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Perioperative Management of Antiplatelet Therapy: A Systematic Review and Meta-analysis

Open AccessPublished:October 21, 2022DOI:https://doi.org/10.1016/j.mayocpiqo.2022.09.006

      Abstract

      Objective

      To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures.

      Methods

      This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database’s inception to July 16, 2020. Meta-analyses were conducted when possible.

      Results

      In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE).

      Conclusion

      This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.

      Abbreviations and Acronyms:

      ACCP/CHEST (American College of Chest Physicians), ASA (acetylsalicylic acid), ATE (arterial thromboembolism), CABG (coronary artery bypass graft), COE (certainty of evidence), CV (cardiovascular), DES (drug-eluting stent), LMWH (low-molecular-weight heparin), MI (myocardial infarction), PE (pulmonary embolism), PICO (patients–interventions–comparators–outcomes), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), RR (relative risk), RCT (randomized clinical trial)
      Antiplatelet therapy is widely used for the secondary prevention of stroke, myocardial infarction (MI), and peripheral arterial disease, with such patients typically receiving single antiplatelet therapy with acetylsalicylic acid (ASA) or dual antiplatelet therapy with ASA and a P2Y12 inhibitor such as clopidogrel or ticagrelor. Given this widespread use of antiplatelet therapy and that such patients, due to their advanced age, are also more likely to require a surgery/procedure, it is not surprising that perioperative management is a frequently encountered clinical scenario. For example, the incidence of noncardiac surgery alone, even after excluding the more commonly needed nonsurgical procedures, after drug-eluting stent implantation was 7% at 1 year, 18% at 2 years, and 22% at 3 years.
      • Gandhi N.K.
      • Abdel-Karim A.R.
      • Banerjee S.
      • Brilakis E.S.
      Frequency and risk of noncardiac surgery after drug-eluting stent implantation.
      Overall, the perioperative management of patients who are receiving antiplatelet therapy and need a surgery/procedure is a common clinical scenario.
      Premature discontinuation of antiplatelet therapy has the potential to expose patients to an increased risk of perioperative acute coronary syndromes, with stent thrombosis being most feared because of its high associated morbidity and mortality. In the nonperioperative setting, premature cessation of antiplatelet therapy after MI confers a 3- to 5-fold increased risk of major adverse cardiac events. In a perioperative setting, a multicenter registry found that patients with a drug-eluting stent who discontinued P2Y12 inhibitor therapy early had a higher risk of death and rehospitalization in the next 11 months.
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • et al.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      In contrast, continuation of antiplatelet therapy without perioperative interruption exposes patients to an increased risk of bleeding, which, in turn, can increase the risk of adverse cardiovascular (CV) events. Therefore, the perioperative management of antiplatelet therapy requires balancing the risk of CV or thrombotic events against the risk of bleeding, the latter of which is driven by the surgery/procedure-related bleeding risk.
      The American College of Chest Physicians (ACCP/CHEST) developed clinical practice guidelines
      • Douketis J.D.
      • Spyropoulos A.C.
      • Spencer F.A.
      • et al.
      Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      in 2012 to address key clinical decisions in this context, including the management of antiplatelet therapy in settings such as coronary artery bypass graft (CABG) surgery, noncardiac surgery, minor procedures, and cardiac device implantation. Since the previous iteration of these guidelines, new antiplatelet drugs have emerged for clinical use alongside new evidence around perioperative antiplatelet management. This systematic review and meta-analysis was commissioned by ACCP/CHEST to support the development of the updated 2022 ACCP/CHEST guidelines.

      Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians clinical practice guideline executive summary. Chest. Published online August 11, 2022. doi:10.1016/j.chest.2022.07.025

      ,
      • Douketis J.D.
      • Spyropoulos A.C.
      • Murad M.H.
      • et al.
      Perioperative management of antithrombotic therapy: an American College of Chest Physicians clinical practice guideline.
      The aim of this review is to summarize and appraise the evidence base regarding prespecified clinical questions related to the perioperative management of patients who are receiving ASA, P2Y12 inhibitors, or combined (dual) antiplatelet therapy. Findings from this systematic review have been incorporated in the guidelines, but this manuscript has not been published elsewhere.

      Methods

      This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The PRISMA checklist is provided in the appendix. The questions of this review and the inclusion and exclusion criteria were established by CHEST/ACCP guideline panel members in a nonregistered protocol using the patients–interventions–comparators–outcomes (PICO) format. The current review includes the direct evidence supporting PICO questions that addressed the perioperative management of antiplatelet therapy.

      Data Source and Search Strategies

      We searched MEDLINE and Epub ahead of print, in-process, and other nonindexed citations; EMBASE; Cochrane Central Register of Controlled Trials; Cochrane Database of Systematic Reviews; and Scopus from each database’s inception to July 16, 2020. The search strategy was designed and executed by a medical reference librarian (L.C.H.) with input from the investigators using controlled vocabulary supplemented with keywords without language restrictions. The search strategy also included anticoagulant therapies, which are presented in a separate manuscript. The details of the search are provided in Supplemental Table 1 (available online at http://www.mcpiqojournal.org).

      Study Selection

      The titles and abstracts were screened by 2 independent reviewers. If considered eligible, full-text articles of the included abstracts were retrieved and reviewed by 2 independent reviewers. Conflicts were resolved by a third reviewer. The eligibility criteria included adult patients (≥18 years who (1) were receiving antiplatelet therapy and required an elective surgery/procedure; (2) were with or without coronary stents; (3) were undergoing noncardiac surgery or CABG; (4) were undergoing minor (dental, dermatologic, or ophthalmologic) procedures; and (5) reported an outcome of interest, including major and minor bleeding,
      • Kaatz S.
      • Ahmad D.
      • Spyropoulos A.C.
      • Schulman S.
      • Anticoagulation S.C.
      Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH.
      arterial or venous thromboembolic events, including MI, stroke, systemic embolism, transient ischemic attack, deep vein thrombosis or pulmonary embolism, and mortality. Definitions of outcomes are provided in Supplemental Table 2 (available online at http://www.mcpiqojournal.org).

      Data Extraction and Risk of Bias Assessment

      Data were extracted from the included studies by 2 independent reviewers using a standardized data extraction form. Disagreements were resolved by a third reviewer. The baseline characteristics of the included studies are shown in Supplemental Table 3 (available online at http://www.mcpiqojournal.org). The risk of bias in the included studies was assessed by 2 independent reviewers. The Cochrane Collaboration’s Risk of Bias 2 tool was used for randomized clinical trials (RCTs). This tool takes into consideration 6 domains: (1) the randomization process, (2) deviations from the intended interventions, (3) missing outcome data, (4) measurement of the outcome, (5) selection of the reported result, and (6) other sources of bias found, as shown in Supplemental Table 4.1 (available online at http://www.mcpiqojournal.org). We summarized the risk of bias in all domains to produce an overall risk of bias for every RCT. For observational studies, we selected items from the Newcastle-Ottawa scale, with a focus on the representativeness of the exposed cohort, the selection of the nonexposed cohort, the ascertainment of exposure and outcomes, the comparability of cohorts, and adequacy of follow-up, as shown in Supplemental Table 4.2 (available online at http://www.mcpiqojournal.org).

