Perioperative Aspirin & POISE-2

Neal Gerstein, MD FASEAssociate Professor, UNM Department of

AnesthesiologyDirector, UNM Division of Cardiac Anesthesia

Disclosures

• None

Objectives

• Review risks of holding aspirin perioperatively.

• To learn when / which procedures aspirin should / should not be held.

• Review POISE-2 methodology.• Examine limitations of POISE-2.• Provide recommendations on

perioperative aspirin management.

Case

• 70 y.o. male for primary TKA• PMH

– TIA 5 years prior– HTN– NIDDM – HLD– Remote tobacco

• Meds– ASA 81 mg/day– Simvastatin– Metformin– Naproxen prn

Background• 100,000,000 non-cardiac operations /year worldwide. • ~ 40% of these patients have / at risk for CV disease.

• Mangano, Anesthesiology 1990

• In the U.S., cardiovascular disease (CAD, CVD, PVD):– Affects >1/3 adults

• Leading cause of morbidity & mortality.• Wolff et al, Ann Int Med 2009• USPTF Ann Int Med 2009

• #1 perioperative complication in patients with CV risk factors → M.I.– Associated mortality rate of 15 – 25%

• Peter et al, Thromb Haemost 2011• Kumar et al, J Gen Int Med 2001

Aspirin’s Role in CV Disease

• Aspirin– platelet aggregation inhibition– thrombosis prevention

• Primary prevention• Secondary prevention– Know aspirin’s indication in these two

contexts

Aspirin in Secondary Prevention

• Most recent AHA/ACC/ACCP guidelines:– Indefinite rx in virtually all with established CAD

or other atherosclerotic disease• ‘unless absolutely contraindicated’• PCI: neuro, cardiac

– 287 study meta-analysis of antiplatelet rx in 135,000 pt’s with CV disease• Aspirin #1 studied rx

– 25% reduction of death from any vascular cause, MI, CVA

Primary Prevention

• Unclear in those without risk factors• Diabetics – 2010 ADA/AHA/ACCF

• Aspirin if increased cardiac risk (10-year risk of cardiac event of >10%). – Men > 50 years / women > 60 years & one of the

following: » Tobacco use» Hypertension» Significant cardiovascular disease family history» Hypercholesterolemia» Albuminuria

Aspirin Pharmacology

Key Points in Aspirin Pharmacology

• 2 isoforms of COX: 1 & 2• Aspirin irreversibly inactivates COX • 170x affinity for COX-1 vs COX-2• A single dose of 30 mg completely

suppresses TXA2 production for 1 week

Aspirin Mechanism

Eur Heart J, Vol 7, May 2005

Platelets – more than just hemostasis

ADP, TXA2

Thrombin coagulation cascade

Inflammatory mediators

Atherosclerosis

Thrombogenicity Neutrophil activation

The ‘Aspirin Withdrawal Syndrome’

‘Aspirin Withdrawal Syndrome’

• Aspirin use is not just an on-off switch

• Complex relationship between platelet: Inhibitio

n

Hemostasis

Inflammation

Aspirin Withdrawal

• Platelet rebound phenomenon in setting of acute aspirin withdrawal.

• This rebound period is characterized by:– Increased thromboxane production– Decreased fibrinolysis

• Leading to a resultant clinical prothrombotic state

• Vial et al, Adv Prostaglandin Thromboxane Leukot Res. 1991

• Beving et al, Blood Coagul Fibrinolysis 1996• Fatah et al, Eur Heart J 1996

• Urine metabolites of TXA2 and PGI2

• Before, during, and after cessation of a 1-week aspirin regimen. –Metabolites (and hence platelet TXA2)

rebound to levels beyond that of study controls.

– Peaked at 7 to 14 days after aspirin withdrawal.

• Measured ‘HHT’ to approximate platelet-TXA2 production– 32 pts who stop aspirin-rx 2 weeks before CABG– 25% of this cohort had 12-HHT levels beyond the

normal range 2 weeks after withdrawal.

• Same investigators, earlier study:– 12-HHT/TXA2 rebound in healthy subjects after

withdrawal of a 1-week aspirin regimen.– Dose dependent

• more rapid rebound with withdrawal of lower aspirin doses.

Rebound affects more than primary hemostasis

• Increase fibrin strength after withdrawal.– Less fibrinolysis when fibrin strength

enhanced.

• Same authors:– demonstrated that patients with more rigid

fibrin networks were more prone to CV events.

Clinically relevant to the Perioperative Period?

Thrombotic Risks of Aspirin Withdrawal in the Perioperative Period

• Aspirin is clearly beneficial for secondary prevention.– 25% RRR in preventing future cardiac or

ischemic events.• ATC BMJ 2002

• Tran et al, JAMA 2004

• Still, typical practice for surgeons and preoperative clinics to council aspirin cessation 7-10 days preoperatively.

• Collet et al, Int J Cardiol 2000

• Cohort 1358 pts admitted for ACS.• Non-user: n=930 (68.%)• Prior-users: n=355 (26.1%)• Recent withdrawals: n=73 (5.4%)

• 2x increase in death rates of ‘withdrawers’ vs prior users / nonusers.

