Ezzati, Christopher J.L. Murray and Mohsen NaghaviAndrew E. Moran, Mohammad H. Forouzanfar, Gregory A. Roth, George A. Mensah, Majid

The Global Burden of Disease 2010 StudyTemporal Trends in Ischemic Heart Disease Mortality in 21 World Regions, 1980 to 2010:

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Ischemic heart disease (IHD) was the leading cause of death worldwide in 2010.1 Age-standardized IHD mor-

tality has declined in high-income nations since 1980, in large part, because of a combination of improved primary prevention (improvements in risk factors) and improved secondary prevention (improved treatment of acute and chronic IHD).2–5 On average, IHD deaths have been pushed to older ages in the high-income regions. However, in the past, the IHD epidemic has evolved variably in different regions and nations.6 In some low- and middle-income regions, accelerated lifestyle changes, economic stresses, and other factors may be leading to increased IHD inci-dence often occurring in middle-aged adults, and changing the late 20th century paradigm of IHD as a disease of the affluent and the elderly.7

Editorial see p 1459 Clinical Perspective on p 1492

Measuring total IHD deaths and age-standardized IHD mor-tality rates is essential for assessing the burden of IHD and planning prevention programs. Global and regional analysis of IHD mortality trends is complicated by numerous factors, including changes in International Classification of Diseases (ICD) categories over time, sparse or low-quality original vital registration data in some regions, and variations in the degree of incorrect coding of IHD deaths. As part of the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2010 Study, we used novel estimation methods to assess the numbers of IHD deaths, IHD mortality rates, and years of life lost (YLL) attrib-utable to IHD for 21 world regions over the years 1980 to 2010, and provide uncertainty ranges for these estimates.

Background—Ischemic heart disease (IHD) is the leading cause of death worldwide. The Global Burden of Diseases, Risk Factors and Injuries 2010 Study estimated global and regional IHD mortality from 1980 to 2010.

Methods and Results—Sources for IHD mortality estimates were country-level surveillance, verbal autopsy, and vital registration data. Regional income, metabolic and nutritional risk factors, and other covariates were estimated from surveys and a systematic review. An estimation and validation process led to an ensemble model of IHD mortality for 21 world regions. Globally, age-standardized IHD mortality has declined since the 1980s, and high-income regions (especially Australasia, Western Europe, and North America) experienced the most remarkable declines. Age-standardized IHD mortality increased in former Soviet Union countries and South Asia in the 1990s and attenuated after 2000. In 2010, Eastern Europe and Central Asia had the highest age-standardized IHD mortality rates. More IHD deaths occurred in South Asia in 2010 than in any other region. On average, IHD deaths in South Asia, North Africa and the Middle East, and sub-Saharan Africa occurred at younger ages in comparison with most other regions.

Conclusions—In most world regions, particularly in high-income regions, age-standardized IHD mortality rates have declined significantly since 1980. High age-standardized IHD mortality in Eastern Europe, Central Asia, and South Asia point to the need to prevent and control established risk factors in those regions and to research the unique behavioral and environmental determinants of higher IHD mortality. (Circulation. 2014;129:1483-1492.)

Key Words: epidemiology ◼ mortality ◼ myocardial ischemia ◼ trends ◼ world health

© 2014 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.004042

Received May 24, 2013; accepted November 4, 2013.From the Division of General Medicine, Department of Medicine, Columbia University Medical Center, New York, NY (A.E.M.); Institute for Health

Metrics and Evaluation, University of Washington, Seattle, WA (M.H.F., G.A.R., C.J.L.M., M.N.); Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA (G.A.R.); Center for Translation Research and Implementation Science (CTRIS), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); and MRC-HPA Centre for Environment and Health and Department of Epidemiology and Biostatistics, Imperial College London, London, UK (M.E.).

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA. 113.004042/-/DC1.

Correspondence to Andrew Moran, MD, MPH, Herbert Irving Assistant Professor of Medicine, Columbia University, Division of General Medicine. Presbyterian Hospital East room 105, 622 West 168th St, New York, NY 10032. E-mail aem35@cumc.columbia.edu

Temporal Trends in Ischemic Heart Disease Mortality in 21 World Regions, 1980 to 2010The Global Burden of Disease 2010 Study

Andrew E. Moran, MD, MPH; Mohammad H. Forouzanfar, PhD; Gregory A. Roth, MD, MPH; George A. Mensah, MD; Majid Ezzati, PhD; Christopher J.L. Murray, MD, DPhil;

Mohsen Naghavi, MD, MPH, PhD

Epidemiology and Prevention

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MethodsDefinition of IHD DeathDetailed IHD mortality definitions and estimation methods are avail-able elsewhere.8,9 In brief, IHD deaths fall into 2 categories: acute myocardial infarction deaths and sudden cardiac deaths. IHD has been consistently defined as an underlying cause of death across ICD revisions (most recently ICD-10 I20–I25 and ICD-9 410–414).8 A proportion of IHD deaths are erroneously assigned on death certifi-cates to either nonfatal ICD conditions (eg, senility) or conditions not defined as an underlying cause of death (eg, heart failure, hyperten-sion, or cardiac conduction disorders). The GBD developed meth-ods for systematically reallocating these undefined or erroneously assigned deaths to IHD based on the total distribution of actual causes of death by the country, sex, age, and year.8,10

