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Heart, Lung and Circulation

Balancing the Risks of Recurrent Ischaemic and Bleeding Events in a Stable Post ACS Population

      Objective

      To better guide decisions regarding antithrombotic treatment in individual patients surviving 6 months following an acute coronary syndrome (ACS) by balancing between subsequent recurrent ischaemic and bleeding risk.

      Methods

      Patients surviving 6 months following an ACS were followed in an Australian registry. Ischaemic (composite of cardiovascular death, myocardial infarction or stroke) and bleeding (≥BARC 2) events were collected. A dual binary outcome modelling strategy was used arriving at a common set of variables from which bleeding and ischaemic risk could be independently determined in individual patients. Patients in whom bleeding rates exceeded composite ischaemic event rates during the follow-up period were identified.

      Results

      The cohort comprised 5,905 patients in whom 215 experienced an ischaemic event and 49 a bleeding event. The single set of variables included in both ischaemic and bleeding models (C-statistics 0.71 and 0.72 respectively) included modified TIGRIS
      long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      1long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      ischaemic score, mode of revascularisation, history of heart failure, anaemia, multivessel disease, readmission within 6 months of index ACS and age >75. In the majority, ischaemic events were more frequent than bleeding events. In higher risk patients post coronary artery bypass grafting (CABG), bleeding events were more frequent than recurrent ischaemic events.

      Conclusion

      The risk of recurrent ischaemic events exceeds bleeding in most patients followed 6 to 24 months following an ACS. Post CABG patients with comorbidities have a higher risk of bleeding over this period during which time attention should be directed towards modifiable bleeding risk factors including requirement for dual antiplatelet therapy.

