Cardiovascular disease mortality based on verbal autopsy in low- and middle-income countries: a systematic review

Abstract Objective To conduct a systematic review of verbal autopsy studies in low- and middle-income countries to estimate the fraction of deaths due to cardiovascular disease. Method We searched MEDLINE®, Embase® and Scopus databases for verbal autopsy studies in low- and middle-income countries that reported deaths from cardiovascular disease. Two reviewers screened the studies, extracted data and assessed study quality. We calculated cause-specific mortality fractions for cardiovascular disease for each study, both overall and according to age, sex, geographical location and type of cardiovascular disease. Findings We identified 42 studies for inclusion in the review. Overall, the cardiovascular disease cause-specific mortality fractions for people aged 15 years and above was 22.9%. This fraction was generally higher for males (24.7%) than females (20.9%), but the pattern varied across World Health Organization regions. The highest cardiovascular disease mortality fraction was reported in the Western Pacific Region (26.3%), followed by the South-East Asia Region (24.1%) and the African Region (12.7%). The cardiovascular disease mortality fraction was higher in urban than rural populations in all regions, except the South-East Asia Region. The mortality fraction for ischaemic heart disease (12.3%) was higher than that for stroke (8.7%). Overall, 69.4% of cardiovascular disease deaths were reported in people aged 65 years and above. Conclusion The burden of cardiovascular disease deaths outside health-care settings in low- and middle-income countries is substantial. Increasing coverage of verbal autopsies in these countries could help fill gaps in cardiovascular disease mortality data and improve monitoring of national, regional and global health goals.


Introduction
Cardiovascular disease is the largest cause of death due to noncommunicable disease globally.2][3] Reportedly, 57% of premature deaths due to cardiovascular diseases in 2019 occurred in low-and middle-income countries, many of which are progressing through the epidemiological transition, and are experiencing a decline in infectious disease mortality along with a concurrent growth in cardiovascular disease mortality. 1,2ence, one target of the sustainable development goals is to reduce premature cardiovascular disease deaths by one third of the level recorded in 2015. 46][7] As a result, estimates of the cause of death in these countries have relied heavily on the modelling of data from the World Health Organization (WHO) and GBD studies.Furthermore, as the data available on cardiovascular disease mortality are limited, these esti-mates have wide uncertainty intervals.Moreover, the actual prevalence may have been underestimated and, consequently, understanding of the burden of cardiovascular disease in many populations may be inadequate. 2erbal autopsy is the recommended method for providing routine information on the cause of death in low-and middle-income countries with low-quality or non-existent civil registration and vital statistics systems, and low coverage of medical certification of the cause of death. 8The prime objective of verbal autopsy is to provide population estimates of the fraction of deaths due to different causes in places where a high proportion of people die at home. 9 Health and Demographic Surveillance System sites and epidemiological research have used verbal autopsy methods for over 50 years and these methods are increasingly being used as part of routine surveillance by civil registration and vital statistics systems. 9,10In a verbal autopsy, an interviewer collects information on signs and symptoms and on any health care sought during the illness that led to a person's death, by questioning a close relative of the deceased person using a standardized questionnaire. 9The most likely cause of death is assigned on the basis of the information collected either by physician-certified verbal autopsy, where at least two physicians review the information and disagreement is resolved by consensus or by a third physician, or by computer-coded verbal autopsy, which uses data-driven algorithms or diagnostic criteria developed by experts. 11The use of verbal autopsy varies within regions and across countries.In 2022, a report by WHO's verbal autopsy reference group revealed that the method had been implemented in several

Study selection and data extraction
We used Covidence software (Covidence, Melbourne, Australia) to remove duplicate studies and manage the systematic review.Two reviewers screened titles and abstracts independently, with a third reviewer resolving any conflicts.After the full-text review, a data extraction form was developed and pre-tested on the first five studies identified by each of the two reviewers independently.After comparing the pre-testing results, the form was revised on the basis of consensus findings.Then, the two reviewers independently extracted data from all studies eligible for inclusion in the systematic review.Their findings were Box

Risk of bias
We assessed both the external and internal validity of each study included, and data quality was assessed from three broad perspectives using a pre-tested, risk-of-bias assessment tool: (i) selection of study population; (ii) nonresponse bias; and (iii) measurement bias. 16We used six original items from the checklist of this tool (items 1 to 6) and four modified items from the checklist (items 7 to 10) based on our research questions.The resulting 10 items used to assess study bias were: (i) how well the study sample represented the national population; (ii) how well the study sampling frame corresponded to the target population; (iii) the sample selection process; (iv) the response rate; (v) case definitions; (vi) use of a validated questionnaire; (vii) the method used to ascertain the cause of death; (viii) the recall period; (ix) translation of the assessment tools; and (x) training of data collectors.Each item was assessed as having a high or low risk of bias and, in general, an item was categorized as high risk if the study provided unclear or insufficient information.No study was excluded from the review on the basis of its quality.Two reviewers conducted independent risk-of-bias assessments.Thereafter, their findings were compared and any discrepancies were resolved by consensus and with the help of a third reviewer.

