Sex and Racial Disparities in Proportionate Mortality of Premature Myocardial Infarction in the United States: 1999 to 2020

Abstract

Background

The incidence of premature myocardial infarction (PMI) in women (<65 years and men <55 years) is increasing. We investigated proportionate mortality trends in PMI stratified by sex, race, and ethnicity.

Methods and Results

CDC WONDER (Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research) was queried to identify PMI deaths within the United States between 1999 and 2020, and trends in proportionate mortality of PMI were calculated using the Joinpoint regression analysis. We identified 3 017 826 acute myocardial infarction deaths, with 373 317 PMI deaths corresponding to proportionate mortality of 12.5% (men 12%, women 14%). On trend analysis, proportionate mortality of PMI increased from 10.5% in 1999 to 13.2% in 2020 (average annual percent change of 1.0 [0.8–1.2, P <0.01]) with a significant increase in women from 10% in 1999 to 17% in 2020 (average annual percent change of 2.4 [1.8–3.0, P <0.01]) and no significant change in men, 11% in 1999 to 10% in 2020 (average annual percent change of −0.2 [−0.7 to 0.3, P=0.4]). There was a significant increase in proportionate mortality in both Black and White populations, with no difference among American Indian/Alaska Native, Asian/Pacific Islander, or Hispanic people. American Indian/Alaska Natives had the highest PMI mortality with no significant change over time.

Conclusions

Over the last 2 decades, there has been a significant increase in the proportionate mortality of PMI in women and the Black population, with persistently high PMI in American Indian/Alaska Natives, despite an overall downtrend in acute myocardial infarction–related mortality. Further research to determine the underlying cause of these differences in PMI mortality is required to improve the outcomes after acute myocardial infarction in these populations.

Nonstandard Abbreviations and Acronyms

AAMR

age‐adjusted mortality rates

AAPC

average annual percent change

PMI

premature myocardial infarction

Clinical Perspective.

What Is New?

• In this national cross‐sectional study, despite the overall declining rates of acute myocardial infarction (MI) mortality, mortality due to premature MI has increased in the United States.

• There were significant racial and sex differences, with increasing premature MI death trends in the White female and Black female populations.

• We also noted persistently high premature MI mortality in American Indian/Alaska Native populations with no improvement over the past 2 decades.

What Are the Clinical Implications?

• Our study suggests that despite notable improvements in therapeutic and secondary preventative measures for treating acute MI, significant demographic inequities exist in premature MI outcomes.

• These findings require urgent public health efforts to address the raging issue.

For decades, cardiovascular disease (CVD) has remained the leading cause of mortality in the United States, with coronary artery disease (CAD) being the most common form of CVD. ¹ , ² In 2020 alone, >900 000 CVD‐related deaths were reported in the United States. ³ Significant improvements in medical therapies for CAD prevention, effective revascularization strategies in acute myocardial infarction (AMI), and preventative efforts to reduce modifiable CVD risk factors have led to breakthrough achievements in reducing the mortality rate due to CAD by more than half since 1980. ⁴ , ⁵ Unfortunately, this phase of rapid deceleration in mortality rates for AMI appears to have stalled in the past decade. While the elderly population received the largest beneficial impact with a steep decline in cardiovascular mortality, there has been a noted deceleration in mortality in the premature CAD group (<65 years in women, <55 years in men) since 2011. ⁶ , ⁷ , ⁸ Similarly, there has been a growing burden of CAD in younger women, with significant disparities in the management of CAD by sex and race. ⁴ A universal definition or diagnostic criteria for premature AMI has not been defined. Most registries and studies and the American College of Cardiology/American Heart Association prevention guidelines have utilized the age cut points of <55 years for first‐degree male relatives and <65 years for first‐degree female relatives to define premature CAD, and for this reason we choose this to define premature myocardial infarction (PMI) in our study. ⁷ , ⁸ Therefore, we sought to study the sex and racial differences in proportionate mortality trends due to PMI in the last 2 decades (1999–2020) using the National Center for Health Statistics death certificate database.