      Keywords

      Introduction

      Dual antiplatelet therapy (DAPT) with aspirin plus an adenosine diphosphate (ADP) receptor antagonist is recommended routinely for 12 months following an acute coronary syndrome (ACS) [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for Dual Antiplatelet Therapy In Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • Mueller C.
      • Valgimigli M.
      • Andreotti F.
      • et al.
      2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      ], following randomised clinical trials comparing DAPT against aspirin alone [
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • Cannon C.P.
      • Emanuelsson H.
      • Held C.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ,
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • Montalescot G.
      • Ruzyllo W.
      • Gottlieb S.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      ] and reinforced in the early drug eluting stent (DES) era where treatment of this duration was recommended to minimise the likelihood of late stent thrombosis [
      • Farb A.
      • Boam A.B.
      Stent thrombosis redux--the FDA perspective.
      ]. However earlier discontinuation can be considered in patients at higher risk of bleeding [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for Dual Antiplatelet Therapy In Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • Mueller C.
      • Valgimigli M.
      • Andreotti F.
      • et al.
      2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      ], a practice that is supported by recent studies suggesting that cessation 6 months or earlier following an ACS may be safe and associated with less bleeding in patients receiving newer generation DES [
      • Palmerini T.
      • Della Riva D.
      • Benedetto U.
      • Bacchi Reggiani L.
      • Feres F.
      • Abizaid A.
      • et al.
      Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients.
      ,
      • Mehran R.
      • Baber U.
      • Sharma S.K.
      • Cohen D.J.
      • Angiolillo D.J.
      • Briguori C.
      • et al.
      Ticagrelor with or without aspirin in high-risk patients after PCI.
      ].
      The duration and intensity of antithrombotic therapy in the post ACS patient appears further influenced by the mode of revascularisation following the event. Observational studies consistently show under-treatment of medically managed (non-revascularised) patients relative to those who have been stented [
      • Prami T.
      • Khanfir H.
      • Deleskog A.
      • Hasvold P.
      • Kyto V.
      • Reissell E.
      • et al.
      Clinical factors associated with initiation of and persistence with ADP receptor-inhibiting oral antiplatelet treatment after acute coronary syndrome: a nationwide cohort study from Finland.
      ,
      • Anastasius M.
      • Lau J.K.
      • Hyun K.
      • D'Souza M.
      • Patel A.
      • Rankin J.
      • et al.
      The underutilisation of dual antiplatelet therapy in acute coronary syndrome.
      ], despite robust evidence of benefit for at least 12 months following the event [
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • James S.K.
      • Roe M.T.
      • Cannon C.P.
      • Cornel J.H.
      • Horrow J.
      • Husted S.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.
      ,
      • Lindholm D.
      • Varenhorst C.
      • Cannon C.P.
      • Harrington R.A.
      • Himmelmann A.
      • Maya J.
      • et al.
      Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial.
      ]. Whether this is justified because of increased bleeding risk has not been systematically studied. Furthermore, DAPT is least frequently prescribed in ACS patients revascularised by CABG when compared to medically managed or stented patients [
      • Anastasius M.
      • Lau J.K.
      • Hyun K.
      • D'Souza M.
      • Patel A.
      • Rankin J.
      • et al.
      The underutilisation of dual antiplatelet therapy in acute coronary syndrome.
      ,
      • Krimly A.
      • Yan R.T.
      • Yan A.T.
      • DeYoung J.P.
      • Gallo R.
      • Steg G.
      • et al.
      Use of clopidogrel post-coronary artery bypass surgery in Canadian patients with acute coronary syndromes.
      ], despite consistent recommendations of at least 12 months of DAPT in this patient cohort [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for Dual Antiplatelet Therapy In Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Verma S.
      • Goodman S.G.
      • Mehta S.R.
      • Latter D.A.
      • Ruel M.
      • Gupta M.
      • et al.
      Should dual antiplatelet therapy be used in patients following coronary artery bypass surgery? A meta-analysis of randomized controlled trials.
      ].
      The risks for recurrent ischaemic and bleeding events are related to, but do differ from, patient to patient and decisions regarding continuation of therapy require a trade-off between continued protection against ischaemic events and the risk of causing significant bleeding [
      • Lindholm D.
      • Sarno G.
      • Erlinge D.
      • Svennblad B.
      • Hasvold L.P.
      • Janzon M.
      • et al.
      Combined association of key risk factors on ischaemic outcomes and bleeding in patients with myocardial infarction.
      ]. There are few tools to predict recurrent ischaemic events in a stable post ACS population; the TIGRIS
      long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      group has developed an ischaemic risk score that predicts composite ischaemic events and total mortality in stable post myocardial infarction patients followed for a further 2 years. This tool has been shown to also predict events in the stable post ACS Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE) population [
      • Pocock S.
      • Brieger D.
      • Gregson J.
      • Chen J.Y.
      • Cohen M.
      • Goodman S.G.
      • et al.
      Predicting risk of cardiovascular events 1-3 years post myocardial infarction using a global registry.
      ]. However, to our knowledge there are none that predict bleeding in this cohort, and, importantly, there are no tools that provided simultaneous assessment of ischaemic and bleeding risk in a stable, post ACS population.
      The CONCORDANCE registry is a prospective observational database collecting data on unselected patients admitted with acute coronary syndromes from 43 hospitals around Australia since 2009 [
      • Aliprandi-Costa B.
      • Ranasinghe I.
      • Turnbull F.
      • Brown A.
      • Kritharides L.
      • Patel A.
      • et al.
      The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE).
      ]. Patients are followed routinely at 6 months following their admission and again at 12 and/or 24 months. These follow-up intervals provide an opportunity to describe and explore predictors of both ischaemic and bleeding outcomes in patients who survive 6 months following their event. In this study, we have used the CONCORDANCE patient dataset to develop a predictive model that allows clinicians to simultaneously balance ischaemic against bleeding risk. Our goal is to better guide decisions regarding antithrombotic (eg DAPT) treatment in individual patients surviving 6 months following an ACS.

      Methods

      Details of the CONCORDANCE study have been published [
      • Aliprandi-Costa B.
      • Ranasinghe I.
      • Turnbull F.
      • Brown A.
      • Kritharides L.
      • Patel A.
      • et al.
      The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE).
      ]. In brief, 43 hospitals around Australia selected to reflect the variety of facilities providing care in rural, regional and urban settings recruited the first 10 patients per month from 2009–18. Patients were contacted by phone and mail at 6 months and further details regarding readmissions and ongoing therapies were collected. Further follow-up was encouraged at either 12 months or 24 months where the same details were collected. For this study, the population of interest was the patient cohort who had survived for 6 months following their index admission, were contacted, and provided further follow-up information at either 12 or 24 months.
      Data recorded for each patient included historical characteristics; revascularisation following their index event: percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), no revascularisation, and any events in the first 6 months following their admission. After 6 months follow-up the ischaemic endpoint of interest was a composite of cardiovascular (CV) death, (re) myocardial infarction (MI) or stroke at 12 or 24 months follow-up. The bleeding endpoint was recorded if the bleeding event required readmission (≥BARC 2) [
      • Mehran R.
      • Rao S.V.
      • Bhatt D.L.
      • Gibson C.M.
      • Caixeta A.
      • Eikelboom J.
      • et al.
      Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.
      ]. The study was approved by the Sydney Local Health District Concord Human Research Ethics Committee (CH62/6/2008-141), and an opt-out consent has been granted. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

