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Kate Leslie, MBBS, MD, M Epi, FANZCARoyal Melbourne Hospital
POISE-2: Aspirin and Clonidine to Prevent Perioperative MI
Scope of this Talk
Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial
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
Magnitude of the Problem
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
PathophysiologyTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
PMI
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
Supply-Demand Mismatch
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
Coronary Thrombosis
Scope of this Talk
Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial
b-blockersTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
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
(n = 4174)
Placebo(n =
4177)
HR (95% CI)
P value
Primary outcome
243(5.8%)
290(6.9%)
0.83(0.70-0.99)
0.04
Cardiovascular death
75 (1.8%)
58 (1.4%)
0.70 (0.57-0.86)
0.14
Non-fatal MI 151(3.6%)
215(5.1%)
0.70(0.56-0.86)
0.0008
Non-fatal cardiac arrest
21 (0.5%)
19 (0.5%)
1.11(0.60-2.06)
0.74
Outcome Metoprolol
(n = 4174)
Placebo(n =
4177)
HR(95% CI)
Pvalue
Death 129 (3.1%)
97 (2.3%)
1.33 (1.02-1.74)
0.03
Stroke 41 (1.0%)
19 (0.5%)
2.17 (1.26-3.73)
0.005
Hypotension
626 (15.0%)
404 (9.7%)
1.55 (1.38-1.74)
<0.0001
Bradycardia
274 (6.6%)
101 (2.4%)
2.71 (2.17-3.39)
<0.0001
Class I Pre-existing b-blockade should be continued (level C)
Class II 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
StatinsTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
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 patientsb-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
(n = 533)
Control(n = 533)
HR(95% CI)
P valu
e
Primary outcome - bisoprolol
2.1% 6.0% 0.34 (0.17-0.67)
0.002
Primary outcome - fluvastatin
3.2% 4.9% 0.65 (0.35-1.10)
0.17Beneficial effect of bisoprolol not modified by fluvastatin
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-agonistsTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
PMI
a2-agonistsTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
PMI
Favours Clonidine Favours Control
1 50.5 0.1 0.05 0.01
Study Clonidine Control Relative Risk (95% CI)
Ellis 0/30 1/31 0.34 (0.01 to 8.13)
Wallace 1/125 4/65 0.13 (0.01 to 1.14)
Quintin 0/11 1/10 0.31 (0.01 to 6.74)
Stuhmeier 1/145 2/152 0.52 (0.05 to 5.72)
I²=0% 0.27 (0.07 to 0.99)2/311 8/258
Perioperative Mortality
Systemic review of 31 RCTs by POISE-2 investigators
Favours Clonidine Favours Control
1 50.5 0.1 0.05 0.01
Study Clonidine Control Relative Risk (95% CI)
Ellis 0/30 2/31 0.21 (0.01 to 4.13)
Wallace 5/125 3/65 0.87 (0.21 to 3.51)
Stuhmeier 0/145 4/152 0.12 (0.01 to 2.14)
POISE-2 Pilot 2/45 2/45 1.00 (0.15, 6.79)
I²=0% 0.61 (0.23, 1.65)7/345 11/293
Perioperative MI
Systemic review of 31 RCTs by POISE-2 investigators
Favours Clonidine Favours Control
1 5 10 500.5 0.1 0.05 0.01
Study Clonidine Control Relative Risk (95% CI)
Wallace 1/125 0/65 1.57 (0.06 to 38.04)
Schneemilch 0/40 5/40 0.09 (0.01 to 1.59)
POISE-2 Pilot 1/45 0/45 3.00 (0.13 to 71.74)
I²=37% 0.69 (0.07, 6.35)2/210 5/150
Perioperative Stroke
Systemic review of 31 RCTs by POISE-2 investigators
Favours Clonidine Favours Control
1 5 10 50 1000.5
Study Clonidine Control Relative Risk (95% CI)
Wright 14/30 0/30 29.00 (1.81 to 465.07)
Pluskwa 12/14 8/15 1.61 (0.96 to 2.70)
Bernard 2/16 0/16 5.00 (0.26 to 96.59)
Bernard 3/25 0/25 7.00 (0.38 to 128.87)
Ellis 2/30 3/31 0.69 (0.12 to 3.84)
Takahasi 17/21 5/17 2.75 (1.28 to 5.92)
Quintin 5/11 2/10 2.27 (0.56 to 9.20)
Park 8/22 2/22 4.00 (0.95 to 16.75)
Owen 14/15 4/14 3.27 (1.41 to 7.56)
Parlow 2/10 0/10 5.00 (0.27 to 92.62)
Matot 2/18 0/18 5.00 (0.26 to 97.37)
Wallace 24/125 11/65 1.13 (0.59 to 2.17)
Sarkar 2/22 1/21 1.91 (0.19 to 19.52)
I²=18% 2.13 (1.47 to 3.09)107/359 36/294
Hypotension (high dose)
Systemic review of 31 RCTs by POISE-2 investigatorsControl Clonidin
eControl Clonidin
e
Favours Clonidine Favours Control
1 5 10 500.5
Study Clonidine Control Relative Risk (95% CI)
Vanderstappen 4/140 2/140 2.00 (0.37 to 10.74)
Stuhmeier 20/145 26/152 0.81 (0.47 to 1.38)
Sia 4/50 3/50 1.33 (0.31 to 5.65)
Mayson 18/24 13/19 1.10 (0.75 to 1.61)
Fehr 10/25 10/25 1.00 (0.51 to 1.97)
Nader 2/7 2/8 1.14 (0.21 to 6.11)
Rhee 5/52 1/26 2.50 (0.31 to 20.31)
Morris 5/21 3/18 1.43 (0.40 to 5.17)
Stapelfeldt 15/17 12/17 1.25 (0.88 to 1.78)
Watanabe 8/22 4/20 1.82 (0.65 to 5.12)
Schneemilch 19/40 5/40 3.80 (1.57 to 9.18)
Lemes 1/33 0/35 3.18 (0.13 to 75.33)
POISE-2 Pilot 13/45 14/45 0.93 (0.49, 1.75)
I²=0% 1.19 (0.98, 1.44)124/621 95/595
Hypotension (low dose)
Systemic review of 31 RCTs by POISE-2 investigatorsControl Clonidin
e
Conclusions
Indications for peri-operative 2-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
PathophysiologyTRIGGERS: surgery, anaesthesia, analgesia, intubation,
extubation, pain, hypothermia, bleeding, anaemia, fasting
InflammationHypercoagulabilityStress state Hypoxic state
Plaquefissuring
Plaquefissuring
Coronarythrombosis
O2
demandO2
delivery
Myocardialischaemia
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 patients160 mg/day aspirin or placebo for 35 days for
PE preventionOutcome 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
10,000 high-risk non-cardiac surgery patients
Aspirin Clonidine Both Neither
30-day incidence of cardiovascular death & non-fatal MI
POISE-2 Trial
Drug Administration Clonidine
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
Aspirin-naïve 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