Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: The BleeMACS score

doi:10.1016/j.ijcard.2017.10.103

International Journal of Cardiology

Volume 254, 1 March 2018, Pages 10-15

https://doi.org/10.1016/j.ijcard.2017.10.103 Get rights and content

Abstract

Background

Accurate 1-year bleeding risk estimation after hospital discharge for acute coronary syndrome (ACS) may help clinicians guide the type and duration of antithrombotic therapy. Currently there are no predictive models for this purpose. The aim of this study was to derive and validate a simple clinical tool for bedside risk estimation of 1-year post-discharge serious bleeding in ACS patients.

Methods

The risk score was derived and internally validated in the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registry, an observational international registry involving 15,401 patients surviving admission for ACS and undergoing percutaneous coronary intervention (PCI) from 2003 to 2014, engaging 15 hospitals from 10 countries located in America, Europe and Asia. External validation was conducted in the SWEDEHEART population, with 96,239 ACS patients underwent PCI and 93,150 without PCI.

Results

Seven independent predictors of bleeding were identified and included in the BleeMACS score: age, hypertension, vascular disease, history of bleeding, malignancy, creatinine and hemoglobin. The BleeMACS risk score exhibited a C-statistic value of 0.71 (95% CI 0.68–0.74) in the derivation cohort and 0.72 (95% CI 0.67–0.76) in the internal validation sample. In the SWEDEHEART external validation cohort, the C-statistic was 0.65 (95% CI 0.64–0.66) for PCI patients and 0.63 (95% CI 0.62–0.64) for non-PCI patients. The calibration was excellent in the derivation and validation cohorts.

Conclusions

The BleeMACS bleeding risk score is a simple tool useful for identifying those ACS patients at higher risk of serious 1-year post-discharge bleeding.

ClinicalTrials.gov Identifier: NCT02466854

Introduction

Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 receptor inhibitor is the standard regimen to prevent atherothrombotic events in patients after acute coronary syndrome (ACS) [1], especially after percutaneous coronary intervention (PCI) with stenting [2]. In the current era, the clinical cardiologist has to face every day to two important issues when prescribing DAPT: Which P2Y12 inhibitor has to be associated with aspirin? And how long DAPT has to be prescribed [3]?

Because thrombotic risk is increased after ACS, guidelines recommend DAPT with the new more potent P2Y12 inhibitors (ticagrelor or prasugrel) [4]. There is no doubt that both prasugrel and ticagrelor are of choice single bond versus clopidogrel in patients with not-high bleeding risk [5], [6]. Regarding the duration of DAPT, the guidelines establish a reference standard of 12 months [4]. Recent evidence suggests that treatment with DAPT beyond the first year may be beneficial in selected groups of patients with low bleeding risk [7], particularly when the ischemic risk is high [8]. However, guidelines state that shorter DAPT regimens might be considered in patients deemed at high bleeding risk [4].

With this background, it is clear that bleeding risk has an important role as a limiting factor for the choice of the type of DAPT (clopidogrel versus ticagrelor/prasugrel) and for the selection of candidates for shorter DAPT regimens (< versus ≥ 12 months). With this study, we aimed to develop a simple risk prediction tool that would allow physicians to objectively estimate the bleeding risk within the first year after hospital discharge for an ACS.

Section snippets

Study design and population

The BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) is a retrospective, observational, multicenter cohort study involving 15,401 consecutive patients. BleeMACS inclusion and exclusion criteria, data collection, and variables have been described previously [9]. Briefly, eligible patients were all consecutive adult patients (≥ 18 years old) discharged with the definitive diagnosis of ACS and underwent in-hospital PCI, with

Bleeding incidence and predictors

Baseline characteristics and outcomes of both BleeMACS derivation and validation cohorts were similar (Supplementary data, page 5–6, eTable 1, eFigure 2).

The incidence rate of bleeding was 3.2 per 100 person-year (95% CI 2.9%–3.6%) in the BleeMACS derivation cohort, and 3.6 (95% CI 3.1%–4.2%) in the BleeMACS internal validation cohort.

Using data from the BleeMACS derivation cohort, after univariate and multivariate analysis (Table 1), we have identified seven independent predictors of bleeding:

Discussion

This study developed and validated, internally and externally, a clinical risk score to predict serious bleeding in the first year after hospital discharge for ACS. The BleeMACS score accurately classified patients into four bleeding risk groups, with acceptable discriminative ability and excellent calibration in two large cohorts (BleeMACS and SWEDEHEART registries), and in clinically important antithrombotic treatment subgroups.