      Statistical Methods

      Numeric variables were summarised using median and interquartile intervals using Kruskal-Wallis test. Categorical variables were summarised using number and percentages and a p-value for the Rao-Scott chi-square test for the general association between the groups and the corresponding levels of the variables. The TIGRIS risk score (without EQ5D on enrolment) was applied to the population and its predictive ability determined. Patients were then grouped into tertiles of ischaemic risk as follows: low risk 0–2, moderate risk 3–4, high risk >4. Next, comparisons between patients who did and did not experience major bleeding on univariate analyses were performed. Those with a p-value of <0.1 and/or were clinically plausible together with TIGRIS risk tertiles were used as starting variables in two logistic regression analyses to predict ischaemic events and major bleeding. Regression analysis was performed within the framework of Generalized Estimating Equations (GEE) for the difference between the groups correcting for any bias in the estimates due to clustering effects by hospitals. The p-values from the Wald tests of individual coefficients of the model were used to identify covariates that might be deleted from both ischaemic and bleeding models. Only variables that were non-significant (at the 5% level) in both models were used as potential candidates for removal. We then assessed whether removal of a covariate in each model produced an important change in the coefficients of the variables remaining in the models. If the variable excluded was an important confounder in at least one model, it was added back into the models. This process continues until no covariates could be deleted from the models, ultimately arriving at a single list of variables common to both models [

      David W. Hosmer, Stanley Lemeshow, May S. Purposeful selection of covariates. Applied Survival Analysis. John Wiley and Sons; 2011.

      ].
      The statistics produced were the odds ratio, 95% confidence interval of the odds ratio and the overall p-value. The analysis was conducted using SAS 9.4 (SAS Institute Inc. Cary, NC, US).

      Results

      Between October 2009 and June 2018, 8,174 patients in the CONCORDANCE registry were contacted and alive 6 months following their ACS. Of these, 4,017 were followed 6 months later and 1,889 were contacted 18 months later. These 5,906 patients (72% of the 6-month cohort) constituted the study population. Consort diagram depicting patient flow is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Consort diagram of patient flow.
      Abbreviation: ACS, acute coronary syndrome.

      Patient Characteristics

      The median age of the population was 65 years, 29% were female. The index event was ST elevation myocardial infarction (STEMI) in 30% and non-ST elevation myocardial infarction (NSTEACS) in 55%. Approximately half received PCI and 9% CABG during their index MI and one-fifth had been readmitted for either a further cardiovascular or bleeding event between their index event and entry into this study. There was a high prevalence of comorbidities, 47% had multivessel disease, 29% had a history of diabetes mellitus, and 29% had prior MI before their index event; over 30% were moderate or high risk of an ischaemic event when graded by the modified TIGRIS risk score. Rate of use of evidence-based therapies was modest with 57% receiving DAPT and 89% receiving a statin. Nine per cent (9%) were taking an oral anticoagulant (OAC) at enrolment in the study (Table 1).
      Table 1Baseline characteristics according to incidence of ischaemic and bleeding events >6-24 months following ACS admission.
      VariableOverall n (%)

      n=5905
      Ischaemic Event n (%)

      n=215
      No Ischaemic Event n (%)

      n=5,690
      P-valueMajor Bleeding Event n (%)

      n=49
      No Major Bleeding Event n (%)

