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Review Articles: Narrative Review Article

A Comprehensive Update on Aspirin Management During Noncardiac Surgery

Gerstein, Neal S. MD, FASE*; Albrechtsen, Cory L. BS; Mercado, Nestor MD, PhD; Cigarroa, Joaquin E. MD§; Schulman, Peter M. MD

Author Information
doi: 10.1213/ANE.0000000000005064

Abstract

Aspirin is integral to the management of cardiovascular (CV) disease (including coronary artery disease [CAD], cerebrovascular disease [CVD], and peripheral arterial disease [PAD]) and is consequently one of the most widely used medications in the world.1 In the United States, aspirin is prescribed to up to 5% of adults on a long-term basis,2 and more than 6 million people take aspirin daily without a clinician’s recommendation.3 The evidence and indications for aspirin use continuously evolve, and recent trials question its efficacy in certain contexts, such as primary prevention.4,5

Up to 5% of all surgical patients over 45 years old experience a major adverse CV event (MACE) within 30 days of surgery.6 Myocardial infarction (MI) is the most common cause of perioperative mortality, and the risk of death from a perioperative MI within 30 days of surgery is 10%.7–11 Although one third of patients undergoing noncardiac surgery who are at risk for major CV complications receive aspirin during the perioperative period, uncertainty remains about how aspirin should be optimally managed perioperatively, and significant practice variability remains.12–16 Limited evidence suggests that continuing aspirin prevents MACE in high-risk patients undergoing noncardiac surgery.16–18 The risks of stopping perioperative aspirin may be amplified by the proinflammatory hypercoagulable state engendered by surgery potentially leading to acute thrombosis and myocardial ischemia.15,19 Moreover, an aspirin withdrawal phenomenon has been postulated, further increasing these thrombotic risks and attendant sequelae.19–21 Conversely, aspirin increases the risk of surgical bleeding potentially leading to hemodynamic instability and myocardial ischemia from supply-demand mismatch.

This review provides a comprehensive, evidence-based update on aspirin management during noncardiac surgery. It summarizes the most recent literature for the use of aspirin in the primary and secondary prevention of CV disease, the evidence for continuing or stopping aspirin in different subsets of patients undergoing noncardiac surgery, and provides management recommendations for the perioperative clinician. We performed a comprehensive PubMed and Medline literature search using the keywords: aspirin, aspirin withdrawal, perioperative, CAD, CVD, peripheral artery disease, and CV disease; we manually reviewed all relevant citations for inclusion.

ASPIRIN USE IN CV DISEASE

Aspirin irreversibly acetylates both cyclooxygenase-1 and cyclooxygenase-2.19 At low doses (75–100 mg daily) typically used for the management of CV disease, the impact on cyclooxygenase-1 predominates, which produces its antithrombotic effects by inhibiting the production of thromboxane A2 (TXA-2) and attenuating platelet aggregation.1,20

Aspirin in the Primary Prevention of CV Disease

Before 2018, aspirin was recommended for men >50 years and women >60 years without established CV disease, provided they had certain CV risk factors (ie, diabetes with certain concomitant risk factors) and a ≥10% risk of developing CV disease within a 10-year period.1,22–24 The cutoff of ≥10% risk of CV disease within 10 years was established to balance the associated increased risk of bleeding with aspirin (primarily gastrointestinal [GI]; rarely, hemorrhagic stroke) against its salutary CV effects. However, beginning in 2018, the results of 3 randomized prospective trials and 2 subsequent large meta-analyses were published challenging prior recommendations.25–27

The Aspirin in Reducing Events in the Elderly (ASPREE)25 trial compared 100 mg of aspirin per day (n = 9525) to placebo (n = 9589) in a healthy elderly population without CV disease over a median follow-up of 4.7 years. No difference was found between the groups in the composite primary end point of death, dementia, or persistent physical disability (hazard ratio [HR] = 1.01, 95% confidence interval [CI], 0.92–1.11; P = .79). Furthermore, while aspirin did not yield a CV benefit, its use resulted in a higher risk of major bleeding (HR = 1.39, 95% CI, 1.18–1.62; P < .001).25

The A Study of Cardiovascular Events iN Diabetes (ASCEND)26 trial randomized 15,480 patients over 40 years old with diabetes and without CV disease to aspirin 100 mg/d or placebo. During a mean follow-up of 7.4 years, aspirin use was associated with a 12% reduction in the rate of serious vascular events (composite of nonfatal MI, nonfatal stroke or transient ischemic attack [TIA], or death from any vascular cause excluding intracranial hemorrhage; rate ratio = 0.88, 95% CI, 0.79–0.97; P = .01). However, the rate of major bleeding (mainly GI and other extracranial events) was 29% greater in the aspirin group (rate ratio = 1.29, 95% CI, 1.09–1.52; P = .003).26 All-cause mortality between the 2 groups was similar (rate ratio = 0.94, 95% CI, 0.85–1.04).

The use of Aspirin to Reduce Risk of Initial Vascular Events in patients at moderate risk of CV disease (ARRIVE)27 trial randomized 12,546 men ≥55 years and women ≥60 years without diabetes or CV disease but at a 10-year CAD risk of 10%–20% to receive 100 mg of daily aspirin or placebo. During a median follow-up of 5 years, there was no difference in the primary efficacy end point (composite of time to first MI, stroke, CV death, unstable angina, or TIA) between the groups (HR = 0.96, 95% CI, 0.81–1.13; P = .60). However, nonfatal GI bleeding was 2-fold higher with aspirin (HR = 2.11, 95% CI, 1.36–3.28; P = .0007).27 There was no difference in the rate of fatal bleeding or all-cause mortality (HR = 0.99, 95% CI, 0.8–1.24; P = .95).

