POISE-2 ASA

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Devereaux PJ, et al. "Aspirin in patients undergoing noncardiac surgery". The New England Journal of Medicine. 2014. 370(16):1494-1503.
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Clinical Question

Among patients with elevated operative risk does perioperative aspirin administration reduce all-cause mortality or non-fatal MI when compared to placebo?

Bottom Line

Among patients with elevated operative risk, perioperative aspirin does not reduce rate of all-cause mortality or non-fatal MI when compared to placebo. It is associated with increased risk of major bleeding.

Major Points

Daily ASA is effective for primary and secondary prevention of MI in non-surgical patients.[1] However, the use of this antiplatelet medication in surgical patients is controversial given its associated bleeding risk. The PEP trial (published in 2000)[2] demonstrated an increased rate of bleeding when aspirin was used in patients undergoing repair of a hip fracture. The medication demonstrated a decreased risk of VTE. Curiously, this trial also showed a small but detectable increased risk of MIs with ASA use. Given these findings, the role of perioperative ASA use was unclear.

The 2014 Perioperative Ischemic Evaluation 2, aspirin arm (POISE-2 ASA) trial randomized 10,010 patients at elevated risk for CV events undergoing non-cardiac surgery to ASA or placebo. The therapy was initiated immediately before the surgery and stopped 7 days following. Those on aspirin at baseline stopped taking their usual dose 3 days before surgery. With 30 days of follow-up, aspirin was not associated with a reduction in the primary outcome of all-cause mortality or non-fatal MI. Additionally, ASA did not alter the rates of MI or VTE. ASA was associated with a small reduction in stroke in those not on the medication at baseline. (The authors note that this may be due to chance given the disproportionate stroke reduction in comparison to the efficacy of the medication in the non-operative setting). Most notably, there was an increased rate of major bleeding with ASA use (4.6% vs. 3.8%) though not in those on ASA at baseline.

Guidelines

ACC/AHA Perioperative CV evaluation and management for non-cardiac surgery (2014, adapted)[3]

  • If non-emergent or non-urgent non-cardiac surgery and no prior coronary stenting, it may be reasonable to continue aspirin when risk of increased cardiac events outweighs risk of bleeding (class IIb, level B)
  • If non-cardiac and non-carotid surgery and no prior coronary stenting, initiation or continuation of ASA is not beneficial (class III, level B) unless risk of ischemic events outweighs risk of surgical bleeding (class III, level C)

Design

  • Multicenter, randomized, double-blind, placebo controlled trial
  • N=10,010
    • Aspirin (n=4,998)
    • Placebo (n=5,012)
  • Setting: 135 centers in 23 countries
  • Enrollment: 2010-2013
  • Follow-up: 30 days
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality or non-fatal MI

Population

Inclusion Criteria

  • Age ≥45 years undergoing in-hospital non-cardiac surgery with ≥1 of the following:
    • CAD
    • PAD
    • Prior stroke
    • Planned major vascular surgery
    • ≥3 of the following 9 risk factors:
      • Age ≥70 years
      • Major surgery defined as intraperitoneal, intrathroacic, retroperitoneal, "major" orthopedic surgery
      • HF
      • Prior TIA
      • DM on oral medication or insulin
      • HTN
      • Preoperative creatinine >2.0 mg/dL (>175 umol/L)
      • Smoking in prior 2 years
      • Emergent or urgent surgery

Exclusion Criteria

  • Hypersensitivity/allergy to aspirin or clonidine
  • Aspirin in prior 72 hours
  • SBP <105 mmHg
  • HR <55 BPM
  • No PPM and second or third degree heart block
  • Active PUD or GIB in prior 6 weeks
  • ICH in prior 6 months
  • SAH or epidural hematoma unless >6 months prior and repaired
  • DES in prior year or BMS in prior 6 weeks
  • Thienopyridine or ticagrelor in prior 72 hours or intent to use in the first 7 post-operative days
  • Use of alpha-2 antagonist, alpha methyldopa, MAOI, or reserpine
  • Planned use or therapeutic anticoagulation in first 3 post-operative days
  • Surgery that is intracranial, a CEA, or retinal
  • Lack of consent or previously enrolled in this trial

Baseline Characteristics

From the aspirin group. Groups were similar.

