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Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death

POST SCD Study
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.117.033427Circulation. 2018;137:2689–2700

    Abstract

    Background:

    Studies of out-of-hospital cardiac arrest and sudden cardiac death (SCD) use emergency medical services records, death certificates, or definitions that infer cause of death; thus, the true incidence of SCD is unknown. Over 90% of SCDs occur out-of-hospital; nonforensic autopsies are rarely performed, and therefore causes of death are presumed. We conducted a medical examiner–based investigation to determine the precise incidence and autopsy-defined causes of all SCDs in an entire metropolitan area. We hypothesized that postmortem investigation would identify actual sudden arrhythmic deaths among presumed SCDs.

    Methods:

    Between February 1, 2011, and March 1, 2014, we prospectively identified all incident deaths attributed to out-of-hospital cardiac arrest (emergency medical services primary impression, cardiac arrest) between 18 to 90 years of age in San Francisco County for autopsy, toxicology, and histology via medical examiner surveillance of consecutive out-of-hospital deaths, all reported by law. We obtained comprehensive records to determine whether out-of-hospital cardiac arrest deaths met World Health Organization (WHO) criteria for SCD. We reviewed death certificates filed quarterly for missed SCDs. Autopsy-defined sudden arrhythmic deaths had no extracardiac cause of death or acute heart failure. A multidisciplinary committee adjudicated final cause.

    Results:

    All 20 440 deaths were reviewed; 12 671 were unattended and reported to the medical examiner. From these, we identified 912 out-of-hospital cardiac arrest deaths; 541 (59%) met WHO SCD criteria (mean 62.8 years, 69% male) and 525 (97%) were autopsied. Eighty-nine additional WHO-defined SCDs occurred within 3 weeks of active medical care with the death certificate signed by the attending physician, ineligible for autopsy but included in the countywide WHO-defined SCD incidence of 29.6/100 000 person-years, highest in black men (P<0.0001). Of 525 WHO-defined SCDs, 301 (57%) had no cardiac history. Leading causes of death were coronary disease (32%), occult overdose (13.5%), cardiomyopathy (10%), cardiac hypertrophy (8%), and neurological (5.5%). Autopsy-defined sudden arrhythmic deaths were 55.8% (293/525) of overall, 65% (78/120) of witnessed, and 53% (215/405) of unwitnessed WHO-defined SCDs (P=0.024); 286 of 293 (98%) had structural cardiac disease.

    Conclusions:

    Forty percent of deaths attributed to stated cardiac arrest were not sudden or unexpected, and nearly half of presumed SCDs were not arrhythmic. These findings have implications for the accuracy of SCDs as defined by WHO criteria or emergency medical services records in aggregate mortality data, clinical trials, and cohort studies.

    Introduction

    Editorial, see p 2701

    Clinical Perspective

    What Is New?

    • In this prospective countywide autopsy study of all deaths attributed to stated cardiac arrest and presumed sudden cardiac deaths over 37 months, 40% were found to have a nonsudden, noncardiac cause of death.

    • Only half (55.8%) of sudden cardiac deaths defined by conventional criteria were autopsy-defined sudden arrhythmic deaths.

    • Sudden death was the first manifestation of cardiac disease for over half of all autopsy-defined sudden arrhythmic deaths.

    • Leading causes of presumed sudden cardiac deaths were coronary disease (32%), occult overdose (13.5%), cardiomyopathy (10%), cardiac hypertrophy (8%), and neurological (5.5%).

    • Ninety-eight percent of sudden arrhythmic deaths had structural heart disease at autopsy.

    What Are the Clinical Implications?

    • Cardiac arrests defined by paramedic criteria and sudden cardiac deaths defined by conventional or retrospective methods, as in most cohort studies or clinical trials, have limited accuracy for actual arrhythmic deaths.

    • These data reflect the decreasing prevalence of coronary disease and increasing prevalence of nonischemic causes; therefore, further inroads into reducing the overall burden of sudden death requires investigation and earlier recognition of nonischemic and nonarrhythmic causes.

    • In contrast to sudden death in the young, the vast majority of sudden arrhythmic death in adults is associated with structural heart disease.

    Sudden cardiac death (SCD) is considered a major cause of worldwide mortality, yet incidence estimates vary widely because of variable data sources and definitions.1,2 Studies based on death certificate review are known to overestimate incidence because of inaccuracies in stated causes of death,3 and investigations relying on emergency medical services (EMS) records4 and epidemiological definitions57 presume cardiac etiology or infer cardiac cause of death. Expert panels have advocated for the use of precise and uniform definitions of SCD and to integrate multiple sources of ascertainment,8 but noncardiac and nonarrhythmic conditions leading to sudden death cannot be excluded without a complete autopsy.9

    The large majority of SCDs occur out of hospital10; therefore, they are unattended and in the jurisdiction of the coroner or medical examiner. Postmortem investigation after these natural deaths is not routine coroner or medical examiner practice because of limited local resources that are focused on accidental or possible criminal deaths. Therefore, autopsy rates for out-of-hospital natural deaths range from 10% in the United States11 to 23% in some European countries.12 Moreover, three-quarters of the 82 sudden arrhythmic deaths (SADs) that were the basis for the original Hinkle-Thaler definition did not have autopsy confirmation.6 Exemplar autopsy studies demonstrating coronary artery disease (CAD) as the cause of ≈80% of SCDs13,14 are thus limited by referral bias of the minority of total SCDs that underwent postmortem investigation. We sought to determine the precise incidence and underlying causes of all incident SCDs in San Francisco County, California via prospective medical examiner surveillance and comprehensive postmortem investigation as part of the San Francisco POST SCD Study(Postmortem Systematic Investigation of Sudden Cardiac Death).