In 2019, 2 meta-analyses examined the use of aspirin in primary prevention and included the 3 aforementioned randomized controlled trials (RCTs). The first analyzed 11 trials with 157,248 subjects and found no difference in the incidence of all-cause mortality with aspirin, including in those with diabetes or with a >7.5% 10-year risk for CV disease. Moreover, aspirin was found to be associated with an increased incidence of major bleeding.4 The second analyzed 13 trials with 164,225 subjects and found that aspirin use was associated with a significant reduction in a composite CV outcome (mortality, nonfatal MI, and nonfatal stroke; HR = 0.89, 95% CI, 0.84–0.94), but also found an increased risk of major bleeding events (HR = 1.43, 95% CI, 1.30–1.56).5

Table 1. - Current Antiplatelet Therapy Recommendations From ACC/AHA Guidelines on the Primary Prevention of Cardiovascular Disease
2019 ACC/AHA Guideline28
Consider for select patients 40- to 70-y old with high CV disease risk but not at increased bleeding risk
COR: IIB (weak but benefit ≥ risk)
LOE: A
Not recommended for patients ≥70-y olda or anyone at increased risk of bleedingb
COR: III (harm)
These updated 2019 guidelines differ from previous ACC/AHA primary prevention guidelines in that the use of aspirin in select high-risk patients is now downgraded from a class I to class IIb recommendation. Moreover, this update recommends against prophylactic aspirin use in patients >70 y or in anyone at increased risk of bleeding regardless of age.
Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; COR, class of recommendation; CV, cardiovascular; LD, limited data; LOE, level of evidence; R, randomized.
aLOE B-R.
bLOE C-LD.

Table 2. - Current American College of Cardiology/American Heart Association Recommendations on Antiplatelet Therapy for Secondary Prevention of CAD
CAD After ACS (NSTEMI or STEMI)29
DAPT Aspirin Monotherapy
Medical management only 12 mo; COR: I Lifelong
s/p Thrombolytic treatment 14 d–12 mo; COR: I Lifelong
s/p BMS or DES 12 mo; COR: I Lifelong
s/p CABG 12 mo; COR: I Lifelong
Stable CAD29
DAPT Aspirin Monotherapy
No history of ACS, PCI, CABG within 12 mo None; COR: III Lifelong
BMS 1 mo; COR: I
>1 mo; COR: IIb
Lifelong
DES 6 mo; COR: I
>6 mo; COR: IIb
Lifelong
s/p CABG 12 mo; COR: IIb Lifelong
CAD may be either in the context of (a) recent ACS with or without an intervention or (b) stable CAD (no ACS or intervention prior 12 mo) with or without a planned intervention. Recommendation classes: class I = strong (benefit >>> risk); class IIa = benefit >> risk; class IIb = weak but with benefit (benefit ≥ risk); class III = harm.
Abbreviations: ACS, acute coronary syndrome; BMS, bare metal stent; CABG, coronary artery bypass grafting; CAD, coronary artery disease; COR, class of recommendation; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; NSTEMI, non–ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST elevation myocardial infarction.

Table 3. - Current American Heart Association/American Stroke Association Recommendations on Antiplatelet Therapy for Secondary Prevention of CVD31
DAPT Aspirin Monotherapy
Minor ischemic stroke or TIA 21 d; COR IIb/LOE B Lifelong
Ischemic stroke or TIA within 30 d due to severe stenosis (70%–99%) of a major intracranial artery 3 mo; COR: IIb/LOE B Lifelong
Ischemic stroke or TIA + AF unable to take oral anticoagulation Unclear duration/may be reasonable; COR: class IIb/LOE B Lifelong
COR: class I/LOE A
Rheumatic MV disease + ischemic stroke or TIA while on adequate VKA regimen Unclear duration but possible benefit
COR: class IIb/LOE C
Ischemic stroke or TIA + native AV or nonrheumatic MV disease without AF Lifelong
COR: I/LOE C
Ischemic stroke or TIA + mechanical MV or AV on VKA Lifelong
COR: I/LOE B
Ischemic stroke or TIA + bioprosthetic MV or AV without other anticoagulants beyond 3–6 mo Lifelong
COR: I/LOE C
Ischemic stroke or TIA + aortic arch atheroma Lifelong
COR: I
Dual antiplatelet agent use and/or addition of a VKA therapy and duration vary based on stroke etiology (ie, vascular stenosis, atrial fibrillation, rheumatic disease, prosthetic mitral, and/or aortic valve). Recommendation classes: class I = strong (benefit >>> risk); class IIa = benefit >> risk; class IIb = weak but with benefit (benefit ≥ risk); class III = harm.
Abbreviations: AF, atrial fibrillation; AV, aortic valve; COR, class of recommendation; CVD, cerebrovascular disease; DAPT, dual antiplatelet therapy; LOE, level of evidence; MV, mitral valve; TIA, transient ischemic attack; VKA, vitamin K antagonist.