IHD Mortality Source DataCause-specific mortality data were gathered from vital registration, verbal autopsy, surveillance systems, surveys/censuses, or police report and aggregated in a central database. Data sources and avail-ability varied substantially among GBD 2010 regions (Tables I and II in the online-only Data Supplement). Causes of death were mapped across revisions and national variations of the ICD over time, incom-plete data were adjusted for reporting bias, erroneously coded deaths were redistributed, deaths were distributed to GBD age categories, and trends were smoothed to eliminate year-to-year fluctuations.1 No gold standard for validating GBD classification and redistribution algorithms exists (such as large-scale autopsy studies), so countries with the most complete vital registration and adherence to recom-mended cause-of-death coding practices were used as the standard. Even in the best of settings, there are problems with erroneous coding of deaths to inappropriate ICD codes, and GBD methods have been demonstrated to improve cause-of-death estimation.11 Overall, num-bers of IHD deaths increased 21.5% after redistribution of undefined- coded deaths to IHD (Table III in the online-only Data Supplement). Globally, 76.9% of deaths incorrectly coded as heart failure, 47.2% incorrectly coded as hypertension, and 89.9% incorrectly coded as all cardiac conduction disorders were redistributed to IHD.9

IHD Mortality ModelsMultilevel IHD mortality regression models were used to improve esti-mation for regions with sparse or outlying mortality data (Online- only Data Supplement Material). Models include fixed effects from covari-ates and nested random effects on super region, region, country, and age. Separate models were developed for males and females. Potential model covariates and their directions of effect were selected based on a comprehensive review by the comparative risk assessment arm of the GBD 2010 study, and included standard IHD risk factors (country mean blood pressure and cholesterol), behavioral variables (physical activity, diet, alcohol consumption), and contextual variables (per capita income, mean education level, and health system access).9 Independent ecologi-cal associations of covariates with IHD mortality were first tested in mixed-effects regressions, adding covariates stepwise, added in order from higher to lower evidence of causal association with IHD in past studies.9 Seventeen covariates produced multivariate coefficients with a plausible direction and were significant at the <0.05 level and were retained for subsequent models. With the use of IHD mortality data and the covariates selected, the Cause of Death Ensemble Model ranked out-of-sample performance of individual IHD mortality statistical models and, with the use of a weighting algorithm, combined the best individ-ual models into ensemble models.12 Out-of-sample predictive validity of the ensemble and individual predictive models were evaluated by ranking each model’s root mean squared error of the natural log of the death rate (the average difference—or error—between model estimates and test set data for each year), the fraction of the time the trend in the prediction matched the temporal trend in the data (trend test), and the proportion of the test data set included in the 95% prediction interval of the model (coverage). All-cardiovascular death and total mortality enve-lopes were estimated independently and used to scale IHD mortality so that the sum of different cardiovascular disease–caused deaths would be equal to the all-cardiovascular disease death envelope, and all-cause deaths would be equal to the total mortality envelope.

Mean body mass index, systolic blood pressure (mm Hg), total cholesterol (mmol/L), and level of tobacco smoking (active smoking prevalence and mean cigarettes per day) were all significant predic-tors of IHD mortality and contributed most frequently to individual IHD models developed for both men and women.9 Alcohol (liters per capita) was the only covariate entered into models without specify-ing the direction of association (ie, not specifying benefit or harm) and contributed to 11% of male models and 42% of female models.

Figure 1. Map of age-standardized ischemic heart disease mortality rate per 100 000 persons in 21 world regions, 2010, the Global Burden of Disease 2010 Study.

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Moran et al Global IHD Mortality Trends, 1980–2010 1485

Contextual covariates such as lower educational status (years per cap-ita), lower income (US dollars per capita), high elevation (percent-age of population dwelling at >1500 m), and high war deaths (rate per 1000 person-years) all contributed more to female than to male ensemble models.9 The prevalence of diabetes mellitus contributed to 30% of male ensemble models, but to zero female models. The root mean squared error of the best male IHD mortality model was 0.58, predicted the correct trend 62% of the time in test data, and included 90% of test data within the 95% confidence intervals around annual estimates. The best female model had a root mean squared error of 0.65, predicted the correct trend 61% of the time in test data sets, and included 91% of the test data within the 95% confidence interval.9

YLL were calculated by multiplying observed IHD deaths for a specific age in the year of interest by the age-specific reference life expectancy estimated by the use of life table methods (eg, 86.0 years at birth).13 Numbers of IHD deaths and YLL attributable to IHD death are reported for all 21 GBD regions for the years 1980 to 2010 (regions listed in Table IV in the online-only Data Supplement). Crude IHD mortality rates were calculated by dividing annual IHD deaths by the total population (all ages) at risk in that year. These rates were also age standardized by the direct method by using the 5-year GBD age categories and the World Health Organization stan-dard population.14 To assist with interpretation, IHD mortality rate trend plots used 7 super regions: Latin America/Caribbean, East Asia/

Figure 2. Total IHD deaths by age group, all world regions (A, males; B, females), 1980 to 2010, the Global Burden of Disease 2010 Study. IHD indicates ischemic heart disease.

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Pacific, South Asia, North Africa/Middle East, sub-Saharan Africa, Eastern Europe/Central Asia, and High Income (Table IV in the online-only Data Supplement).

ResultsThere were >7.0 million IHD deaths worldwide in 2010, in comparison with 4.5 million IHD deaths in 1980, 5.2 million in 1990, and 6.3 million in 2000 (Table V in the online-only Data Supplement). In 2010, the highest age-standardized IHD death rates were concentrated in a cluster of regions extend-ing from Eastern Europe and Central Asia to Central Europe, North Africa/Middle East, and South Asia (Figure 1). High age-standardized IHD death rates were also found in the Caribbean region. Of all global IHD deaths in the year 2010, 25.6% occurred in persons <65 years of age (95% confidence interval, 25.9%–27.8%), in comparison with 26.5% in 1980 (95% confidence interval, 23.9%–26.6%).