Conclusion

In this study, we have developed and externally validated for the first time a quantitative clinical tool to predict post-discharge bleeding in patients with ACS. The BleeMACS score demonstrated good discrimination and excellent calibration, and performed satisfactorily on external validation cohort. A BleeMACS score calculator was available in a mobile app (BleeMACS risk score, for iTunes and Android). Further studies are need to assess the impact of prospective use of BleeMACS score in the

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

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Cited by (66)

Incidence and outcomes of high bleeding risk patients with type 1 and type 2 myocardial infarction in a community-based cohort: Application of the Academic Research Consortium High Bleeding Risk Criteria
2024, International Journal of Cardiology
The incidence and outcomes of high bleeding risk (HBR) patients in a community cohort according to the Academic Research Consortium (ARC) criteria is not known. We hypothesized that HBR is common and associated with worse outcomes for all-comers with myocardial infarction.
We prospectively collected all patients with cardiac troponin T > 99th percentile upper limit of normal (≥0.01 ng/mL) in Olmsted County between 2003 and 2012. Events were retrospectively classified as type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI), or myocardial injury. Patients were further classified as HBR based on the “ARC-HBR definition.” Outcomes included all-cause mortality, cardiovascular mortality, recurrent MI, stroke, and major bleeding.
2419 patients were included in the final study; 1365 were classified as T1MI and 1054 as T2MI. Patients were followed for a median of 5.5 years. ARC-HBR was more common in T2MI than T1MI (73% vs 46%, p < 0.001). Among patients with T1MI, HBR was associated with higher all-cause mortality (HR 3.7, 95% CI 3.2–4.5, p < 0.001), cardiovascular mortality (4.7, 3.6–6.3, p < 0.001), recurrent MI (2.1, 1.6–2.7, p < 0.001), stroke (4.9, 2.9–8.4, p < 0.001), and major bleeding (6.5, 3.7–11.4, p < 0.001). For T2MI, HBR was similarly associated with higher all-cause mortality (HR 2.1, 95% CI 1.8–2.5, p < 0.001), cardiovascular mortality (2.7, 1.8–4.0, p < 0.001), recurrent MI (1.7, 1.1–2.6, p = 0.02) and major bleeding (HR 15.6, 3.8–63.8, p < 0.001).
HBR is common among unselected patients with T1MI and T2MI and is associated with increased overall and cardiovascular mortality, recurrent cardiovascular events, and major bleeding on long-term follow up.
Bleeding and Ischemic Risks of Ticagrelor Monotherapy After Coronary Interventions
2023, Journal of the American College of Cardiology
In TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), among high-risk patients undergoing percutaneous coronary intervention (PCI), ticagrelor monotherapy vs continuation of dual antiplatelet therapy (DAPT) with aspirin and ticagrelor after completing a 3-month course of DAPT was associated with reduced bleeding, without an increase in ischemic events.
This investigation sought to study the clinical benefit of ticagrelor monotherapy vs DAPT by simultaneously modeling its associated potential bleeding benefits and ischemic harms on an individual patient basis.
Multivariable Cox regression models for: 1) Bleeding Academic Research Consortium type 2, 3, or 5 (BARC-2/3/5); and 2) cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke (major adverse cardiac and cerebrovascular event [MACCE]) were developed using stepwise forward variable selection. The coefficients in the BARC-2/3/5 and MACCE models were used to calculate bleeding and ischemic risk scores, respectively, for each patient (excluding the coefficient for randomized treatment).
In the total study group (N = 7,119), BARC-2/3/5 occurred in 391 (5.5%) patients, and MACCE occurred in 258 (3.6%). There was a consistent reduction in bleeding events associated with ticagrelor monotherapy compared with DAPT across both bleeding and ischemic risk strata (P interaction = 0.54 and 0.11, respectively). Importantly, this benefit associated with ticagrelor monotherapy was not offset by an increase in MACCE at any level of bleeding or ischemic risk.
Three months after PCI, discontinuing aspirin and maintaining ticagrelor monotherapy reduces bleeding in both higher–bleeding risk and lower–bleeding risk patients compared with continued DAPT. This benefit does not appear to be offset by greater ischemic risk. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)
Validation of Academic Research Consortium for High Bleeding Risk Definition in East-Asian Patients
2023, JACC: Asia
Clinical applicability of the Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria in East-Asian patients receiving potent antiplatelet therapy for acute coronary syndromes (ACS) is still undetermined.
The purpose of this study was to validate the ARC definition for HBR in East-Asian patients with ACS for invasive management
