1. A Systematic Review On The Hazards Of Aspirin Discontinuation Among 50279 Patients With Or At Risk For Coronary Artery Disease Giuseppe Biondi Zoccai Hemodynamics and Cardiovascular Interventions Service Abano Terme Hospital, Abano Terme (PD) and Institute of Cardiology, University of Turin, Turin gbiondizoccai@gmail.com

2. Funding and conflict of interest disclosure None None

3. Background The role of aspirin in patients with coronary artery disease (CAD) is well established 1 The role of aspirin in patients with coronary artery disease (CAD) is well established 1 Patients however happen to discontinue aspirin according to physician advice or unsupervised 2 Patients however happen to discontinue aspirin according to physician advice or unsupervised 2 To date, there is no conclusive evidence on the risk of aspirin withdrawal in such patients, despite several reports on its potentially ominous consequences 3 To date, there is no conclusive evidence on the risk of aspirin withdrawal in such patients, despite several reports on its potentially ominous consequences 3 1 – ATC BMJ 20022 – Eagle Am J Med 2004 3 - McFadden Lancet 2004

4. Objectives We aimed to systematically search, appraise, and pool clinical studies reporting on the impact of aspirin discontinuation among patients with or at risk for CAD We aimed to systematically search, appraise, and pool clinical studies reporting on the impact of aspirin discontinuation among patients with or at risk for CAD

5. Study search and selection BioMedCentral, Google Scholar, and PubMed were searched, without language restrictions BioMedCentral, Google Scholar, and PubMed were searched, without language restrictions Inclusion criteria: a) human studies, b) reporting on the quantitative appraisal of the cardiovascular risk of aspirin withdrawal, and c) in patients at risk for or with established coronary artery disease Inclusion criteria: a) human studies, b) reporting on the quantitative appraisal of the cardiovascular risk of aspirin withdrawal, and c) in patients at risk for or with established coronary artery disease Exclusion criteria: a) non-human setting, b) duplicate reporting (in which case the manuscript reporting the largest sample or the longest follow-up was selected), c) inability to compute risk estimates due to case report or series design Exclusion criteria: a) non-human setting, b) duplicate reporting (in which case the manuscript reporting the largest sample or the longest follow-up was selected), c) inability to compute risk estimates due to case report or series design

6. Data abstraction and appraisal We abstracted: authors, journal, years of conduct and publication, study design, sample size, patient characteristics, index diagnosis, prevention stage (primary vs secondary), lesion characteristics, raw numbers and risks for death, myocardial infarction, stroke, major adverse cardiovascular events (as defined and reported by each investigator) and major bleeding We abstracted: authors, journal, years of conduct and publication, study design, sample size, patient characteristics, index diagnosis, prevention stage (primary vs secondary), lesion characteristics, raw numbers and risks for death, myocardial infarction, stroke, major adverse cardiovascular events (as defined and reported by each investigator) and major bleeding Quality of included studies was appraised according to the Cochrane Collaboration methods Quality of included studies was appraised according to the Cochrane Collaboration methods

7. Data analysis and synthesis A random effect model with generic inverse variance weighting was used to compute risk estimates by means of RevMan 4.2 A random effect model with generic inverse variance weighting was used to compute risk estimates by means of RevMan 4.2 Hypothesis testing was set at the 2-tailed 0.05 level Hypothesis testing was set at the 2-tailed 0.05 level A 2-tailed 0.10 p value at chi-square test was considered as cutoff for statistical heterogeneity A 2-tailed 0.10 p value at chi-square test was considered as cutoff for statistical heterogeneity Small study bias was appraised with funnel plots and Egger test Small study bias was appraised with funnel plots and Egger test

8. Review process 612 citations retrieved from database searches 31 complete articles assessed according to the selection criteria 6 studies finally included in the systematic review 581 titles/abstracts excluded because non-relevant 25 articles excluded according to explicit inclusion/exclusion criteria

9. Included studies

10. Major excluded studies

11. Clinical impact of aspirin withdrawal in included studies

12. Quality appraisal of included studies

13. Study or Risk estimate (random model) Risk estimate sub-category 95% CI Year Coronary artery disease Collet Ferrari Newby Subtotal (95% CI) Heterogeneity: P = 0.60, I² = 0% Overall effect: P < 0.00001 Coronary artery stenting Iakovou Subtotal (95% CI) Heterogeneity: not applicable Overall effect: P < 0.00001 Coronary artery bypass grafting Dacey Mangano Subtotal (95% CI) Heterogeneity: P = 0.76, I² = 0% Overall effect: P = 0.002 Total (95% CI) 89.78 [29.90, 269.60] 2.05 [1.08, 3.89] 2004 2.13 [1.42, 3.22] 2005 1.72 [1.54, 2.38] 2006 1.82 [1.52, 2.18] 2005 1.82 [1.02, 3.23] 2000 2.44 [1.61, 3.70] 2002 2.20 [1.58, 3.08] 3.14 [1.75, 5.61] Heterogeneity: P < 0.00001, I² = 89.8% Overall effect: P = 0.0001 0.1 0.2 0.5 1 2 5 10 Favors withdrawal Favors control 30 100 300 Meta-analysis

14. Additional analyses On average 10.66 (95% confidence interval 10.25-11.07) days elapsed between drug withdrawal and thrombotic events On average 10.66 (95% confidence interval 10.25-11.07) days elapsed between drug withdrawal and thrombotic events Testing for publication bias yielded non- significant results (P=0.107 at Egger test) Testing for publication bias yielded non- significant results (P=0.107 at Egger test) Selecting one of the subgroups only, or excluding one study at a time, did not determine major changes in direction or magnitude of statistical findings Selecting one of the subgroups only, or excluding one study at a time, did not determine major changes in direction or magnitude of statistical findings

15. Proposal for management of aspirin discontinuation in patients undergoing surgery HISTORY AND PHYSICAL EXAM and EVALUATION OF SURGICAL RISK MINOR SURGERY CORONARY ARTERY BYPASS GRAFT CONTINUE ASPIRIN MAJOR SURGERY (excluding CABG) LOW RISK OF MAJOR BLEED HIGH RISK OF MAJOR BLEED RECENT CORONARY STENT IMPLANTATION? CONTINUE ASPIRIN + TNP OR RESCHEDULE AFTER >1 MONTHS yes STOP ASPIRIN FOR 3 DAYS HEPARIN BRIDGE RX no CONTINUE ASPIRIN

16. Conclusions Aspirin withdrawal has ominous prognostic implication in subjects with or at moderate-to-high risk for CAD Aspirin withdrawal has ominous prognostic implication in subjects with or at moderate-to-high risk for CAD While awaiting for randomized trials, aspirin discontinuation in such patients should be advocated only when bleeding risk clearly overwhelms that of atherothrombotic events While awaiting for randomized trials, aspirin discontinuation in such patients should be advocated only when bleeding risk clearly overwhelms that of atherothrombotic events

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