The number of IHD deaths increased most since 1980 in the ≥80-years age group, the same group in which about half

of all female IHD deaths occurred in 2010 (Figure 2). Rarely, IHD deaths were recorded in infants and children, perhaps because of incorrect cause-of-death reporting. Crude IHD mortality rates in the High Income super regions were among the highest in the world in 1980, but declined substantially by 2005 (Figure I in the online-only Data Supplement). By far the highest crude rates of IHD deaths and the steepest increase since 1980 were observed in the regions of the former Soviet Union (Eastern Europe/Central Asia), especially among males. The South Asia and East Asia/Pacific super regions also saw steady crude IHD death rate increases after 1980.

When mortality rates were age standardized, in comparison with the crude rates, IHD death rates emerged as distinctly higher in North Africa/Middle East and South Asia, 2 regions with younger populations (average age <65 years; Tables 1 and 2, Figure 3). South Asia’s age-standardized death rates increased from ≈1985 to 2000; more recently rates there appear to have leveled off. Age-standardized IHD mortality remained low in sub-Saharan Africa from 1980 to 2010. The largest proportional

Table 1. Age-Standardized IHD Mortality per 100 000 persons, by Region, Males, 1990, 2005, 2010, the Global Burden of Disease 2010 Study

Males

GBD 2010 Super Region 1990 2005 2010

GBD 2010 Region Mean Lower Upper Mean Lower Upper Mean Lower Upper

High income

Asia Pacific, high income 69 60 73 49 45 56 46 42 52

Europe, Western 183 169 192 106 103 122 93 89 108

Australasia 209 190 216 99 94 116 91 83 108

North America, high income 226 209 238 135 129 155 120 112 139

Latin America, Southern 164 154 180 119 113 138 108 102 125

Eastern Europe/Central Asia

Europe, Central 285 263 302 226 215 246 201 192 222

Europe, Eastern 393 380 430 545 497 566 434 396 454

Asia, Central 395 382 427 441 411 459 400 366 430

Latin America/Caribbean

Latin America, Tropical 159 142 170 119 113 139 113 106 132

Latin America, Central 130 121 144 115 101 120 117 103 124

Latin America, Andean 92 85 102 73 66 80 70 63 78

Caribbean 177 163 189 149 144 168 144 137 162

East Asia/Pacific

Asia, Southeast 110 102 124 108 102 132 111 104 133

Asia, East 61 53 86 83 67 91 84 65 92

Oceania 122 106 185 117 101 179 115 98 168

North Africa / Middle East

North Africa / Middle East 228 217 263 197 183 214 189 171 204

South Asia

Asia, South 143 133 165 166 137 178 162 133 186

Sub-Saharan Africa

Sub-Saharan Africa, Southern 122 93 134 76 69 96 77 68 96

Sub-Saharan Africa, East 79 65 87 61 55 76 60 54 77

Sub-Saharan Africa, Central 112 84 134 103 84 124 112 91 135

Sub-Saharan Africa, West 52 47 69 60 54 73 63 56 77

GBD indicates Global Burden of Diseases, Injuries, and Risk Factors; and IHD, ishemic heart disease.

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increase in age-standardized IHD mortality between 1990 and 2010 occurred in East Asian males (38% increase), although the absolute rate remained comparatively low. On average, IHD deaths occurred at the youngest ages in North Africa/Middle East, South Asia, and sub-Saharan Africa (Figure 4).

Eastern Europe/Central Asia experienced steep increases in the age-standardized IHD death rate after 1990 (around the time of the breakup of the Soviet Union); age-standardized rates there declined starting in the mid-2000s (Figure 3).

Among the high-income regions, age-standardized IHD mortality rates decreased most in Australasia (≈51% decrease from 1990 to 2010), Western Europe (46% decrease), and North America (43% decrease; Tables 1 and 2). The lowest age-standardized IHD mortality rates over the period 1980 to 2010 were observed in the sub-Saharan Africa, Andean Latin America, and Asia/Pacific regions.

Regional totals of YLL attributable to IHD were highest in regions with larger populations, high IHD mortality rates, and younger average age at IHD death. The highest YLL in all years

was observed in South Asia (a 72% increase since 1990), fol-lowed by Eastern Europe (Table 3, Table VI in the online-only Data Supplement). Despite having among the lowest IHD death rates in the world, East Asia ranked third in IHD YLL in 2010 and has experienced the largest proportional increase in YLL since 1990 (78% higher) because of its large and aging popula-tion. Driven both by lower IHD death rates and older average age at IHD death, the most remarkable decreases in YLL from 1990 to 2010 occurred in the high-income regions of Australasia (34% decrease) and Western Europe (32% decrease).