Summary measures
Low-and middle-income countries were identified using the World Bank's classification for 2019 to 2020. 17Car-diovascular diseases were defined using WHO's 2016 verbal autopsy list and the International statistical classification of diseases and related health problems, 10th revision. 9,18The total number of cardiovascular disease deaths was calculated by summing the numbers of deaths from stroke, ischaemic heart disease and other cardiac diseases.The same method was used to calculate cardiovascular disease deaths by sex and age.We used consistent age ranges for all studies to derive age-based distributions.Data are presented as numbers and percentages.
The cause-specific mortality fraction (hereafter mortality fraction) was used to quantify the percentage of deaths in a population due to a particular cause.For each study, we calculated separate mortality fractions for all cardiovascular diseases, stroke, ischaemic heart disease and other cardiac diseases in individuals aged 15 years and above.For different age groups, the cardiovascular disease cause-specific mortality fraction was calculated as the total number of cardiovascular disease deaths in that age group divided by the total number of deaths reported by verbal autopsy in the same age group.We also calculated mortality fractions for these conditions for each sex.Low-and middle-income countries were grouped together into WHO regions.To calculate regional mortality fractions, we added all cardiovascular disease deaths and verbal autopsy deaths, respectively, reported by countries in the same WHO region.Regional mortality fractions for stroke, ischaemic heart disease and other cardiac diseases were calculated using the same method.

Results
In total, 749 studies were identified from the database search and experts' suggestions.After 411 duplicate publications were removed, the titles and abstracts of 338 studies were screened, 157 studies underwent full-text review and 42 were finally included in the systematic review (Fig. 1).

Study characteristics
The verbal autopsy data collection period of the studies included in the review ranged from 1992 to 2020   Verbal autopsy and cardiovascular deaths Ajay Acharya et al.

Study design
No For some studies, the total number of participants does not equal the sum of male and female participants because of rounding or reporting errors.
(. ..continued)The results of verbal autopsies were either certified by a physician or medical officer or coded using a data-driven computer algorithm, such as InterVA or SmartVA. c For some studies, the total number of participants does not equal the sum of male and female participants because of rounding or reporting errors.

Study setting
48][49][50]52 Overall, the cardiovascular disease mortality fraction was higher in urban than in rural settings: 25.6% versus19.4%,respectively.In the African Region, the cardiovascular disease mortality fraction was higher in urban than rural populations (22.2% versus 10.5%, respectively), whereas in the South-East Asia Region it was higher in rural than urban populations (32.1% versus 26.1%, respectively).

Differences by age
Seven studies reported cardiovascular disease deaths in the age groups 15 to 49 years, 50 to 64 years and 65 years or older (Table 5). 19,26,28,34,35,42,44In these studies, 69.4% of cardiovascular disease deaths were reported in people aged 65 years or older, and 20.2% were reported in people aged 50 to 64 years.
Six studies reported cardiovascular disease deaths in the age groups 15 to 59 years and 60 years or older (Table 6). 23,33,41,49,50,56Among these studies, 80.5% of cardiovascular disease deaths were reported in people aged 60 years or older.

Type of cardiovascular disease
Overall in people aged 15 years or older, the mortality fraction for ischaemic heart disease (12.3%) was higher than that for stroke (8.7%) and for other or unspecified heart disease (1.5%; Table 7).The pattern was similar in the South-East Asia Region.In the African Region, however, the mortality fraction for stroke (4.2%) was higher than that for ischaemic heart disease (0.8%).

Risk of bias
The findings of the risk-of-bias assessments in the 42 studies are shown in Fig. 2. Overall, 83% (35/42) of studies had poorly reported or unclear information on how representative the study target population was of the national population.Moreover, 76% (32/42) of studies did not report whether the verbal autopsy questionnaire had been translated into a local language.Information on whether the recall period between the person's death and the verbal autopsy was appropriate (i.e.under 3 months) was either absent or unclear in 64% (27/42) of studies.Full details of the risk-of-bias assessments for individual studies are available from the data repository. 12