We analyzed data from the TICAKOREA (Ticagrelor Versus Clopidogrel in Asian/Korean Patients With ACS Intended for Invasive Management) trial and randomly assigned 800 Korean ACS subjects to receive, in a 1:1 ratio, ticagrelor or clopidogrel. Patients were considered HBR if they met at least 1 major or 2 minor ARC-HBR criteria. The primary bleeding endpoint was Bleeding Academic Research Consortium 3 or 5 bleeding and the primary ischemic endpoint was a major adverse cardiovascular event (MACE) (a composite of cardiovascular death, myocardial infarction, or stroke) at 12 months.
Among 800 randomized patients, 129 (16.3%) were categorized HBR patients. HBR patients, compared with non-HBR patients, had a higher incidence of Bleeding Academic Research Consortium 3 or 5 bleeding (10.0% vs 3.7%; HR: 2.98; 95% CI: 1.52-5.86; P < 0.001) and MACE (14.3% vs 6.1%; HR: 2.35; 95% CI: 1.35-4.10; P = 0.002). The relative treatment effect of ticagrelor or clopidogrel on primary bleeding and ischemic outcomes were different between each group.
This study validates the ARC-HBR definition in Korean ACS patients. Approximately 15% of patients qualified as HBR patients who were at increased risk not only for bleeding but also for thrombotic events. The clinical application of ARC-HBR to determine the relative effect of different antiplatelet regiments should be further investigated. (Safety and Efficacy of Ticagrelor Versus Clopidogrel in Asian/KOREAn Patients with Acute Coronary Syndromes Intended for Invasive Management [TICA KOREA]; NCT02094963)
Incidence, Timing, and Causes of Late Bleeding After TAVR in an Asian Cohort
2022, JACC: Asia
Citation Excerpt :
These variables predicting late bleeding in our study were considerable factors used to estimate the cumulative incidence of future bleeding events.17-19 and postdischarge bleeding after PCI as well.20-21 Considering the risk of late bleeding in patients on antiplatelet therapy, it is important to evaluate the dynamic change of the antithrombotic regime and drug information at the time of late bleeding.
Data regarding the incidence, predictive factors, and clinical outcomes of post-transcatheter aortic valve replacement (TAVR) bleeding is limited in the Asian cohort.
This study sought to assess the predictors and prognostic impact of post-TAVR late bleeding.
This study used the Japanese multicenter registry data to analyze 2,518 patients (mean age: 84.3 ± 5.2 years) who underwent TAVR. Late bleeding was defined as any postdischarge bleeding events after TAVR. Baseline characteristics, predictive factors, and clinical outcomes including death and rehospitalization were assessed in patients with and without late bleeding events.
The cumulative incidence rate of all and major late bleeding and ischemic stroke were 7.4%, 5.2%, and 3.4%, respectively, 3 years after TAVR. The independent predictive factors of late bleeding were low platelet count, high score (≥4) on the clinical frailty scale, and a New York Heart Association functional class III/IV. The cumulative mortality rates up to 3 years were significantly higher in patients with late bleeding than in those without bleeding (P < 0.001). The multivariate Cox regression analysis revealed that late bleeding, included as a time-varying covariate in the model, was associated with an increased risk of mortality following TAVR (HR: 5.63; 95% CI: 4.28-7.41; P < 0.001).
Late bleeding after TAVR was not a rare complication, and it significantly increased long-term mortality. It should be carefully managed, especially when it is predictable in the high-risk cohort, and efforts should be taken to reduce bleeding complications even after a successful procedure.
Comparison of original and modified Academic Research Consortium for High Bleeding Risk definitions in real-world practice
2022, Journal of Cardiology
Citation Excerpt :
Several bleeding prediction scores have been developed. Each score includes different items, and even the weights of common items vary [5–9]. Such differences in risk scores make prediction of bleeding events after PCI difficult.
The Academic Research Consortium for High Bleeding Risk (ARC-HBR) defined high bleeding risk (HBR) in patients undergoing percutaneous coronary intervention. We have reported a simplified HBR (S-HBR), excluding six items with prevalences under 1% from ARC-HBR. The Japanese Circulation Society developed an HBR specific to Japanese (J-HBR), adding three items to ARC-HBR in consideration of ethnicity. Data comparing each HBR are scarce.
Patients treated with second-generation drug-eluting stents between January 2010 and December 2013 were enrolled, in whom all items of ARC-HBR, and the incidences of major bleeding and ischemic events were examined. Also, the diagnostic values of ARC-HBR, S-HBR, and J-HBR at 1 and 7 years post procedure were compared by using receiver-operating characteristic curves.