  • Demographics: Age 68.6 years, male 52.0%
  • Eligibility:
    • Vascular disease: Any 32.7%, CAD 23.1%, PAD 8.8%, stroke 5.0%
    • Major vascular surgery: Any 4.9%
    • Risk: Meeting ≥3 of 9 criteria 83.3%, major surgery (intraperitoneal, intrathoracic, retroperitoneal, major orthopedic) 78.2%, emergency surgery 7.1%, age ≥70 years 52.8%, diabetes on medication 37.5%, creatinine >2.0 mg/dL 3.3%, prior HF 3.7%, prior TIA 3.6%, prior HTN 85.6%, smoking in prior 2 years 25.9%
  • Non-eligibility PMH: CABG 4.8%, PCI 4.7%, HD in prior week 1.4%
  • Surgery: Any 99.1%, orthopedic 38.2%, general 26.8%, urologic or gynecologic 16.7%, vascular 6.2%, thoracic 5.9%, other 8.6%
  • Baseline labs: Hgb 13.3 g/dL
  • Time to surgery: ≤24 hours 95.6%, 24-48 hours 0.9%, ≥48 hours 3.5%
  • Medications in prior 24 hours: Prophylactic anticoagulant 12.6%, therapeutic anticoagulant 4.5%, NSAID 32.0%, COX-2 inhibitor 5.3%, statin 41.9%, beta-blocker 28.9%, P2Y12 inhibitor 1.2%

Interventions

  • Randomization to a group with stratification according to baseline ASA use as either initiation stratum (not on ASA at baseline) or continuation stratum (on ASA at baseline)
    • ASA - ASA 200 mg PO just before surgery then 100 mg PO qday for 30 days (initiation stratum) or 7 days (continuation stratum)
    • Placebo
  • Those on aspirin at baseline were required to stop taking the medication ≥3 days before surgery and did not restart the medication until 7 days after surgery
Patients were also randomized to clonidine or placebo, which is out of the scope of this summary.

Outcomes

Presented as aspirin vs. placebo.

Primary Outcome

All-cause mortality or non-fatal MI
7.0% vs. 7.1% (HR 0.99; 95% CI 0.86-1.15; P=0.92)
Initiation: 6.5% vs. 6.6% (HR 0.99; 95% CI 0.81-1.21; P=0.92)
Continuation: 7.7% vs. 7.8% (HR 1.00; 95% CI 0.81-1.23; P=0.97)

Secondary Outcomes

All-cause mortality, non-fatal MI, or non-fatal stroke
7.2% vs. 7.4% (HR 0.98; 95% CI 0.85-1.13; P=0.80)
Initiation: 6.6% vs. 6.9% (HR 0.95; 95% CI 0.78-1.17; P=0.64)
Continuation: 8.1% vs. 8.0% (HR 1.01; 95% CI 0.82-1.25; P=0.90)
All-cause mortality, non-fatal MI, cardiac revascularization, non-fatal PE, non-fatal DVT
8.0% vs. 8.1% (HR 0.99; 95% CI 0.86-1.14; P=0.90)
Initiation: 7.3% vs. 7.6% (HR 0.97; 95% CI 0.80-1.17; P=0.73)
Continuation: 9.0% vs. 8.8% (HR 1.02; 95% CI 0.83-1.24; P=0.86)

Additional Analyses

Mortality
All-cause: 1.3% vs. 1.2% (HR 1.05; 95% CI 0.74-1.49; P=0.78)
Initiation: 1.4% vs. 1.3% (HR 1.01; 95% CI 0.64-1.58; P=0.98)
Continuation: 1.2% vs. 1.1%; HR 1.12; 95% CI 0.65-1.95; P=0.67)
Cardiovascular: 0.7% vs. 0.7% (HR 1.00; 95% CI 0.63-1.60; P=0.99)
Initiation: 0.7% vs. 0.7% (HR 1.01; 95% CI 0.53-1.90; P=0.99)
Continuation: 0.7% vs. 0.7% (HR 1.00; 95% CI 0.50-2.00; P=1.00)
Cardiac
MI: 6.2% vs. 6.3% (HR 0.98; 95% CI 0.84-1.15; P=0.85)
Initiation: 5.6% vs. 5.7% (HR 0.98; 95% CI 0.79-1.22; P=0.86)
Continuation: 6.9% vs. 7.0% (HR 0.99; 95% CI 0.79-1.24; P=0.93)
Cardiac revascularization: 0.3% vs. 0.3% (HR 0.77; 95% CI 0.37-1.58; P=0.47)
Initiation: 0.1% vs. 0.2% (HR 0.43; 95% CI 0.11-1.67; P=0.22)
Continuation: 0.5% vs. 0.5% (HR 1.00; 95% CI 0.42-2.40; P=1.00)
Non-fatal cardiac arrest: 0.2% vs. 0.2% (HR 0.75; 95% CI 0.32-1.79: P=0.52)
Initiation: 0.1% vs. 0.3% (HR 0.50; 95% CI 0.15-1.67; P=0.22)
Continuation: 0.2% vs. 0.2% (HR 1.25; 95% CI 0.34-4.66; P=0.74)
New clinically important AF: 2.2% vs. 1.9% (HR 1.16; 95% CI 0.88-1.53; P=0.28)
AF with angina, HF, or hypotension or requiring rate controlling medication, antiarrhythmic, or cardioversion.
VTE/thrombus
PE: 0.7% vs. 0.6% (HR 1.07; 95% CI 0.65-1.74; P=0.79)
DVT: 0.5% vs. 0.7% (HR 0.72; 95% CI 0.43-1.20; P=0.20)
Peripheral arterial thrombus: 0.3% vs. 0.3% (HR 0.87; 95% CI 0.41-1.83; P=0.71)
Amputation
0.2% vs. 0.3% (HR 0.77; 95% CI 0.34-1.76; P=0.54)
Cardiovascular rehospitalization
1.4% vs. 1.1% (HR 1.30; 95% CI 0.91-1.86; P=0.15)
AKI requiring HD
0.7% vs. 0.4% (HR 1.75; 95% CI 1.00-3.09; P=0.05)
Initiation: 0.5% vs. 0.4% (HR 1.28; 95% CI 0.58-2.83; P=0.54)
Continuation: 0.9% vs. 0.4% (HR 2.41; 95% CI 1.05-5.51; P=0.04)
P-value for interaction 0.28

