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Concord Hospital, and ANZAC Institute University of Sydney, Sydney, NSW, AustraliaSchool of Health Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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.
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) [
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).
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).
] 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 [
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).
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 [
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.
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 [
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.
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.
]. 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 [
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).
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 [
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 [
]. 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 [
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 [
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) [
]. 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 [
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.
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.
Variable
Overall n (%) n=5905
Ischaemic Event n (%) n=215
No Ischaemic Event n (%) n=5,690
P-value
Major 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)
<0.0001
73 (64, 81)
65 (55, 74)
<0.0001
<65 years
2,887 (49)
69 (32)
2,818 (50)
<0.0001
13 (27)
2,874 (49)
<0.0001
65-74 years
1,613 (27)
59 (27)
1,554 (27)
12 (24)
1,601 (27)
≥75 years
1,398 (24)
87 (40)
1,311 (23)
24 (49)
1,374 (23)
Female
1,683 (29)
72 (33)
1,611 (28)
0.1249
14 (29)
1,669 (29)
0.9883
Aboriginal/Torres Strait Islander
351 (6.1)
25 (12)
326 (5.9)
0.0005
1 (2.1)
350 (6.1)
0.3655
Risk Factors
Hypertension
3,612 (61)
159 (74)
3,453 (61)
<0.0001
37 (76)
3,575 (61)
0.0292
Dyslipidaemia
3,336 (57)
139 (65)
3,197 (56)
0.0008
27 (55)
3,309 (57)
0.82
Never smoked
2,149 (36)
96 (45)
2,053 (36)
0.0485
25 (51)
2,124 (36)
0.0478
Ex-smoker
2,114 (36)
68 (32)
2,046 (36)
19 (39)
2,095 (36)
Current smoker
1,626 (28)
51 (24)
1,575 (28)
5 (10)
1,621 (28)
Diabetes
1,568 (27)
89 (41)
1,479 (26)
<0.0001
17 (35)
1,551 (26)
0.3035
Characteristics of Index Event
STEMI/new LBBB
1,781 (30)
44 (20)
1,737 (31)
<0.0001
9 (18)
1,772 (30)
0.2652
NSTEMI/UA
4,124 (70)
171 (80)
3,953(69)
40 (82)
4,084 (70)
Treatment of Index Event
CABG
544 (9)
9 (4)
535 (9)
<0.0001
5 (10)
539 (9)
0.1002
PCI
2,851 (48)
57 (27)
2,794 (49)
16 (33)
2,835 (48)
Medical
2,510 (43)
149 (69)
2,361 (41)
28 (57)
2,482 (42)
Re-hospitalised for heart disease or bleeding event between hospital discharge and 6 months
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 Risk
Ischaemic Risk
Odds ratio (95% CI)
P-value
Odds ratio (95% CI)
P-value
TIGRIS 0-2
0.47 (0.18, 1.28)
0.178
0.43 (0.18-1.0)
0.131
TIGRIS 3-4
0.72 (0.26, 1.98)
0.58 (0.31-1.09)
TIGRIS 5+
1.00
1.00
Age ≥75
2.66 (1.3, 5.45)
0.007
1.08 (0.63-1.85)
0.780
Anaemia
0.81 (0.35, 1.91)
0.638
1.98 (1.38-2.83)
<0.001
Rehospitalised <6 months post-ACS
1.87 (0.9, 3.86)
0.092
1.95 (1.26-3.03)
0.003
CABG
1.74 (0.55, 5.5)
0.540
0.56 (0.22-1.44)
0.086
Medical management only
1.5 (0.66, 3.42)
1.42 (0.84-2.4)
PCI
1.00
1.00
Prior heart failure
2.26 (1.2, 4.26)
0.012
1.56 (0.98-2.47)
0.061
Multivessel disease
1.38 (0.62, 3.09)
0.428
1.34 (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.
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 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 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 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.
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 [
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).
], 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 [
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.
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 [
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.
] 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 [
] 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 [
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.
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 [
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 [
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).
]. 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 [
]. 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 [
]; 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 [
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 [
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.
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).
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).
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.
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.
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.
The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE).
Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
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.
Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
Time-dependent associations between actionable bleeding, coronary thrombotic events, and mortality following percutaneous coronary intervention: results from the PARIS registry.
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