    Methods

    The authors declare that all supporting data and analytic methods are available within the article and in the online-only Data Supplement.

    Setting

    The study population included all residents and inhabitants of San Francisco County, California (population: 805 235, 46.9 square miles).15 Ten adult hospitals, 3 EMS agencies (with the San Francisco Fire Department responding to >85% of all 911 activations), and a single Office of the Chief Medical Examiner serve the County. All out-of-hospital and unattended deaths must be reported to the medical examiner by California state law. The study was approved by the University of California, San Francisco institutional review board and had additional institutional review board approval at all 10 San Francisco County adult hospitals and 3 EMS agencies to obtain medical records.

    Inclusion Criteria

    SCD was defined by World Health Organization (WHO) criteria (WHO-defined SCD): sudden unexpected death either within 1 hour of symptom onset (event witnessed), or within 24 hours of having been observed alive and symptom free (unwitnessed).7 Subjects otherwise meeting WHO criteria who had recent admission for myocardial infarction were included. Out-of-hospital cardiac arrest (OHCA) required an EMS primary impression of cardiac arrest, consistent with the Cardiac Arrest Registry to Enhance Survival (CARES).4 OHCA deaths were defined as (1) OHCA victims who died in the field or emergency department if the event was witnessed or active resuscitation was performed; or (2) unwitnessed natural deaths if the victim was last observed alive and symptom free within 24 hours, with no active resuscitation but primary EMS impression of cardiac arrest. Resuscitated OHCA victims surviving to hospital admission, whether they subsequently died as an inpatient or survived, were considered OHCA survivors rather than SCDs.

    The following deaths were excluded: (1) subjects with severe noncardiac chronic and terminal illness in which imminent death was not unexpected, including terminal cancer; (2) end-stage renal disease on dialysis; (3) hospice residents; (4) subjects with an identifiable noncardiac etiology of death at presentation, including evidence of drug abuse/overdose at the scene (eg, intravenous needles, empty pill bottles), clear life-threatening trauma, homicide, or suicide; (5) subjects who had hospital admission within the prior 30 days for noncardiac illness or surgical procedure.

    Prospective Surveillance and Identification of WHO-Defined SCDs

    From February 1, 2011, to March 1, 2014, we performed daily surveillance of all consecutive San Francisco County out-of-hospital deaths. Each morning, EMS records and medical examiner investigator scene reports of all unattended (not under the care of a physician within 3 weeks for an active medical condition) out-of-hospital deaths from the previous day were reviewed by a cardiac electrophysiologist (Z.H.T.) and the Assistant Medical Examiner (E.M.) to identify all OHCA deaths, 18 to 90 years of age, for detailed autopsy, including toxicology and histology. All OHCA deaths underwent a full autopsy (described below), except in rare cases where the family objected to autopsy. We obtained comprehensive medical records from the 10 San Francisco County adult hospitals and EMS records for all cases. Out-of-county medical records were also obtained.

    Subjects under the care of a physician within 3 weeks of death (ie, office visit for active medical condition or inpatient care) are considered attended by the medical examiner. Under these circumstances, the attending physician is contacted by the forensic investigator and asked to infer cause of death to sign the death certificate; once the death certificate is signed, these attended deaths are no longer in the jurisdiction of the medical examiner and are therefore ineligible for autopsy. We interviewed each attending physician who signed a death certificate and reviewed EMS and complete medical records to determine whether any such attended deaths met criteria for WHO-defined SCDs; those meeting criteria were included in WHO-defined SCD incidence calculations but not autopsied. To determine total San Francisco County mortality and to ascertain for any WHO-defined SCDs missed, we retrieved and reviewed all county death certificates quarterly for location, death certificate–stated cause of death, and circumstances of death by forensic investigator reports to cross-check with cases obtained via medical examiner surveillance.

    Postmortem Investigation

    All identified OHCA deaths, except the rare cases that did not receive next-of-kin agreement, underwent complete external and internal postmortem examination performed by a single board-certified forensic pathologist (Assistant Medical Examiner E.M.) according to a prospectively developed protocol for examining all cavities and tissues including thorough heart and brain examinations.16 Every autopsy was further reviewed in full by a cardiac pathologist and the chief of the University of California, San Francisco Autopsy Service (P.C.U.).

    Cardiac Examinations

    Hearts were excised, weighed, and dissected systematically before careful examination for gross evidence of cardiovascular pathology including acute myocardial infarction or scar denoting healed myocardial infarction. The major extramural coronary arteries were cut in cross section every 5 mm to identify atherosclerotic plaques, thrombi, dissecting hematomas, or other stenoses. In addition to samples of coronary artery lesions, samples of myocardium for histology were taken from 5 standard locations: septum, posterobasal, lateral, midanterior left ventricular free wall, and right ventricular free wall. An extra section of the high septum was also taken for histological examination of the conduction system. Histological sections were stained with hematoxylin and eosin and trichrome and independently examined by 2 pathologists (E.M. and P.C.U.).

    Examination of Other Organs and Tissues

    A comprehensive examination of the internal organs of the thorax, abdomen, and cranial vault were performed according to established autopsy methods.17 Complete details of the autopsy procedure are provided in the online-only Data Supplement Appendix.

    Postmortem vitreous chemistries (electrolytes, creatinine, urea nitrogen, and glucose) were obtained for all subjects. Toxicology (blood and urine) was obtained for all subjects ≤75 years and for subjects ≥75 years without obvious cause of death (eg, acute myocardial infarction, intracranial hemorrhage, saddle pulmonary embolus) on gross examination at autopsy.