The study sample consisted of 3430 patients. Mean follow-up period was 2299 ± 904 days. The incidence of major bleeding at 1 and 7 years in each definition was as follows: ARC-HBC, 3.3% and 10.6%; S-HBR, 3.3% and 10.7%; and J-HBR, 2.9% and 10.0%. The diagnostic value of J-HBR for major bleeding at 1 year was lower than that of ARC-HBR (C statistics 0.64 vs. 0.68, p < 0.001). Other diagnostic values of S-HBR and J-HBR were comparable to those of ARC-HBR.
S-HBR was as useful as ARC-HBR in predicting both short- and long-term HBR, and J-HBR is useful for predicting long-term HBR.
Cancer patients with acute coronary syndrome have non-superior bleeding risk compared to patients with similar characteristics – a propensity score analysis from the ProACS registry
2022, Revista Portuguesa de Cardiologia
The management of acute coronary syndrome (ACS) in malignancy is challenging due to higher bleeding risk.
We analyzed patients with cancer (active or in the previous five years) prospectively included in the ProACS registry between 2010 and 2019. Our aim was to assess safety (major bleeding, primary endpoint) and secondary efficacy endpoints (in-hospital mortality and combined in-hospital mortality, reinfarction and ischemic stroke) of ACS treatment. Propensity score matching analysis (1:1) was further performed to better understand predictors of outcomes.
We found 934 (5%) cancer patients out of a total of 18 845 patients with ACS. Cancer patients had more events: major bleeding (2.9% vs. 1.5%), in-hospital mortality (5.8% vs. 3.4%) and the combined endpoint (7.4% vs. 4.9%). The primary endpoint was related to cancer diagnosis (OR 1.97), previous bleeding (OR 7.09), hemoglobin level (OR 4.94), atrial fibrillation (OR 3.50), oral anticoagulation (OR 3.67) and renal dysfunction. Mortality and the combined secondary endpoint were associated with lower use of invasive coronary angiography and antiplatelet and neurohormonal blocker therapy. After propensity score matching (350 patients), there were no statistically significant differences in endpoints between the populations.
Bleeding risk was not significant higher in the cancer population compared to patients with similar characteristics, nor were mortality or ischemic risk. The presence of cancer should not preclude simultaneous ACS treatment.
A abordagem da síndrome coronária aguda (SCA) na doença oncológica é desafiante dado o seu elevado risco hemorrágico.
Análise de doentes com doença oncológica (ativo ou nos cinco anos prévios) incluídos prospetivamente no registo ProACS, entre 2010 e 2019. Os autores avaliaram a segurança (hemorragia major – objetivo primário) e eficácia (mortalidade intra-hospitalar; reenfarte e acidente vascular cerebral isquémico – objetivo secundário composto) do tratamento da SCA. Uma análise de emparelhamento de score de propensão (1:1) foi realizada para avaliar os preditores dos resultados.
Avaliámos 934 (5%) doentes oncológicos de um total de 18 845 doentes com SCA. Os doentes com cancro tiveram mais eventos: hemorragia major (2,9% versus 1,5%), mortalidade intra-hospitalar (5,8% versus 3,4%) e objetivo secundário composto (7,4% versus 4,9%). O objetivo primário relacionou-se com o diagnóstico de cancro (OR 1,97), hemorragia prévia (OR 7,09), nível de hemoglobina (OR 4,94), fibrilhação auricular (OR 3,50), anticoagulação oral (OR 3,67) e disfunção renal. A mortalidade e o objetivo secundário composto associaram-se a uma menor realização de coronariografia invasiva e utilização de terapêutica antiagregante ou de bloqueio neuro-hormonal. Após análise de emparelhamento de score de propensão (350 doentes), não se verificaram diferenças estatisticamente significativas entre as populações relativamente aos objetivos propostos.
O risco hemorrágico não é significativamente superior na população oncológica quando comparado com doentes com características similares, assim como o risco isquémico e de mortalidade. O diagnóstico de cancro não deve impedir o tratamento contemporâneo da SCA.

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Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: The BleeMACS score

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study design and population

Bleeding incidence and predictors

Discussion

Conclusion

Conflict of interest

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J Am Coll Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

JACC Cardiovasc Interv.

J. Am. Coll. Cardiol.

JACC Cardiovasc Interv.

J. Am. Coll. Cardiol.

Am. J. Cardiol.

Individualizing duration of dual antiplatelet therapy after acute coronary syndrome or percutaneous coronary intervention

Circulation

Ticagrelor versus clopidogrel in patients with acute coronary syndromes

N. Engl. J. Med.

Prasugrel versus clopidogrel in patients with acute coronary syndromes

N. Engl. J. Med.

DAPT study investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention

JAMA