Association of QT-Prolonging Medications With Risk of Autopsy-Defined Causes of Sudden Death

This case-control study evaluates the association between QT-prolonging medications and autopsy-defined sudden arrhythmic death vs nonarrhythmic sudden death in an autopsy cohort. Question What is the association of QT-prolonging medications with the risk of sudden cardiac death when adjudicated by autopsy as arrhythmic or nonarrhythmic death? Findings In this countywide, case-control autopsy study of 525 presumed sudden cardiac deaths defined by standard consensus criteria and 104 matched control deaths due to trauma, QT-prolonging medications were associated with increased odds of presumed sudden cardiac death compared with deaths due to trauma; however, autopsy demonstrated that this increased risk was specific for nonarrhythmic but not arrhythmic cause of death. Meaning Studies using consensus criteria for sudden cardiac death that presume arrhythmic cause may overestimate the association of QT-prolonging medications with the risk of sudden arrhythmic death. Importance QT-prolonging medications (QTPMs) are a reported risk factor for sudden cardiac death (SCD) when defined by consensus criteria that presume an arrhythmic cause. The effect of QTPM on autopsy-defined sudden arrhythmic death (SAD) is unknown. Objective To evaluate the association between QTPM and autopsy-defined SAD vs nonarrhythmic cause of sudden death. Design, Setting, and Participants This prospective countywide case-control study included World Health Organization-defined (presumed) SCD cases who underwent autopsy as part of the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study (POST SCD) to determine arrhythmic or nonarrhythmic cause, and control deaths due to trauma (hereinafter referred to as trauma controls) in San Francisco County, California, from February 1, 2011, to March 1, 2014. Multivariate regression was used to evaluate the association of QTPM with the risk of presumed SCD, autopsy-defined SAD, and non-SAD compared with trauma controls. Medication exposure, determined by prescription lists and postmortem toxicologic findings, was used to calculate a summative QTPM exposure score (range, 0-20). Data were analyzed from September 1, 2018, to June 15, 2019. Exposure QT-prolonging medication exposure, as measured by QTPM score (1 indicated low; 2-4, moderate; and >4, high). Main Outcomes and Measures Death due to trauma, presumed SCD, and autopsy-defined non-SAD and SAD with no postmortem findings of extracardiac cause. Results A total of 629 patients (mean [SD] age, 61.4 [15.7] years; 439 men [69.8%]) were included, 525 with presumed SCDs and 104 traumatic death controls. Individuals with presumed SCDs had higher exposure and were more likely to be taking any QTPM (291 [55.4%] vs 28 [26.9%]; P < .001) than trauma controls. Use of QTPMs was associated with increased risk of presumed SCD in low (odds ratio [OR], 2.25 [95% CI, 1.03-4.96]; P = .04) and high (OR, 6.70 [95% CI, 1.47-30.67]; P = .01) exposure groups. After autopsy adjudication, use of QTPMs was associated with increased risk of non-SAD (low-risk OR, 2.88 [95% CI, 1.18-6.99; P = .02]; moderate-risk OR, 2.62 [95% CI, 1.20-5.73; P = .02]; and high-risk OR, 14.22 [95% CI, 2.91-69.30; P = .001]) but not SAD in all exposure groups. This association was attenuated by the exclusion of occult overdose non-SADs in the highest exposure group. Conclusions and Relevance These findings confirm the association between QTPMs and presumed SCD; however, after autopsy, this risk was specific for nonarrhythmic causes of sudden death. Studies using consensus SCD criteria may overestimate the association of QTPMs with the risk of SAD.