    Cardiac implantable electronic device interrogation was performed on all cases with a permanent pacemaker or implantable cardioverter-defibrillator (ICD). Terminal rhythm was determined from device interrogation, correlating events stored on the device with the timing of the arrest from EMS documentation and medical examiner scene investigation.18

    Adjudication of Inclusion and Cause of Death

    A multidisciplinary committee including the Assistant Medical Examiner (E.M.), a cardiac pathologist (P.C.U.), a neurologist (A.S.K.), and 2 cardiologists/cardiac electrophysiologists (J.E.O. and Z.H.T.) reviewed comprehensive premortem medical records, forensic investigator reports (including scene investigations, and witness and next-of-kin interviews), EMS records, medication prescriptions, and detailed autopsy, toxicology, and histology findings for all OHCA deaths to determine whether they met criteria for a WHO-defined SCD and to adjudicate a single final cause of death. Autopsy-defined SAD was a death for which no identifiable nonarrhythmic cause of death was found (eg, acute cerebrovascular accident, viscus perforation, tamponade, vascular rupture, pulmonary embolism, hemorrhage, lethal toxicology/occult overdose, acute heart failure with pulmonary edema), but may have had underlying or associated cardiac disease. Per usual forensic toxicology protocol, lethal serum or tissue levels (ie, ethanol levels >0.5 mg/L, opiates >0.3 mg/L) were used in the absence of other pathological findings that could explain sudden death as evidence for occult overdose as the cause of death.19,20 For WHO-defined SCDs with pathological evidence of chronic ethanol or opiate/heroin use (ie, hepatic findings, needle track marks), higher lethal thresholds (ethanol >0.7 mg/L, opiates >0.5 mg/L) were used.

    Statistical Analysis

    The characteristics of the study sample were summarized using proportions. For between-group comparisons, we used χ2 and Fisher exact tests as appropriate. To make the 525 WHO-defined SCDs with autopsy representative of the demographic and risk factor distribution of the overall set of 630 WHO-defined SCDs, we used inverse probability weights, based on a logistic model using demographics and risk factors to predict having an autopsy. The resulting weights were used to estimate the proportion of autopsy-defined SADs among all SCD cases, with or without autopsy. Incidence of autopsy-defined SAD was estimated using person-time methods, and compared across demographic subgroups using Poisson models. Analyses used Stata Version 14.2 (StataCorp LP). A 2-tailed P < 0.05 was considered statistically significant.

    Results

    A total of 20 440 deaths occurred in San Francisco County during the 37-month study period (Figure 1). Of these, 12 671 out-of-hospital, emergency department, and unexpected inpatient deaths were reported to the medical examiner: 2021 were due to nonnatural (eg, trauma, homicide) causes, 2012 did not meet age criteria, and 3862 were inpatient, nursing home, or hospice deaths (Table I in the online-only Data Supplement). The medical examiner considered 1120 reported out-of-hospital deaths as attended deaths because of active medical care within 3 weeks, thus out of medical examiner jurisdiction and ineligible for autopsy. Of these, 89 (7.9%) met criteria for WHO-defined SCD after comprehensive records review and interviews with the attending or treating physicians who signed the death certificate. Via prospective daily surveillance of the remaining 3656 unattended out-of-hospital deaths, we identified 912 deaths attributed to OHCA with primary EMS impression of cardiac arrest. Next-of-kin of 16 subjects with (2%) OHCA deaths declined autopsy for religious reasons; thus, 896 subjects with (98%) OHCA deaths underwent the protocol autopsy. At adjudication, of the 896 OHCA deaths, 371 (41%) did not meet WHO criteria for SCD (ie, were not sudden or unexpected, Table I in the online-only Data Supplement), leaving 525 adjudicated autopsied WHO-defined SCDs during the study period. Thus, we identified 630 (525 autopsied + 16 declined autopsy + 89 under recent medical care) WHO-defined SCDs over 37 months for a countywide WHO SCD incidence of 29.6/100 000 person-years, accounting for 3.4% (630/18,443) of total adult mortality. Autopsy rates were 98.2% (896/912) for OHCA deaths and 83.3% (525/630) for WHO-defined SCDs.

    Figure 1.

    Figure 1. Identification of WHO-defined SCDs in the San Francisco POST SCD Study (Postmortem Systematic Investigation of Sudden Cardiac Death) February 1, 2011, to March 1, 2014. Identification of WHO-defined SCDs via active medical examiner surveillance of all out-of-hospital deaths in San Francisco County February 1, 2011, to March 1, 2014. County death certificates for every death were reviewed for location, circumstances, and cause of death. EMS records and forensic investigator reports were reviewed for all out-of-hospital natural deaths between the ages of 18 and 90 years. All OHCA deaths referred for autopsy underwent comprehensive review of medical records and medical examiner records, and those meeting WHO criteria underwent full adjudication. A total of 20 440 deaths occurred in San Francisco County during the 37-month study period (Figure 1). Of these, 12 671 out-of-hospital, ED, and unexpected inpatient deaths were reported to the medical examiner: 2021 were due to nonnatural (eg, trauma, homicide) causes, 2012 did not meet age criteria, 3862 were inpatient, nursing home, or hospice deaths (Table I in the online-only Data Supplement). The medical examiner considered 1120 reported out-of-hospital deaths as attended deaths because of active medical care within 3 weeks; thus, out of medical examiner jurisdiction and ineligible for autopsy. Of these, 89 (7.9%) met criteria for WHO-defined SCD after comprehensive records review and interviews with the attending or treating physicians who signed the death certificate (Table II in the online-only Data Supplement). Via prospective daily surveillance of the remaining 3656 unattended out-of-hospital deaths, we identified 912 OHCA deaths with primary EMS impression of cardiac arrest. Next-of-kin of 16 (2%) subjects with OHCA deaths declined autopsy for religious reasons; thus, 896 (98%) subjects with OHCA deaths underwent the protocol autopsy. At adjudication, 371 OHCA deaths did not meet WHO criteria for SCD, leaving 525 adjudicated autopsied WHO-defined SCDs during the study period. Thus we identified 630 (525 autopsied + 16 declined autopsy + 89 under recent medical care) WHO-defined SCDs over 37, accounting for 3.4% (630/18 443) of total adult mortality. Autopsy rates were 98.2% (896/912) for OHCA deaths and 83.3% (525/630) for WHO-defined SCDs. DC indicates death certificate; ED, emergency department; EMS, emergency medical services; MD, medical, doctor; ME, medical examiner; OHCA, out-of-hospital cardiac arrest; OOH, out of hospital; SCD, sudden cardiac death; and WHO, World Health Organization.