METHODS

We used the Centers for Disease Control and Prevention Wide‐ranging Online Data for Epidemiologic Research database from January 1999 to December 2020 to identify AMI‐related deaths in the United States. ⁹ , ¹⁰ The data are obtained from death certificates. Each death certificate contains a single underlying cause of death and up to 20 additional multiple causes, as well as limited patient‐level sociodemographic data. The underlying cause of death is defined as the “disease or injury which initiated the train of events leading directly to death,” while the multiple cause of death refers to comorbid conditions considered as contributing to death. For this study, we included AMI using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10) codes I21‐ I22 listed as multiple causes of death. The multiple causes of death data are compiled by the National Center for Health Statistics at the CDC. This database has been previously used in several other studies to analyze nationwide trends in CVD mortality. ¹¹ , ¹² Population estimates were extracted from the Census Bureau estimates of US national populations. The population estimates are US Census Bureau estimates of US national, state, and county resident populations. We obtained population estimates to analyze the overall rates of deaths related to AMI. Race and ethnicity were assessed in accordance with standards from the US Office of Management and Budget. Ethnicity was categorized as Hispanic, non‐Hispanic Black/African American, or non‐Hispanic White. Race was classified as American Indian or Alaskan Native, Asian/Pacific Islander, Black or African American, and White. Race and ethnicity information from the census are based on self‐identification. The Centers for Disease Control and Prevention Wide‐ranging Online Data for Epidemiologic Research database is anonymized and publicly available data, so the study was exempt from the informed consent and institutional review board. Although there has been no universally described definition of PMI, we used a similar criterion described in other studies with a cut‐off of <65 years in women and <55 years in men to assess PMI mortality. ¹³ We followed STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies and the American Heart Association's disparities guidelines checklist as described in Tables S1 and S2, respectively. The authors declare that all supporting data are available within the article and its online supplementary files.

The proportionate mortality of PMI was calculated by the total number of PMI‐related deaths divided by the total number of AMI deaths reported in that year. PMI‐related crude and age‐adjusted mortality rates (AAMR) were also calculated. Crude mortality rates were calculated by dividing the PMI‐related deaths by the corresponding US population. AAMR was calculated based on the year 2000 estimated US population distribution. ¹⁴ All AAMRs are reported as per 100 000. Stata software version 17.0 (StataCorp LP, College Station, TX) and the Joinpoint regression program (version 4.9.1.0; National Cancer Institute) were used to assess trends in PMI‐related mortality. ¹⁵ We determined the temporal trends in PMI‐related mortality by using log‐linear regression models, ensuring linear segments with consistent rate changes. We applied joinpoint segmented regression based on published methodological guidelines to identify inflection points in the temporal trends of PMI‐related mortality from 1999 to 2020. ¹⁶ , ¹⁷ The temporal trends observed in our study remain unadjusted because the data lack covariates. For data containing 22 to 26 time points, the guidelines recommend that the analysis identify a maximum of 4 joinpoints across the study period. In the current investigation, 22 years were included; therefore, the joinpoint regression statistical software was set to determine a maximum of 4 joinpoints where significant temporal variation existed in the trend. The software suggested best‐fit models with corresponding joinpoints. Therefore, zero to a maximum of 4 joinpoints were allowed to be identified. Joinpoint allows the use of grid search. The grid search method has a finite number of discrete locations that are tested to find the best model fit. The Grid Search method (2, 2, 0), permutation test, and parametric method were used to estimate annual percent change and 95% CIs. ¹⁸ The average annual percent change (AAPC) over 22 years was then calculated using a weighted average of the slope coefficients of the underlying joinpoint regression line with weights equal to the length of each segment divided by 22. AAPC was considered increasing or decreasing if the slope describing the change in proportionate mortality differed from 0 using a 2‐tailed t test with P values <0.05 considered statistically significant. Analyses were further stratified by race, sex, and Hispanic origin.