      n=5856
      P-value
      Age, median (IQI)65 (55, 74)71 (61, 82)65 (55, 74)<0.000173 (64, 81)65 (55, 74)<0.0001
      <65 years2,887 (49)69 (32)2,818 (50)<0.000113 (27)2,874 (49)<0.0001
      65-74 years1,613 (27)59 (27)1,554 (27)12 (24)1,601 (27)
      ≥75 years1,398 (24)87 (40)1,311 (23)24 (49)1,374 (23)
      Female1,683 (29)72 (33)1,611 (28)0.124914 (29)1,669 (29)0.9883
      Aboriginal/Torres Strait Islander351 (6.1)25 (12)326 (5.9)0.00051 (2.1)350 (6.1)0.3655
      Risk Factors
      Hypertension3,612 (61)159 (74)3,453 (61)<0.000137 (76)3,575 (61)0.0292
      Dyslipidaemia3,336 (57)139 (65)3,197 (56)0.000827 (55)3,309 (57)0.82
      Never smoked2,149 (36)96 (45)2,053 (36)0.048525 (51)2,124 (36)0.0478
      Ex-smoker2,114 (36)68 (32)2,046 (36)19 (39)2,095 (36)
      Current smoker1,626 (28)51 (24)1,575 (28)5 (10)1,621 (28)
      Diabetes1,568 (27)89 (41)1,479 (26)<0.000117 (35)1,551 (26)0.3035
      Characteristics of Index Event
      STEMI/new LBBB1,781 (30)44 (20)1,737 (31)<0.00019 (18)1,772 (30)0.2652
      NSTEMI/UA4,124 (70)171 (80)3,953(69)40 (82)4,084 (70)
      Treatment of Index Event
      CABG544 (9)9 (4)535 (9)<0.00015 (10)539 (9)0.1002
      PCI2,851 (48)57 (27)2,794 (49)16 (33)2,835 (48)
      Medical2,510 (43)149 (69)2,361 (41)28 (57)2,482 (42)
      Re-hospitalised for heart disease or bleeding event between hospital discharge and 6 months1,187 (20)89 (41)1,098 (19)<0.000117 (35)1,170 (20)0.0078
      Comorbidities
      Multi-vessel disease2,298 (47)71 (55)2,227 (46)0.010923 (62)2,275 (46)0.0726
      Prior MI1,687 (29)114 (53)1,573 (28)<0.000118 (37)1,669 (29)0.1184
      Chronic renal failure436 (7)47 (22)389 (7)<0.00018 (16)428 (7)0.0256
      Anaemia1,175 (20)87 (41)1,088 (19)<0.000115 (32)1,160 (20)0.0517
      Exertional angina pectoris1,248 (21)81 (38)1,167 (21)<0.000116 (33)1,232 (21)0.1053
      Prior heart failure793 (13)77 (36)716 (13)<0.000118 (37)775 (13)<0.0001
      Previous percutaneous coronary intervention1,208 (20)66 (31)1,142 (20)0.000810 (20)1,198 (20)0.9930
      Previous coronary artery bypass graft679 (11)53 (25)626 (11)<0.000019 (18)670 (11)0.2421
      Previous atrial fibrillation547 (9)40 (19)507 (9)<0.00019 (18)538 (9)0.0249
      Previous bleed99 (2)7 (3)92 (2)0.07851 (2)98 (2)0.8274
      Previous stroke/transient ischemic attack370 (6)26 (12)344 (6)0.00165 (10)365 (6)0.3001
      Peripheral arterial disease326 (6)35 (16)291 (5)<0.00015 (10)321 (5)0.0563
      Lung disease660 (11)43 (20)617 (11)<0.00017 (14)653 (11)0.4666
      TIGRIS tertiles 0-23,952 (68)68 (32)3,884 (69)<0.000119 (40)3,933 (68)<0.00001
      TIGRIS tertiles 3-41,495 (26)83 (40)1,412 (25)18 (38)1,477 (26)
      TIGRIS tertiles 5+389 (7)59 (28)330 (6)11 (23)378 (7)
      Medications 6 Months Post-ACS
      Dual antiplatelet therapy3,380 (57)121 (56)3,259 (57)0.788622 (45)3,358 (57)0.0429
      Oral anticoagulant515 (9)29 (13)486 (9)0.02478 (16)507 (9)0.0706
      ACE/ARB3,922 (71)134 (69)37,88 (71)0.451129 (62)3,893 (71)0.1112
      Beta blocker3,967 (69)146 (72)3,821 (69)0.506533 (67)3,934 (69)0.9413
      Lipid lowering therapy4,954 (89)173 (87)4,781 (89)0.332937 (79)4,917 (89)0.0242
      Abbreviations: ACS, acute coronary syndrome; IQI, interquartile interval; STEMI, ST-elevation myocardial infarction; LBBB, left bundle branch block; NSTEMI, non-ST elevation myocardial infarction; UA, unstable angina; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; MI, myocardial infarction; ACE, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; TIGRIS, long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      During follow-up 215 patients (3.64%) experienced an ischaemic event (CV death [n=42], MI [n=155] or stroke [n=36]) and 49 (0.83%) a bleeding event requiring hospitalisation. Patients who experienced ischaemic events were older and more likely to have experienced a STEMI, have multiple comorbidities, been readmitted subsequent to their index ACS, and be managed without revascularisation, but to have had prior revascularisation procedures before their index event. There were no differences in receipt of evidence-based therapies, but patients with ischaemic events were more likely to have received an OAC than those without.
      Patients experiencing bleeding events were also older, more likely to have chronic kidney disease (CKD), prior heart failure (HF), atrial fibrillation and hypertension and also more likely to have been readmitted following their index event. They were more likely to be treated with an angiotensin receptor blocker (ARB) but less likely to be receiving DAPT (45% vs 57%, p=0.04) and numerically more likely to be receiving OAC (16% vs 9%, p=0.07).