    Mean age of the 525 autopsied WHO-defined SCDs was 62.8 years, 69% were male and reflected the diverse population of San Francisco County; half were in the lowest income tertile (Table 121). WHO-defined SCDs without autopsy (n=105, most of whom had received recent medical care) were a decade older (mean age, 73.1 years) and more likely to be Asian (P=0.0013).

    Table 1. Demographic Characteristics of WHO-Defined SCDs and Reference Populations

    WHO-Defined SCDs With AutopsyWHO-Defined SCDs Without AutopsyP Value WHO-Defined SCDs With Autopsy vs Without Autopsy*San Francisco Adult Population 201121US Adult Population 201121
    N525105705 364232 556 019
    Age, mean±SD62.8±14.573.1±11.6<0.0001
    Age range, y18–9037–89
    Male, n (%)362 (69)74 (70)0.82358 410 (51)112 848 136 (49)
    Race, n (%)
     Asian110 (21)37 (35)0.0001235 089 (33)11 299 490 (5)
     Black81 (15)8 (8)39 383 (6)27 630 124 (12)
     Hispanic40 (8)8 (8)99 337 (14)32 478 615 (14)
     White279 (53)44 (42)310 496 (44)156 622 672 (67)
     Other15 (3)8 (8)21 059 (3)4 525 118 (2)
    Median income, N46097
     Tertile 1, n (%)231 (50)42 (43)0.35275 092 (39)184 288 905 (79)
     Tertile 2, n (%)136 (30)28 (29)232 770 (33)16 631 720 (7)
     Tertile 3, n (%)93 (20)27 (28)197 502 (28)31 635 394 (14)

    SCD indicates sudden cardiac death; and WHO, World Health Organization.

    *For age, t test assuming unequal variance; for categorical, Fisher exact test.

    Includes American Indians, Alaskan Natives, and Native Hawaiians.

    Median income analysis restricted to residents of San Francisco.

    Autopsy-Defined Causes of Death

    Autopsy-defined SADs that in 98% of patients occurred in the setting of structural heart disease accounted for 55.8% (293/525), nonarrhythmic cardiac causes of death 4.2% (22/525), and noncardiac causes of death 40% (210/525) of all WHO-defined SCDs (Figure 2A). Leading autopsy-defined causes of death for WHO-defined SCDs were coronary artery disease (CAD, 32%), occult overdose (13.5%), cardiomyopathy (10%), cardiac hypertrophy (8%), and neurological (5.5%). Of 168 cases with CAD causes, one-third (52 cases) had postmortem findings of acute CAD (35 with acute coronary lesion, 17 with histological evidence of acute myocardial infarction). Of 17 cases with pacemaker or ICD, 4 were adjudicated to have device concern (3: undersensing, software error, inappropriate device selection) or hardware failure (1). Occult overdose (n=71) was the leading noncardiac cause of death for WHO-defined SCDs. Lethal toxicological levels of opiates were found in 61% (43/71) of the occult overdoses; all these SCDs had a primary EMS impression of cardiac arrest and none had evidence or suspicion of drug use at the scene. The second largest group of noncardiac cause of death for WHO-defined SCDs was sudden neurological deaths, which included acute cerebrovascular accident, intracranial hemorrhage, and sudden unexplained death in epilepsy.15

    Figure 2.