Table 4. - Antiplatelet Therapy Recommendations Based on Current American College of Cardiology/American Heart Association Guidelines on the Management of Patients With Lower Extremity Peripheral Artery Disease33
DAPT Aspirin or Clopidogrel Monotherapy
Symptomatic (claudication or prior lower extremity revascularization) PAD Unclear duration
COR: IIb/LOE moderate-quality from 1 or more RCTs or meta-analyses of moderate-quality RCTs
Lifelong
COR: I/LOE A
Symptomatic/after recent lower extremity revascularization Unclear duration
COR: IIb/LOE randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, physiological or mechanistic studies in humans
Asymptomatic PAD (ABI ≤ 0.90) Lifelong
COR: IIa/LOE expert opinion
Asymptomatic PAD with borderline ABI (0.91–0.99) Lifelong
COR: IIb/LOE moderate-quality
Aspirin or clopidogrel monotherapy is lifelong therapy in all clinical scenarios with unclear duration for DAPT use. Recommendation classes: class I = strong (benefit >>> risk); class IIa = benefit >> risk; class IIb = weak but with benefit (benefit ≥ risk); class III = harm.
Abbreviations: ABI, ankle brachial index; COR, class of recommendation; DAPT, dual antiplatelet therapy; LOE, level of evidence; PAD, peripheral arterial disease; RCT, randomized controlled trial.

The results of these studies led the American College of Cardiology (ACC)/American Heart Association (AHA) to publish their latest Guideline on the Primary Prevention of Cardiovascular Disease in 2019 (Table 1),28 in which the use of aspirin in select high-risk patients was downgraded from class I to IIb.28 Furthermore, the guideline now recommends against prophylactic aspirin use in patients >70 years or in anyone at increased risk of bleeding regardless of age (class III).

Aspirin for Secondary Prevention of CV Disease

Low-dose aspirin therapy provides significant net clinical benefit for patients at risk for subsequent events secondary to existing CV disease (CAD, CVD, and PAD). Current guidelines for the secondary prevention of CV disease recommend antiplatelet regimens based on CV disease type, clinical context (ie, with or without recent acute coronary syndrome [ACS]), and chronicity as outlined in Tables 2–4.

The benefit of aspirin in secondary prevention was conclusively demonstrated by the 2002 Antithrombotic Trialists’ Collaboration (ATC) meta-analysis.30 This study evaluated 16 randomized trials in 71,912 high-risk patients with established CV disease and found that antiplatelet therapy (principally aspirin) reduced all-cause mortality, nonfatal MI, and nonfatal stroke in these high-risk patients to a more significant degree than it increased nonfatal extracranial bleeding.30 The most current ACC/AHA guideline on the management of CAD recommends lifelong aspirin in nearly all pertinent clinical scenarios.29

Similarly, the most recent AHA/American Stroke Association guideline on secondary stroke prevention gives lifelong antiplatelet therapy (aspirin, clopidogrel, or aspirin/dipyridamole combination) a class I recommendation in patients with a history of ischemic stroke or TIA.31 In a metaregression analysis of 11 placebo-controlled trials examining the use of aspirin for secondary stroke prevention, aspirin was associated with a relative risk reduction of 15% (95% CI, 6–23).32 The ATC meta-analysis also demonstrated that antiplatelet therapy led to a relative risk reduction from recurrent ischemic stroke of approximately 22% with a number needed to treat of 28 over 2.5 years.30

Finally, for patients with established PAD, the ATC meta-analysis also demonstrated a 23% (P = .004) reduction in recurrent serious vascular events (MI, stroke, and vascular death) with the use of an antiplatelet agent.30 The current AHA/ACC guideline considers daily aspirin or clopidogrel a class I recommendation in patients with symptomatic PAD (ie, claudication or prior lower extremity revascularization) to reduce the risk of MI, stroke, and vascular death.33

THE ASPIRIN WITHDRAWAL SYNDROME

Given the importance of aspirin in managing CV disease, it is logical to postulate that its temporary discontinuation may increase CV risk. Concern for an “aspirin withdrawal syndrome” is supported by limited evidence.19,21,34–36 Doutremepuich et al,34 measuring intravascular thrombus and emboli in an animal model, demonstrated a prothrombotic state peaking 8–10 days after a single aspirin dose, consistent with a withdrawal syndrome. Vial et al37 measured urine metabolites of TXA-2 (a product of activated platelets with prothrombotic and vasoconstrictor properties) before, during, and after cessation of a 1-week aspirin regimen and found these metabolites exceeded levels beyond those in controls. The peak metabolite concentrations occurred 7–14 days after aspirin withdrawal. Beving et al36 measured a platelet metabolite (12-L-hydroxy5,8,10-heptadecatrienoic acid [12-HHT]) in 32 patients whose aspirin therapy was held 2 weeks before coronary bypass surgery. Fourteen days after cessation, 25% of the cohort had 12-HHT levels exceeding the normal range. These same investigators had previously reported a similar 12-HHT rebound in healthy subjects after cessation of a 1-week aspirin regimen.35 In both trials by Beving et al,36 the platelet function rebound effect was dose dependent, with a faster rebound associated with the withdrawal of low-dose aspirin.35,36 In a clinical context, Rodríguez et al38 completed a case-control study of nearly 40,000 adults prescribed aspirin for secondary prevention of CV disease. They found those who recently stopped taking aspirin had a significantly increased risk of nonfatal MI- or CAD-related death combined (rate ratio = 1.43, 95% CI, 1.12–1.84) and nonfatal MI alone (rate ratio = 1.63, 95% CI, 1.23–2.14). However, the association between recently stopping low-dose aspirin and the risk of death from CAD was not significant (rate ratio = 1.07, 95% CI, 0.67–1.69).38 Another cohort study by Sundström et al39 evaluated over 600,000 patients using aspirin for either primary or secondary prevention and found that discontinuing aspirin in the absence of major bleeding or surgery was associated with a >30% increased risk of CV events. Conversely, Alcock et al21 administered daily aspirin to 11 healthy subjects and examined the impact on platelet function sampled at baseline and then at 7, 14, and 21 days after the final aspirin dose. At each of the time points when aspirin was stopped, no evidence of increased platelet aggregation or rebound effect was found.21

