Risk of out-of-hospital cardiac arrest (OHCA) and anticholinergic burden in Taiwan: a case-crossover and case-case-time-control study

Background: Recently, some studies have indicated that the dysregulation of the parasympathetic system and immunomodulation due to the anticholinergic effect might negatively impact the cardiovascular system. We hypothesize that such dysregulated effects could lead to fatal arrhythmia and subsequently cause out-of-hospital cardiac arrest (OHCA). Therefore, this study aims to investigate the association between anticholinergic burden and OHCA. Since various characteristics among patients might contribute to the occurrence of OHCA and lead to potential bias, we applied the case-crossover design to adjust for unmeasured confounding factors within individuals. Furthermore, we will also adjust for exposure time trends to reduce bias by applying the case-case-time-control (CCTC) design.

Objectives: To evaluate the association between anticholinergic burden and OHCA in the Taiwan older population.

Methods: The study applied both case-crossover and CCTC design. The individuals enrolled in Taiwan's National Health Insurance Research Database (NHID) from 2011 to 2021 were included. We identified the patients with age ≧ 65 with incident OHCA event. The index date (day0) was defined as the date of the OHCA diagnosis, and the hazard period, washout period, and referent period were defined retrospectively (30 days for each period). For CCTC design, we matched each case with 1 “future case” on age and sex to adjust for exposure time trends. The baseline period was within 1 year period before the index date. To quantify anticholinergic burden, 5 different score systems were used. For each system, we categorized the scores into 3 groups: low (0 points), moderate (1-2 points), and high (≧3 points). Odds ratios (ORs) and 95% confidence intervals (CIs) between the hazard period and referent period were obtained by conditional logistic regression.

Results: We identified 173,974 cases of OHCA for case-crossover design and 102,498 case-control pairs for CCTC design. The case-crossover analysis of OHCA from low to moderate or high burden groups were listed as follows respectively: ADS, 1.62 (1.58,1.67) and 2.56 (2.49,2.63); ACB, 1.56 (1.52,1.61) and 2.21 (2.15,2.27); GABS, 1.55 (1.50,1.60) and 2.76 (2.68,2.84); mACB, 1.54 (1.49,1.59) and 2.2 (2.14,2.26); KABS, 1.66 (1.61,1.71) and 2.38 (2.31,2.44). For CCTC analysis, ADS, 1.40 (1.33,1.48) and 2.09 (1.99,2.20); ACB, 1.40 (1.33,1.48) and 1.93 (1.84,2.02); GABS, 1.39 (1.31,1.47) and 1.95 (1.86,2.05); mACB, 1.37 (1.29,1.44) and 2.20 (2.09,2.32); KABS, 1.45 (1.37,1.53) and 2.02 (1.93,2.12).

Conclusions: According to our study, even after adjusting for the exposure time trends, anticholinergic burden might still be associated with the risk of OHCA in Taiwan, especially for those with higher anticholinergic burden.