Regional disparities and risk factors of mortality among patients at high risk of sudden cardiac death in emerging countries: a nonrandomized controlled trial

Sudden cardiac death (SCD) remains a leading cause of cardiovascular mortality worldwide. The burden of SCD varies by geographic region, although global data are somewhat limited. In developed countries, such as the United States of America (USA) and the Netherlands, SCD incidence rate estimates range from 53 to 117 per 100,000 persons per year, while in emerging countries, such as China and India, SCD incidence rate estimates range from 41.8 to 181 per 100,000 persons per year [1, 2]. Data indicate that various causes, risks and predisposing conditions vary in prevalence according to factors such as geographic region and ethnicity, influencing the incidence of SCD [3]. However, comprehensive data on patients with high SCD risk in emerging countries are lacking, and disease management strategies and resources vary substantially by geographic region.

There is substantial evidence in favour of implantable cardioverter-defibrillators (ICDs) as therapy for the prevention of SCD. However, ICD utilization remains low in emerging countries, especially in primary prevention (PP) patients [4]. In 2017, the ICD implantation rates per million persons in China and India were 2.9 and 2.6, respectively, while the rate was 280 per million persons in the USA [5]. Previous evidence supporting ICD utilization as a therapy to prevent SCD came from developed, high-income regions such as North America and Europe, with little information from other geographic regions. Thus, the benefits of ICD implantation in emerging countries need to be further demonstrated.

In this sub-analysis of the Improve Sudden Cardiac Arrest (SCA) study, we aimed to deepen our understanding of the SCD phenotype in emerging countries, identify risk factors for death and guide the allocation of medical resources in emerging countries where data are limited. In addition, we analysed differences between the Improve SCA study and previous large-scale clinical trials conducted in developed countries.

Between March 2014 and July 2017, 4222 patients were enrolled with a mean follow-up of 21.6 ± 10.2 months. A total of 3889 patients were included in the analysis presented here with 333 patients excluded. There were 2696 (69.3%) PP patients and 1193 (30.7%) secondary prevention (SP) patients, and the percentages of PP and SP patients implanted with ICDs (or CRT-Ds) were 51.9% and 89.4%, respectively.

The Improve SCA registry is the first international registry to study patients with high SCD risk in emerging countries. The key results of this subanalysis of the Improve SCA registry were as follows: (1) There was significant heterogeneity among patients with high SCD risk in emerging countries. The influence of geographic region on patient characteristics, therapy utilization and clinical outcomes in terms of mortality and SCD was significant. (2) In addition to the variables identified in previous studies, geographic region and ICD use were associated with all-cause mortality in a Cox regression analysis, both individually and after accounting for other baseline factors. (3) Primary prophylactic ICDs/CRT-Ds implantation was associated with 36% lower all-cause mortality risk and an 80% lower SCD risk in the Improve SCA registry, which appeared to be higher than that in most previous landmark PP studies.

Our results revealed striking geographic variations in clinical characteristics, therapy utilization and outcomes among patients. The percentage of PP and SP patients without ICDs/CRT-Ds was highest in South Asia. Patients from South Asia had the lowest rate of ICDs/CRT-Ds implantation and the highest rate of SCD. These results are consistent with the Asian SCD in Heart Failure (ASIAN-HF) registry [15, 16]. In the present study, patients from South Asia also had the highest rates of myocardial infarction and the lowest usage rates of ACEIs/ARBs, which may also contribute to the high rate of SCD independent of the low rate of ICDs/CRT-Ds implantation (see also ¹⁴). An important difference between these two patient cohorts was that the patients enrolled in the Improve SCA met the class I indication for ICDs/CRT-Ds implantation according to ACC/AHA/HRS or ESC guideline recommendations, while patients enrolled in the ASIAN-HF study had HF and an LVEF < 40% or ≥ 50%, and it was assumed that all ICD-eligible patients were implanted for PP [16, 17]. Patients from Southeast Asia had the highest comorbidity burden of hypertension and diabetes, the lowest LVEF and the least ACEI/ARB use. These are plausible reasons why the rate of all-cause mortality was highest among PP patients in Southeast Asia [18]. These results are also consistent with the ASIAN-HF registry study; when compared with patients from South and East Asia, patients from Southeast Asia had the highest rate of comorbidities and all-cause mortality as well [15].

