Background: There are no methods for classifying multimorbid patients with ischemic heart disease (IHD), although such methods might be clinically useful due to the marked differences in presentation and disease-course. Methods: A population-based cohort study from a Danish secondary care setting of patients with IHD (2004-2016) and subjected to a coronary angiography (CAG) or coronary computed tomography angiography (CCTA). Data sources were The Danish National Patient Registry, in-hospital laboratory data, and genetic data from Copenhagen Hospital Biobank. Comorbidities included diagnoses assigned prior to presentation of IHD. Patients were clustered my means of the Markov Clustering Algorithm based on the entire spectrum of registered multimorbidity. The two prespecified outcomes were: New ischemic events (including death from IHD causes) and death from non-IHD causes. Patients were followed from date of CAG/CCTA until one of the two outcomes occurred or end of follow-up, whichever came first. Biological and clinical appropriateness of clusters was assessed by comparing risks (estimated from Cox proportional hazard models) in clusters and by phenotypic and genotypic enrichment analyses, respectively. Findings: In a cohort of 72,249 patients with IHD (mean age 63.9 years, 63.1% males), 31 distinct clusters (C1-31, 67,136 patients) were identified. Comparing each cluster to the 30 others, eight clusters (9,590 patients) had statistically significantly higher (five clusters) or lower (three clusters) risk of new ischemic events; 18 clusters (35,982 patients) had a higher (11 clusters) or lower (seven clusters) risk of death from non-IHD causes. All clusters at increased risk of new ischemic events, associated with risk of death from non-IHD causes as well. Cardiovascular or inflammatory diseases were the commonly enriched in clusters (13), and distributions for 24 laboratory test results differed significantly across clusters. Polygenic risk scores for atrial fibrillation and diabetes were increased in x and y clusters respectively. Conclusions: Clustering of patients with IHD based on comorbidities identified subgroups of patients with significantly different clinical outcomes. This novel approach may support differentiation of treatment intensity dependent on expected outcomes.

S.B. has ownership in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK Abello and managing board memberships in Proscion A/S and Intomics A/S. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

This work was financially supported by Novo Nordisk Foundation (Grants NNF17OC0027594 and NNF14CC0001) and the Innovation Fund Denmark via the NordForsk project PM Heart (5184-00102B).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by The National Ethics Committee (1708829, 'Genetics of CVD' - a genome-wide association study on repository samples from Copenhagen Hospital Biobank), The Danish Data Protection Agency (ref: 514-0255/18-3000, 514-0254/18-3000, SUND-2016-50), The Danish Health Data Authority (ref: FSEID-00003724 and FSEID-00003092), and The Danish Patient Safety Authority (3-3013-1731/1/). Danish personal identification numbers were pseudonymized prior to any analysis.

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Yes

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The code and data used in this study to generate the results are available upon reasonable request to the authors.