      Statistical Analyses and Certainty of Evidence

      Binary data from comparative studies (RCTs and cohort studies) were reported as a risk ratio (relative risk; RR) with associated 95% CIs. We pooled the outcomes across studies using the restricted maximum likelihood random-effects model and estimated heterogeneity using the Mantel-Haenszel model and the I2 statistic where possible. Heterogeneity was deemed low, moderate, and high when I2 values were <30%, 30%-60%, and >60%, respectively. All statistical analyses were conducted using R 4.2.0.

      R version 4.2.0. The R Project for Statistical Computing; 2022. R: The R Project for Statistical Computing (r-project.org)

      To rate the certainty of evidence (COE) in the comparative estimates of direct evidence, the Grading of Recommendations, Assessments, Development and Evaluation approach was used.
      GRADE. The GRADE working group.
      RCTs start at high certainty, whereas non-RCTs start at low certainty. Certainty was rated down for risk of bias, imprecision, indirectness, inconsistency, and publication bias. Precision was judged on the basis of whether CIs crossed the null as a target of certainty.
      • Zeng L.
      • Brignardello-Petersen R.
      • Hultcrantz M.
      • et al.
      GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines 6. Rating the quality of evidence--imprecision.

      Results

      The study selection process is shown in the PRISMA flow diagram shown in the Figure. A total of 38 studies were included that addressed 6 PICO questions.
      Figure thumbnail gr1
      FigureSelection of Studies for Inclusion in the Systematic Review and Meta-analysis.