    Figure 2. Adjudicated etiologies of autopsied WHO-defined SCDs. A, Adjudicated etiologies of autopsied WHO-defined SCDs after review of comprehensive medical records, EMS records, complete autopsy, toxicology, and postmortem chemistries. Autopsy-defined SADs had no identifiable extracardiac (eg, pulmonary embolism, hemorrhage, lethal toxicology) or nonarrhythmic (tamponade, acute HF) cause of death. The first % is of total WHO-defined SCDs, the second % is of cause of death category. Overall, autopsy-defined SADs accounted for 56% of all WHO-defined SCDs, 4% were cardiac nonarrhythmic cause of death, and 40% were noncardiac cause of death. Autopsy-Defined SAD (N=293): Acute CAD (n=52), acute coronary lesions 35, acute MI 17; Chronic CAD (n=116), chronic coronary lesions 41; healed MI 45; hypertensive CAD 16; ischemic CM 14; Cardiomyopathy (n=53), alcoholic 16; amyloidosis 2; ARVD 1; drug-induced CM 3; HIV cardiomyopathy 1; CM with valve prolapse 1; noncompaction 1; nonischemic/dilated/idiopathic 27; stress CM 1; Hypertrophy (including HCM) (n=44), hypertensive heart disease 35; HCM 6; unspecified hypertrophy 3; Primary electric disease (n=7), complete heart block 1, short QT syndrome 1, unspecified 5; Other arrhythmic (n=21), acquired long QT syndrome 1, bicuspid aortic valve 1, MINOCA – Acute 4, MINOCA – Healed 4, CIED concern 3, CIED failure 1, myocarditis 2, acute AVR failure 1, mitral valve prolapse 2, critical aortic stenosis 3. Cardiac, Nonarrhythmic (N=22): Acute MI with pump failure 4, acute MI with rupture + tamponade 12, acute or chronic heart failure 5, pericarditis 1. Noncardiac (N=210): acute renal failure (n=6); aortic dissection (n=14); aspiration/asphyxia (n=5); chemical overdose (n=71), opiates 40, nonopiates 31; GI (n=15), GI hemorrhage 7, incarcerated/strangulated hernia 4, bowel obstruction 2, hepatorenal failure/pancreatitis 1,; liver failure 1; hyperglycemia/DKA (n=9); infection (n=23), pneumonia 12, sepsis 6, other infection 5; neurological (n=29), intracranial hemorrhage 18, SUDEP 7, aneurysm rupture 2, acute CVA 1, other neurological (Huntington disease) 1; pulmonary embolism (n=19); other noncardiac (n=19), acute alcohol withdrawal 1, disseminated cancer 1, hypothermia 1, other hemorrhage 2, other trauma 4, end-stage COPD 4, obstructive sleep apnea 1, aortic aneurysm rupture 2, renal artery dissection 1, iliac arterial dissection 1, pulmonary artery dissection 1. B, Adjudicated etiologies of witnessed versus unwitnessed WHO-defined SCDs after review of comprehensive medical records, EMS records, complete autopsy, toxicology, and postmortem chemistries. Autopsy-defined SADs accounted for 65% of witnessed and 53% of unwitnessed WHO-defined SCDs (OR,1.62; 95% CI, 1.06–2.48; P=0.024). Witnessed: Autopsy-defined SAD N=78 (acute CAD n=16 [20%], chronic CAD n=35 [45%], cardiomyopathy n=9 [11%], hypertrophy n=10 [13%], primary electric disease n=2 [3%], other arrhythmic n=6 [8%]). Unwitnessed: Autopsy-defined SAD N=215 (acute CAD n=36 [17%], chronic CAD n=81 [38%], cardiomyopathy n=44 [20%], hypertrophy n=34 [16%], primary electric disease n=5 [2%], other arrhythmic n=15 [7%]). C, Adjudicated etiologies of WHO-defined SCDs age 18 to 39 versus age ≥40. Autopsy-defined SADs accounted for a similar proportion of WHO-defined SCDs age 18 to 39 (19/32, 59%) versus age ≥40 (274/493, 56%), P=0.68. Age 18 to 39: Autopsy-defined SADs N=19 (acute CAD n=1 [5%], chronic CAD n=3 [16%], cardiomyopathy n=8 [42%], hypertrophy n=4 [21%], primary electric disease n=3 [16%]). Age ≥40: Autopsy-defined SADs N=274 (acute CAD n=51 [19%], chronic CAD n=113 [41%], cardiomyopathy n=45 [16%], hypertrophy n=40 [15%], primary electric disease n=4 [1%], other arrhythmic n=21 [8%]). ARVD indicates arrhythmogenic right ventricular dysplasia; CAD, coronary artery disease; CI, confidence interval; CIED, cardiac implantable electronic device; CM, cardiomyopathy; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DKA, diabetic ketoacidosis; EMS, emergency medical services; GI, gastrointestinal; HCM, hypertrophic cardiomyopathy; HF, heart failure; MI, myocardial infarction; MINOCA, myocardial infarction with nonobstructive coronary arteries; OR, odds ratio; SAD, sudden arrhythmic death; SCD, sudden cardiac death; SUDEP, sudden unexplained death in epilepsy; and WHO, World Health Organization.

    Of the 371 OHCA deaths excluded as nonsudden at adjudication, 142 were autopsy-defined SAD (Figure I in the online-only Data Supplement); therefore, less than half of 896 deaths with EMS primary impression of cardiac arrest in the study period were autopsy-defined SAD ([142 nonsudden+293 meeting WHO criteria])/896=48.6%).

    The proportion of total WHO-defined SCDs attributable to autopsy-defined SAD was significantly greater in witnessed (78/120=65.0%) versus unwitnessed cases (215/405=53.1%, P=0.024; Figure 2B), and in men (220/362=60.8%) in comparison with women (73/163=44.8%, P=0.0006). Autopsy-defined SADs accounted for a similar proportion of WHO-defined SCDs age 18 to 39 (19/32, 59%) versus age ≥40 (274/493, 56%, P=0.68; Figure 2C). Presumed cause of death as stated by the attending or treating physicians on the death certificate was cardiac for 101 of the 105 WHO-defined SCDs that did not undergo autopsy (Table II in the online-only Data Supplement).

    Incidence of Autopsy-Defined SAD

    Countywide incidence of autopsy-defined SAD, weighted to account for the 105 (16.7%) WHO-defined SCDs not autopsied, was 17/100 000 person-years (Figure 3). Incidence rates for WHO-defined SCD and autopsy-defined SAD were >2- and 3-fold 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 SADs, at 44.6% and 54.8%, respectively.

    Figure 3.