DiscussionIn the overall GBD study, IHD was the leading cause of death worldwide in 2010.1 Our analysis of IHD mortality trends found that global age-standardized IHD mortality has declined since 1980. At the regional level, another, more complex story emerged: the age-standardized IHD death rate has declined steeply since 1980 in the Western, high-income regions, but has increased in Eastern Europe, Central Asia, South Asia, and

Table 2. Age-Standardized IHD Mortality per 100 000 Persons, by Region, Females, 1990, 2005, 2010, the Global Burden of Disease 2010 Study

Females

GBD 2010 Super Region 1990 2005 2010

GBD 2010 Region Mean Lower Upper Mean Lower Upper Mean Lower Upper

High income

Asia Pacific, high income 44 38 46 28 26 33 27 24 31

Europe, Western 96 85 99 58 56 71 51 49 65

Australasia 113 99 118 58 53 75 55 49 69

North America, high income 126 111 131 83 77 107 76 68 100

Latin America, Southern 84 78 90 62 59 76 58 54 70

Eastern Europe/Central Asia

Europe, Central 161 154 169 131 123 139 117 110 125

Europe, Eastern 224 216 246 272 245 284 235 209 245

Asia, Central 243 238 262 254 241 265 225 213 242

Latin America/Caribbean

Latin America, Tropical 105 95 111 78 73 91 73 68 88

Latin America, Central 86 79 94 77 69 82 74 68 82

Latin America, Andean 72 63 80 60 54 69 55 49 64

Caribbean 133 122 139 116 111 133 112 105 150

East Asia/Pacific

Asia, Southeast 76 69 84 70 65 90 68 63 86

Asia, East 52 46 79 60 45 65 57 40 65

Oceania 79 57 137 86 63 140 87 63 137

North Africa / Middle East

North Africa / Middle East 155 148 173 134 123 143 123 114 131

South Asia

Asia, South 109 98 131 112 89 124 106 86 120

Sub-Saharan Africa

Sub-Saharan Africa, Southern 74 55 83 57 49 76 52 43 72

Sub-Saharan Africa, East 59 45 65 49 42 55 47 41 55

Sub-Saharan Africa, Central 86 67 104 80 65 96 83 68 100

Sub-Saharan Africa, West 62 53 79 59 49 75 59 49 77

GBD indicates Global Burden of Diseases, Injuries, and Risk Factors; and IHD, ishemic heart disease.

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East Asia. Reflecting its large population and relatively young average age at IHD death, the South Asia region had the high-est number of life-years lost to premature IHD deaths.

An IHD epidemic emerged in Eastern Europe and Central Asia after the breakup of the Soviet Union in the early 1990s: this group of regions has had by far the highest crude and age- standardized IHD death rates of any region. Eastern Europe and Central Asia regions experienced a combined 21 million YLL in 2010 because of IHD, second only to South Asia, despite having less than a fifth of South Asia’s population. The

reasons for high IHD death rates in the Eastern Europe region are under debate: peak IHD death-rate years have coincided with economic downturns, and the greatest fluctuations have occurred in the nonmyocardial infarction (ie, cardiac arrest, atherosclerotic heart disease, and other IHD) portion of IHD deaths.15 There is strong evidence that heavy alcohol exposure is the cause of many deaths ascribed to IHD in this region, although the causal pathway needs to be better defined.15,16

Perhaps most concerning are high age-standardized IHD death rates in regions like North Africa/Middle East and

Figure 3. Age-standardized ischemic heart disease mortality rate per 100 000 persons by super region and globally (A, males; B, females), 1980 to 2010, the Global Burden of Disease 2010 Study.

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South Asia where deaths occurred at younger ages on aver-age, meaning IHD deaths were more likely to occur in pro-ductive, working-age adults. This represents the greatest loss for families and national economies.7,17 In the over-all GBD 2010 study, regions such as South, Central, and East Asia; Central, Andean, and Tropical Latin America; and North Africa/Middle East stood out for having a dou-ble burden of YLL owing to cardiovascular and infectious diseases.

Dietary patterns have shifted worldwide in both high- and low-income regions to more consumption of edible oils, ani-mal fats, and sugar-sweetened beverages.18 Earlier adoption of unhealthy lifestyles and higher risk factor exposures at younger ages may, in part, explain the increasing incidence of IHD at younger ages in regions like South Asia.19,20 East Asia (composed mostly of China) was another region with an IHD mortality increase in our analysis: in an earlier GBD study analysis of cholesterol trends, East Asia was among the few

Figure 4. Average age at the time of IHD death by super region and globally (A, males; B, females), 1980 to 2010, the Global Burden of Disease 2010 Study. IHD indicates ischemic heart disease.

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regions that experienced an increase in mean cholesterol after 1980.21 However, not all IHD epidemics are the same; there are past examples of IHD mortality declines in the face of adverse cholesterol or tobacco trends.22 Our analysis shows that, at a global level, traditional risk factors like tobacco smoke, high cholesterol, and high blood pressure play a cen-tral role in explaining regional differences in IHD mortality rates. Because no causal direction was specified and patterns of alcohol use were not distinguished (ie, binge or heavy compared with moderate alcohol consumption), our analy-sis did not accurately characterize the association of alcohol consumption with IHD. Regional air pollution level was not a significant covariate in the IHD mortality models, but epi-demiological research has established air pollution as a risk factor for IHD,23 and its contribution will be explored in sub-sequent GBD analyses.

The association of lower regional economic and educa-tional status with higher IHD rates suggests that many regions are undergoing an epidemiological transition to higher IHD death rates often associated with economic development.