RESULTS

Between 1999 and 2020, a total of 3 017 826 AMI‐related deaths occurred. Of these, 373 317 were PMI‐related deaths (Figure 1). This corresponds to proportionate mortality of 12.5% (Table and Figure S1) The crude and AAMR of overall AMI‐related deaths showed a substantial decreased trends throughout the study period in both men (crude, 76.14 [75.68–76.61]) in 1999 to 40.14 (39.84–40.45) in 2020; AAMR, 96.083 (95.49–96.68) in 1999 to 35.45 (35.17–35.72) in 2020] and women (crude, 66.99 [66.57–67.42] in 1999 to 32.51 (32.23–32.79) in 2020; AAMR, 56.32 [55.96–56.68] in 1999 to 24.93 [24.71–25.15] in 2020) (Table S3). While the total number of PMI‐related deaths per year decreased during the study period (20 969 deaths in 1999 to 14 446 deaths in 2020), trend analysis showed an overall increased proportionate mortality of PMI from 10.5% in 1999 to 13.2% in 2020 with an AAPC of 1.0 (0.8–1.2, P<0.01). (Table S4) The increased proportionate mortality of PMI was primarily seen during the initial years from 1999 to 2006 and, after that, remained stable until the end of the study period by 2020 (Figure S1).

Figure 1. Yearly trends of AMI‐ and PMI‐related deaths during 1999 to 2020.

AMI indicates acute myocardial infarction; and PMI, premature myocardial infarction.

Table 1.

Proportionate Mortality of Premature Myocardial Infarction Stratified by Sex, Race, and Ethnicity During 1999 to 2020

	American Indian or Alaska Native n=88 362 592	Asian or Pacific Islander n=371 914 051	Black n=919 034 937	White n=5 367 000 000	Hispanic n=1 077 280 338	Total n=6 746 200 000
Overall trends in different races
Overall AMI deaths (n)	14 055	58 120	318 009	2 627 642	157 869	3 017 826
Overall PMI deaths (n)	3211	7018	65 925	297 163	24 058	373 317
Overall proportional mortality of PMI	23%	12%	21%	11%	15%	12.5%
Proportional mortality from 1999 to 2020	19.8% to 21.7%	12% to 12%	18% to 21%	10% to 12%	14% to 15%	10.5% to 13.2%
AAPC from 1999 to 2020	0 (95% CI −0.9 to 0.8), P=0.9	−0.1 (95% CI −0.5 to 0.3), P=0.7	0.6 (95% CI 0.4 to 0.9); P <0.01	1 (95% CI 0.5 to 1.4), P <0.01	0.3 (95% CI −0.4 to 1.0), P=0.4	1.0 (95% CI 0.8 to 1.2), P <0.01
Sex‐based trends in different races
Men	21%	13%	18%	11%	15%	12%
Men proportional mortality trends	18.5 to 18.3%	12% to 12%	17% to 17%	10% to 9%	14% to 14%	11% to 10%
AAPC proportional mortality male	−0.8 (95% CI −1.4 to −0.1), P=0.01	0 (95% CI −0.5 to 0.5), P=0.8	0 (95% CI −0.4 to 0.4), P=0.9	−0.4 (95% CI −0.8 to 0.1), P=0.1	0.2 (95% CI −0.3 to 0.7), P=0.4	−0.2 (95% CI −0.7 to 0.3), P=0.4
Female	26%	11%	24%	13%	16%	14%
Female proportional mortality trends	22% to 27%	13% to 12%	20% to 27%	9% to 16%	15% to 17%	10% to 17%
AAPC proportional mortality female	0.7 (95% CI, −0.1 to 1.5), P=0.06	−0.2 (95% CI, −0.7 to 0.4), P=0.06	1.4 (95% CI, 1.2 to 1.6), P <0.01	2.6 (95% CI, 1.8 to 3.3), P <0.01	1.1 (95% CI, 0.4 to 1.8) P=0.002	2.4 (95% CI, 1.8 to 3.0), P <0.01

AAPC indicates average annual percent change; AMI, acute myocardial infarction; and PMI, premature myocardial infarction.

Trends in PMI‐Related Mortality By Sex

Overall proportionate mortality of PMI was higher in women than men (14% versus 12%). There was a steady increase in proportionate mortality throughout the study period from 10% in 1999 to 17% in 2020 in women with an AAPC of 2.4 (1.8– 3.0, P <0.01). There was an initial increase in the trend of proportionate mortality in men until 2005, then had a gradual decline in later years with no significant overall change during the study period (11% in 1999 to 10% in 2020, AAPC −0.2 [−0.7 to 0.3, P=0.4]). (Figure 2, Table, and Table S5).

Figure 2. Yearly proportionate mortality trends of PMI in men and women during 1999 to 2020.

