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Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis


Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer–Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.

Clinical Trial Registration ATLAS ACS-2 TIMI 46: Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: Unique Identifier: NCT00809965. GEMINI ACS-1: Unique Identifier: NCT02293395. PIONEER-AF PCI: Unique Identifier: NCT01830543.

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Acute coronary syndrome






Dual antiplatelet therapy


Major adverse cardiovascular events


Myocardial infarction


Percutaneous coronary intervention


Thrombolysis in myocardial infarction


Vitamin K Antagonist


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Correspondence to C. Michael Gibson.

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All authors report research grant support from Janssen Pharmaceuticals Inc.

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Gibson, W.J., Nafee, T., Travis, R. et al. Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis. J Thromb Thrombolysis 49, 1–9 (2020).

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  • Machine learning
  • Personalized medicine
  • Acute coronary syndrome
  • Major adverse cardiovascular events
  • Super learner