The populations of many of the transitioning regions (eg, South and East Asia, Latin America/Tropical [Brazil], and North Africa/Middle East) are enormous, and the continued development of these regions depends in part on successfully addressing the threat of cardiovascular disease. To succeed in stemming the tide of IHD mortality in younger adults in the 21st century, as many high-income regions did during the last decades of the 20th century, low- and middle-income regions may need to develop new approaches, emphasizing improved healthcare delivery infrastructure, universal health insurance and affordable essential medicines, and selected population- wide prevention interventions.24,25 Along with the public health community’s emphasis on prevention, the impact of improved access to acute cardiac care should not be forgot-ten. Aspirin and a β-blocker for all acute myocardial infarc-tions and revascularization using low-cost thrombolytic for ST-elevation myocardial infarctions are often life-saving and may be affordable in low-resource settings.26

The strengths of this analysis of global trends in IHD mor-tality were the collection of a comprehensive set of national

Table 3. Years of Life Lost Owing to IHD, Males And Females, by Region, 1990, 2005, and 2010, the Global Burden of Disease 2010 Study

GBD 2010 Super Region 1990 2005 2010

GBD 2010 Region Mean Lower Upper Mean Lower Upper Mean Lower Upper

High income

Asia Pacific, high income 1 798 146 1 620 244 1 900 184 1 812 636 1 692 038 2 018 899 1 920 451 1 752 565 2 116 832

Europe, Western 12 860 688 11 929 341 13 404 064 8 807 634 8 566 677 9 942 095 8 428 017 8 135 515 9 554 209

Australasia 615 515 569 455 632 471 405 899 388 773 462 917 419 557 392 876 482 962

North America, high income 9 769 603 9 109 634 10 256 781 8 060 007 7 735 522 9 068 844 7 825 615 7 351 893 8 948 068

Latin America, Southern 952 977 904 836 1 037 283 933 315 898 505 1 032 393 945 652 905 779 1 055 796

Eastern Europe/Central Asia

Europe, Central 5 597 369 5 242 998 5 831 784 5 089 778 4 920 576 5 468 643 4 835 548 4 650 986 5 210 929

Europe, Eastern 13 363 422 13 020 191 14 332 364 21 395 103 19 746 998 22 075 817 17 671 525 16 219 642 18 315 709

Asia, Central 2 434 441 2 366 917 2 603 885 3 358 046 3 149 985 3 497 223 3 344 003 3 095 362 3 565 863

Latin America/Caribbean

Latin America, Tropical 2 341 808 2 193 945 2 534 789 2 779 536 2 657 763 3 083 571 3 015 732 2 872 578 3 380 191

Latin America, Central 1 762 410 1 637 594 1 905 648 2 366 529 2 129 444 2 484 887 2 827 557 2 550 462 3 012 726

Latin America, Andean 312 129 293 583 351 584 426 970 358 663 456 209 437 785 377 164 474 416

Caribbean 694 309 647 297 739 747 759 499 733 454 832 392 839 991 797 218 1 046 637

East Asia/Pacific

Asia, Southeast 4 818 933 4 360 138 5 246 287 6 704 804 6 383 138 7 672 710 7 765 379 7 361 080 8 864 297

Asia, East 9 449 260 8 689 819 12 168 368 15 493 412 13 436 409 16 405 168 16 795 598 13 989 156 17 913 060

Oceania 71 723 61 923 98 564 107 351 90 631 150 617 122 337 102 152 165 558

North Africa / Middle East

North Africa / Middle East 6 521 855 6 049 947 7 091 033 7 995 777 7 402 525 8 517 971 8 822 768 7 968 594 9 343 464

South Asia

Asia, South 17 300 420 16 157 871 19 323 777 27 628 587 23 082 187 29 334 998 29 759 902 24 854 218 33 295 998

Sub-Saharan Africa

Sub-Saharan Africa, Southern 439 982 351 244 477 998 531 476 491 026 653 461 514 823 468 185 632 563

Sub-Saharan Africa, East 1 414 599 1 148 746 1 545 838 1 628 544 1 446 234 1 803 904 1 781 311 1 600 930 2 000 006

Sub-Saharan Africa, Central 508 418 404 775 597 259 666 283 576 079 770 551 805 163 697 096 940 718

Sub-Saharan Africa, West 1 492 723 1 274 743 1 714 206 1 890 019 1 683 958 2 126 861 2 146 457 1 913 551 2 462 752

GBD indicates Global Burden of Diseases, Injuries, and Risk Factors; and IHD, ishemic heart disease.

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Moran et al Global IHD Mortality Trends, 1980–2010 1491

mortality data from a variety of sources, adjustments for biases introduced by ICD version changes and for death reg-istration coding practices, and methods for accounting for and describing covariate parameter and statistical model selection uncertainty. Limitations of the analysis include incomplete data for many regions, especially sub-Saharan Africa, and the ecological nature of the associations found between covari-ates and IHD mortality. Unexpectedly, diabetes mellitus con-tributed more to male models than to female models, findings that may be explained by the inclusion of nontraditional IHD predictor covariates in the models that absorbed some of these covariates’ effects, or differential competing risk with other causes of death in males in comparison with females.

ImplicationsThe decline in IHD mortality in high-income regions since 1980 is a success story. More troubling are the very high IHD mortality rates in Eastern Europe and Central Asia in 2010, and increased IHD mortality occurring in relatively young adults in South Asia. IHD prevention in the 21st century must extend the control of established risk factors from high- income to low- and middle-income regions while addressing newer social and behavioral determinants of IHD mortality observed in developing regions.

Acknowledgments We sincerely thank the many study participants and investigators of the studies contributing data to this analysis.

Sources of FundingThis research was supported by the Bill and Melinda Gates Foundation, an American Heart Association Postdoctoral Fellowship to Dr Roth, and US National Heart, Lung, and Blood Institute award K08 HL089675-01A1, and a Columbia University Irving Scholarship to Dr Moran.