    Figure 3. Adjusted incidence rates for OHCA deaths, WHO-defined SCDs, and autopsy-defined SADs in San Francisco County February 1, 2011, to March 1, 2014. Adjusted incidence rates per 100 000 person-years for all observed OHCA deaths, WHO-defined SCDs, and autopsy-defined SADs in San Francisco County from February 1, 2011, to March 1, 2014. Adult countywide incidence rates of OHCA death and WHO-defined SCD over 37 months were 46/100 000 and 29.6/100 000 person-years, respectively. OHCA death and WHO-defined SCD incidence rates both include the 89 identified WHO-defined SCDs that were considered attended by the medical examiner (because of recent medical care <3 weeks before death) and 16 OHCA deaths that did not undergo autopsy. After comprehensive records review and adjudication, 371 OHCA deaths initially identified by CARES OHCA criteria were excluded as not meeting WHO SCD criteria at presentation. Sex- and race-specific incidence rate ratios (IRR) for all WHO-defined SCD and weighted autopsy-defined SAD are shown. Weighted countywide incidence of autopsy-defined SAD was 17/100 000 person-years, accounting for the 89 WHO-defined SCDs without autopsy. Autopsy-defined SAD accounted for a weighted proportion of 57.4% of all WHO SCDs. Incidence rate ratios for WHO SCD and autopsy-defined SAD were over 2- and 3-fold higher in men versus women, respectively (P<0.0001), and highest in blacks (P>0.0001), lowest in Hispanics (P=0.0018). Blacks (45%) and Hispanics (54.6%) had the lowest proportion of WHO-defined SCDs that were autopsy-defined SADs. Other race includes American Indian/Alaskan Natives, Native Hawaiians, and other Pacific Islanders. CARES indicates Cardiac Arrest Registry to Enhance Survival; OHCA, out-of-hospital cardiac arrest; SAD, sudden arrhythmic death; SCD, sudden cardiac death; and WHO, World Health Organization.

    Impact of Prior Medical History

    Comprehensive past medical records were obtained for 94% (492/525) of all WHO-defined SCDs; 24 WHO-defined SCDs (5%) were known to be previously healthy with no medical conditions, with similar proportions in autopsy-defined SAD and non-SAD groups (Table 2). Less than half of WHO-defined SCDs (224/525, 43%) had prior cardiac history, with a similar proportion in autopsy-defined SADs (131/293, 45%) and non-SADs (93/232, 40%); therefore, sudden death was the first manifestation of cardiac disease for more than half of all adult WHO-defined SCDs (301/525, 57%) and autopsy-defined SADs (162/293, 55%) in San Francisco County. History of hypertension, dyslipidemia, and congestive heart failure was more common in autopsy-defined SADs, whereas history of seizure disorder, psychiatric disorder, alcohol abuse, and illicit drug use was more common in non-SADs (Table 2).

    Table 2. Premortem Conditions in WHO-Defined SCDs, Autopsy-Defined SADs, and Non-SADs

    WHO-Defined SCDAutopsy-Defined SADNon-SADP Value Autopsy-Defined SAD vs Non-SAD
    N525293232-
    Medical records unobtainable, n (%)33 (6)15 (5)18 (8)
    Confirmed no medical history, n (%)24 (5)15 (5)9 (4)
    History of, n (%)
     Hypertension290 (55)175 (60)115 (50)0.023
     Diabetes mellitus117 (22)72 (25)45 (19)0.14
     Dyslipidemia157 (30)108 (37)49 (21)<0.0004
     Any cardiac history*224 (43)131 (45)93 (40)0.34
     Myocardial infarction76 (14)49 (17)27 (12)0.07
     Congestive heart failure68 (13)47 (16)21 (9)0.022
     Atrial fibrillation/atrial flutter50 (10)27 (9)23 (10)0.39
     Aortic stenosis (moderate or severe)6 (1)3 (1)3 (1)>0.99
     Mitral valve prolapse8 (2)5 (2)3 (1)>0.99
     Chronic kidney disease (non–end-stage renal disease)58 (11)33 (11)25 (11)0.72
     Seizure disorder39 (7)14 (5)25 (11)0.029
     Cerebrovascular accident33 (6)18 (6)15 (6)0.99
     Psychiatric disorder143 (27)61 (21)82 (35)0.005
     Chronic obstructive pulmonary disease64 (12)32 (11)32 (14)0.41
     Nonmetastatic cancer63 (12)40 (14)23 (10)0.26
     Tobacco use211 (40)115 (39)96 (41)0.72
     Alcohol abuse122 (23)57 (19)65 (28)0.014
     Illicit drug use79 (15)27 (9)52 (22)0.001

    SAD indicates sudden arrhythmic death; SCD, sudden cardiac death; and WHO, World Health Organization.

    *Includes prior diagnosis of coronary artery disease, cardiomyopathy, atrial fibrillation/atrial flutter, permanent pacemaker, implantable cardioverter-defibrillator, considered for device, Brugada syndrome, Wolff-Parkinson-White syndrome, left bundle-branch block, left ventricular hypertrophy, ischemia, myocardial infarction, ventricular tachycardia, 3rd degree heart block, acute coronary syndrome, valvular disease (not including aortic sclerosis), endocarditis, angina, coronary vasospasm, arrhythmia not otherwise specified, cardiomegaly, congenital cardiac anomaly, atrial tachycardia, pericardial effusion, mitral prolapse, 2nd degree heart block, intraventricular conduction delay, supraventricular tachycardia, early repolarization, and moderate or severe: aortic or mitral stenosis, aortic, mitral, tricuspid, or pulmonary regurgitation.

    Includes a prior diagnosis of anxiety, bipolar, depression, schizophrenia, posttraumatic stress disorder, mood disorders, psychosis, borderline personality disorder, obsessive compulsive disorder, and insomnia.