In summary, some limited evidence suggests that abrupt aspirin withdrawal leads to hyperthrombosis and some observational data have demonstrated an association between aspirin cessation and adverse CV events. Although the mechanism for an aspirin withdrawal syndrome has not been completely elucidated, it is likely related to platelet hyperactivity characterized by increased TXA production and decreased fibrinolysis. The true clinical significance of aspirin withdrawal remains unclear and ripe for further investigation.

ASPIRIN DURING THE PERIOPERATIVE PERIOD

How aspirin should be optimally managed in patients undergoing noncardiac surgery is a vexing problem with significant clinical implications. Given the nonperioperative data demonstrating the beneficial role of aspirin in secondary prevention along with the adverse impact of a potential aspirin withdrawal syndrome and the proinflammatory hypercoagulable perioperative period—it is reasonable to assume that stopping aspirin might increase perioperative CV risk. Conversely, since perioperative adverse CV events are predominantly the result of supply-demand mismatch rather than acute thrombosis, it is plausible that continuing aspirin may confer little CV protection and may alternatively increase CV risk if excessive bleeding ensues.

In 2010, Oscarsson et al18 published the first of several trials designed to determine the impact of aspirin cessation versus continuation in those at high risk for perioperative MACE. Two-hundred twenty patients were randomized to receive 75 mg aspirin or placebo starting 7 days preoperatively and continued 3 days postoperatively. Patients in the placebo group previously taking aspirin had it restarted on postoperative day 3. Included patients had to undergo elective high- or intermediate-risk noncardiac surgery and have at least one of the following cardiac risk factors: CAD, congestive heart failure, renal impairment, stroke, or insulin-dependent diabetes mellitus. Exclusion criteria were unstable CAD, decompensated heart failure, shock, allergy to aspirin, age <18 years, prior GI or intracranial bleeding, use of warfarin/clopidogrel/methotrexate, or presence of a coronary stent. The study was terminated early due to the contemporaneous release of ACC/AHA guidelines during the study recruitment period recommending perioperative aspirin continuation in high-risk patients along with a study amendment to exclude patients with coronary stents, both of which negatively affected recruitment ability.40 Though the investigators reported that the primary end point (postoperative myocardial injury) was not significantly different between groups (3.7% aspirin versus 9.0% placebo; P = .10), aspirin continuation resulted in a 7.2% absolute risk reduction (95% CI, 1.3–13) and 80% relative risk reduction (95% CI, 9.2–95) for the trial’s secondary end point of postoperative MACE. No significant differences in bleeding complications were observed between groups, although the trial was not powered for this outcome.

A second trial, Impact of Preoperative Maintenance or Interruption of Aspirin on Thrombotic and Bleeding Events After Elective Noncardiac Surgery (STRATAGEM), which was multicenter, randomized, and placebo controlled, enrolled 291 patients already taking an antiplatelet agent (predominantly aspirin) for secondary prevention and scheduled to undergo intermediate- or high-risk noncardiac surgery. The placebo group (n = 146) had their aspirin or alternative antiplatelet agent held 10 days preoperatively, and the treatment group (n = 145) had their antiplatelet agent continued or their regimen switched to 75 mg of aspirin starting 10 days preoperatively. All patients had their initial antiplatelet therapy restarted as soon as it was deemed safe postoperatively. Notable exclusion criteria included patients undergoing carotid endarterectomy (CEA), recent MACE, or presence of a drug-eluting stent (DES; but not bare metal stent [BMS]). Although the study was terminated early due to recruitment difficulties and thus underpowered, no difference in the primary outcome was found, which consisted of a composite score of major thrombotic and bleeding events within 30 days of surgery (0.67 aspirin versus 0.65 placebo group; P = .94).41

Due to the relatively small size of the 2 aforementioned studies and conflicting results, a larger trial was subsequently conducted in an attempt to answer the aspirin cessation versus continuation question more definitively. The 2014 PeriOperative ISchemia Evaluation-2 (POISE-2) trial was a randomized double-blind, multinational, multicenter controlled trial that evaluated the outcome of continuing or stopping low-dose (200 mg initially followed by 100 mg/d for 30 days) aspirin in 10,010 “at-risk” patients undergoing noncardiac surgery.16 At-risk patients were those over 45 years old with 1 of 5 inclusion criteria: CAD, PAD, stroke, undergoing major vascular surgery (except CEA), or presence of ≥3 of 9 risk factors (≥70 years, undergoing major surgery, heart failure, TIA, diabetes, hypertension, serum creatinine >2.0 mg/dL, smoking within 2 years of surgery, emergent/urgent surgery). Patients were stratified into 2 initial groups based on whether they were taking aspirin before the study (continuation strata) or aspirin-naive (initiation strata). Patients in these 2 stratum were then randomized to receive either aspirin or placebo, resulting in 4 final groups: (1) no prior aspirin use followed by perioperative aspirin, (2) no prior aspirin use followed by placebo only, (3) prior aspirin use followed by perioperative aspirin, and (4) prior aspirin use followed by 7 days of placebo and then returning to aspirin for the final 23 days of follow-up. Important exclusion criteria included BMS within 6 weeks of randomization or DES within 1 year of randomization. No difference was found among groups or strata in the primary outcome of a composite of death or nonfatal MI within 30 days of surgery. Major bleeding, mostly at the surgical site, was greater in the aspirin group (4.6% vs 3.8%; P = .04); however, no differences were reported in either “clinically important hypotension” or “life-threatening” bleeding between groups. Because of these findings, the authors concluded that perioperative aspirin continuation does not confer a benefit in terms of MACE and may contribute to excess blood loss.