      Question 1. Stopping Antiplatelet Agents Before Elective Surgery/Procedure

      Stopping ASA ≤7 days vs >7 days

      We included 1 RCT
      • Gulpinar K.
      • Ozdemir S.
      • Ozis E.
      • Sahli Z.
      • Demirtas S.
      • Korkmaz A.
      A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?.
      and 1 cohort study
      • Mikkola R.
      • Wistbacka J.O.
      • Gunn J.
      • et al.
      Timing of preoperative aspirin discontinuation and outcome after elective coronary artery bypass graft surgery.
      that reported on 699 patients who stopped receiving ASA either ≤7 days or >7 days before the surgery/procedure. The risk of bias for the cohort study and RCT was moderate. Compared with stopping ASA >7 days, stopping ASA ≤7 days was not associated with a statistically significant difference in the risk of major bleeding, major thromboembolism (any outcomes: ischemic stroke, transient ischemic attack, MI, pulmonary embolism [PE], venous thromboembolism, or vascular death), and MI, as summarized in the Table, with very low COE.
      TableOutcomes: Perioperative Management of Antiplatelet Therapy
      ASA, acetylsalicylic acid; RCT, Randomized clinical trial.
      OutcomeFindings, relative risk (95% CI)Study design and sample sizeCertainty of evidence
      When the number of events was very low (<10), we considered rating down by 2-3 levels unless the sample size was large (>2000-4000). An arbitrary cutoff of the relative risk reduction of 25% was used as a cutoff for lowering certainty in precision by 2 levels. RCTs start at high certainty, whereas non-RTCs start at low certainty. Certainty was rated down for risk of bias, imprecision, indirectness, inconsistency, and publication bias. Precision was judged on the basis of whether confidence intervals crossed the null as a target of certainty. Certainty of evidence
      Stopping ASA ≤7 d vs >7 d before elective surgery/procedure
      Major bleeding0.78 (0.01-38.4)1 RCT
      • Zeng L.
      • Brignardello-Petersen R.
      • Hultcrantz M.
      • et al.
      GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings.
      ; 80
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      0.81 (0.36-1.85)1 comparative observational
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines 6. Rating the quality of evidence--imprecision.
      ; 619
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Major thromboembolism0.78 (0.01-38.5)1 RCT
      • Zeng L.
      • Brignardello-Petersen R.
      • Hultcrantz M.
      • et al.
      GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings.
      ; 80
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Myocardial infarction0.26 (0.01-6.21)Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Continuing vs stopping ASA ≤7 d before elective surgery/procedure
      Major bleeding0.87 (0.18-4.13)3 RCTs
      • Gulpinar K.
      • Ozdemir S.
      • Ozis E.
      • Sahli Z.
      • Demirtas S.
      • Korkmaz A.
      A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?.
      • Mikkola R.
      • Wistbacka J.O.
      • Gunn J.
      • et al.
      Timing of preoperative aspirin discontinuation and outcome after elective coronary artery bypass graft surgery.
      • Antolovic D.
      • Rakow A.
      • Contin P.
      • et al.
      A randomised controlled pilot trial to evaluate and optimize the use of anti-platelet agents in the perioperative management in patients undergoing general and abdominal surgery—the APAP trial (ISRCTN45810007).
      ; 179
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      0.95 (0.23-3.90)2 comparative observational
      • Engheta A.
      • Abianeh S.H.
      • Atri A.
      • Sanatkarfar M.
      Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial.
      ,
      • Ong W.
      • Shen T.
      • Tan W.B.
      • Lomanto D.
      Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?.
      ; 306
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Major thromboembolism1.00 (0.02-48.6)1 RCT
      • Gulpinar K.
      • Ozdemir S.
      • Ozis E.
      • Sahli Z.
      • Demirtas S.
      • Korkmaz A.
      A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?.
      ; 52
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      0.62 (0.05-7.37)2 comparative observational
      • Engheta A.
      • Abianeh S.H.
      • Atri A.
      • Sanatkarfar M.
      Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial.
      ,
      • Ong W.
      • Shen T.
      • Tan W.B.
      • Lomanto D.
      Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?.
      ; 306
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Myocardial infarction1.96 (0.13-30.25)2 comparative observational
      • Engheta A.
      • Abianeh S.H.
      • Atri A.
      • Sanatkarfar M.
      Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial.
      • Ong W.
      • Shen T.
      • Tan W.B.
      • Lomanto D.
      Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?.
      ; 83
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      0.95 (0.06-14.8)2 RCTs
      • Gulpinar K.
      • Ozdemir S.
      • Ozis E.
      • Sahli Z.
      • Demirtas S.
      • Korkmaz A.
      A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?.
      ,
      • Antolovic D.
      • Rakow A.
      • Contin P.
      • et al.
      A randomised controlled pilot trial to evaluate and optimize the use of anti-platelet agents in the perioperative management in patients undergoing general and abdominal surgery—the APAP trial (ISRCTN45810007).
      ; 109
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Continuing ASA vs placebo before elective surgery/procedure
      Major bleeding1.31 (1.15-1.50)5 RCTs
      • Hanalioglu S.
      • Sahin B.
      • Sahin O.S.
      • et al.
      Effect of perioperative aspirin use on hemorrhagic complications in elective craniotomy for brain tumors: results of a single-center, retrospective cohort study.
      • Rahman M.
      • Donnangelo L.L.
      • Neal D.
      • Mogali K.
      • Decker M.
      • Ahmed M.M.
      Effects of perioperative acetyl salicylic acid on clinical outcomes in patients undergoing craniotomy for brain tumor.
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      • Oscarsson A.
      • Gupta A.
      • Fredrikson M.
      • et al.
      To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      ; 28,062
      High
      Stroke1.00 (0.7-1.44)5 RCTs
      • Hanalioglu S.
      • Sahin B.
      • Sahin O.S.
      • et al.
      Effect of perioperative aspirin use on hemorrhagic complications in elective craniotomy for brain tumors: results of a single-center, retrospective cohort study.
      • Rahman M.
      • Donnangelo L.L.
      • Neal D.
      • Mogali K.
      • Decker M.
      • Ahmed M.M.
      Effects of perioperative acetyl salicylic acid on clinical outcomes in patients undergoing craniotomy for brain tumor.
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      • Oscarsson A.
      • Gupta A.
      • Fredrikson M.
      • et al.
      To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      ; 28,062
      High
      Major thromboembolism0.75 (0.59-0.95)3 RCTs
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      • Oscarsson A.
      • Gupta A.
      • Fredrikson M.
      • et al.
      To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      ; 17,832
      High
      Myocardial infarction1.05 (0.63-1.77)3 RCTs
      • Hanalioglu S.
      • Sahin B.
      • Sahin O.S.
      • et al.
      Effect of perioperative aspirin use on hemorrhagic complications in elective craniotomy for brain tumors: results of a single-center, retrospective cohort study.
      • Rahman M.
      • Donnangelo L.L.
      • Neal D.
      • Mogali K.
      • Decker M.
      • Ahmed M.M.
      Effects of perioperative acetyl salicylic acid on clinical outcomes in patients undergoing craniotomy for brain tumor.
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      ; 27,674
      High
      Mortality1.01 (0.14-7.05)1 RCT
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      ; 291
      Low
      wide CI, including substantial benefits and harms and/or small sample size.
      Continuing vs stopping antiplatelet agents in patients with coronary stents at high risk or low-moderate risk for cardiovascular events
      Major bleeding0.96 (0.02-46.05)1 RCT
      • Tytgat S.H.
      • Laman D.M.
      • Rijken A.M.
      • et al.
      Emboli rate during and early after carotid endarterectomy after a single preoperative dose of 120 mg acetylsalicylic acid--a prospective double-blind placebo controlled randomised trial.
      ; 43
      Low
      wide CI, including substantial benefits and harms and/or small sample size.
      0.58 (0.19-1.83)1 comparative observational
      • Mantz J.
      • Samama C.M.
      • Tubach F.
      • et al.
      Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.
      ; 27
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Major thromboembolism0.96 (0.02-46.05)1 RCT
      • Tytgat S.H.
      • Laman D.M.
      • Rijken A.M.
      • et al.
      Emboli rate during and early after carotid endarterectomy after a single preoperative dose of 120 mg acetylsalicylic acid--a prospective double-blind placebo controlled randomised trial.
      ; 43
      Low
      wide CI, including substantial benefits and harms and/or small sample size.
      1.07 (0.88-1.31)1 comparative observational
      • Mantz J.
      • Samama C.M.
      • Tubach F.
      • et al.
      Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.
      ,
      • Chu E.W.
      • Chernoguz A.
      • Divino C.M.
      The evaluation of clopidogrel use in perioperative general surgery patients: a prospective randomized controlled trial.
      ; 568
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Continuing vs stopping antiplatelet agents in patients undergoing coronary artery bypass graft
      Major bleeding1.68 (1.29-2.18)3 RCTs
      • Hawn M.T.
      • Graham L.A.
      • Richman J.S.
      • Itani K.M.
      • Henderson W.G.
      • Maddox T.M.
      Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
      • Capodanno D.
      • Musumeci G.
      • Lettieri C.
      • et al.
      Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery.
      • Deja M.A.
      • Kargul T.
      • Domaradzki W.
      • et al.
      Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial.
      ; 1073
      Moderate
      wide CI, including substantial benefits and harms and/or small sample size.
      1.10 (0.93-1.30)12 comparatives observational
      • Janssen P.
      • Claassens D.
      • Willemsen L.
      • Bergmeijer T.
      • Klein P.
      • Ten Berg J.
      Perioperative management of antiplatelet treatment in patients undergoing isolated coronary artery bypass grafting in Dutch cardiothoracic centres.
      • Lee J.
      • Jung C.-W.
      • Jeon Y.
      • et al.
      Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized study.
      • Al-Lawati A.A.
      • Muthuswamy V.
      Continuing aspirin causes higher drainage even under full protection with antifibrinolytics.
      • Bybee K.A.
      • Powell B.D.
      • Valeti U.
      • et al.
      Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
      • Deng Y.
      • Pisklak P.V.
      • Lee V.-V.
      • et al.
      Association between preoperative aspirin-dosing strategy and mortality after coronary artery bypass graft surgery.
      • Emmiler M.
      • Ayoğlu R.U.
      • Tekinalp Ö.H.
      • Arslan Ş.
      Off-pump coronary artery bypass grafting under clopidogrel treatment.
      • Fox K.A.
      • Mehta S.R.
      • Peters R.
      • et al.
      Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
      • Gielen C.L.
      • Bruggemans E.F.
      • Stijnen T.
      • et al.
      Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
      • Hongo R.H.
      • Ley J.
      • Dick S.E.
      • Yee R.R.
      The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting.
      • Huang J.
      • Donneyong M.
      • Trivedi J.
      • et al.
      Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations.
      • Shi J.
      • Ji H.
      • Ren F.
      • et al.
      Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial.
      • Wu H.
      • Wang J.
      • Sun H.
      • et al.
      Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting.
      ; 11,466
      Low
      Arterial thromboembolism1.20 (1.00-1.44)2 comparatives observational
      • Deng Y.
      • Pisklak P.V.
      • Lee V.-V.
      • et al.
      Association between preoperative aspirin-dosing strategy and mortality after coronary artery bypass graft surgery.
      ,
      • Gielen C.L.
      • Bruggemans E.F.
      • Stijnen T.
      • et al.
      Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
      ; 3525
      Low
      1.29 (0.41-4.02)2 RCTs
      • Hawn M.T.
      • Graham L.A.
      • Richman J.S.
      • Itani K.M.
      • Henderson W.G.
      • Maddox T.M.
      Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
      ,
      • Sharifi M.
      • Kamali A.
      • Ghandi Y.
      Effect of sustained use of aspirin until the time of surgery on outcomes following coronary artery bypass grafting: a randomized clinical trial.
      ; 831
      Low
      wide CI, including substantial benefits and harms and/or small sample size.
      Mortality1.20 (0.47-3.01)5 RCTs
      • Hawn M.T.
      • Graham L.A.
      • Richman J.S.
      • Itani K.M.
      • Henderson W.G.
      • Maddox T.M.
      Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
      • Capodanno D.
      • Musumeci G.
      • Lettieri C.
      • et al.
      Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery.
      • Deja M.A.
      • Kargul T.
      • Domaradzki W.
      • et al.
      Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial.
      • Mishra P.K.
      • Thekkudan J.
      • Sahajanandan R.
      • et al.
      The role of point-of-care assessment of platelet function in predicting postoperative bleeding and transfusion requirements after coronary artery bypass grafting.
      • Sharifi M.
      • Kamali A.
      • Ghandi Y.
      Effect of sustained use of aspirin until the time of surgery on outcomes following coronary artery bypass grafting: a randomized clinical trial.
      ; 1186
      Low
      wide CI, including substantial benefits and harms and/or small sample size.
      0.79 (0.49-1.28)10 comparatives observational
      • Janssen P.
      • Claassens D.
      • Willemsen L.
      • Bergmeijer T.
      • Klein P.
      • Ten Berg J.
      Perioperative management of antiplatelet treatment in patients undergoing isolated coronary artery bypass grafting in Dutch cardiothoracic centres.
      • Lee J.
      • Jung C.-W.
      • Jeon Y.
      • et al.
      Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized study.
      • Al-Lawati A.A.
      • Muthuswamy V.
      Continuing aspirin causes higher drainage even under full protection with antifibrinolytics.
      • Bybee K.A.
      • Powell B.D.
      • Valeti U.
      • et al.
      Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
      ,
      • Emmiler M.
      • Ayoğlu R.U.
      • Tekinalp Ö.H.
      • Arslan Ş.
      Off-pump coronary artery bypass grafting under clopidogrel treatment.
      • Fox K.A.
      • Mehta S.R.
      • Peters R.
      • et al.
      Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
      • Gielen C.L.
      • Bruggemans E.F.
      • Stijnen T.
      • et al.
      Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
      • Hongo R.H.
      • Ley J.
      • Dick S.E.
      • Yee R.R.
      The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting.
      • Huang J.
      • Donneyong M.
      • Trivedi J.
      • et al.
      Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations.
      • Shi J.
      • Ji H.
      • Ren F.
      • et al.
      Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial.
      ; 8676
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      Management of antiplatelet agents around minor procedures (dental)
      Major bleeding0.95 (0.27-3.38)3 RCTs
      • Xiao F.
      • Wu H.
      • Sun H.
      • Pan S.
      • Xu J.
      • Song Y.
      Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients.
      • Goldhammer J.E.
      • Marhefka G.D.
      • Daskalakis C.
      • et al.
      The effect of aspirin on bleeding and transfusion in contemporary cardiac surgery.
      • Ardekian L.
      • Gaspar R.
      • Peled M.
      • Brener B.
      • Laufer D.
      Does low-dose aspirin therapy complicate oral surgical procedures?.
      ; 155
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Minor bleeding2.1 (0.88-5.00)1 RCT
      • Xiao F.
      • Wu H.
      • Sun H.
      • Pan S.
      • Xu J.
      • Song Y.
      Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients.
      ; 39
      Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Management of antiplatelet agents around minor procedures (ophthalmological)
      Major bleeding0.65 (0.15-2.90)1 RCT
      • Brennan M.
      • Valerin M.
      • Noll J.
      • et al.
      Aspirin use and post-operative bleeding from dental extractions.
      ; 39
      Low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Major thromboembolism0.67 (0.01-32.25)Very low
      See Cochrane Risk of Bias Tool table.
      ,
      wide CI, including substantial benefits and harms and/or small sample size.
      Minor bleeding1.45 (0.07-30.25)1 comparative observational
      • Eapen B.V.
      • Baig M.
      • Avinash S.
      An assessment of the incidence of prolonged postoperative bleeding after dental extraction among patients on uninterrupted low dose aspirin therapy and to evaluate the need to stop such medication prior to dental extractions.
      ; 4340
      Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Stroke0.29 (0.02-4.64)Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Myocardial Infarction2.00 (0.1-39.4)Very low
      wide CI, including substantial benefits and harms and/or small sample size.
      ,
      See the Newcastle-Ottawa risk of bias table.
      Major thromboembolism: any outcomes: ischemic stroke, transient ischemic attack, myocardial infarction, peripheral embolism, venous thromboembolism, or vascular death. Major bleeding defined following the International Society on Thrombosis and Haemostasis standards as having a symptomatic presentation and fatal bleeding and/or bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more or leading to transfusion of 2 or more units of whole blood or red blood cells.
      a ASA, acetylsalicylic acid; RCT, Randomized clinical trial.
      b When the number of events was very low (<10), we considered rating down by 2-3 levels unless the sample size was large (>2000-4000). An arbitrary cutoff of the relative risk reduction of 25% was used as a cutoff for lowering certainty in precision by 2 levels. RCTs start at high certainty, whereas non-RTCs start at low certainty. Certainty was rated down for risk of bias, imprecision, indirectness, inconsistency, and publication bias. Precision was judged on the basis of whether confidence intervals crossed the null as a target of certainty. Certainty of evidence
      c See Cochrane Risk of Bias Tool table.
      d wide CI, including substantial benefits and harms and/or small sample size.
      e See the Newcastle-Ottawa risk of bias table.