      Development of Ischaemic and Bleeding Models

      The modified TIGRIS risk model contained many of the variables associated with ischaemic and or bleeding events on univariate analysis (Appendix Table 1). The score was predictive of ischaemic (C statistic 0.74 [0.71, 0.78]) and bleeding (C statistic 0.67 [0.59-0.79]) events. For these analyses, patients were grouped into tertiles of TIGRIS risk. Following multivariable regression modelling with the goal of obtaining a set of common variables in both models, the following variables remained: TIGRIS risk tertile, mode of revascularisation at index MI, age ≥75, anaemia, rehospitalisation for heart disease or a bleeding event following index ACS, prior HF and multivessel disease (Table 2). The predictive characteristics and calibration of the final models were good: C statistic 0.71 (0.66–0.76), and Loess smoothing function 0.75 for the ischaemic events and C statistic 0.72 (0.62–0.82) and Loess smoothing function 0.75 for bleeding events (Figure 2).
      Table 2Common variable bleeding and ischaemic models.
      Bleeding RiskIschaemic Risk
      Odds ratio (95% CI)P-valueOdds ratio (95% CI)P-value
      TIGRIS 0-20.47 (0.18, 1.28)0.1780.43 (0.18-1.0)0.131
      TIGRIS 3-40.72 (0.26, 1.98)0.58 (0.31-1.09)
      TIGRIS 5+1.001.00
      Age ≥752.66 (1.3, 5.45)0.0071.08 (0.63-1.85)0.780
      Anaemia0.81 (0.35, 1.91)0.6381.98 (1.38-2.83)<0.001
      Rehospitalised <6 months post-ACS1.87 (0.9, 3.86)0.0921.95 (1.26-3.03)0.003
      CABG1.74 (0.55, 5.5)0.5400.56 (0.22-1.44)0.086
      Medical management only1.5 (0.66, 3.42)1.42 (0.84-2.4)
      PCI1.001.00
      Prior heart failure2.26 (1.2, 4.26)0.0121.56 (0.98-2.47)0.061
      Multivessel disease1.38 (0.62, 3.09)0.4281.34 (0.96-1.86)0.081
      Abbreviations: CI, confidence interval; ACS, acute coronary syndrome; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; TIGRIS, long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      Figure thumbnail gr2
      Figure 2Calibration plot for the final ischaemic and bleeding models showing observed vs predicted events.
      Loess smoothing value = 0.75.