• Average time b/w cessation-cardiac event = 11.9 days.

• Scheduled surgery = 64% cases. • Multivariate analysis:– Antiplatelet cessation• Independent predictor of both death and major

ischemic events.

• Meta-analysis of retrospective studies (1970-2004)– n=49590 (14981 on aspirin)

• CV risks associated with perioperative withdrawal of aspirin vs bleeding risks when continued.

• Withdrawal preceded:– 10.2% of acute cardiovascular events.– 6.1% of lower limb ischemic events.

• Mean timing of event after discontinuation of aspirin: – 8.5 days for coronary events.– 25.8 days for a lower limb event.

• Retrospective case–control– 309 admissions over 2 years with

diagnosis of CVA or TIA & use of long-term aspirin before the index event. • Compared to 309 age- and sex- matched

controls with a history of CVA or TIA on long-term aspirin and no acute event in previous 6 months.

• CVA/TIA: – 13 patients vs 4 controls had discontinued

aspirin in previous 4 weeks: • 4.2% vs 1.3%, P = .03• Odds ratio 3.34 (95% CI: 1.07–10.39)

• Most common reason for aspirin discontinuation:– Surgery

• Mean interval between aspirin d/c and CVA:– 9.5 days

• Days elapsed between aspirin d/c and thrombotic events:– 10.66 • (95% CI 10.25–11.07)

• “… further confirms the major detrimental impact of aspirin withdrawal across a large spectrum of subjects at risk for de-novo or recurrent cardiovascular events.”

• Randomized double blind placebo-controlled.– 220 high-risk patients (PCI excluded).–Undergoing intermediate- to high- risk

noncardiac surgery.

• Randomized to:– daily low-dose aspirin (75mg) or placebo

• 7 days before surgery until 3 days post-procedure

• Aspirin held if needed in placebo group

Inclusion (one of the following)– CAD– Heart failure– Renal impairment– CVA– TIA– Insulin-dep DM

Exclusion– Unstable CAD– Decompensated HF– Shock– Aspirin allergy– < 18 yo– History of ICH, GIB– Rx with warfarin, clopidogrel,

mtx– Vascular surgery

High-risk surgery (large fluid shifts; known cardiac risk

>5%)

• Esophageal• Liver• Pancreatic

Intermediate-risk (cardiac risk 1-5%)

• Head & neck• Intraperitoneal• Intrathoracic• Major ortho• Prostate

• Primary endpoint– Postoperative myocardial damage (TnT)

• Secondary endpoints (any with first 30 days postop):– MACE

• acute MI• cardiac arrest• severe arrhythmia• CV death

– Cardio-cerebrovascular complications• MACE or stroke/TIA

– Perioperative blood loss and major bleeding

• Aspirin use: – Absolute risk reduction = 7.2% [95% CI 1.3–13%]– NNT = 14 [95% CI 7.6–78]

• Majority of patients having MACE had it early postop. – 1 in aspirin group and 8 in the placebo group had

MACE within:• 1st 3 postop days

– (P=0.02).

• Patients on chronic aspirin rx pre-study (n=196; 90% of the study population):

– MACE+ : 10 in placebo vs 1 receiving aspirin – (P=0.03).

What about increased EBL?!

• Prospective blinded placebo-control • To evaluate risk of recurrent

bleeding with low-dose aspirin in pts with actively bleeding peptic ulcers (PU).– Eligible: • active PU bleed & cont. need for aspirin.

Ann Intern Med. 2010;152(1):1-9

• 41 studies - 49,590 patients (14,981 on aspirin)– 12 retrospective obs., 19 prospective obs., 10

randomized

• Dental, biopsies, multi-level spine, THA, major vascular/CEA, ENT, neurosurg, and TURP’s.

• No change in bleeding complications, except:

• TURP/Prostate procedures– aspirin users: 0.4–5.0 units of red blood cells, VS control

patients 0.3–1.7 units

• Randomized double blind placebo-controlled– 220 high-risk CAD patients

• Undergoing intermediate- to high- risk noncardiac surgery.

• Randomized to:– daily low-dose aspirin or placebo

Dermatologic

Chu et al, J Am Acad Dermatol 2011Alcalay et al, Dermatol Surg 2004

• Reviewed bleeding complications: biopsies, excisions, and Mohs procedures while on aspirin– No significant events; do not stop aspirin

Cook-Norris et al, J Am Acad Dermatol 2011• Retrospective analysis, 220 patients, 363 procedures

on DUAL anti-platelet rx (aspirin + clopidogrel)• There were significant wound-related complications

– none life-threatening

• Attributed majority of problems to combination or the clopidogrel

Vascular

Rosenbaum et al, Ann Vasc Surg 2010• Retrospective review of various antiplatelet regimes

in CEA• 260 patients, 171 continued aspirin perioperatively

– Neck hematoma – no difference– Other bleeding complications – no difference

Burdess et al, Ann Surg 2010• Prospective; lower extremity vascular• All on aspirin ± clopidogrel• No statistical difference in major or minor bleeding

on dual APA• Aspirin alone did not impact bleeding-related issues

Vascular - Lindblad et al, Stroke 1993

• Vascular surgeons blinded to aspirin use in CEA: – Could not differentiate patients on

aspirin from patients off aspirin just from bleeding behavior

Urologic - Renal transplantation

Eng et al, Clin Transplant 2011– Retrospective• 59 on aspirin preop vs 213 no anti-platelet

agent

–No significant differences in:• Transfusion requirements• Change in hemoglobin• Hospital LOS

Urologic – Prostate Surgery - 1

• Aspirin may cause significant bleeding complications in TURP procedures.– vascular bed– endogenous urokinase

• 2 studies from 1990’s:– Increased bleeding and need for significant

more blood products in TURP patients on aspirin.