However, POISE-2 has been criticized for a number of shortcomings that temper its interpretations. Approximately one third of all study patients assigned to the aspirin group had a definitive primary or secondary indication for aspirin, and it is also unclear if patients in the continuation stratum were using aspirin for an appropriate ACC/AHA guideline-based indication. In addition, vascular surgery, which has the highest associated risk of MACE among all types of noncardiac surgery, accounted for only 4.9% of high-risk procedures. Moreover, patients undergoing CEA were excluded, and only those with a coronary stent were <10% of recruited subjects, both further affecting the generalizability of the results. Hence, it is likely that a majority of the patients in the study were at low rather than high baseline risk for perioperative MACE.42 The results were also confounded by the postoperative administration of antithrombotic agents. By postoperative day 3, 65% of patients received prophylactic anticoagulation, 4.0%–4.5% of patients in both groups received therapeutic anticoagulation, and 1.2% of patients in both groups received a P2Y12 inhibitor.42 Seven safety outcomes were separately evaluated in POISE-2, of which only major bleeding was significant, though no differences in life-threatening bleeding or significant hypotension were reported.

In 2014, based on POISE-2 and the other evidence available at the time, the ACC/AHA published their latest “Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery,” which concluded that patients without a coronary stent should not have aspirin initiated perioperatively.43 However, it suggested that continuing aspirin is reasonable for patients already receiving it for secondary prevention of CV disease when major noncardiac surgery is planned and the perceived risk of a MACE is greater than the risk of bleeding. In part due to remaining uncertainty about the effect of perioperative aspirin withdrawal on higher-risk patients, a 2018 subgroup analysis of POISE-2 was conducted to specifically determine how aspirin should be managed in patients undergoing vascular surgery.42,44 Of the 10,010 patients in POISE-2, 603 underwent vascular surgery, including 319 in the continuation stratum and 284 in the initiation stratum. No interaction with the primary outcome (ie, composite of death or MI at 30 days) was found for type of surgery or aspirin stratum and no difference between patients undergoing surgery for aneurysm or occlusive disease. There was also no subgroup interaction for major or life-threatening bleeding. Thus, the authors concluded that perioperative aspirin withdrawal did not increase CV or vascular occlusive complications and that it is therefore not necessary to start aspirin preoperatively in patients undergoing vascular surgery.44 They also concluded that continuing aspirin in patients already receiving it might be reasonable, since its continuation did not increase the risk of major bleeding. However, they cautioned that since even clinically unimportant bleeding may be associated with MI, an argument could be made for stopping rather than continuing aspirin in patients undergoing vascular surgery but acknowledged that larger studies would be necessary to more definitively answer this question. Finally, the authors noted that patients undergoing CEA were entirely excluded from POISE-2. Since perioperative aspirin proved beneficial for CEA surgery in both a prior RCT (although there was no placebo group) and large observational trial, they recommended continuing aspirin in patients undergoing CEA.45,46

Patients With Coronary Stents Undergoing Noncardiac Surgery.

Retrospective and observational data demonstrate that perioperative ischemic events and mortality occur more frequently when noncardiac surgery is performed soon after coronary stenting.47 Patients undergoing percutaneous coronary intervention (PCI) revascularization following an ACS and who undergo noncardiac surgery shortly thereafter are at highest risk. For example, in a retrospective cohort study by Cruden et al,48 the risk of perioperative death and ischemic cardiac events occurred more frequently when noncardiac surgery was performed within 42 days of stent implantation (42.4% vs 12.8% beyond 42 days; P < .001), especially in patients revascularized after an ACS (65% vs 32%; P = .037). In 2013, another retrospective cohort study was performed by Hawn et al49 and found that time between PCI and surgery was associated with MACE (<6 weeks, 11.6%; 6 weeks to <6 months, 6.4%; 6–12 months, 4.2%; >12–24 months, 3.5%; P < .001). After adjustment, the 3 factors most strongly associated with MACE were nonelective surgical admission (adjusted odds ratio [AOR], 4.77; 95% CI, 4.07–5.59), history of MI in the 6 months preceding surgery (AOR, 2.63; 95% CI, 2.32–2.98), and a revised cardiac risk index >2 (AOR, 2.13; 95% CI, 1.85–2.44).49 In 2018, a substudy of POISE-2 subjects was published evaluating 470 POISE-2 subjects with prior PCI to specifically evaluate the risk of stopping or continuing aspirin in these patients.50 This analysis found that perioperative aspirin as compared with placebo reduced the risk of the primary outcome (composite of death and nonfatal MI). This beneficial effect, which differed from the effect found in patients without prior PCI, was driven by a reduction in MI (adjusted risk reduction = 5.9%, 95% CI, 1.0–10.8).50 Finally, POISE-2 excluded patients within 6 weeks of BMS implantation or within 1 year of DES implantation. Because the POISE-2 investigators did not anticipate enrolling patients with a history of PCI who were not otherwise excluded, a PCI subgroup analysis was not initially planned or conducted. Thus, ACC/AHA recommendations for the perioperative management of patients with coronary stents did not include data from POISE-2 and instead were largely based on the preceding observational studies. In 2020, Sessler et al51 reexamined POISE-2 data for outcomes at 1 year after enrollment. The authors reported similar findings with regard to aspirin’s lack of effect on the primary outcome (composite of death or nonfatal MI) in the original entire cohort. However, in the subgroup of 470 patients with prior PCI, similar to the 30-day analysis,50 perioperative aspirin continuation had a net benefit on the primary outcome that persisted at 1 year (prior PCI: HR = 0.58, 95% CI, 0.35–0.95 versus no history of PCI: HR = 1.03, 95% CI, 0.91–1.16; P for interaction = .033).51