Multivariate Cox regression modelling demonstrated that ICD implantation was a protective factor for all-cause mortality (HR = 0.652, 95% CI = 0.495–0.860, p = 0.0024) in PP patients. As such, our data confirmed the utility of the ICDs for the PP of SCD, which had been demonstrated by previous landmark trials [8‐14, 19]. Unlike previous studies, these first prospective multinational data from emerging countries highlight the important influence of geographic region on all-cause mortality. After multivariate-adjusted Cox regression analysis, assuming proportional hazards across time, PP patients from East Asia were associated with all-cause mortality, and SP patients with ICDs/CRT-Ds from Latin America and the Middle East and Africa were associated with all-cause mortality. Therefore, the data suggest that regional variations in all-cause mortality might be due to factors that are not well described or measured in the current literature. These factors may include health-care quality, access, the level of patient education, infrastructure, environmental factors and genetics.

Previous landmark trials have included patient populations with low ethnic diversity and predominantly included patients from HI countries. Ethnic differences in SCD have not been fully explored, and the few studies that have explored the issue have yielded inconsistent results. According to a cohort study of residents in the USA, Asian American patients had a lower risk of SCD than African American and White patients [20]. The limited data may have contributed to the perception that Asian patients may be at lower risk of SCD and thus less likely to benefit or have unknown benefits from ICD therapy. For reasons such as this, it remains important to understand the survival of non-White patients or patients from non-HI countries who receive an ICD for PP in clinical practice. However, there are limited data on this topic. Unlike previous registries, the Improve SCA PP population contained more Asian patients (89.8%) and more patients from UMI and LMI countries (71.3%) (Table 3). Although there was no head-to-head comparison between patients from Asia and North America or Europe, ICDs/CRT-Ds implanted for PP in the Improve SCA registry showed superior trends in reducing the rates of all-cause mortality and SCD. The reduction in all-cause mortality, incorporating time-to-event analysis, was 36% in the Improve SCA PP patients with ICDs/CRT-Ds, which appeared to be higher than those seen in previous studies from the 2000s, which ranged from 13 to 36%^17–23. The reduction in the SCD rate was 80% among PP-implanted patients in the Improve SCA study, which was a rate lower only than that in the EU-CERT-ICD registry (84%) [14]. The reduction rates of all-cause mortality and SCD were similar to those of previous single trials conducted in emerging countries [21]. Therefore, our study with more Asian patients and more patients from UMI/LMI countries prospectively confirmed the benefit found in previous studies for prophylaxis PP patients. There may be several explanations for this. The simplest explanation is that better medical treatment reduces the risk of death. Guideline-directed medical therapy such as ACEIs/ARBs, angiotensin receptor neprilysin inhibition and beta blocker could reduce all-cause mortality and SCD as demonstrated by previous studies [18, 22‐24]. However, the use of beta blocker was lower in the Improve SCA study than in those studies conducted after 2010. And the use of ACEIs/ARBs was lowest in the Improve SCA study when compared with previous studies, and the protective effect of ACEIs/ARBs was demonstrated after multivariate adjustment in this study and previous work [18, 22, 23]. These data also suggest that efforts to improve the uptake of guideline-directed medical therapy in emerging countries are warranted. Another reason may be that most patients in this study were from UMI/LMI countries. It has been previously demonstrated that the incidence of SCD is relatively high in geographic areas with lower socioeconomic status [25] and that the all-cause mortality rate among patients from UMI/LMI countries was higher than that among patients from HI countries [26]. Last but not least, patients from UMI/LMI countries had lower implantation rates of ICDs/CRT-Ds when compared with those from HI countries. Implantation of ICDs/CRT-Ds has already been demonstrated to significantly reduce the rates of all-cause mortality and SCD¹⁷⁻²³. These data may help emerging countries expand their reimbursement guidelines to include ICDs/CRT-Ds for the PP of SCA and convince regulators to provide coverage for the implantation of ICDs/CRT-Ds in PP patients. Although ICDs/CRT-Ds reduce the rate of all-cause mortality and SCD, they are still associated with risk for long-term complications such as lead dislodgement, lead failure and endocarditis [27, 28]. Therefore, large-scale and long follow-up clinical trials with head-to-head comparisons may still be needed.

These first prospective multinational data from emerging countries highlight the significant heterogeneity among patients with a high risk of SCD in these countries and the important influence of geographical region on patient characteristics and outcomes. Independent predictors of all-cause mortality identified in this study may aid in the risk-stratified targeting of limited resources for SCD prevention in emerging countries. Finally, in view of the benefits of ICDs/CRT-Ds implantation in PP patients in emerging countries, improvement in the implantation rate of ICDs/CRT-Ds is extremely urgent.