      Continuing vs Stopping ASA ≤7 days

      Another subset of studies compared stopping ASA within ≤7 days before surgery to continuing ASA throughout the elective surgery. We included 3 RCTs
      • Antolovic D.
      • Rakow A.
      • Contin P.
      • et al.
      A randomised controlled pilot trial to evaluate and optimize the use of anti-platelet agents in the perioperative management in patients undergoing general and abdominal surgery—the APAP trial (ISRCTN45810007).
      • Engheta A.
      • Abianeh S.H.
      • Atri A.
      • Sanatkarfar M.
      Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial.
      • Ong W.
      • Shen T.
      • Tan W.B.
      • Lomanto D.
      Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?.
      and 2 cohort studies
      • Hanalioglu S.
      • Sahin B.
      • Sahin O.S.
      • et al.
      Effect of perioperative aspirin use on hemorrhagic complications in elective craniotomy for brain tumors: results of a single-center, retrospective cohort study.
      ,
      • Rahman M.
      • Donnangelo L.L.
      • Neal D.
      • Mogali K.
      • Decker M.
      • Ahmed M.M.
      Effects of perioperative acetyl salicylic acid on clinical outcomes in patients undergoing craniotomy for brain tumor.
      that reported on 485 patients. The risk of bias for cohort studies and RCT was moderate. There was no statistically significant difference in the risk of major bleeding, as shown in Supplemental Figure 1 (available online at http://www.mcpiqojournal.org), major thromboembolism, and MI, as summarized in the Table, with very low COE.

      Patients randomized to ASA perioperatively vs Placebo

      Another subset of studies compared continuing ASA through elective surgery to placebo (not taking ASA) before surgery. We included 5 RCTs
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      • Oscarsson A.
      • Gupta A.
      • Fredrikson M.
      • et al.
      To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      • Tytgat S.H.
      • Laman D.M.
      • Rijken A.M.
      • et al.
      Emboli rate during and early after carotid endarterectomy after a single preoperative dose of 120 mg acetylsalicylic acid--a prospective double-blind placebo controlled randomised trial.
      • Mantz J.
      • Samama C.M.
      • Tubach F.
      • et al.
      Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.
      that reported on 28,062 patients. The risk of bias for the RCTs was low. Compared with patients who received placebo perioperatively, ASA continuation was associated with an increased risk of major bleeding (RR, 1.31; 95% CI, 1.15-1.50; high COE) and a lower risk of major thromboembolism (RR, 0.75; 95% CI, 0.59-0.95; high COE). There was no statistically significant difference in the risk of MI, stroke and mortality, with high COE for MI and stroke and low COE for mortality.