The ACC/AHA concluded that the risk of stent thrombosis is highest during the perioperative period in the first 4–6 weeks after stent implantation, and the risk of DES thrombosis is likely elevated for patients undergoing noncardiac surgery for about 6 months after DES implantation. Consequently, the following recommendations were made: (1) patients undergoing noncardiac surgery during the first 4–6 weeks after BMS or DES implant should have dual antiplatelet therapy (DAPT) continued unless the risk of bleeding outweighs the risk of stent thrombosis, and (2) patients with coronary stents who must have a P2Y12 inhibitor stopped for noncardiac surgery should have aspirin continued whenever possible. The current generation of DES stents has a higher safety profile than BMS and first-generation DES. The risk of stent thrombosis perioperatively is likely lower with the current-generation stents. Certain patient and stent characteristics are associated with an increased risk of in-stent thrombosis (Table 5). These variables need to part of the decision-making process when considering stopping or continuing perioperative antiplatelet agents.

Finally, a 2018 Cochrane meta-analysis examined continuation versus cessation of antiplatelet agents (aspirin, clopidogrel, or both) in elective noncardiac surgery (primarily abdominal, orthopedic, urologic, and gynecologic) in patients with at least 1 CV disease risk factor.52 The review included 5 RCTs (3 of which were ongoing studies) with a total of 666 adults and compared those who continued their single or dual antiplatelet regimen throughout the perioperative interval with those who discontinued their regimen at least 5 days preoperatively. Statistically significant distinctions were not found in any analyzed outcome, but the reported 95% CIs were also too wide to permit conclusions of equivalence. The authors did not find mortality differences between groups at 30 days (risk ratio = 1.21, 95% CI, 0.34–4.27) or at 6 months (risk ratio = 1.21, 95% CI, 0.34–4.27). There were also no significant differences in the incidence of a variety of ischemic events (peripheral ischemia, CVA, or MI) by 30 days postoperatively (risk ratio = 0.67, 95% CI, 0.25–1.77). Regarding blood loss, antiplatelet continuation versus cessation did not significantly impact blood loss requiring transfusion (risk ratio = 1.37, 95% CI, 0.83–2.26) or blood loss requiring additional surgery (risk ratio = 1.54, 95% CI, 0.31–7.58). With regard to mortality, bleeding necessitating surgery, and ischemic events, the authors described their findings as “low certainty” (true effect may be substantially different from the estimate of the effect) and for bleeding requiring transfusion, the findings are “moderate certainty” (true effect is likely close to the estimate of the effect but with the possibility that it is substantially different). Overall, these findings should be interpreted cautiously due to significantly limited evidence from a very small number of studies with few events leading to wide effect-estimate CIs.52

FUTURE DIRECTIONS

The body of literature examining antiplatelet agent efficacy in CV disease continues to expand, with much research focused on the use of nonaspirin antiplatelet agents (ie, P2Y12 inhibitors) as monotherapy in certain CV disease contexts, varying time courses of DAPT, and potential ways to better optimize antithrombotic regimens to mitigate against bleeding risks.

Shortening the Duration of DAPT

Derived from an initial trial of almost 16,000 patients with stable and unstable CAD undergoing PCI with a DES, Franzone et al53 reported the GLOBAL LEADERS Adjudication Substudy (GLASSY), a follow-up prespecified ancillary study of A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation trial (“GLOBAL LEADERS”).54 The GLASSY study was an international open-label randomized trial examining the impact of low-dose aspirin (75–100 mg) plus ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy (n = 3794) versus 1 of 2 DAPT regimens, which were considered controls: aspirin and clopidogrel if stable CAD or aspirin and ticagrelor if recent ACS for 12 months, followed by aspirin monotherapy for 12 months (n = 3791).53 The GLASSY study used 2 independent coprimary end points for both safety (Bleeding Academic Research Consortium type 3 or 5 bleeding) and efficacy (composite of all-cause mortality, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization) of the experimental intervention using both noninferior and superiority methodology for both end points. After 2 years, as compared to the control group, the coprimary efficacy end point occurred less in the experimental group (7.14% vs 8.41%, rate ratio = 0.85, 95% CI, 0.72–0.99; P for noninferiority <.001), but did not achieve superiority (P = .0465, α of 2.5%). For the safety end point related to bleeding, there were identical rates between groups (2.48% for both; rate ratio = 1.00, 95% CI, 0.75–1.33; P for superiority = .99). However, in a follow-up post hoc study to the initial GLOBAL LEADERS trial, no difference was found in the risk of the primary end point between single-vessel and multivessel PCI patients, but there was a significant relationship favoring the experimental arm in the multivessel PCI subgroup to reduce death or recurrent MI.54,55 The interpretation of these findings should be tempered due to the inherent problems of subgroup analyses. However, in contrast to current standard antiplatelet regimens, patients undergoing multivessel PCI may benefit from long-term ticagrelor monotherapy after completion of 4 weeks of DAPT.56