• Wierod et al, Scand J Urol Nephrol 1998• Thurston et al, Br J Urol 1993

Urologic – Prostate Surgery - 2

Ala-Opas et al, Scand J Urol Nephrol 1996

• Chronic - 250mg/day • TURP • No greater EBL than nonusers –aspirin users: 358 mL vs nonusers: 478 mL

Urologic – Prostate Surgery - 3Nielsen et al, Scand J Urol Nephrol 2000

• Prospective, randomized, double-blind, placebo-controlled.• 150 mg continued perioperatively.• Intraop blood loss:

– no difference• Postop blood loss:

– aspirin group (n=26) significantly higher vs placebo (n=27)• median 284ml vs median 144ml, P=0.011

– No significant differences in: • Foley catheter removal• LOS• Transfusion requirements

– Their group recommended holding aspirin for 10 days preoperatively.

General / Trauma Surgery

Ferraris et al, Surg Gyn Obst 1983• Small (n=52) observational study• ‘Unplanned’ appendectomy &

cholecystectomy• No impact on bleeding-related

complications• No additional need for transfusion

General / Trauma Surgery

Ott et al, J Trauma 2010• Retrospective, 212 patients adm to L-1 trauma

center (excluding head injuries)• 67 on aspirin, clopidogrel, warfarin, or combo– Total LOS - increased

• 11.5 days vs 8.8 days, P = 0.04

– ICU LOS – no difference• 4.7 days vs 3.9 days, P = 0.5

– Injury Severity Score – no difference• 21.4 vs 21.0, P = 0.76

– Mortality – no difference• 13.4% users vs 9.7% nonusers, P = 0.41.

Orthopedic Surgery - Hip fracture / Femoral neck fractures

Thaler et al, J Trauma 2010• Used PFA in 98 patients on chronic

aspirin rx• 64 (65%) had true impaired platelet

function

Neurosurgery

POISE-2 – PeriOperative Ischemic Evaluation

POISE-2

• Evaluation of the effect of ‘low-dose’ aspirin vs placebo–Non-cardiac surgery– July 2010 - Dec 2013– 135 hospitals / 23 countries– Primary endpoint:• 30-day composite risk of death & nonfatal

MI

POISE-2 - Methods

Initiation- 200mg ASA just before surgery & continued 100mg

for 30-days post-op.

Continuation (daily ASA use pre-op for 4/6 weeks)- stopped aspirin for at least 3 days pre-op- ‘placebo group’ to preop ASA dose after 7-days - ‘aspirin group’ restarted with 100mg postop

No aspirin

No aspirin 3 days preop >>>

Placebo x 7 days postop >>>

Usual dose for balance

200 mg preop >>>

100 mg/d x 30 days post-op

No aspirin 3 days preop >>>

200 mg preop >>>

100 mg/d postop x 7 days >>>

Usual dose for balance

Problem 1 – High-risk Population?

Problem 2 – Placebo Group really Placebo?

• Placebo group:– 2821 IS patients received no aspirin

during study period– 2191 CS returned to usual aspirin dose

within 7 days

• Hence, 44% (2191 / (2821 + 2191)) of Placebo Group was actually on aspirin for 23 of 30 day follow-up

Problem 3 – Additional Anticoagulants

Bleeding – 1/7 ‘Safety Outcomes’

• POISE-2 … far from final word

POISE-2 Issues

• Only ~1/3 aspirin-patients were on appropriate indications.

• 4-4.5% in each group received therapeutic anti-coagulant.

• 1.2% in each group received P2Y12 inhibitors.

• Safety of aspirin withdrawal in pts with prior percutaneous coronary interventions not fully elucidated.

• Placebo (?) vs aspirin.

Summary• Temporary cessation of aspirin rx should only be

considered for procedures:– risk of bleeding > > risk of a major adverse CV event

• 2 major groups of procedures to consider when contemplating aspirin cessation:– 1) Additional / excessive EBL would lead to worse outcomes:

• intracranial surgery• spinal canal procedures• posterior chamber eye surgery• middle ear surgery• possibly prostate surgery

• Korinth M, Acta Neurochir 2006• Chassot et al, BJA 2007

• Korinth et al, Eur Spine 2007

– 2) Procedures in which an increase in surgical blood loss to have minimal consequences: • no change in transfusion requirements or no increase in major

morbidity or mortality.• Samana et al, Can J Anes 2002

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