    Presenting Rhythm and Symptoms

    Initial rhythm at EMS arrival was asystole for nearly all 405 unwitnessed WHO-defined SCDs, whereas ventricular fibrillation (VF) and asystole each accounted for one-third and pulseless electric activity 13% of the 120 witnessed WHO-defined SCDs (Figure II in the online-only Data Supplement). For the witnessed WHO-defined SCDs, mean time to EMS arrival was similar for all rhythms (P=0.34, Figure III in the online-only Data Supplement). Ventricular tachycardia (VT)/VF predicted autopsy-defined SAD (39/43, 91%) and pulseless electric activity non-SAD (13/15, 87%, P<0.001 for both, Table III in the online-only Data Supplement). The proportions of autopsy-defined SAD versus non-SAD were similar for all other rhythms. Two-thirds of WHO-defined SCDs and autopsy-defined SCDs presented suddenly with no known symptoms (Table IV in the online-only Data Supplement).

    Discussion

    In the POST SCD study, capturing nearly all deaths attributed to stated OHCA and presumed SCDs in an entire ethnically diverse metropolitan area over 37 months, 40% of OHCA deaths were not sudden and only half (55.8%) of SCDs defined by conventional epidemiological criteria were proven to be SAD after postmortem investigation. We leveraged the medicolegal authority of the county medical examiner for complete prospective surveillance of all out-of-hospital deaths, which are reported as mandated by state law, to initially identify OHCA deaths as defined by CARES criteria for comprehensive autopsy. We then obtained EMS and comprehensive medical records to refine these to WHO-defined SCDs and adjudicate their causes of death with pre- and postmortem data. Although we have previously demonstrated the high fidelity of medical examiner surveillance for WHO-defined SCDs in San Francisco,16 in this investigation we further cross-checked all death certificates filed in the county to ensure that we did not miss any cases during the study period.

    Estimates of the annual incidence of OHCA and SCD vary widely depending on data sources for case ascertainment, the definitions used, and the methods employed. Indeed, SCD incidence rates in San Francisco would be >50% higher if CARES OHCA criteria rather than the WHO definition were used. Restricted to WHO-defined cases, SCD incidence in San Francisco is notably lower than contemporaneous estimates,8 which may be because of the exclusion of OHCA survivors and the diverse source population. Postmortem investigation then allowed us to further refine SCD incidence to autopsy-defined SAD incidence, approximately half that using the WHO definition.

    Death certificates are known to overestimate SCD rates,3 and the cause of death on death certificates is often unreliable22 because nonforensic autopsies are rarely performed11 and protocols and guidelines for autopsies in suspected SCDs vary widely. Noncardiac conditions that occur rapidly, such as vascular or viscus rupture, hemorrhage, or pulmonary embolism, cannot be excluded without a full autopsy, and the recent American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on SCD prevention includes recommendations on postmortem evaluation of SCD.23 Autopsy rates of SCDs in community-based cohorts and clinical trials range from 11% to 27%,3,6,24 reflecting typical forensic practice of low priority for natural deaths. A recent medical examiner–based study in Hennepin County, MN, reported an apparent 62% autopsy rate of 71 SCDs aged 25 to 59 over 3 years; however, 580 potential sudden deaths with existing illness that did not undergo autopsy were excluded; thus, the calculated SCD incidence was only 15% of expected.25 If these uninvestigated sudden deaths were included, the actual autopsy rate was 10%. In San Francisco County before the prospective POST SCD study, the prevailing medical examiner autopsy rate was 43% of WHO-defined SCDs16; in the present study, autopsy rates were doubled to 83% of WHO-defined SCDs and 98% of OHCA deaths ages 18 to 90.

    We performed vitreous chemistries in all subjects, and blood and urine toxicology for subjects <75 years or ≥75 years that did not have an obvious cause of death on gross examination. Lethal levels of opiates were the culprit in over half of the 71 WHO-defined SCDs found to be due to occult overdose, a reflection of the ongoing US opioid epidemic, urban, suburban, and rural alike.26 Because none of the WHO-defined SCDs 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; overdoses and other metabolic emergencies may be underrecognized as underlying causes of sudden death.

    Our results confirm substantial racial and sex differences in contemporary SCD epidemiology. Rates of WHO-defined SCD and autopsy-defined SAD were highest in blacks and lowest in Hispanics, whereas the proportion of WHO-defined SCD attributable to autopsy-defined SAD in both populations was significantly lower than for whites. We found significant differences in the distribution of noncardiac causes and marked sex differences: autopsy-defined SAD 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.

    Although a central tenet of SCD epidemiology is that CAD accounts for ≈80% of SCDs,9,27 autopsy studies supporting this premise were limited by referral bias of the minority of community sudden deaths referred for postmortem investigation.13 In contrast, our study reflects the contemporary epidemiology and underlying causes of nearly every incident SCD in San Francisco, and confirms recent secular trends of the decreasing prevalence of CAD28 and increasing prevalence of nonischemic causes. Indeed, the classic presentation of acute coronary lesion or pathological evidence of acute myocardial infarction leading to arrhythmic death was found in only 10% of WHO-defined SCDs overall and 18% of autopsy-defined SADs. A third of autopsy-defined SADs were attributable to nonischemic cardiomyopathies and cardiac hypertrophy without histological evidence of hypertrophic cardiomyopathy. We have recently reported on sudden neurological deaths15 and cardiac implantable electronic device concerns18 as previously unrecognized causes of presumed SCD. Cardiac nonarrhythmic causes (eg, heart failure with pulmonary edema, tamponade) also accounted for 4% of SCDs. Therefore, because SAD is the only phenotype of SCD rescued by automated external defibrillators and ICDs and the intended focus of genetic association and risk studies of SCD, it is essential to distinguish SAD from nonarrhythmic causes of SCD.