PMI indicates premature myocardial infarction.

Trends in PMI‐Related Mortality By Race and Ethnicity

There was a significant increase in proportionate mortality of PMI‐related deaths in Black people (18% in 1999 to 21% in 2020, AAPC of 0.6 [0.4–0.9]; P <0.01), White people (10% in 1999 to 12% in 20 201 AAPC of 1 [0.5–1.4], P <0.01) and non‐Hispanic people (10% in 1999 to 13% in 2020, AAPC of 1 [0.8–1.2], P <0.01) with no statistical difference in PMI mortality among American Indian/Alaskan Native people, Asian/Pacific Islander people, and Hispanic people between 1999 and 2020. (Figures 3, 4, 5, Table, and Tables S6–S8). Further stratification based on sex showed a significant increase in the proportionate mortality of PMI in the respective female populations of Black women [20%–27%, AAPC of 1.4 (1.2–1.6, P <0.01)], White women (9%–16%, AAPC 2.6 [1.8–3.3, P <0.01]), Hispanic women [15%–17%, AAPC of 1.1 (0.4–1.8, P <0.01)] and non‐Hispanic women (10%–17%, AAPC of 2.5 [95% CI, 1.9–3.2]; P <0.01]. White women have a significantly higher AAPC of 2.6 compared with Black women (1.4) and Hispanic women (1.1). There was a trend towards an increase in proportionate mortality of PMI in the American Indian/Alaskan Native female population, but it was not statistically significant [22%–27%, AAPC of 0.7 (0.1–1.5, P=0.06)]. There was a significant increase in the American Indian/Alaskan Native male population (18.5%–18.3%, AAPC of −0.8 [1.4 to −0.1]; P=0.01). In contrast to other races, the Asian or Pacific Islander population had a higher proportionate mortality of PMI in men (13%) than in women (11%). There remained no significant difference in the trends of PMI proportionate mortality in the respective male populations of all races and ethnicities (Table, Figure 5, Tables S9–S14). Figure 6 illustrates the temporal trends of proportional mortality of PMI in the United States between 1999 and 2020.

Figure 3. Yearly proportionate mortality trends of PMI by race: 1999 to 2020.

PMI indicates premature myocardial infarction.

Figure 4. Yearly proportionate mortality trends of PMI in Hispanic people and non‐Hispanic people during 1999 to 2020.

PMI indicates premature myocardial infarction.

Figure 5. Yearly proportionate mortality trends of PMI among all races and ethnicities stratified by sex during 1999 to 2020.

A, White people, (B) Black people, (C) Asian people, (D) American Indian people, (E) Hispanic people, and (F) non‐Hispanic people. PMI indicates premature myocardial infarction.

Figure 6. Temporal trends of proportional mortality of PMI in the United States between 1999 and 2020.

AAPC indicates average annual percentage change; AMI, acute myocardial infarction; and PMI, premature myocardial infarction.

DISCUSSION

Our study provides the most contemporary data on mortality trends due to PMI with considerable sex and racial variations during the years 1999 to 2020 in the United States. The principal findings of our study were (1) During the years 1999 to 2020 there was a steady decline in mortality due to AMI; however, proportionate mortality due to PMI has increased from 10.5% in 1999 to 13.2% in 2022; (2) The proportionate mortality due to PMI increased in women from 10% in 1999 to 17% in 2020 with no significant increase in PMI in men; (3) The most significant increase in PMI occurred in the Black and White female population; and (4) The PMI mortality rates are considerably higher in the American Indian/Alaskan Native and Black populations compared with other races.