DisclosuresThe perspectives expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of Health, Department of Health and Human Services, or any other gov-ernment entity.

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CLINICAL PERSPECTIvEIschemic heart disease (IHD) leads to lost life-years and disability in high-, middle-, and lower-income regions and is the world’s leading cause of death. Monitoring the trends in IHD mortality in diverse world regions requires analyzing a variety of data sources and using statistical modeling that accounts for sparse data in some regions. The Global Burden of Disease 2010 Study estimated IHD mortality in 21 world regions. Since 1980, age-standardized IHD mortality has declined in most world regions, particularly high-income regions. During the same period, age-standardized IHD mortality increased in Eastern Europe, Central Asia, and South Asia. When estimated by using a standard method, age-standardized IHD mortality has trended favorably in most regions since 1980, but unfavorably in a few others. The causes of rising rates in IHD hot-spot regions merit more detailed investigation. Prevention and acute care quality improvements are needed in low- and middle- income regions, where IHD patients die at relatively young ages.

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1

Supplemental Material

Supplemental Methods:

Cause of Death Ensemble Model (CODEm) methods.

Here we summarize ensemble modeling and CODEm methods; interested readers can access more detailed

information about the CODEm method and ensemble modeling elsewhere.1

In brief, ensemble models combine predictions of multiple individual models. Ensemble models estimated

in a variety of fields have demonstrated smaller prediction error than the best individual model. Another

advantage of ensemble models is that they capture not only input parameter uncertainty, but also

uncertainty stemming from model specification. In order to combine predictions from multiple models

(varying in model form, outcome definition, and covariate selection), individual model results are usually

weighted before averaging to produce ensemble estimates.

CODEm worked with two main model forms: linear mixed effects models and spatial-temporal models.

Linear mixed effects models assumed fixed effects of covariates, and hierarchical random effects by super-

region, region, country, and age. Spatial-temporal models begin with the mixed effects models, but

remove the random country effect, instead calculating residuals (predicted – observed estimate) and

performing local regressions on nearby data (in the dimensions of country (“space”) and time (year).

Gaussian Process Regression was used to carry forward sampling and non-sampling variance in the source

data. Two types of dependent cause of death variables were used: mortality rates and “cause fraction”

(e.g., proportion of IHD mortality in all-cardiovascular disease mortality or all-cause mortality). The two

model forms (mixed effects linear models and spatial-temporal models) and two outcome definitions (rate

and cause fraction) led to four model “families” (four combinations of form and outcome) contributing to

ensemble models.

Covariates were added stepwise to models, in order of a prior literature-based assumptions about causal

association and strength of association, and kept in models if the covariate showed estimated direction of

association and if the multivariate covariate coefficient was significant at the <0.05 level.

Biological/physiological covariates (e.g., country mean blood pressure or cholesterol), behavioral covariates

(country mean dietary consumption and physical activity level) and contextual covariates (e.g., mean

education level, per capita income, and health system access) were examined.2 A complete list of

covariates contributing to the IHD mortality models is available elsewhere.3 Multiple models were

developed from combinations of covariate sets in all four model families. We decided to apply more

2

weight to predictions from models that performed better out-of-sample, using monotonically declining

weights based on the model’s performance rank.

Supplemental References

1. Foreman KJ, Lozano R, Lopez AD, Murray CJ. Modeling causes of death: An integrated approach using codem. Population health metrics. 2012;10:1

2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095-2128

3. Forouzanfar MH, Moran AE, Flaxman AD, Roth G, Mensah GA, Ezzati M, Naghavi M, Murray CJ. Assessing the global burden of ischemic heart disease, part 2: Analytic methods and estimates of the global epidemiology of ischemic heart disease in 2010. Glob Heart. 2012;7:331-342

Supplemental Table 1: Site-years by decade and source type for the GBD 2010 Study IHD mortality

analysis.

Source Type 1980-1989 1990-1999 2000-2011

Surveillance 0 27 24

Verbal autopsy 14 23 40

Vital Registration 808 966 940

3

Supplemental Table 2: Site-years by GBD 2010 region for the IHD mortality analysis.

GBD Super Region GBD Region Site-years of IHD mortality data

High Income

Asia Pacific, High Income 92

Europe, Western 605

Australasia 56

North America, High Income 60

Latin America, Southern 87

Eastern Europe/Central Asia

Europe, Central 274

Europe, Eastern 194

Asia, Central 186

Latin America/Caribbean

Latin America, Tropical 59

Latin America, Central 218

Latin America, Andean 56

Caribbean 409

East Asia/Pacific

Asia, Southeast

144

Asia, East

71

Oceania

15

North Africa / Middle East 136

South Asia 54

Sub-Saharan Africa

Sub-Saharan Africa, Southern

102

Sub-Saharan Africa, East

18

Sub-Saharan Africa, Central

0

Sub-Saharan Africa, West

8

4

Supplemental Table 3: Increase in IHD deaths due to allocation of specific ill-defined or “undefined-

coded” deaths to IHD, and proportion of deaths coded to specific codes assigned to IHD.