Subgroup Analysis

There was no difference in the primary outcome for comparisons of initiation vs. continuation of aspirin, non-vascular vs. vascular surgery, revised cardiac risk index score, and history of vascular disease.

Adverse Events

Bleeding
Life-threatening: 1.7% vs. 1.5% (HR 1.19; 95% CI 0.88-1.63; P=0.26)
Initiation: 1.7% vs. 1.7% (HR 1.05; 95% CI 0.70-1.56; P=0.82)
Continuation: 1.7% vs. 1.2% (HR 1.46; 95% CI 0.89-2.41; P=0.13)
Fatal bleed or led to hypotension requiring inotrope/vasopressor support, emergent surgery, or ICH.
Major: 4.6% vs. 3.8% (HR 1.23; 95% CI 1.01-1.49; P=0.04)
Initiation: 4.6% vs. 3.5% (HR 1.34; 95% CI 1.03-1.74; P=0.03)
Continuation: 4.6% vs. 4.1% (HR 1.11; 95% CI 0.84-1.48; P=0.47)[4]
P-value for interaction 0.35
Resulting in Hgb ≤7 g/dL requiring ≥2 units pRBC, Hgb drop ≥5 g/dL requiring ≥2 units pRBC, transfusion of ≥4 units pRBC in 24 hours, requiring an intervention to stop bleeding (embolization, superficial vascular repair, or nasal packing), or bleeding in dangerous area (retroperitoneal, intraspinal, intraocular). Excludes those classified as life-threatening bleeds.
Significant hypotension
42.9% vs. 41.8% (HR 1.03; 95% CI 0.97-1.09; P=0.37)
Stroke
0.3% vs. 0.4% (HR 0.84; 95% CI 0.43-1.64; P=0.62)
Initiation: 0.1% vs. 0.4% (HR 0.25; 95% CI 0.07-0.89; P=0.03)
Continuation: 0.6% vs. 0.3% (HR 1.86; 95% CI 0.74-4.66; P=0.19)
P-value for interaction 0.01
HF
0.9% vs. 0.8% (HR 1.16; 95% CI 0.75-1.79; P=0.50)
Infection
9.8% vs. 9.9% (HR 0.99; 95% CI 0.87-1.12; P=0.86)
Sepsis: 4.9% vs. 5.2% (HR 0.94; 95% CI 0.79-1.13; P=0.52)

Criticisms

  • Potentially underpowered to detect MI benefit
  • Few patients had prior PCI so these findings may not be applicable to that group[5]

Funding

  • Canadian Institutes of Health
  • National Health and Medical Research Council of Australia
  • Spanish Ministry of Health and Social Policy
  • Bayer provided aspirin and Boehringer Ingelheim provided clonidine and funding

Further Reading

  1. ATT Collaboration. "Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials." The Lancet. 2009;373(9678):1849-1860.
  2. PEP trial investigators. "Primary prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial." The Lancet. 2000;355(9212):1295-1302.
  3. Fleisher LA, et al. "2014 ACC/AHA guidelines on perioperative cardiovascular evaluation and management of patients undergoing non-cardiac surgery." Journal of the American College of Cardiology. 2014. E-published 2014-08.
  4. [1]
  5. Vaishnava P and Eagle KA. "Editorial: The yin and yang of perioperative medicine." The New England Journal of Medicine. 2014;370;16:1554-1555.