Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials

Summary

Background

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y₁₂ inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose.

Methods

A total of 14 963 patients treated with DAPT after coronary stenting—largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation—were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12–24 months) or short (3–6 months) treatment in relation to baseline bleeding risk.

Findings

The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61–0·85) in the derivation cohort, and 0·70 (0·65–0·74) in the PLATO trial validation cohort and 0·66 (0·61–0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (p_interaction=0·007), and exerted a significant ischaemic benefit only in this latter group.

Interpretation

The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration.

Funding

None.

Introduction

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor reduces ischaemic recurrences in patients with coronary artery disease treated with coronary stents.1, 2, 3 However, this benefit is counterbalanced by higher bleeding risk, which is linearly related to the treatment duration. Both ischaemic and bleeding risks have potential to negatively impact prognosis.⁴ As a result, although 12 months of DAPT after stenting has been commonly suggested, the optimal duration of treatment is still debated.5, 6

Shortening DAPT duration from 12 months to 6 or 3 months significantly reduced bleeding liability.⁴ However, a prolonged treatment beyond 12 months reduced both stent-related and non-stent-related ischaemic events in selected patients who tolerated the first year of treatment without bleeding.4, 7

International guidelines encourage weighting bleeding risk before selection of treatment duration and suggest a shorter than 12 month treatment regimen in patients at high bleeding risk.5, 6 No standardised tool exists to weigh bleeding risk at the time of DAPT initiation. A prediction rule was recently proposed for patients who tolerated 12 month DAPT to select those eligible for treatment prolongation.⁸ This strategy cannot be applied earlier, at the time of treatment initiation, to select a shorter than 12 month treatment duration in patients at high bleeding risk. Thus, no standardised algorithm is available for defining optimal DAPT duration at the time of coronary stent implantation.

Research in context

Evidence before this study

Spontaneous bleeding during treatment with dual antiplatelet therapy (DAPT) is the most common complication after coronary stenting, and its incidence increased with the introduction of novel and more potent antithrombotic agents. Despite recommendations from international guidelines, methods to gauge out-of-hospital bleeding risk in patients treated with DAPT are limited. A dedicated risk score specifically designed to predict spontaneous on-DAPT bleeding events might improve risk assessment and support clinicians' decisions with respect to dual antiplatelet therapy.

We searched PubMed without language or date restrictions for publications until Sept 30, 2016, about bleeding risk scores in patients treated with DAPT. We used the search terms “percutaneous coronary intervention”, “coronary stent”, “acute coronary syndrome”, “stable coronary artery disease”, “bleeding risk score”, “bleeding”, “antiplatelet therapy”, “dual antiplatelet therapy”, “clopidogrel”, “prasugrel”, and “ticagrelor”. We excluded articles regarding antithrombotic treatment in atrial fibrillation, concomitant use of oral anticoagulants, and risk prediction models for in-hospital bleeding. We identified two reports focused on out-of-hospital events in patients treated with DAPT, and one was only applicable after a 12 month course with DAPT was completed without complications.

Added value of this study

We propose a novel risk score for the prediction of out-of-hospital bleeding in patients treated with DAPT using age, creatinine clearance, white-blood-cell count, haemoglobin, and history of bleeding. The PRECISE-DAPT score is a simple bedside risk assessment tool, which can be easily implemented in everyday clinical practice, and that might be particularly useful for its applicability at the time of treatment initiation. The PRECISE-DAPT score showed potential to identify patients at high bleeding risk (score ≥25) who might benefit from a shortened (ie, <12 months) DAPT duration. Patients not at high bleeding risk (score <25) might receive a standard (ie, 12 months) or prolonged (ie, >12 months) treatment without being exposed to significant bleeding liability.

Implication of all the available evidence

Our study provides awareness to clinicians regarding out-of-hospital bleeding risk factors in patients treated with DAPT after coronary stent implantation and offers an objective and standardised tool to quantify such risk in clinical practice. Systematic evaluation of these predictors with the novel PRECISE-DAPT bleeding risk score has potential to support clinical decision making with respect to the optimal duration of DAPT, selecting patients at high bleeding risk (score ≥25) to a shorter treatment and patients at non-high risk to a standard or long treatment.

We created a bleeding risk score for patients treated with DAPT after coronary stent implantation, in a large pooled dataset of contemporary randomised clinical trials implementing different DAPT duration strategies. We externally validated this novel risk score in two independent cohorts of patients treated with percutaneous coronary intervention (PCI) from a large randomised clinical trial and a contemporary real-world registry. The score was retrospectively applied among patients randomly assigned to a shortened or prolonged DAPT duration to assess ischaemic and bleeding outcomes according to each bleeding risk category with each DAPT regimen.