Disease/ICD code pertinent to undefined code

Percent increase in IHD

death due to assignment

of each undefined code (

21.5% total increase)

Percent proportion of

each of undefined codes

assigned to IHD

Some ill-defined from R00-R99 3.4% 13.8%

Hypertension 3.1% 47.2%

R54: Senility 2.9% 20.6%

All cardiac conduction disorders 2.4% 89.9%

Atherosclerosis 2.4% 40.0%

All ill-def. descriptions of heart disease 1.8% 47.3%

DIC, Cardiac arrest ,Acute respiratory failure and

Coma 1.7% 25.6%

I50: Heart failure 1.5% 76.9%

J81: Pulmonary oedema 0.5% 76.3%

All encephalopathy and Cerebral oedema 0.5% 66.8%

Embolism & thrombosis 0.3% 40.1%

Cardiogenic shock and other Shock 0.3% 55.2%

All disorders of electrolyte & fluid balance 0.2% 13.0%

I99:Oth. & unspec. disorders of circulatory system 0.2% 48.2%

Ill-defined (result of age and sex restriction) 0.1% 13.6%

Ill-defined: from M09-M99 0.1% 19.0%

Pneumonitis 0.1% 2.7%

Ill-defined: from N39.3-N97.8 0.1% 21.9%

Renal failure 0.1% 0.8%

Fever ,Malasia, Febrile and convulsions unknown

origin <0.5% 8.2%

Ill-defined: from F32-F99 <0.5% 16.3%

Cardiac sign and symptom <0.5% 70.7%

Ill-defined: from D10-D36.9 <0.5% 16.1%

Ill-defined: from G43-G58.9 <0.5% 14.6%

Different Paralytic syndrome and palsy syndrome <0.5% 2.2%

5

Ill-defined: from L01-L98.9 <0.5% 15.9%

Unspecified liver disease <0.5% 0.9%

Ill-defined: from H00-H99 <0.5% 14.4%

Ill-defined: from K00-k14.9 <0.5% 17.9%

Ill-defined: from A00-B99 <0.5% 14.2%

Ill-defined: from Q10-Q84.9 <0.5% 4.7%

Ill-defined: from J30-J35.9 <0.5% 11.2%

Undefined ICD code <0.5% 31.6%

All unspecified parasitic diseases <0.5% 0.1%

Supplemental Table 4: Global Burden of Disease, Injuries and Risk Factors 2010 Study Region and

Country List.

Super Region Region

Country

East Asia/Pacific

Asia, East China

Korea, Democratic People's

Republic of

Taiwan

Asia, Southeast Cambodia

Indonesia

Lao People's Democratic

Republic

Malaysia

Maldives

Myanmar

Philippines

Sri Lanka

Thailand

Timor-Leste

6

Viet Nam

Oceania Fiji

Kiribati

Marshall Islands

Micronesia, Federated States of

Papua New Guinea

Samoa

Solomon Islands

Tonga

Vanuatu

Eastern Europe/Central Asia

Asia, Central Armenia

Azerbaijan

Georgia

Kazakhstan

Kyrgyzstan

Mongolia

Tajikistan

Turkmenistan

Uzbekistan

Albania

Europe, Central Bosnia and Herzegovina

Bulgaria

Croatia

Czech Republic

Hungary

Macedonia, the Former Yugoslav

Republic of

Montenegro

Poland

Romania

7

Serbia

Slovakia

Slovenia

Europe, Eastern Belarus

Estonia

Latvia

Lithuania

Moldova

Russian Federation

Ukraine

High Income

Asia Pacific, High Income Brunei Darussalam

Japan

Korea, Republic of

Singapore

Australasia Australia

New Zealand

Europe, Western Andorra

Austria

Belgium

Cyprus

Denmark

Finland

France

Germany

Greece

Iceland

Ireland

Israel

Italy

Luxembourg

Malta

8

Netherlands

Norway

Portugal

Spain

Sweden

Switzerland

United Kingdom

Latin America, Southern Argentina

Chile

Uruguay

North America, High

Income Canada

United States

Latin America/Caribbean

Caribbean Antigua and Barbuda

Bahamas

Barbados

Belize

Cuba

Dominica

Dominican Republic

Grenada

Guyana

Haiti

Jamaica

Saint Lucia

Saint Vincent and the

Grenadines

Suriname

Trinidad and Tobago

Latin America, Andean Bolivia

Ecuador

9

Peru

Latin America, Central Colombia

Costa Rica

El Salvador

Guatemala

Honduras

Mexico

Nicaragua

Panama

Venezuela

Latin America, Tropical Brazil

Paraguay

North Africa / Middle East

North Africa / Middle East Algeria

Bahrain

Egypt

Iran, Islamic Republic of

Iraq

Jordan

Kuwait

Lebanon

Libyan Arab Jamahiriya

Morocco

Occupied Palestinian Territory

Oman

Qatar

Saudi Arabia

Syrian Arab Republic

Tunisia

Turkey

United Arab Emirates

Yemen

10

South Asia

Asia, South Afghanistan

Bangladesh

Bhutan

India

Nepal

Pakistan

Sub-Saharan Africa

Sub-Saharan Africa, Central Angola

Central African Republic

Congo

Congo, the Democratic Republic

of the

Equatorial Guinea

Gabon

Sub-Saharan Africa, East Burundi

Comoros

Djibouti

Eritrea

Ethiopia

Kenya

Madagascar

Malawi

Mauritius

Mozambique

Rwanda

Seychelles

Somalia

Sudan

Tanzania, United Republic of

Uganda

Zambia

Sub-Saharan Africa, Southern Botswana

11

Lesotho

Namibia

South Africa

Swaziland

Zimbabwe

Sub-Saharan Africa, West Benin

Burkina Faso

Cameroon

Cape Verde

Chad

Cote d'Ivoire

Gambia

Ghana

Guinea

Guinea-Bissau

Liberia

Mali

Mauritania

Niger

Nigeria

Sao Tome and Principe

Senegal

Sierra Leone

Togo

12

Supplemental Table 5: Annual IHD deaths, males and females, by region, 1980-2010, the Global Burden of Disease 2010 Study

