Introduction

The American College of Cardiology and American Heart Association define sudden cardiac death (SCD) as a natural death due to cardiac causes, heralded by abrupt loss of consciousness.¹ Another analgous, widely adopted definition developed by the World Health Organization (WHO) defines SCD as sudden unexpected death either within 1 hour of symptom onset (witnessed) or within 24 hours of having been observed alive and symptom free (unwitnessed).² The Cardiac Arrrest Registry to Enhance Survival uses emergency medical service (EMS) primary impression of cardiac arrest to define out-of-hospital cardiac arrests (OHCAs).³ However, given the inherent unexpected nature of these deaths, many of which are unwitnessed, reliably applying these epidemiologic definitions and verifying cardiac cause is difficult. The gold standard for determination of cause of death is autopsy, but given logistical and cost considerations, autopsy-confirmed cases compose only a small minority in SCD studies and cohorts.^3-5 Instead, almost all studies have relied on death certificate review,⁶ EMS records,³ and/or epidemiologic definitions to ascertain cases of SCD.^2,4,7 Thus nearly all SCDs are presumed cardiac. Given the inconsistency in ascertainment of cases, incidence estimates of SCD vary widely. In the San Fransisco POST SCD (Postmortem Systematic Investigation of Sudden Cardiac Death) study, we sought to assess the precise incidence and underlying causes of all incident WHO-defined SCDs and deaths due to stated OHCA in San Francisco County, California, via prospective medical examiner surveillance and comprehensive postmortem autopsy investigation.⁸

Methods

By California state law, all out-of-hospital deaths are reported to the medical examiner. In the San Francisco POST SCD Study, we used prospective surveillance of all out-of-hospital deaths by the medical examiner to identify OHCA deaths and WHO-defined SCDs in San Francisco County over a 37-month period (January 2011 to February 2014). In this period, total mortality in San Francisco County was 20,440 deaths, all of which were reviewed to ensure that we did not miss any WHO-defined SCDs.

Comprehensive premortem data (EMS records, all available medical records, the medical examiner forensic scene investigation, and family, primary physician, and witness interviews) were then combined with systematic postmortem investigation (full autopsy, detailed cardiac examinations, toxicology, and histology) to adjudicate cause of death. We classified cause of death into three primary categories: autopsy-defined sudden arrhythmic death, which required no extracardiac cause of death or acute heart failure; non-arrhythmic cardiac death (acute pump failure and tamponade); and non-cardiac death.

Findings

Medical Examiner Surveillance for OHCA Deaths and WHO-Defined SCDs

From a total countywide mortality of 20,440 over the 37-month period, 12,671 out of hospital, emergency department, and unexpected inpatient deaths were reported to the medical examiner:

• 2,021 were due to non-natural (e.g., trauma or homicide) causes
• 2,012 did not meet age criteria
• 3,862 were inpatient, nursing home, or hospice deaths

Via daily screening of EMS records for the remaining 4,776 natural out-of-hospital or emergency department deaths, we identified 912 OHCA deaths, 896 (98%) of which were autopsied. After adjudication, including a comprehensive review of EMS and past medical records and interviews with family and investigators, we excluded 371 of 912 OHCA deaths (40%) as non-sudden or non-cardiac pre-autopsy (i.e., did not meet WHO criteria for SCD) to arrive at a final cohort of 541 WHO-defined SCDs, 525 (97%) of which were autopsied.

Autopsy-Defined Causes of Death

Of the 525 autopsied WHO-defined SCDs, 315 (60%) were cardiac in etiology:

• 293 (56%) arrhythmic
• 22 (4%) cardiac but non-arrhythmic (e.g., tamponade or acute heart failure)

Of the 371 non-sudden OHCA deaths, 142 were arrhythmic at autopsy; therefore, less than half of 896 deaths with an EMS primary impression of cardiac arrest were autopsy-defined sudden arrhythmic death ([142 nonsudden + 293 meeting WHO criteria])/896 = 48.6%).

