Kate Leslie, MBBS, MD, M Epi, FANZCA Royal Melbourne Hospital POISE-2: Aspirin and Clonidine to Prevent Perioperative MI

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


b-blockersTRIGGERS: surgery, anaesthesia, analgesia, intubation,



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,



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


a2-agonistsTRIGGERS: surgery, anaesthesia, analgesia, intubation,



Plaquefissuring

Plaquefissuring

Coronarythrombosis

O2

demandO2

delivery

Myocardialischaemia

PMI

a2-agonistsTRIGGERS: surgery, anaesthesia, analgesia, intubation,



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


1 50.5 0.1 0.05 0.01


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



1 5 10 500.5 0.1 0.05 0.01


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



1 5 10 50 1000.5


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


1 5 10 500.5


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


Aspirin Mode of Action

Primary and secondary MI prevention

PathophysiologyTRIGGERS: surgery, anaesthesia, analgesia, intubation,



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


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

Documents

Kate Leslie, MBBS, MD, M Epi, FANZCA Royal Melbourne Hospital POISE-2: Aspirin and Clonidine to Prevent Perioperative MI