      Balancing Ischaemic and Bleeding Risk

      To better reflect clinical risk assessment, patients were stratified by modified TIGRIS ischaemic risk tertiles (high, intermediate and low), and by mode of therapy at the time of their index event: PCI, medical treatment alone, or CABG. For patients revascularised by PCI at the time of their index event, the risk of recurrent ischaemic events was greater than the risk of bleeding across all ischaemic risk strata (Figure 3). Patients who were not revascularised had a high likelihood of ischaemic events when compared to revascularised patients and the ischaemic risk consistently exceeded bleeding risk (Figure 4). Patients who had undergone CABG had the lowest risk of further ischaemic events (Figure 5). In this cohort, certain subgroups could be identified in whom readmission for bleeding exceeded readmission for ischaemic events. Clinical features characterising these patients were combinations of age>75, readmission since index presentation, and history of HF.
      Figure thumbnail gr3
      Figure 3Bubble graphs showing ischaemic vs bleeding risk 6–18 months following acute coronary syndrome in patients who had undergone percutaneous coronary intervention.
      Each circle represents patients with a cluster of risk factors. The size of the circle is proportional to the number of patients. The line is drawn where bleeding risk equals ischaemic risk.
      Abbreviation: TIGRIS, long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      Figure thumbnail gr4
      Figure 4Bubble graphs showing ischaemic vs bleeding risk 6–18 months following acute coronary syndrome in patients who had not undergone revascularisation.
      Each circle represents patients with a cluster of risk factors. The size of the circle is proportional to the number of patients. The line is drawn where bleeding risk equals ischaemic risk.
      Abbreviation: TIGRIS, long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.
      Figure thumbnail gr5
      Figure 5Bubble graphs showing ischaemic vs bleeding risk 6–18 months following acute coronary syndrome in patients who had undergone coronary artery bypass grafting.
      Each circle represents patients with a cluster of risk factors. The size of the circle is proportional to the number of patients. The line is drawn where bleeding risk equals ischaemic risk.
      Abbreviation: TIGRIS, long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease.