Of the 210 WHO-defined SCDs (40%) found to be non-cardiac, occult overdose (n = 71; 13.5% of overall WHO-defined SCDs) was the leading cause of death, followed by sudden neurological deaths (n = 29; 5.5%). The latter included acute cerebrovascular accident, intracranial hemorrhage, and sudden unexplained death in epilepsy. Other notable non-cardiac causes of death included infection (n = 23; 4%), pulmonary embolism (n = 19; 4%), gastrointestinal etiology including hemorrhage (n = 15; 3%), and aortic dissection (n = 14; 3%).

Incidence of Autopsy-Defined Sudden Arrhythmic Death

Adult countywide incidence rates of OHCA death and WHO-defined SCD were 46/100,000 and 29.6/100,000 person-years, respectively. Countywide incidence of autopsy-defined sudden arrhythmic death, weighted to account for the 105 (16.7%) WHO-defined SCDs not autopsied, was 17/100 000 person-years. Incidence rates for WHO-defined SCD and autopsy-defined sudden arrhythmic death were >twofold and threefold higher in men versus women, respectively (p < 0.0001), highest in Blacks (p > 0.0001), and lowest in Hispanics (p = 0.0018). Blacks and Hispanics had the lowest proportion of autopsy-defined sudden arrhythmic deaths, at 44.6% and 54.8%, respectively, and Asians and Whites had the highest proportion, at 61.9% and 59.6%, respectively. Autopsy-defined sudden arrhythmic deaths accounted for 65% of witnessed and 53% of unwitnessed WHO-defined SCDs (odds ratio 1.62; 95% confidence interval, 1.06-2.48; p = 0.024). Autopsy-defined sudden arrhythmic deaths accounted for a similar proportion of WHO-defined SCDs age 18-39 (19/32, 59%) versus age ≥40 (274/493, 56%), p = 0.68.

Implications and Conclusions

In this prospective countywide autopsy study of all deaths attributed to stated cardiac arrest and presumed SCDs, 40% of OHCA deaths were non-sudden or non-cardiac, and only half (55.8%) of SCDs defined by conventional epidemiological criteria were proven to be sudden arrhythmic death after postmortem investigation. The San Francisco POST SCD Study was the first to use the medical examiner system as a robust surveillance method for these out-of-hospital/ emergency department deaths and to systematically employ postmortem investigation to determine the underlying causes of 97% these deaths. We demonstrate that OHCA criteria inaccurately identifies sudden events or cardiac cause and that the WHO SCD criteria poorly specifies SCD or sudden arrhythmic death when verified by autopsy. Given that just over half of presumed SCDs were actually autopsy-defined sudden arrhythmic death, WHO criteria overestimate incidence of autopsy-defined sudden arrhythmic death by almost double.

Our study uncovered key, previously unrecognized causes of misclassified SCDs, including sudden neurologic deaths,⁹ human immunodeficiency virus,¹⁰ cardiac implantable electronic device problems,¹¹ and occult overdoses. Though none of the WHO-defined (presumed) SCDs that were found to be due to occult overdose had evidence or suspicion of drug use at the scene and all had a primary EMS impression of cardiac arrest, lethal levels of opiates were the culprit in over half of these presumed SCDs, reflecting the ongoing national opioid epidemic. Therefore, further inroads into reducing the overall public health burden of sudden death also requires investigation and earlier recognition of non-cardiac and non-arrhythmic causes.

We also confirmed substantial racial and sex differences in contemporary SCD epidemiology and underlying causes. Rates of WHO-defined (presumed) SCD and autopsy-defined sudden arrhythmic death were highest in Blacks and lowest in Hispanics, whereas the proportion of presumed SCD attributable to autopsy-defined sudden arrhythmic death in both populations was significantly lower than for Whites. We found significant differences in the distribution of non-cardiac causes and marked sex differences: autopsy-defined sudden arrhythmic death accounted for 61% of WHO-defined SCDs in men but only 45% in women. These findings reinforce the importance of SCD investigations in women and diverse populations.