    Although many of the SCDs initially found in asystole may have started as VT/VF, mean EMS response times for witnessed cases were similar across all rhythms. An initial rhythm of VT/VF was highly specific (91%) yet not perfectly predictive for autopsy-defined SAD. For example, ICD documentation and treatment of VF did not always represent definitive evidence of SAD: a 59-year-old man with heart failure, ICD, and unwitnessed SCD was found to have a large subarachnoid hemorrhage that caused neurocardiogenic VF.15 Pulseless electric activity was found in 13% of witnessed cases, and a 2013 National Heart, Lung, and Blood Institute workshop identified this condition as an SCD research priority, in part, because of its lower survival versus VT/VF.29 This may be explained by the fact that 87% of cases presenting with pulseless electric activity were attributable to nonarrhythmic and noncardiac causes of death; therefore, further inroads into reducing the public health burden of sudden death requires investigation and earlier recognition of nonarrhythmic causes.

    Prior studies have typically identified SCD outcomes retrospectively, relying on death certificates or ex post facto retrieval of event and medical records and application of WHO or Hinkle-Thaler criteria to determine underlying cause.3,3032 The WHO-defined SCDs and autopsy-defined SADs in this report represent the entirety of these deaths in the community over a 3-year period. The positive predictive value of WHO SCD criteria for autopsy-defined SAD was 55.8% in the POST SCD Study. Because approximately half of deaths attributed to OHCA and WHO-defined SCDs were found to be nonarrhythmic after postmortem examination, it is difficult to identify SCDs with a high degree of accuracy by using conventional methods; therefore, one may consider deaths meeting WHO criteria as sudden deaths rather than as sudden cardiac deaths. Although comprehensive autopsies are not practical in most clinical trials and population, observational, or molecular association studies, understanding the limits of current criteria used to define SCD is important for interpreting the results.

    This study has several limitations. Standardized investigations and prospective premortem data collection as done in cohort studies were not possible in the population-based POST SCD study. However, we collected all available premortem data for nearly every WHO-defined SCD; therefore, these records reflect typical population medical care in the entire metropolitan area. Although the population of the United States is rapidly diversifying with no majority ethnicity projected by the US Census Bureau by 2043,33 our findings in a diverse area such as San Francisco may not be entirely generalizable to other populations. Despite evaluating more comprehensive data per SCD than any other study to date, the exact cause of death sometimes remains unclear and is subject to interpretation. Similar to many other SCD cohorts and studies, we included unwitnessed sudden deaths, for which the timeline of suddenness is less certain. Conversely, an unknown number of solitary deaths that may have been sudden could have been missed by our criteria because no witnesses were available to verify that the victim had been alive and well within 24 hours. Therefore, although we have demonstrated the limited specificity and positive predictive value of the WHO criteria for autopsy-defined SAD, the sensitivity of WHO criteria for all SADs in San Francisco is unknown. Although some studies may include resuscitated OHCA victims with substantial hemodynamic or neurological sequelae as SCDs, these cases were considered OHCA survivors rather than SCDs because they did not die suddenly. Because the medical examiner considered a patient who died within 3 weeks of physician care attended, OHCAs in such patients may have been missed, although we confirmed that >90% of these deaths were not sudden. Last, our protocol did not include genetic testing, which may be helpful for unexplained SCDs with negative autopsy, accounting for up to 40% of SCDs in pediatric/young adult populations.34 However, nearly all adult SCDs in POST SCD had an identifiable gross, histological, or toxicological cause of death; therefore, genetic testing may have helped identify the underlying cause for only the 7 cases (1.3%) that may be considered unexplained (primary electric disease with negative autopsy).

    In conclusion, in this prospective postmortem investigation of nearly all out-of-hospital WHO-defined SCDs in an entire ethnically diverse metropolitan area, just over half of presumed SCDs were actually autopsy-defined SAD. These data provide an unbiased, real-world picture of the contemporary epidemiology, burden, and underlying causes of sudden death in the community, and have implications for the accuracy of SCDs and aggregate mortality data as defined by death certificates or conventional criteria in clinical trials and cohort studies. Our methods may also provide an outline for medical examiner or coroner protocols for the systematic examination of these out-of-hospital natural deaths, which are rarely investigated in the community.

    Acknowledgments

    The authors are indebted to Nikolas Lemos, PhD, for expert review of all toxicological analyses in the POST SCD study. The authors thank A. Bedigian and J. Probert for assistance with figures and tables. The authors are grateful for the efforts of all forensic investigators in the Office of the Chief Medical Examiner and EMS personnel in San Francisco County. Dr Tseng contributed to the study conception and design, analysis and interpretation of data, acquisition of study funding, and drafting of the article. Dr Olgin contributed to study conception and design, analysis and interpretation of data, and critical revision of the article. Dr Ursell contributed to study conception and design, analysis and interpretation of data, and critical revision of the article. Dr Vittinghoff contributed to analysis of data and critical revision of the article. Dr Kim contributed to acquisition of data and critical revision of the article. Drs Sporer, Yeh, and Colburn, N.M. Clark, and R. Khan contributed to acquisition of data and critical revision of the article. Dr Hart contributed to study conception and design and critical revision of the article. Dr Moffatt contributed to study conception and design, acquisition of data, analysis and interpretation of data, and critical revision of the article.

    Footnotes

    Sources of Funding, see page 2699

    http://circ.ahajournals.org

    The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.117.033427/-/DC1.

    Zian H. Tseng, MD, MAS, Professor of Medicine in Residence, Cardiac Electrophysiology Section, University of California, San Francisco, 500 Parnassus Avenue, Box 1354, San Francisco, CA 94143-1354. E-mail

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