      Discussion

      In this study we provide direct comparison between the risks of further ischaemic events and bleeding events in patients who have survived 6 months following an ACS. Using a novel, simple multivariable modelling technique which used common variables to predict recurrent ischaemic and bleeding events in individual patients, we show that for most patients surviving 6 months following an ACS, the ongoing risk of a recurrent ischaemic event exceeds the risk of readmission for bleeding during follow-up, regardless of their ischaemic risk profile. In some patients who have been revascularised surgically however, the risk of bleeding exceeds that of recurrent ischaemic events.
      While trials of dual antiplatelet therapy in patients with an ACS have shown a benefit for at least the first 12 months [
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • Mueller C.
      • Valgimigli M.
      • Andreotti F.
      • et al.
      2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      ,
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • Cannon C.P.
      • Emanuelsson H.
      • Held C.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ], emerging data in patients treated with newer drug eluting stents suggest that shorter durations of DAPT may be associated with less bleeding and no apparent ischaemic penalty [
      • Palmerini T.
      • Della Riva D.
      • Benedetto U.
      • Bacchi Reggiani L.
      • Feres F.
      • Abizaid A.
      • et al.
      Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients.
      ,
      • Mehran R.
      • Baber U.
      • Sharma S.K.
      • Cohen D.J.
      • Angiolillo D.J.
      • Briguori C.
      • et al.
      Ticagrelor with or without aspirin in high-risk patients after PCI.
      ,
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • Kolodziejczak M.
      • Buffon A.
      • Brouwer M.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      ]. In addition, compliance with DAPT among the broader post ACS patient populations during the first 12 months following an ACS has been shown to be suboptimal and to decline over time [
      • Prami T.
      • Khanfir H.
      • Deleskog A.
      • Hasvold P.
      • Kyto V.
      • Reissell E.
      • et al.
      Clinical factors associated with initiation of and persistence with ADP receptor-inhibiting oral antiplatelet treatment after acute coronary syndrome: a nationwide cohort study from Finland.
      ,
      • Bueno H.
      • Pocock S.
      • Danchin N.
      • Annemans L.
      • Gregson J.
      • Medina J.
      • et al.
      International patterns of dual antiplatelet therapy duration after acute coronary syndromes.
      ] and identifying clinical patient cohorts in whom ongoing ischaemic risk exceeds bleeding risk may allow efforts to be directed to patients where the benefit is greater, thus lowering the impact of therapeutic attrition.
      To enhance the clinically applicability of our findings, we began our modelling exercise with a validated tool shown to predict recurrent ischaemic events in a stable post MI population, the TIGRIS risk index. This was developed in >9,000 patients and incorporated 10 variables into an integer score, therefore limiting the total number of factors that needed to be considered in our models. The TIGRIS index had been previously validated in our CONCORDANCE cohort [
      • Pocock S.
      • Brieger D.
      • Gregson J.
      • Chen J.Y.
      • Cohen M.
      • Goodman S.G.
      • et al.
      Predicting risk of cardiovascular events 1-3 years post myocardial infarction using a global registry.
      ] and for the current analysis we modified this index by removing the EQ5D variables as these were either not collected or only available in a small subset of our patients. This modified score remained predictive of ischaemic events, and as expected given the commonality of factors predicting bleeding and recurrent ischaemia, it was also predictive of bleeding events. Through the addition of significant and clinically plausible bleeding predictive factors to the TIGRIS risk tertile, two models containing a common set of clinical variables were developed, that predicted recurrent ischaemia and bleeding respectively. The models demonstrated good discriminatory capacity and calibration with C statistics and smoothing functions exceeding 0.7.
      The translation of the findings from this observational registry into clinical recommendations requires an appreciation that absolute event rates are key determinants of the magnitude of both benefits and harms of antithrombotic therapy. In all patients undergoing PCI regardless of ischaemic risk, recurrent ischaemic events were more frequent that bleeding events in our cohort. This does contrast with emerging studies suggesting that shorter duration of DAPT may be safe from an ischaemic perspective in ACS patients following placement of the newer generation drug eluting stents [
      • Palmerini T.
      • Della Riva D.
      • Benedetto U.
      • Bacchi Reggiani L.
      • Feres F.
      • Abizaid A.
      • et al.
      Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients.
      ,
      • Vranckx P.
      • Valgimigli M.
      • Juni P.
      • Hamm C.
      • Steg P.G.
      • Heg D.
      • et al.
      Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial.
      ]. However these randomised clinical trials typically selected lower risk cohorts of patients rather than the unselected ACS patients included in our observational study [
      • Steg P.G.
      • Lopez-Sendon J.
      • Lopez de Sa E.
      • Goodman S.G.
      • Gore J.M.
      • Anderson Jr., F.A.
      • et al.
      External validity of clinical trials in acute myocardial infarction.
      ].
      Among patients who are not revascularised at the time of their index event, the importance of DAPT is well described [
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • James S.K.
      • Roe M.T.
      • Cannon C.P.
      • Cornel J.H.
      • Horrow J.
      • Husted S.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.
      ]. While the ongoing ischaemic risk is well documented in the first 12 months following an ACS. Our findings indicate that regardless of clinical comorbidities, this risk extends out to at least 2 years which should be taken into consideration during follow-up evaluation.
      Although recommended in guidelines, the evidence supporting DAPT in the post-bypass setting is not as robust as for the other subgroups [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for Dual Antiplatelet Therapy In Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • Cannon C.P.
      • Emanuelsson H.
      • Held C.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ,