Given our findings, substantial misclassification is likely present in existing OHCA and SCD studies from community-based cohorts or as defined in clinical trials by retrospective and/or epidemiologic criteria, given very low prevailing autopsy rates (11-27%).^4-6

The poor specificity of the WHO SCD criteria was not unexpected. In fact, skepticism over epidemiologic definitions and presumption of arrhythmic causes of sudden death dates back to Hinkle & Thaler's original 1985 classification of cardiac deaths in which they comment, "There are probably errors of classification."⁴ Although comprehensive autopsies are not practical in most clinical trials and population or cohort studies, understanding the limits of current criteria used to define SCD and sudden arrhythmic death is important for interpreting results of previous and future studies.^12-16 Because sudden arrhythmic death is the only type of sudden death rescued by automatic external defibrillators and implantable cardioverter-defibrillators and is the intended focus of molecular association and risk studies of SCD, it is essential to distinguish sudden arrhythmic death from non-arrhythmic causes. We highlight these key distinctions in Figure 1.

Figure 1: OHCA Death Vs. WHO-Defined SCD Vs. Autopsy-Defined Sudden Arrhythmic Death

References

1. Al-Khatib SM, Yancy CW, Solis P, et al. 2016 AHA/ACC Clinical Performance and Quality Measures for Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. Circ Cardiovasc Qual Outcomes 2017;10:e000022.
2. Sudden cardiac death. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser 1985;726:5-25.
3. McNally B, Robb R, Mehta M, et al. Out-of-hospital cardiac arrest surveillance --- Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005--December 31, 2010. MMWR Surveill Summ 2011;60:1-19.
4. Hinkle LE Jr, Thaler HT. Clinical classification of cardiac deaths. Circulation 1982;65:457-64.
5. Pouleur AC, Barkoudah E, Uno H, et al. Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. Circulation 2010;122:597-602.
6. Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol 2004;44:1268-75.
7. American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology), Buxton AE, Calkins H, et al. ACC/AHA/HRS 2006 key data elements and definitions for electrophysiological studies and procedures: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology). Circulation 2006;114:2534-70.
8. Tseng ZH, Olgin JE, Vittinghoff E, et al. Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD Study. Circulation 2018;137:2689-700.
9. Kim AS, Moffatt E, Ursell PC, Devinsky O, Olgin J, Tseng ZH. Sudden neurologic death masquerading as out-of-hospital sudden cardiac death. Neurology 2016;87:1669-73.
10. Tseng ZH, Secemsky EA, Dowdy D, et al. Sudden cardiac death in patients with human immunodeficiency virus infection. J Am Coll Cardiol 2012;59:1891-6.
11. Tseng ZH, Hayward RM, Clark NM, et al. Sudden Death in Patients With Cardiac Implantable Electronic Devices. JAMA Intern Med 2015;175:1342-50.
12. Chatterjee NA, Moorthy MV, Pester J, et al. Sudden Death in Patients With Coronary Heart Disease Without Severe Systolic Dysfunction. JAMA Cardiol 2018;3:591-600.
13. Deo R, Norby FL, Katz R, et al. Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population. Circulation 2016;134:806-16.
14. Tseng ZH. Sudden Cardiac Deaths-WHO Says They Are Always Arrhythmic? JAMA Cardiol 2018;3:556-8.
15. Olgin JE. Efficacy of a Wearable Cardioverter-Defibrillator after Myocardial Infarction: Results of the Vest Prevention of Early Sudden Death Trial (VEST). Presented at the American College of Cardiology Scientific Sessions; March 10, 2018.
16. Pocock SJ, Collier TJ. Critical Appraisal of the 2018 ACC Scientific Sessions Late-Breaking Trials From a Statistician's Perspective. J Am Coll Cardiol 2018;71:2957-69.

Keywords: American Heart Association, Aneurysm, Dissecting, Autopsy, Cause of Death, Confidence Intervals, Coroners and Medical Examiners, Death Certificates, Death, Sudden, Cardiac, Defibrillators, Implantable, Emergency Medical Services, Emergency Service, Hospital, Epilepsy, European Continental Ancestry Group, Heart Failure, Hispanic Americans, Hospices, Incidence, Inpatients, Intracranial Hemorrhages, Medical Records, Nursing Homes, Odds Ratio, Opiate Alkaloids, Out-of-Hospital Cardiac Arrest, Prospective Studies, Pulmonary Embolism, Registries, Retrospective Studies, Sex Characteristics, Research Personnel, Stroke, World Health Organization, Arrhythmias, Cardiac

< Back to Listings