Year 1980 1985 1990 1995 2000 2005 2010

Asia Pacific, High Income

102,725

109,964

113,347

119,074

127,826

142,299

166,853

Europe, Western 970,818

970,646

929,366

885,249

831,709

745,285

745,590

Australasia 41,780

43,058

42,128

40,280

36,551

34,436

37,738

North America, High Income

726,848

739,737

703,057

685,624

655,069

613,831

619,377

Europe, Central 281,482

309,389

331,497

346,890

334,231

340,145

344,139

Latin America, Southern

55,206

55,958

56,753

55,837

60,488

61,990

65,106

Europe, Eastern 741,533

800,386

834,783

1,079,003

1,125,919

1,219,386

1,115,213

Asia, East 359,016

416,822

472,158

604,981

787,789

873,827

992,163

Latin America, Tropical

94,861

106,649

111,338

125,006

134,071

146,546

166,596

Latin America, Central

68,099

75,836

91,521

106,884

121,056

137,658

166,532

Asia, Southeast 140,306

166,005

215,719

262,910

292,138

325,325

383,323

Asia, Central 119,401

125,561

138,157

168,986

167,981

179,638

184,167

Latin America, Andean

11,409

13,599

15,575

16,870

19,425

21,917

24,350

North Africa / Middle East

205,187

226,276

263,978

307,579

336,802

371,325

418,019

Caribbean 29,407

34,962

40,315

46,384

47,019

49,183

54,576

Asia, South 433,832

500,273

704,833

915,207

1,090,272

1,186,987

1,323,551

13

Oceania 1,604

1,980

2,552

3,027

3,377

3,949

4,581

Sub-Saharan Africa, Southern

16,883

18,131

20,094

22,420

22,275

22,721

24,103

Sub-Saharan Africa, East

42,241

47,965

54,706

59,459

60,780

66,701

75,673

Sub-Saharan Africa, Central

15,508

17,923

20,272

22,699

24,269

27,481

33,306

Sub-Saharan Africa, West

37,140

42,668

49,641

56,603

66,515

72,152

84,315

14

Supplemental Table 6: Years of life lost (YLL) due to IHD, males and females, by region, 1980-2010, the Global Burden of Disease 2010 Study

Year 1980 1985 1990 1995 2000 2005 2010

Asia Pacific, High Income

1,878,938

1,917,315

1,798,146

1,737,100

1,762,044

1,812,636

1,920,451

Europe, Western 14,926,890

14,170,528

12,860,688

11,636,179

10,352,545

8,807,634

8,428,017

Australasia 702,407

676,014

615,515

542,832

461,622

405,899

419,557

North America, High Income

11,282,204

10,796,930

9,769,603

9,285,417

8,665,142

8,060,007

7,825,615

Europe, Central 4,825,839

5,233,820

5,597,369

5,724,146

5,306,431

5,089,778

4,835,548

Latin America, Southern

1,045,640

984,106

952,977

918,531

965,586

933,315

945,652

Europe, Eastern 12,195,199

12,864,701

13,363,422

19,080,796

19,691,217

21,395,103

17,671,525

Asia, East 7,514,092

8,485,632

9,449,260

11,905,005

14,940,087

15,493,412

16,795,598

Latin America, Tropical

2,148,570

2,308,880

2,341,808

2,542,240

2,669,026

2,779,536

3,015,732

Latin America, Central

1,440,409

1,546,425

1,762,410

2,025,428

2,188,620

2,366,529

2,827,557

Asia, Southeast 3,194,862

3,774,990

4,818,933

5,720,044

6,153,507

6,704,804

7,765,379

Asia, Central 2,038,453

2,110,414

2,434,441

3,126,687

3,140,725

3,358,046

3,344,003

Latin America, Andean

244,027

283,086

312,129

328,017

386,016

426,970

437,785

North Africa / Middle East

5,254,483

5,639,548

6,521,855

7,338,169

7,613,176

7,995,777

8,822,768

Caribbean 561,395

639,033

694,309

741,590

737,508

759,499

839,991

Asia, South 10,961,439

12,583,981

17,300,420

21,750,749

25,316,742

27,628,587

29,759,902

15

Oceania 45,732

55,796

71,723

85,162

93,788

107,351

122,337

Sub-Saharan Africa, Southern

380,082

402,485

439,982

501,979

525,788

531,476

514,823

Sub-Saharan Africa, East

1,095,487

1,239,823

1,414,599

1,551,138

1,554,534

1,628,544

1,781,311

Sub-Saharan Africa, Central

395,017

450,581

508,418

560,763

597,068

666,283

805,163

Sub-Saharan Africa, West

1,138,204

1,293,544

1,492,723

1,723,077

1,858,139

1,890,019

2,146,457

Totals 83,269,368

87,457,630

94,520,731

108,825,050

114,979,311

118,841,204

121,025,168

16

Supplemental Figure 1a. Males: Crude Ischemic Heart Disease Mortality Rate per 100,000 persons by Super Region and Globally, 1980-2010, the Global Burden of Disease 2010 Study.

17

Supplemental Figure 1b. Females: Crude Ischemic Heart Disease Mortality Rate per 100,000 persons by Super Region and Globally, 1980-2010, the Global Burden of Disease 2010 Study.