Co-Occurring Diseases and Mortality in Patients With Chronic Heart Disease, Modeling Their Dynamically Expanding Disease Portfolios: Nationwide Register Study.

Background: Medical advances in managing patients with chronic heart disease (HD) permit the co-occurrence of other chronic diseases due to increased longevity, causing them to become multimorbid. Previous research on the effect of co-occurring diseases on mortality among patients with HD often considers disease counts or clusters at HD diagnosis, overlooking the dynamics of patients' disease portfolios over time, where new chronic diseases are diagnosed before death. Furthermore, these studies do not consider interactions among diseases and between diseases, biological and socioeconomic variables, which are essential for addressing health disparities among patients with HD. Therefore, a mapping of the effect of combinations of these co-occurring diseases on mortality among patients with HD considering such interactions in a dynamic setting is warranted.

Objective: This study aimed to examine the effect of the co-occurring diseases of patients with HD on mortality, modeling their dynamically expanding chronic disease portfolios while identifying interactions between the co-occurring diseases, socioeconomic and biological variables.

Methods: This study used data from the national Danish registries and algorithmic diagnoses of 15 chronic diseases to obtain a study population of all 766,596 adult patients with HD in Denmark from January 1, 1995, to December 31, 2015. The time from HD diagnosis until death was modeled using an extended Cox model involving chronic diseases and their interactions as time-varying covariates. We identified interactions between co-occurring diseases, socioeconomic and biological variables in a data-driven manner using a hierarchical forward-backward selection procedure and stability selection. We mapped the impact on mortality of (1) the most common disease portfolios, (2) the disease portfolios subject to the highest level of interaction, and (3) the most severe disease portfolios. Estimates from interaction-based models were compared to an additive model.

Results: Cancer had the highest impact on mortality (hazard ratio=6.72 for male individuals and 7.59 for female individuals). Excluding cancer revealed schizophrenia and dementia as those with the highest mortality impact (top 5 hazard ratios in the 11.72-13.37 range for male individuals and 13.86-16.65 for female individuals for combinations of 4 diseases). The additive model underestimated the effects up to a factor of 1.4 compared to the interaction model. Stroke, osteoporosis, chronic obstructive pulmonary disease, dementia, and depression were identified as chronic diseases involved in the most complex interactions, which were of the fifth order.

Conclusions: The findings of this study emphasize the importance of identifying and modeling disease interactions to gain a comprehensive understanding of mortality risk in patients with HD. This study illustrated that complex interactions are widespread among the co-occurring chronic diseases of patients with HD. Failing to account for these interactions can lead to an oversimplified attribution of risk to individual diseases, which may, in cases of multiple co-occurring diseases, result in an underestimation of mortality risk.