Discussion
We found that the overall cardiovascular disease mortality fraction among people in low-and middle-income countries aged 15 years or older was 22.9%, and that the mortality fraction was generally higher in males than females.Moreover, the mortality fraction varied with age, geographical location and the type of cardiovascular disease.The highest burden of cardiovascular disease deaths was reported in WHO's Western Pacific Region, followed by the South-East Asia Region and the African Region.The cardiovascular disease mortality fraction was higher in urban than rural populations in all regions except the South-East Asia Region.We also found that the mortality fraction was generally higher for ischaemic heart disease than stroke, though stroke deaths were more common in Africa.
Verbal autopsy is an important data source for the GBD, which produces global, regional and national estimates of the frequency of different causes of death. 1 Our review provides new data on cardiovascular disease mortality from published verbal autopsy studies that may not previously have been included in GBD estimates, and which could increase the representativeness of global estimates.Moreover, our review provides data on rural and urban populations and on regions where information on cardiovascular disease mortality is scarce because there is no adequate death registration system.The inclusion of verbal autopsy data from regions and population groups that are underrepresented in existing global estimates will help make estimates for these regions more balanced and accurate.Although our review did not include data from the WHO Region of the Americas, verbal autopsy is not needed in most of the region because the cause of death is recorded by medical certification, except in some very remote communities where verbal autopsy is used (e.g. in Colombia). 61lthough our findings may not be generalizable to a global or national level, a comparison with GBD estimates is helpful.Our overall estimate of the cardiovascular disease mortality fraction of 22.9% is lower than that estimated by the 2019 GBD study (the most recent), which found a cardiovascular disease mortality fraction of 32% across all age groups globally. 1In addition, our review found a higher cardiovascular disease mortality fraction in males than females overall, which was not in agreement with the 2019 GBD estimates. 1Nevertheless, the regional sex differences in cardiovascular disease mortality fraction we found in our review were consistent with GBD estimates. 1Our observations that the mortality fraction for ischaemic heart disease was higher than that for stroke, and that the cardiovascular disease mortality fraction was higher in older than younger age groups, were similar to GBD findings. 1he differences between our review's findings and GBD estimates could be due to the lack of generalizability of our study data.Our review included few studies from the Western Pacific, Eastern Mediterranean or European Regions, or from high-income countries where death due to cardiovascular disease is more common. 1In addition, the studies included in our review mainly focused on deaths at home, which are most frequently assessed by verbal autopsy.By contrast, the GBD estimates mortality fractions for all deaths in all countries and regions. 2 Moreover, GBD estimates of the global cardiovascular disease mortality fraction are affected by a lack of data from some countries, notably countries with a high proportion of deaths in the community, such as those in sub-Saharan Africa and South-East Asia, 3 which may help explain why our cardiovascular disease mortality fraction estimates were lower.Our review suggests that the verbal autopsy method can help fill gaps in cardiovascular disease mortality data for low-and middle-income countries that do not have adequate vital registration systems, and can be a valuable tool for identifying different types of cardiovascular death in the community.
Most studies (32/42) in our review were surveillance studies and did not report whether the study population was comparable with the national population in terms of age, sex, socioeconomic status or any other factor.Surveillance studies would be more valuable if they reported the characteristics of the study population, which, in turn, would help establish the generalizability of the study's findings.Moreover, to minimize assessment errors, studies should report  a For some studies, the number for all age groups also included individuals aged under 15 years.Verbal autopsy and cardiovascular deaths Ajay Acharya et al.
whether the verbal autopsy questionnaire has been translated into a local language, and the time delay between death and the autopsy interview; the diagnosis is more likely to be correct if the time delay is short. 8ur systematic review had several limitations.First, the number of studies included varied considerably between regions.In addition, the studies included diverse population groups and involved different autopsy methods.The resulting heterogeneity between the studies may limit the generalizability and comparability of our findings at regional and country levels.Second, our review calculated the cardiovascular disease mortality fraction only for individuals aged 15 years or older, because most studies included in the review reported cardiovascular disease mortality in that age range and not in younger age groups.Although focusing on older individuals provides valuable insights into the prevalence of death due to cardiovascular disease, including younger individuals would have helped identify emerging trends and assisted public health planning.Furthermore, the variation in age group categories between studies limited our ability to achieve a complete understanding of cardiovascular mortality across all age groups.Verbal autopsy studies should publish their results in a greater number of age groups, as this would Verbal autopsy and cardiovascular deaths Ajay Acharya et al.
enable the influence of age on cardiovascular disease mortality to be better investigated.Third, as mentioned, the generalizability of our study results was limited because most studies included were surveillance studies conducted in one specific geographical area, and most considered deaths occurring outside of a health-care setting.The use of a standardized assessment tool and cross-validation with other national and international data would increase the generalizability of verbal autopsy study findings to other populations. 9ourth, as we only calculated the cardiovascular disease mortality fraction for verbal autopsy deaths and not for all deaths, the mortality fraction is likely to differ from that derived from deaths in hospital or other locations.Finally, this systematic review included all data irrespective of when they had been collected.Although including only recent studies would have provided the most up-to-date data on cardiovascular mortality, we wanted our review to include as many large studies as possible.As the mortality fraction for cardiovascular disease has been increasing in lowand middle-income countries, the use of more recent data would likely have produced a higher mortality fraction.Moreover, newer studies may have used improved data collection methods and have been better at attributing the cause of death to cardiovascular disease.For example, computer-coded verbal autopsy has become more popular and has been shown to be more accurate for confirming death due to heart disease than physician-certified verbal autopsy. 62he verbal autopsy method also has limitations.The consistency of the symptoms reported by relatives during the verbal autopsy interview has been reported as low, especially when interviews take place a long time after the death. 63Nevertheless, despite the low consistency, reported symptoms were generally sufficient for assigning the cause of death, 63 which is important given that verbal autopsy is only source of information about the cause of death at the population level in many low-and middle-income countries. 64Future studies involving verbal autopsies should focus on minimizing recall bias by using validated questionnaires, and should ensure interviews take place within 3 months of the mourning period. 8The studies in our review used different methods to ascertain the cause of death, with nearly half using the physiciancertified method.A previous systematic review showed that physician-certified verbal autopsy was relatively poor at confirming heart disease compared with computer-coded verbal autopsy, though it was based on only three studies of hos-pital deaths. 65More data are needed to understand the performance of different verbal autopsy methods in confirming different types of death, especially death at home.Verbal autopsy findings are specific to the population or setting in which the autopsies are conducted and it is, therefore, difficult to generalize them to other contexts.Recently, however, verbal autopsy has become routine in some settings.In particular, it has become part of civil registration and vital statistics systems in countries such as Bangladesh. 53As a result, data on deaths due to cardiovascular disease and other causes will become more generalizable.Future studies using these data could validate verbal autopsy findings across diverse populations and geographical areas.
In many settings, the quality of verbal autopsy data directly affects health policy.A systematic review of 66 validation studies of verbal autopsy published in 2022 compared the cause of death assigned by verbal autopsy to the cause of death assigned by other methods such as autopsy diagnosis and hospital diagnosis. 66The review found that the majority of studies reported an acceptable level of agreement between verbal autopsy and the comparison method as assessed, using measures such as chance-corrected concordance, kappa coefficients, sensitivity, specificity or the positive predictive value.Was the recall period (i.e.time between death and verbal autopsy) appropriate?
Was a validated or recognized method used to ascertain the cause of death?
Was the study instrument that measured the parameter of interest shown to have good reliability and validity?
Was an acceptable case definition used?
Was the likelihood of non-response bias minimal?
Was random selection used to select the sample or was a census undertaken?
Was the sampling frame a true or close representation of the target population?
Was the study' s target population a close representation of the national population?
Conclusión La carga de fallecimientos por enfermedad cardiovascular fuera de los centros de atención sanitaria en los países con ingresos medios y bajos es considerable.El aumento de la cobertura de las autopsias verbales en estos países podría ayudar a subsanar la falta de datos sobre mortalidad por enfermedad cardiovascular, y mejorar el control de los objetivos de salud a nivel nacional, regional y mundial.