      Question 2. Continuation vs Stopping Antiplatelet Agents in Patients With Coronary Stents at High Risk or Low-Moderate Risk for CV Events

      We included 1 RCT
      • Chu E.W.
      • Chernoguz A.
      • Divino C.M.
      The evaluation of clopidogrel use in perioperative general surgery patients: a prospective randomized controlled trial.
      and 2 cohort studies
      • Sharma A.K.
      • Ajani A.E.
      • Hamwi S.M.
      • et al.
      Major noncardiac surgery following coronary stenting: when is it safe to operate?.
      ,
      • Hawn M.T.
      • Graham L.A.
      • Richman J.S.
      • Itani K.M.
      • Henderson W.G.
      • Maddox T.M.
      Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
      that reported on 638 patients with coronary artery stents (mixed population; high risk or low-moderate risk for CV events) who continued antiplatelet agents perioperatively or stopped antiplatelet agents 7 to 10 days before the procedure/surgery. The risk of bias for the cohort studies was moderate and for the RCT was low.
      Compared with stopping antiplatelet therapy, continuing antiplatelet therapy perioperatively was not associated with a statistically significant difference in the risk of major bleeding and major thromboembolism, as summarized in the Table, with low to very low COE for RCT and cohort studies, respectively.

      Question 3. Bridging vs No Bridging in Patients with Coronary Stents and Receiving Antiplatelet Agents

      We included 1 cohort study
      • Capodanno D.
      • Musumeci G.
      • Lettieri C.
      • et al.
      Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery.
      that reported on 215 patients who received bridging with low-molecular-weight heparin (LMWH) compared with 264 patients with no bridging during interruption of antiplatelet agents. The risk of bias for the cohort study was moderate. Compared with no bridging during interruption, bridging with LMWH was associated with a statistically significant increase in the risk of major bleeding (RR, 1.86; 95% CI, 1.24-2.79) and thromboembolism (RR, 26.2; 95% CI, 1.56-441.6; very low COE).

      Question 4. Continuation vs Stopping Antiplatelet Agents in Patients Undergoing CABG

      We included 17 studies (5 RCTs
      • Deja M.A.
      • Kargul T.
      • Domaradzki W.
      • et al.
      Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial.
      • Mishra P.K.
      • Thekkudan J.
      • Sahajanandan R.
      • et al.
      The role of point-of-care assessment of platelet function in predicting postoperative bleeding and transfusion requirements after coronary artery bypass grafting.
      • Sharifi M.
      • Kamali A.
      • Ghandi Y.
      Effect of sustained use of aspirin until the time of surgery on outcomes following coronary artery bypass grafting: a randomized clinical trial.
      • Janssen P.
      • Claassens D.
      • Willemsen L.
      • Bergmeijer T.
      • Klein P.
      • Ten Berg J.
      Perioperative management of antiplatelet treatment in patients undergoing isolated coronary artery bypass grafting in Dutch cardiothoracic centres.
      • Lee J.
      • Jung C.-W.
      • Jeon Y.
      • et al.
      Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized study.
      and 12 cohorts
      • Al-Lawati A.A.
      • Muthuswamy V.
      Continuing aspirin causes higher drainage even under full protection with antifibrinolytics.
      • Bybee K.A.
      • Powell B.D.
      • Valeti U.
      • et al.
      Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
      • Deng Y.
      • Pisklak P.V.
      • Lee V.-V.
      • et al.
      Association between preoperative aspirin-dosing strategy and mortality after coronary artery bypass graft surgery.
      • Emmiler M.
      • Ayoğlu R.U.
      • Tekinalp Ö.H.
      • Arslan Ş.
      Off-pump coronary artery bypass grafting under clopidogrel treatment.
      • Fox K.A.
      • Mehta S.R.
      • Peters R.
      • et al.
      Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
      • Gielen C.L.
      • Bruggemans E.F.
      • Stijnen T.
      • et al.
      Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
      • Hongo R.H.
      • Ley J.
      • Dick S.E.
      • Yee R.R.
      The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting.
      • Huang J.
      • Donneyong M.
      • Trivedi J.
      • et al.
      Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations.
      • Shi J.
      • Ji H.
      • Ren F.
      • et al.
      Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial.
      • Wu H.
      • Wang J.
      • Sun H.
      • et al.
      Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting.
      • Xiao F.
      • Wu H.
      • Sun H.
      • Pan S.
      • Xu J.
      • Song Y.
      Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients.
      • Goldhammer J.E.
      • Marhefka G.D.
      • Daskalakis C.
      • et al.
      The effect of aspirin on bleeding and transfusion in contemporary cardiac surgery.
      ) that reported on 12,621 patients. The risk of bias for RCTs and cohort studies was low-to-moderate and moderate-to-high, respectively. Compared with stopping of antiplatelet therapy, continuation of antiplatelet therapy was associated with a statistically significant increase in the risk of major bleeding in the 3 RCTs (RR, 1.68; 95% CI, 1.29-2.18), as shown in Supplemental Figure 2 (available online at http://www.mcpiqojournal.org), with moderate COE. There was no statistically significant difference in the risk of arterial thromboembolism (ATE) events, summarized in the Table, and mortality, as shown in Supplemental Figure 3 (available online at http://www.mcpiqojournal.org). The COE was low for mortality.

      Question 5. Management of Antiplatelet Agents Around Minor (Dental) Procedures

      We included 3 RCTs
      • Ardekian L.
      • Gaspar R.
      • Peled M.
      • Brener B.
      • Laufer D.
      Does low-dose aspirin therapy complicate oral surgical procedures?.
      • Brennan M.
      • Valerin M.
      • Noll J.
      • et al.
      Aspirin use and post-operative bleeding from dental extractions.
      • Eapen B.V.
      • Baig M.
      • Avinash S.
      An assessment of the incidence of prolonged postoperative bleeding after dental extraction among patients on uninterrupted low dose aspirin therapy and to evaluate the need to stop such medication prior to dental extractions.
      that reported on 155 patients who were undergoing minor dental procedures. The risk of bias in these RCTs was moderate. Compared with stopping antiplatelet therapy between 7 and 10 days before the procedure/surgery, continuation of antiplatelet therapy was not associated with a statistically significant difference in the risk of major bleeding, as shown in Supplemental Figure 4 (available online at http://www.mcpiqojournal.org), and minor bleeding, summarized in the Table, with very low COE.

      Question 6. Management of Antiplatelet Agents Around Minor (Ophthalmological) Procedures

      We included 1 RCT
      • Winker K.P.
      • Beaulieu R.
      • Bevill L.
      • Mishulin A.
      • Black E.H.
      Effects of aspirin on postoperative bruising and bleeding complications in upper eyelid surgery.
      and 1 cohort study
      • Katz J.
      • Feldman M.A.
      • Bass E.B.
      • et al.
      Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery.
      that reported on 4382 patients. The risk of bias for these cohort studies and the RCT was high to-moderate. Compared with stopping, continuation of antiplatelet therapy was not associated with a statistically significant difference in the risk of major bleeding, stroke, MI, and other major thromboembolism events, as summarized in the Table, with low to very low COE.