P2Y12 Inhibitor Monotherapy

The use of P2Y12 inhibitor monotherapy in lieu of aspirin in the context of CAD and CVD has been described as far back as 1996.57–59 The Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy Versus Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-CHOICE) comprising almost 3000 patients from 33 different sites in Korea compared P2Y12 inhibitor monotherapy (clopidogrel, prasugrel, or ticagrelor) after 3 months of DAPT post-PCI versus a conventional 12 months of DAPT. The primary outcome included major adverse cardiac and cerebrovascular events, to include a composite of all-cause death, MI, or stroke at 12 months after the index PCI procedure. P2Y12 inhibitor monotherapy was found noninferior to DAPT for the primary outcome (2.9% vs 2.5%; 1-sided 95% CI, −∞ to 1.3; P = .007). No intergroup differences were found in any of the following: the cumulative rates of the primary end point components at 12 months (all-cause death, MI, and stroke), the risk of stent thrombosis, or the per-protocol analysis versus the intention-to-treat analyses. Moreover, the rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group compared to the DAPT group (HR = 0.58, 2.0% vs 3.4%, 95% CI, 0.34–0.97; P = .4).60 In a second recent study, the Short and Optimal Duration of Dual Antiplatelet Therapy After Evirolimus-Eluting Cobalt-Chromium Stent (STOPDAPT-2) trial, 3045 patients received either 1 month of DAPT followed by clopidogrel monotherapy or 12 months of DAPT with aspirin and clopidogrel.61 Similar to the SMART-CHOICE trial, 1-month’s duration of DAPT followed by clopidogrel was found to be both noninferior and superior to 12-month DAPT for the primary end point of CV death, MI, stroke, stent thrombosis, or major or minor bleeding at 12 months, occurring in 2.36% of 1 month DAPT versus 3.70% of 12-month DAPT (HR = 0.64, 95% CI, 0.42–0.98; noninferiority [P < .001] and superiority [P = .04]). The secondary bleeding end point was found also superior in the 1-month group (0.41% 1-month DAPT versus 1.54% with 12-month DAPT; HR = 0.26, 95% CI, 0.11–0.64; P = .004).61

In both the STOPDAPT-2 and SMART-CHOICE trials, DAPT cessation followed by P2Y12 inhibitor monotherapy as a post-PCI strategy had previously not been intensely studied aside from 1 trial, the aforementioned GLOBAL LEADERS trial. Nonetheless, P2Y12 monotherapy after DAPT is supported by the known pharmacodynamic effects of greater intense platelet inhibition by P2Y12 inhibitors as compared to aspirin.62,63 In addition, a number of factors impacting the generalizability of both the STOPDAPT-2 and SMART-CHOICE trials, which were conducted in East Asian populations, need to be considered. A large percentage of PCI procedures performed in Japan (STOPDAPT-2) and South Korea (SMART-CHOICE) use intravascular imaging intraprocedurally in contrast to minimal use in the United States or Europe.62 P2Y12 inhibitors are impacted by body mass index (BMI), whereby higher BMIs are associated with lower drug responses and poor inhibition of platelet reactivity.64,65 The average BMI in both trials was 24–25, which is lower than the average US BMI of 30 reported in similar trials.66 Finally, cytochrome P2C19 (CYP2C19), the principal hepatic enzyme involved in converting clopidogrel to its active metabolite, has over 25 alleles with major phenotypes ranging from ultrarapid metabolizer to poor metabolizers.67 The most important loss-of-function allele for the CYP2C19 enzyme is (*2), leading to poor metabolism, and is found in higher percentages of East Asians (29%–35%) as compared to Caucasians (12%–15%).68 Appreciation of these aforementioned issues is warranted as clinicians factor how to modify current clinical practice.

Finally, the Ticagrelor With or Without Aspirin in High-Risk Patients After PCI (TWILIGHT) trial examined the safety and efficacy of a shorter-duration (3 months) DAPT with ticagrelor and aspirin followed by ticagrelor monotherapy versus conventional 12 months DAPT (ticagrelor and aspirin) in 7119 patients receiving PCI with a DES and with ≥1 high-risk bleeding or ischemia characteristic. TWILIGHT investigators found that short-duration DAPT followed by ticagrelor monotherapy for 12 months resulted in less bleeding compared with the conventional 12 months longer-duration DAPT among study patients (4.0% vs 7.1%; HR = 0.56; 95% CI, 0.45–0.68, P < .001). Moreover, there was noninferiority for ischemic rates (all-cause mortality, stroke, and MI) between both groups (3.9% for both; difference, −0.06% points; 95% CI, 0.97–0.84; HR = 0.99; 95% CI, 0.78–1.25, P < .001 for noninferiority).69 See Supplemental Digital Content, Table 1, http://links.lww.com/AA/D140, for study details.