Search strategies, systematic review of verbal autopsies in low-and middle- income countries, 1992-2022
1.

Table 3 . Cause-specific mortality fraction for cardiovascular disease, by sex and WHO region, systematic review of verbal autopsies in low-and middle-income countries, 1992-2022 WHO region No. studies Parameter for people aged ≥ 15 years No. deaths recorded by verbal autopsy No. deaths due to cardiovascular disease Cause-specific mortality fraction for cardiovascular disease, %
WHO: World Health Organization.a For some regions, the total number of participants does not equal the sum of male and female participants because of rounding or reporting errors in individual studies.Bull World Health Organ 2023;101:571-586| doi: http://dx.doi.org/10.2471/BLT.23.289802Verbal autopsy and cardiovascular deaths Ajay Acharya et al.

Table 4 . Cause-specific mortality fraction for cardiovascular disease, by study setting and WHO region, systematic review of verbal autopsies in low-and middle- income countries, 1992-2022 Study setting and WHO region No. studies Parameter for people aged ≥ 15 years
WHO: World Health Organization.

Table 6 . Cardiovascular disease deaths, by age group (15-59 years and ≥ 60 years), systematic review of verbal autopsies in low-and middle-income countries, 1992-2022 Study author, country Cardiovascular disease deaths All age groups a 15-59 years ≥ 60 years
a For some studies, the number for all age groups also included individuals aged under 15 years.Bull World Health Organ 2023;101:571-586| doi: http://dx.doi.org/10.2471/BLT.23.289802

Table 7 . Cause-specific mortality fraction, by type of cardiovascular disease, systematic review of verbal autopsies in low-and middle- income countries, 1992-2022 Study author, country a Verbal autopsy findings in people aged ≥ 15 years
ND: not determined.a We grouped countries by World Health Organization regions.Bull World Health Organ 2023;101:571-586| doi: http://dx.doi.org/10.2471/BLT.23.289802