      Discussion

      We conducted a systematic review and meta-analysis to support the development of the ACCP/CHEST clinical practice guidelines. The current review summarizes the evidence from 38 studies addressing 6 PICO questions relating to the perioperative management of antiplatelet therapy. Overall, although there have been considerable advances in knowledge, especially pertaining to the perioperative management of ASA in noncardiac surgery and CABG, data remained limited as was the certainty in the various outcomes. This precluded the development of strong practice recommendations relating to perioperative management of antiplatelet therapy.
      In patients receiving single antiplatelet therapy with ASA alone, the available literature suggested no difference between perioperative continuation or interruption of ASA in terms of major bleeding and thromboembolic events. The Pulmonary Embolism Prevention (PEP) trial that included patients requiring hip fracture repair or joint replacement who were randomized to receive ASA started preoperatively or placebo found a reduction in the risk for venous thromboembolism but an increased risk of major bleeding and no effect on MI.
      • O'Brien J.
      • Duncan H.
      • Kirsh G.
      • et al.
      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
      The Perioperative Ischemic Evaluation 2 (POISE-2) randomized trial conducted in patients at risk for coronary artery diseases undergoing noncardiac surgery found that continuing ASA or starting it preoperatively decreased the risk of major thromboembolism but increased the risk of major bleeding, with no significant effect on CV events, including MI.
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      No direct evidence was available about the perioperative management of clopidogrel, prasugrel, or ticagrelor in noncardiac surgery.
      No prospective studies have assessed perioperative management of clopidogrel, prasugrel, or ticagrelor in noncardiac surgery. Retrospective cohort studies of clopidogrel suggest an increased risk of bleeding with perioperative clopidogrel continuation. Thus, making decisions in this context relies on indirect evidence. For example, a retrospective cohort analysis of patients undergoing coronary artery bypass or single-valve surgery has found that ticagrelor exposure 0-72 hours before cardiac surgery was associated with an increased risk of major bleeding complications. On the other hand, ticagrelor exposure 72-120 hours before surgery was not associated with a clinically relevant increase in major bleeding complications.
      • Kremke M.
      • Gissel M.S.
      • Jensen M.J.
      • Thomassen S.A.
      • Jakobsen C.J.
      The association between a three-day ticagrelor discontinuation and perioperative bleeding complications.
      In terms of heparin bridging in patients with coronory stents who are on antiplatelet agents and required treatment interruption before elective surgery, bridging with LMWH was associated with increased bleeding risk and no difference in the risk of ATE. Therefore, a rationale for bridging may only exist in selected high-risk patients, for example, in those with 3 months of coronary stent. There is limited evidence overall on a bridging approach in patients with coronary stents at low or moderate-high risk of CV events.
      An analysis of 5 RCTs
      • Deja M.A.
      • Kargul T.
      • Domaradzki W.
      • et al.
      Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial.
      • Mishra P.K.
      • Thekkudan J.
      • Sahajanandan R.
      • et al.
      The role of point-of-care assessment of platelet function in predicting postoperative bleeding and transfusion requirements after coronary artery bypass grafting.
      • Sharifi M.
      • Kamali A.
      • Ghandi Y.
      Effect of sustained use of aspirin until the time of surgery on outcomes following coronary artery bypass grafting: a randomized clinical trial.
      • Janssen P.
      • Claassens D.
      • Willemsen L.
      • Bergmeijer T.
      • Klein P.
      • Ten Berg J.
      Perioperative management of antiplatelet treatment in patients undergoing isolated coronary artery bypass grafting in Dutch cardiothoracic centres.
      • Lee J.
      • Jung C.-W.
      • Jeon Y.
      • et al.
      Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized study.
      and 12 cohort studies
      • Al-Lawati A.A.
      • Muthuswamy V.
      Continuing aspirin causes higher drainage even under full protection with antifibrinolytics.
      • Bybee K.A.
      • Powell B.D.
      • Valeti U.
      • et al.
      Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
      • Deng Y.
      • Pisklak P.V.
      • Lee V.-V.
      • et al.
      Association between preoperative aspirin-dosing strategy and mortality after coronary artery bypass graft surgery.
      • Emmiler M.
      • Ayoğlu R.U.
      • Tekinalp Ö.H.
      • Arslan Ş.
      Off-pump coronary artery bypass grafting under clopidogrel treatment.
      • Fox K.A.
      • Mehta S.R.
      • Peters R.
      • et al.
      Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
      • Gielen C.L.
      • Bruggemans E.F.
      • Stijnen T.
      • et al.
      Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
      • Hongo R.H.
      • Ley J.
      • Dick S.E.
      • Yee R.R.
      The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting.
      • Huang J.
      • Donneyong M.
      • Trivedi J.
      • et al.
      Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations.
      • Shi J.
      • Ji H.
      • Ren F.
      • et al.
      Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial.
      • Wu H.
      • Wang J.
      • Sun H.
      • et al.
      Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting.
      • Xiao F.
      • Wu H.
      • Sun H.
      • Pan S.
      • Xu J.
      • Song Y.
      Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients.
      • Goldhammer J.E.
      • Marhefka G.D.
      • Daskalakis C.
      • et al.
      The effect of aspirin on bleeding and transfusion in contemporary cardiac surgery.
      that evaluated patients undergoing CABG surgery found an increased risk of major bleeding in patients who continued antiplatelet agents, although the bleeding outcomes assessed varied and results were not always presented according to antiplatelet drug type. The Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS)
      • Myles P.S.
      • Smith J.A.
      • Forbes A.
      Stopping vs. Continuing aspirin before coronary artery surgery.
      trial, which assessed perioperative initiation of ASA against no initiation found no increased risk for surgical-site bleeding. When considering the postoperative complications of antiplatelet agents, the timing of cessation before CABG surgery was deemed an important determinant of bleeding risk. A meta-analysis evaluating clopidogrel interruption before CABG reported that a shorter period (<5 days) of clopidogrel interruption was associated with less CV events and a lower bleeding risk compared with a longer period of interruptions (>5 days).
      • Cao C.
      • Indraratna P.
      • Ang S.C.
      • et al.
      Should clopidogrel be discontinued before coronary artery bypass grafting for patients with acute coronary syndrome? A systematic review and meta-analysis.
      Despite the widespread prescription of antiplatelets in the clinical setting, it was surprising to find very limited data about this clinical scenario.
      In settings of minor procedures, such as dental, ophthalmologic, or dermatologic procedures in which patients are receiving antiplatelet therapy, the available literature suggests no major risk of bleeding or ATE events with periprocedural ASA continuation. In dermatologic procedures, 1 meta-analysis of RCTs and observational studies found no greater risk of hemorrhagic complications with continuation of ASA and no evidence of long-term morbidity.
      • Isted A.
      • Cooper L.
      • Colville R.J.
      Bleeding on the cutting edge: A systematic review of anticoagulant and antiplatelet continuation in minor cutaneous surgery.
      Data on the rate of complications of clopidogrel appear to be low. However, data on ASA continuation in patients undergoing cataract surgery suggested a low incidence of major bleeding, supporting the continued use of ASA.
      • Katz J.
      • Feldman M.A.
      • Bass E.B.
      • et al.
      Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery.
      Similarly, data on stopping ASA before vitreoretinal surgery indicated no difference in terms of hemorrhagic complications.
      • Narendran N.
      • Williamson T.H.
      The effects of aspirin and warfarin therapy on haemorrhage in vitreoretinal surgery.
      This review has 2 major limitations. First, firm conclusions were precluded by the limited evidence base, as reflected by the small number of high-quality studies directly addressing the perioperative management of antiplatelet therapy. Second, certainty in the estimates of effect was low for many PICO questions and associated outcomes, thereby requiring greater reliance on indirect evidence from nonrandomized studies or other clinical contexts to develop practice recommendations. These limitations are consistent with what others have described in this field. A systematic evaluation of 10 guidelines for perioperative management of dual antiplatelet therapy has demonstrated limited rigor and lack of evidence and consensus.
      • Wang X.
      • Tang B.
      • Liu Y.
      • et al.
      Clinical practice guidelines for management of dual antiplatelet therapy in patients with noncardiac surgery: a critical appraisal using the AGREE II instrument.
      The strengths of this systematic review relate to the close working relationship with experts from CHEST/ACCP who developed a priori clinical question and inclusion criteria and. A panel from CHEST/ACCP will use this evidence along with other contextual and implementation factors, such as patients’ values and preferences, feasibility, and acceptability, to develop practical advice for clinicians.