      • Bhatt D.L.
      • Chew D.P.
      • Hirsch A.T.
      • Ringleb P.A.
      • Hacke W.
      • Topol E.J.
      Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery.
      ]. Randomised studies of aspirin plus clopidogrel versus aspirin alone have not shown any reduction in mortality or ischaemic events in CABG patients, while those comparing clopidogrel to ticagrelor or prasugrel have reported reductions in mortality, albeit with some heterogeneity on meta-analysis [
      • Verma S.
      • Goodman S.G.
      • Mehta S.R.
      • Latter D.A.
      • Ruel M.
      • Gupta M.
      • et al.
      Should dual antiplatelet therapy be used in patients following coronary artery bypass surgery? A meta-analysis of randomized controlled trials.
      ]. Ours is the first analysis to highlight the relative risk of bleeding versus recurrent ischaemic events in stable patients >6 months following CABG. Factors that predicted increased bleeding included a combination of age >75, a history of heart failure, multivessel disease, or readmission in the 6 months following their ACS event. These factors presumably identify a less robust cohort with poor reserve following the stresses of major surgery explaining their greater predisposition to bleeding events.
      Our patient cohort was heterogeneous in terms of the antithrombotic therapy received 6 months following the ACS, and factors driving continuation versus cessation of therapy could not be determined. In addition, antithrombotics are frequently ceased 3 months following an ACS now; we did not collect data on therapies at this time point so could not examine this. Nor could we attribute risk of bleeding to antithrombotic therapies; in fact the use of DAPT was associated with less bleeding in our cohort, indicative of the confounding by intention bias inherent in observational studies whereby these treatments are preferentially directed towards patients at lower risk of bleeding. Only 57% remained on DAPT, consistent with other cohort studies [
      • Bueno H.
      • Pocock S.
      • Danchin N.
      • Annemans L.
      • Gregson J.
      • Medina J.
      • et al.
      International patterns of dual antiplatelet therapy duration after acute coronary syndromes.
      ]; and is likely to have contributed to the ongoing ischaemic risk observed in many of our patients, suggesting that longer duration of therapy may have been of benefit in a significant proportion of our patients.
      This study does suffer from the known limitations of observational studies, including a reliance on selected data verification processes and limited outcomes adjudication. We identified only 49 bleeding events in our cohort which may have impacted on our capacity to reliably model this outcome although objective assessments of the discrimination and calibration of our bleeding model were quite robust. Furthermore, bleeding requiring hospitalisation (corresponding to BARC ≥2 bleeding) collected in this dataset is less severe than bleeding definitions included in net clinical endpoints in a number of randomised trials and other descriptive studies [
      • Baber U.
      • Leisman D.E.
      • Cohen D.J.
      • Gibson C.M.
      • Henry T.D.
      • Dangas G.
      • et al.
      Tailoring antiplatelet therapy intensity to ischemic and bleeding risk.
      ,
      • Ducrocq G.
      • Schulte P.J.
      • Budaj A.
      • Cornel J.H.
      • Held C.
      • Himmelmann A.
      • et al.
      Balancing the risk of spontaneous ischemic and major bleeding events in acute coronary syndromes.
      ,
      • Yeh R.W.
      • Secemsky E.A.
      • Kereiakes D.J.
      • Normand S.L.
      • Gershlick A.H.
      • Cohen D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
      ]. However our decision to assign equal weighting to the composite ischaemic endpoint was informed by the knowledge that bleeding of this intensity has been associated with a 2.3-fold increase in mortality, comparable to that associated with coronary thrombotic events, one of the components of our ischaemic composite endpoint [
      • Baber U.
      • Dangas G.
      • Chandrasekhar J.
      • Sartori S.
      • Steg P.G.
      • Cohen D.J.
      • et al.
      Time-dependent associations between actionable bleeding, coronary thrombotic events, and mortality following percutaneous coronary intervention: results from the PARIS registry.
      ].
      In conclusion, our study is the first to focus exclusively on an unselected population who have survived 6 months following their ACS. We describe and apply a modelling technique simultaneously predicting both recurrent ischaemic and clinically significant bleeding events over the ensuing 6–18 months which allows a direct comparison of the risks of each of these events according to individual patient characteristics. In patients either treated with PCI or not revascularised, ongoing ischaemic risk continues to outweigh bleeding risk during the 6-18 month follow-up period, suggesting ongoing antithrombotic therapy be prioritised. Conversely, in particular comorbid patients revascularised with CABG, the risk of bleeding outweighs recurrent ischaemic events. Attention to modifiable bleeding risk factors including requirement for ongoing DAPT should be taken into consideration during ongoing evaluation of these patients.
      Our study illustrates the heterogeneity of the ACS population with regards to ischaemic versus bleeding risk, particularly when stratified by revascularisation strategy. We believe this work, once validated in other cohorts, represents an important step in the development of a tool to guide personalised decision making with anti-thrombotics following an ACS.

      Competing Interests

      None.

      Funding

      KH is supported by NHMRC Investigator Grant (Emerging leadership 1) [APP1196724].

      Contributorship

      DB and MDS participated in the design of the study. MDS and KH performed the statistical analysis. DB, MDS, KH, DC participated in the interpretation of the results. DB drafted the manuscript and all authors critically reviewed and refined the manuscript. All authors read and approved the final manuscript.

      Acknowledgements

      The CONCORDANCE registry has been funded by grants to the Sydney Local Health District from Sanofi Aventis, Astra Zeneca, Eli Lilly, Boehringer Ingelheim, the Merck Sharp and Dohme/Schering Plough joint venture, and the National Heart Foundation of Australia. The sponsors played no role in the design, analysis, or interpretation of data or findings. The authors would like to acknowledge the contribution of all the CONCORDANCE investigators and their patients to this registry.

      Supplementary Data

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