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POISE-2: Aspirin and Clonidine to Prevent Perioperative MI

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 a 2 -agonists Aspirin The POISE-2 Trial.

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POISE-2: Aspirin and Clonidine to Prevent Perioperative MI

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

  2. Scope of this Talk Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial

  3. 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 5million suffer perioperative cardiac event Despite magnitude of problem no proven safe and effective prophylactic interventions Magnitude of the Problem

  4. 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

  5. Pathophysiology TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  6. 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

  7. 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

  8. Scope of this Talk Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial

  9. b-blockers TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  10. 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)

  11. 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)

  12. 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

  13. Statins TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  14. 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

  15. Fluvastatin Both Neither Bisoprolol 0-30 day pre-op & 30-day post-op open-label treatment 30-day incidence of cardiovascular death & non-fatal MI 1000 intermediate-risk non-cardiac surgery patients b-blocker and statin naive

  16. Beneficial effect of bisoprolol not modified by fluvastatin

  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

  18. Scope of this Talk Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial

  19. a2-agonists TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  20. a2-agonists TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  21. Perioperative Mortality Systemic review of 31 RCTs by POISE-2 investigators

  22. Perioperative MI Systemic review of 31 RCTs by POISE-2 investigators

  23. Perioperative Stroke Systemic review of 31 RCTs by POISE-2 investigators

  24. Hypotension (high dose) Control Control Clonidine Clonidine Systemic review of 31 RCTs by POISE-2 investigators

  25. Hypotension (low dose) Control Clonidine Systemic review of 31 RCTs by POISE-2 investigators

  26. 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

  27. Scope of this Talk Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial

  28. Aspirin Mode of Action Primary and secondary MI prevention

  29. Pathophysiology TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring • O2 demand O2 delivery Coronary thrombosis Myocardial ischaemia PMI

  30. 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

  31. 13,356 hip fracture patients 160 mg/day aspirin or placebo for 35 days for PE prevention

  32. 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

  33. 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 widespreaduse for perioperative primary prevention is not currently justified

  34. Scope of this Talk Pathophysiology of perioperative MI Measures to prevent perioperative MI a2-agonists Aspirin The POISE-2 Trial

  35. Clonidine Both Neither Aspirin 30-day incidence of cardiovascular death & non-fatal MI POISE-2 Trial 10,000 high-risk non-cardiac surgery patients

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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)

  41. 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

  42. Thank You

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