      Conclusion

      Although the perioperative management of patients who are receiving antiplatelet therapy is a common clinical occurrence, there is a relative dearth of high-quality studies that directly address whether to continue or interrupt antiplatelet therapy, the timing of interruption, and the role of bridging therapy. The current best available evidence is derived from a few randomized trials with methodological limitations that only address perioperative continuation or interruption before noncardiac and CABG surgery. For all other clinical scenarios, including the management of patients who are receiving non-ASA single antiplatelet therapy or dual antiplatelet agents, and for those who require minor (nonsurgical) procedures, there is only nonrandomized evidence or indirect evidence to inform practice recommendations. It is, therefore, not surprising that strong recommendations are lacking in the area of perioperative antiplatelet management. This review highlights the urgent need for further research to address these gaps in knowledge, especially as the prevalence of patients taking one or more antiplatelet agents is increasing with an ageing population and such patients are most likely to require a surgery/procedure.

      Potential Competing Interests

      Dr James Douketis reported consulting fees and honoraria from Up-to-Date, Merck Manual, Pfizer, Leo Pharma, Sanofi, Janssen, Servier, and PhaseBio. The other authors report no competing interests.

      Author Contributions

      Conception and design: S.S., M.H.M.; analysis and interpretation: S.S., T.N., M.H.M.; data collection: S.S., M.U., M.F., B.H., T.N., S.S., D.N.F., A.N., R.A., M.O.S., N.R., L.C.H.; writing the article: S.S., A.C.S., J.D.D., M.H.M.; critical revision of the article: S.S., M.U., M.F., B.H., T.N., S.S., D.N.F., M.S., A.N., R.A., N.R., L.C.H., M.O.S.; final approval of the article: S.S., M.U., M.F., M.S., B.H., T.N., S.S., D.N.F., A.N., R.A., M.O.S., N.R., L.C.H.; obtaining funding: M.H.M.

      Supplemental Online Material

      References

        • Gandhi N.K.
        • Abdel-Karim A.R.
        • Banerjee S.
        • Brilakis E.S.
        Frequency and risk of noncardiac surgery after drug-eluting stent implantation.
        Catheter Cardiovasc Interv. 2011; 77: 972-976
        • Spertus J.A.
        • Kettelkamp R.
        • Vance C.
        • et al.
        Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
        Circulation. 2006; 113: 2803-2809
        • Douketis J.D.
        • Spyropoulos A.C.
        • Spencer F.A.
        • et al.
        Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: e326S-e350S
      1. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians clinical practice guideline executive summary. Chest. Published online August 11, 2022. doi:10.1016/j.chest.2022.07.025

        • Douketis J.D.
        • Spyropoulos A.C.
        • Murad M.H.
        • et al.
        Perioperative management of antithrombotic therapy: an American College of Chest Physicians clinical practice guideline.
        Chest. 2022;
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Kaatz S.
        • Ahmad D.
        • Spyropoulos A.C.
        • Schulman S.
        • Anticoagulation S.C.
        Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH.
        J Thromb Haemost. 2015; 13: 2119-2126
      2. R version 4.2.0. The R Project for Statistical Computing; 2022. R: The R Project for Statistical Computing (r-project.org)

