardiac surgery patients
b-blocker and statin naive
Bisoprolol
Fluvastatin
Both
Neither
0-30 day pre-op & 30-day post-op open-label treatment
30-day incidence of cardiovascular death & non-fatal MI
Treated
Control
(n = 533) (n = 533)
Primary outcome bisoprolol
2.1%
6.0%
Primary outcome fluvastatin
3.2%
4.9%
HR
(95% CI)
0.34
(0.17-0.67)
0.65
(0.35-1.10)
P
value
0.002
Beneficial effect of bisoprolol not modified by fluvastatin
0.17
Conclusions

Indications for peri-operative statin use




Continuation of preoperative use
Initiation for medical indication
Inclusion in an RCT
Widespread use for perioperative primary
prevention is not currently justified
Scope of this Talk
Pathophysiology of perioperative MI
 Measures to prevent perioperative MI
 a2-agonists
 Aspirin
 The POISE-2 Trial

a2-agonists
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI
a2-agonists
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI
Perioperative Mortality
Systemic review of 31 RCTs by POISE-2 investigators
Perioperative MI
Systemic review of 31 RCTs by POISE-2 investigators
Perioperative Stroke
Systemic review of 31 RCTs by POISE-2 investigators
Hypotension (high dose)
Control
Control
Clonidine
Clonidine
Systemic review of 31 RCTs by POISE-2 investigators
Hypotension (low dose)
Control
Clonidine
Systemic review of 31 RCTs by POISE-2 investigators
Conclusions

Indications for peri-operative a2-agonists




Continuation of preoperative use
HR, BP, pain control peri-operatively
Inclusion in an RCT (POISE-2)
Widespread use for perioperative primary
prevention is not currently justified
Scope of this Talk
Pathophysiology of perioperative MI
 Measures to prevent perioperative MI
 a2-agonists
 Aspirin
 The POISE-2 Trial

Aspirin Mode of Action
Primary and secondary MI prevention
Pathophysiology
TRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
Inflammation
Hypercoagulability
Plaque
fissuring
Stress state
Plaque
fissuring
Coronary
thrombosis
O2
demand
Hypoxic state
O2
delivery
Myocardial
ischaemia
PMI

Meta-analysis of anti-platelet RCTs in non-operative setting




195 RCTs involving 135,640 patients and 17,207 major
vascular events
Aspirin reduced nonfatal MI by 1/3, nonfatal stroke by 1/4 and
mortality by 1/6
Low-dose aspirin (75-150 mg daily) as effective but less
gastrotoxic than higher doses
In acute settings initial loading dose of aspirin160 mg of aspirin
(sufficient to provide rapid and complete inhibition of TXA2
mediated platelet aggregation) may be required
13,356 hip fracture patients
160 mg/day aspirin or placebo for 35 days for PE prevention
Outcome
Aspirin
(n=6,679)
Placebo
(n=6,677)
Hazard ratio
(95% CI)
PE
46
81
0.43 (0.18-0.60)
MI
105
79
1.33 (1.00-1.78)
Transfusion
197
157
1.24 (1.10-1.53)

No monitoring for MI


2/3 of perioperative MIs are clinically silent
Increased risk of MI in aspirin



may be a chance finding
have resulted from bleeding and supply-demand mismatch
is inconsistent with large body of evidence for primary
and secondary prevention of MI in non-operative setting
Conclusions



Non-operative trials suggest benefit
PEP Trial suggested increased MI and bleeding
Perioperative aspirin use is highly variable
• No perioperative aspirin -  MI
• Perioperative aspirin -  bleeding

Perioperative aspirin indicated in specific
circumstances but widespread use for
perioperative primary prevention is not
currently justified
Scope of this Talk
Pathophysiology of perioperative MI
 Measures to prevent perioperative MI
 a2-agonists
 Aspirin
 The POISE-2 Trial

POISE-2 Trial
10,000 high-risk non-cardiac surgery patients
Aspirin
Clonidine
Both
Neither
30-day incidence of cardiovascular death & non-fatal MI
Drug Administration

Clonidine



Aspirin-naïve



0.2 mg orally or matching placebo 2-4 h preop
Transdermal patch (0.2 mg/day) or placebo patch
preop and removed 72 h after surgery
160 mg orally or matching placebo 2-4 h preop
160 mg orally or matching placebo for 30 days
Aspirin-taking




Cease aspirin 3 days preop
160 mg orally or matching placebo 2-4 h preop
160 mg orally or matching placebo for 7 days
Recommence own aspirin
Inclusion Criteria




Undergoing noncardiac surgery
≥45 years of age
Expected to stay at least one postoperative night
Fulfills one or more of the following 5 criteria:
•
•
•
•
•
History of coronary artery disease
History of peripheral vascular disease
History of stroke
Undergoing major vascular surgery
Any 3 of 9 risk factors
Exclusion criteria










Aspirin within 72 h of surgery
Hypersensitivity or allergy to aspirin or clonidine
SBP <105 mm Hg
HR <55 bpm without a pacemaker
2º or 3º heart block without pacemaker
Active PUD or GI bleed within 6 weeks
Intracranial haemorrhage within 6 months
Subarachnoid haemorrhage
Epidural haematoma
Taking alpha-2 agonist, alpha methyldopa, reserpine,
ticagrelor or thienopyridine
More exclusion criteria





Drug-eluting stent within 1 year
Bare-metal stent within 6 weeks
Planned use during first 3 days after surgery
• Therapeutic dose anticoagulation
• Therapeutic sc or iv antithrombotic agent
Undergoing intracranial surgery, carotid endarterectomy
or retinal surgery
Prior enrolment in POISE-2
The POISE-2 Study Group



Lead by PHRI in Canada
150-200 centres in 31 countries
20 centres in Australia and NZ



Endorsed by the ANZCA trials group
Funded by NHMRC grant in our region
Contact the ANZCA Trials Group (www.anzca.edu.au)
Conclusions




No pharmacologic intervention currently
proven to be both effective and safe
Reasonable to continue preoperative treatment
with b-blockers, a2-agonists and statins
Reasonable to continue preoperative treatment
with aspirin where risk of withdrawal is high
and risk of bleeding is low
Essential to randomise patients to POISE-2
Thank You