CONCLUSIONS AND RECOMMENDATIONS

The optimal management of aspirin in the perioperative period continues to evolve in parallel with emerging new data involving CV disease management. Perioperative aspirin management balances the inherent thromboembolic risks of cessation against the bleeding risks associated with continuation. Hence, patient-specific CV risk factors including disease severity and coexisting therapies (ie, PCI) with associated specific risks (Table 5) along with the planned surgical or procedural activities all need to be considered in the aggregate with all decision-making. Nonetheless, recommendations on perioperative aspirin cessation or continuation using the available clinical data from studies in high-risk patients along with the nonclinical aspirin studies is conflicting and does not enable a simplified or unified answer. This may be due to in part to variations in study methodology, including the definitions of high-risk patients, high-risk surgeries, aspirin dosing, and use of nonaspirin anticoagulants.

Table 5. - Patient and Intracoronary Stent Characteristics Associated With an Increased Risk of In-Stent Thrombosis29,70
Stent Variables Patient Variables
Use of first-generation DES ACS presentation
Undersized stent Diabetes
Stent under-deployment LVEF <40%
Small stent diameter Chronic kidney disease (ie, creatinine clearance <60 mL/min)
Long stent length (ie, > 60 mm) Diffuse multivessel disease
Bifurcated stents; bifurcation with 2 stents implanted
Previous stent thrombosis on adequate antiplatelet therapy
≥3 coronary artery lesions treated
≥3 stents implanted
Treatment of a chronic total occlusion
These variables need to be factored into decision-making with regard to perioperative antiplatelet continuation versus cessation in patients with an intracoronary stent.
Abbreviations: ACS, acute coronary syndrome; DES, drug-eluting stent; LVEF, left ventricular ejection fraction.

Although pertinent ACC/AHA guidelines on CV disease management provide a basic framework for aspirin management and the POISE-2 trial findings provide some insight into the safety of perioperative aspirin cessation in some contexts, much uncertainty on perioperative aspirin still exists. Although the findings of POISE-2 suggest that continuation does not confer a CV benefit and may be harmful due to excess blood loss, there are multiple study-related issues that obfuscate whether temporary aspirin cessation in high-risk patients is safe or not. High-risk patients taking lifelong aspirin for a guideline-based primary or secondary indication should likely have their aspirin therapy continued throughout the perioperative period for the majority of surgical and interventional procedures except when undergoing a closed-space procedure, intramedullary spine, or transurethral prostate surgery. The following recommendations are a synthesis of available data. See the Figure for a guide to decision-making in patients taking aspirin who present for elective noncardiac surgery.

Figure.
Figure.:
Decision-making recommendations for patients taking aspirin who present for elective surgery.
  • 1. For the majority of patients using aspirin for primary CV disease prevention, preoperative aspirin cessation is safe. See Table 1. It should be highlighted that the current literature underpinning primary prevention recommendations is derived from a context outside the perioperative period and does not specifically address the cessation versus continuation risks and benefits in this context. Importantly, many patients start aspirin without seeking a physician’s opinion; hence, careful attention to identifying self-prescribing of aspirin should be part of routine perioperative assessment. In these patients, the drug may be safely discontinued 7 days preoperatively, as by definition, it is being used for primary prevention and there should be full return of platelet function in this timeframe.
  • 2. For patients prescribed aspirin for secondary prevention but without a coronary stent, it is not fully clarified as to the safety of preoperative aspirin cessation. This lack of direction is a function of POISE-2’s exclusion of this high-risk patient group, as well as a continued paucity of prospective data specifically addressing this issue. The limited data that do exist suggest that continuing aspirin might be prudent, but data that are more robust are needed. Nonetheless, as described in Table 2, noncoronary stented patients with high CV disease risk should likely have aspirin continued throughout the perioperative period unless undergoing closed-spaced procedure or procedure with high-bleeding risk that is not easily controlled (ie, transurethral urologic procedures).

The overall dataset for the reduction of MACE by the continuation of antiplatelet agents in stable ischemic heart disease patients undergoing noncardiac surgery is negative. In the context of recent ACS, patients should ideally be on DAPT for 1 year, but if surgery is urgent (ie, cancer operation), it should proceed while continuing aspirin monotherapy at a minimum. Recent data suggest that, in the absence of noncardiac surgery, a shortened duration of DAPT appears safe with the continuation of monotherapy as outlined above; whether this extends to those undergoing noncardiac surgery remains unknown.

  • 3. For patients with CVD and PAD, there are also minimal prospective data, but the totality of observational data and guideline recommendations suggest stopping preoperative aspirin is associated with significant risk, especially within the timeframes described in Table 2, and likely should be continued throughout the perioperative period.

DISCLOSURES

Name: Neal S. Gerstein, MD, FASE.

Contribution: This author conceived the original concept and helped in manuscript conception, drafting, and editing.

Name: Cory L. Albrechtsen, BS.

Contribution: This author conceived the original concept and helped in manuscript conception, drafting, and editing.

Name: Nestor Mercado, MD, PhD.

Contribution: This author helped draft and edit the manuscript.

Name: Joaquin E. Cigarroa, MD.

Contribution: This author helped draft and edit the manuscript.

Name: Peter M. Schulman, MD.

Contribution: This author conceived the original concept and helped in manuscript conception, drafting, and editing.

This manuscript was handled by: Stefan G. De Hert, MD.

FOOTNOTES

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