      3. GRADE. The GRADE working group.
        (Accessed October 18, 2022.)
        https://www.gradeworkinggroup.org/
        Date accessed: October 18, 2022
        • Zeng L.
        • Brignardello-Petersen R.
        • Hultcrantz M.
        • et al.
        GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings.
        J Clin Epidemiol. 2021; 137: 163-175
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • et al.
        GRADE guidelines 6. Rating the quality of evidence--imprecision.
        J Clin Epidemiol. 2011; 64: 1283-1293
        • Gulpinar K.
        • Ozdemir S.
        • Ozis E.
        • Sahli Z.
        • Demirtas S.
        • Korkmaz A.
        A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?.
        J Korean Surg Soc. 2013; 85: 185-190
        • Mikkola R.
        • Wistbacka J.O.
        • Gunn J.
        • et al.
        Timing of preoperative aspirin discontinuation and outcome after elective coronary artery bypass graft surgery.
        J Cardiothorac Vasc Anesth. 2012; 26: 245-250
        • Antolovic D.
        • Rakow A.
        • Contin P.
        • et al.
        A randomised controlled pilot trial to evaluate and optimize the use of anti-platelet agents in the perioperative management in patients undergoing general and abdominal surgery—the APAP trial (ISRCTN45810007).
        Langenbecks Arch Surg. 2012; 397: 297-306
        • Engheta A.
        • Abianeh S.H.
        • Atri A.
        • Sanatkarfar M.
        Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial.
        Daru. 2016; 24: 1-3
        • Ong W.
        • Shen T.
        • Tan W.B.
        • Lomanto D.
        Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?.
        Surg Endosc. 2016; 30: 5542-5549
        • Hanalioglu S.
        • Sahin B.
        • Sahin O.S.
        • et al.
        Effect of perioperative aspirin use on hemorrhagic complications in elective craniotomy for brain tumors: results of a single-center, retrospective cohort study.
        J Neurosurg. 2019; 132: 1529-1538
        • Rahman M.
        • Donnangelo L.L.
        • Neal D.
        • Mogali K.
        • Decker M.
        • Ahmed M.M.
        Effects of perioperative acetyl salicylic acid on clinical outcomes in patients undergoing craniotomy for brain tumor.
        World Neurosurg. 2015; 84: 41-47
        • Devereaux P.J.
        • Mrkobrada M.
        • Sessler D.I.
        • et al.
        Aspirin in patients undergoing noncardiac surgery.
        N Engl J Med. 2014; 370: 1494-1503
        • Oscarsson A.
        • Gupta A.
        • Fredrikson M.
        • et al.
        To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.
        Br J Anaesth. 2010; 104: 305-312
        • O'Brien J.
        • Duncan H.
        • Kirsh G.
        • et al.
        Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.
        Lancet. 2000; 355: 1295-1302
        • Tytgat S.H.
        • Laman D.M.
        • Rijken A.M.
        • et al.
        Emboli rate during and early after carotid endarterectomy after a single preoperative dose of 120 mg acetylsalicylic acid--a prospective double-blind placebo controlled randomised trial.
        Eur J Vasc Endovasc Surg. 2005; 29: 156-161
        • Mantz J.
        • Samama C.M.
        • Tubach F.
        • et al.
        Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.
        Br J Anaesth. 2011; 107: 899-910
        • Chu E.W.
        • Chernoguz A.
        • Divino C.M.
        The evaluation of clopidogrel use in perioperative general surgery patients: a prospective randomized controlled trial.
        Am J Surg. 2016; 211: 1019-1025
        • Sharma A.K.
        • Ajani A.E.
        • Hamwi S.M.
        • et al.
        Major noncardiac surgery following coronary stenting: when is it safe to operate?.
        Catheter Cardiovasc Interv. 2004; 63: 141-145
        • Hawn M.T.
        • Graham L.A.
        • Richman J.S.
        • Itani K.M.
        • Henderson W.G.
        • Maddox T.M.
        Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
        JAMA. 2013; 310: 1462-1472
        • Capodanno D.
        • Musumeci G.
        • Lettieri C.
        • et al.
        Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery.
        Thromb Haemost. 2015; 114: 423-431
        • Deja M.A.
        • Kargul T.
        • Domaradzki W.
        • et al.
        Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial.
        J Thorac Cardiovasc Surg. 2012; 144: 204-209
        • Mishra P.K.
        • Thekkudan J.
        • Sahajanandan R.
        • et al.
        The role of point-of-care assessment of platelet function in predicting postoperative bleeding and transfusion requirements after coronary artery bypass grafting.
        Ann Card Anaesth. 2015; 18: 45-51
        • Sharifi M.
        • Kamali A.
        • Ghandi Y.
        Effect of sustained use of aspirin until the time of surgery on outcomes following coronary artery bypass grafting: a randomized clinical trial.
        Thorac Cardiovasc Surg. 2018; 66: 442-451
        • Janssen P.
        • Claassens D.
        • Willemsen L.
        • Bergmeijer T.
        • Klein P.
        • Ten Berg J.
        Perioperative management of antiplatelet treatment in patients undergoing isolated coronary artery bypass grafting in Dutch cardiothoracic centres.
        Neth Heart J. 2017; 25: 482-489
        • Lee J.
        • Jung C.-W.
        • Jeon Y.
        • et al.
        Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized study.
        PloS One. 2017; 12e0180466
        • Al-Lawati A.A.
        • Muthuswamy V.
        Continuing aspirin causes higher drainage even under full protection with antifibrinolytics.
        Thorac Cardiovasc Surg. 2013; 61: 726-730
        • Bybee K.A.
        • Powell B.D.
        • Valeti U.
        • et al.
        Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
        Circulation. 2005; 112: I
        • Deng Y.
        • Pisklak P.V.
        • Lee V.-V.
        • et al.
        Association between preoperative aspirin-dosing strategy and mortality after coronary artery bypass graft surgery.
        Ann Surg. 2015; 262: 1150-1156
        • Emmiler M.
        • Ayoğlu R.U.
        • Tekinalp Ö.H.
        • Arslan Ş.
        Off-pump coronary artery bypass grafting under clopidogrel treatment.
        Turk J Thorac Cardiovasc Surg. 2016; 24: 659-666
        • Fox K.A.
        • Mehta S.R.
        • Peters R.
        • et al.
        Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
        Circulation. 2004; 110: 1202-1208
        • Gielen C.L.
        • Bruggemans E.F.
        • Stijnen T.
        • et al.
        Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding?.
        Eur J Cardiothorac Surg. 2015; 48: e64-e70
        • Hongo R.H.
        • Ley J.
        • Dick S.E.
        • Yee R.R.
        The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting.
        J Am Coll Cardiol. 2002; 40: 231-237
        • Huang J.
        • Donneyong M.
        • Trivedi J.
        • et al.
        Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations.
        Ann Thorac Surg. 2015; 99: 1975-1981
        • Shi J.
        • Ji H.
        • Ren F.
        • et al.
        Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial.
        JAMA Surg. 2013; 148: 538-547
        • Wu H.
        • Wang J.
        • Sun H.
        • et al.
        Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting.
        Ann Thorac Surg. 2015; 99: 576-580
        • Xiao F.
        • Wu H.
        • Sun H.
        • Pan S.
        • Xu J.
        • Song Y.
        Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients.
        PLoS One. 2015; 10e0116311
        • Goldhammer J.E.
        • Marhefka G.D.
        • Daskalakis C.
        • et al.
        The effect of aspirin on bleeding and transfusion in contemporary cardiac surgery.
        PLoS One. 2015; 10e0134670
        • Ardekian L.
        • Gaspar R.
        • Peled M.
        • Brener B.
        • Laufer D.
        Does low-dose aspirin therapy complicate oral surgical procedures?.
        J Am Dent Assoc. 2000; 131: 331-335
        • Brennan M.
        • Valerin M.
        • Noll J.
        • et al.
        Aspirin use and post-operative bleeding from dental extractions.
        J Dent Res. 2008; 87: 740-744
        • Eapen B.V.
        • Baig M.
        • Avinash S.
        An assessment of the incidence of prolonged postoperative bleeding after dental extraction among patients on uninterrupted low dose aspirin therapy and to evaluate the need to stop such medication prior to dental extractions.
        J Maxillofac Oral Surg. 2017; 16: 48-52
        • Winker K.P.
        • Beaulieu R.
        • Bevill L.
        • Mishulin A.
        • Black E.H.
        Effects of aspirin on postoperative bruising and bleeding complications in upper eyelid surgery.
        Ophthalmic Plast Reconstr Surg. 2020; 36: 575-578
        • Katz J.
        • Feldman M.A.
        • Bass E.B.
        • et al.
        Risks and benefits of anticoagulant and antiplatelet medication use before cataract surgery.
        Ophthalmology. 2003; 110: 1784-1788
        • Kremke M.
        • Gissel M.S.
        • Jensen M.J.
        • Thomassen S.A.
        • Jakobsen C.J.
        The association between a three-day ticagrelor discontinuation and perioperative bleeding complications.
        Eur J Cardiothorac Surg. 2019; 55: 714-720
        • Myles P.S.
        • Smith J.A.
        • Forbes A.
        Stopping vs. Continuing aspirin before coronary artery surgery.
        N Engl J Med. 2016; 374: 728-737
        • Cao C.
        • Indraratna P.
        • Ang S.C.
        • et al.
        Should clopidogrel be discontinued before coronary artery bypass grafting for patients with acute coronary syndrome? A systematic review and meta-analysis.
        J Thorac Cardiovasc Surg. 2014; 148: 3092-3098
        • Isted A.
        • Cooper L.
        • Colville R.J.
        Bleeding on the cutting edge: A systematic review of anticoagulant and antiplatelet continuation in minor cutaneous surgery.
        J Plast Reconstr Aesthet Surg. 2018; 71: 455-467
        • Narendran N.
        • Williamson T.H.
        The effects of aspirin and warfarin therapy on haemorrhage in vitreoretinal surgery.
        Acta Ophthalmol Scand. 2003; 81: 38-40
        • Wang X.
        • Tang B.
        • Liu Y.
        • et al.
        Clinical practice guidelines for management of dual antiplatelet therapy in patients with noncardiac surgery: a critical appraisal using the AGREE II instrument.
        J Clin Pharm Ther. 2022; 47: 652-661