Although the overall mortality due to AMI has consistently declined in the past 2 decades, we have demonstrated a significant increase in the proportionate mortality due to PMI. Previous studies have reported a similar pattern of stagnation or worsening premature AAMR due to cardiometabolic causes since 2011. ¹⁹ Data from Centers for Disease Control and Prevention Wide‐ranging Online Data for Epidemiologic Research showed that the rate of decline in CVD mortality has slowed across all age groups and increased among adults aged 55 to 64 by 4% from 2011 to 2017. ²⁰ In contrast, the elderly population continues to show a decline in mortality due to CVD, leading to an overall decline in CVD mortality and hence concealing age‐related demographic heterogeneity in CVD mortality patterns. ²¹ The increase in PMI mortality may be attributed to the growing prevalence of cardiovascular risk factors in nonelderly adults, in addition to age and sex‐based disparities in CVD treatment. ²² The National Health and Nutrition Examination Survey (NHANES 2017–2018) has reported that the prevalence of obesity in adults has increased from 27.5% in 1999 to 2000 to 43% in 2017 to 2018, while the prevalence of severe obesity has doubled from 3.1% in 1999 to 2000 to 6.9% in 2017 to 2018 in the United States. ²³ Similarly, the prevalence of diabetes has increased in alarming proportions from 2.5% in 1990 to 8.7% in 2019. ²⁴ The rising prevalence of chronic kidney disease, physical inactivity, and increasing salt consumption in younger adults may also contribute to rising premature CAD. ²⁵ , ²⁶ Furthermore, the risk of arteriosclerotic cardiovascular disease by our current risk assessment tools often underestimates the risk in younger patients, resulting in underutilization of primary preventive strategies, particularly in women. ¹⁹ Secondary preventive strategies after AMI are used less often in women and even less so in young women. ²⁷ , ²⁸ , ²⁹ Prior studies have demonstrated that women under the age of 55 years with an AMI had lower rates of revascularization, less prescription of guideline‐directed medical therapies, and higher comorbidities when compared with men. ³⁰ , ³¹ , ³² , ³³ Data from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study showed that younger women with AMI also had a significantly higher rate of all‐cause rehospitalization at 1 year compared with men (34.8% versus 23%). ³⁰ , ³⁴ , ³⁵

The proportionate mortality of PMI in women has increased almost 2‐fold over the past 30 years, with no measurable change in men from 1990 to 2020. Our findings are similar to prior studies that have shown women have worse outcomes compared with men after AMI. ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² Differences in clinical presentation, lack of recognition and delay in care, limited access to preventive care, and the presence of an inherent bias contribute to the rising disparity in the recognition and treatment of CVD in young women. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ Women also have a higher prevalence of myocardial infarction with nonobstructive coronary artery disease, and while patients with myocardial infarction with nonobstructive coronary artery disease have a similar mortality rate compared with AMI with obstructive coronaries, myocardial infarction with nonobstructive coronary artery disease is still often presumed to be benign and is less aggressively treated with secondary preventive therapies, potentially contributing to the increase in the mortality risk in women. ⁴⁸ In the United States, the in‐hospital mortality has been demonstrated to be higher in women than in men with ST‐segment–elevation myocardial infarction (STEMI), but the outcomes for non–ST‐segment–elevation myocardial infarction has not shown a difference based on sex. ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ For patients with STEMI, the rates of angiography and coronary interventions are less for women and women are more likely to experience longer door‐to‐balloon time than men. ⁵⁶ , ⁵⁷ In addition, lower rates of radial access for angiography, lower prescription rates, and adherence to potent P2Y12 inhibitors due to a higher risk of bleeding and lower referrals for cardiac rehabilitation confer challenges in the post‐MI care of women. ⁵⁶ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ Interestingly, an observational study examining 12 different countries demonstrated that young women with STEMI had higher 30‐day mortality compared with men, even after adjusting for medications, rates of primary percutaneous coronary intervention, and co‐existing comorbidities, suggesting sex‐related pathophysiological differences in clinical outcomes. ⁵⁵ In contrast, 1 observational Finnish study reported that although young women with AMI, including both STEMI and non–ST‐segment–elevation myocardial infarction, received fewer guidelines‐directed treatment when compared with young men, the long‐term cardiovascular outcomes were worse for young men after AMI, after adjusting for baseline comorbidities and treatment differences. ⁶²

The mortality rates due to PMI have shown the highest increase in the Black population, followed by the White population in the past 2 decades. Additionally, American Indian/Alaska Native people had an alarmingly high rate of proportionate mortality of PMI (men 21%, women 26%) with no improvement in the mortality rates over 20 years. There was no significant increase in mortality rates in Asian/Pacific Islanders people or Hispanic people over the analyzed period. Although in our subgroup analysis, we found the highest mortality due to PMI in Black women and the American Indian/Alaskan Native population, the greatest increase in PMI over 22 years was observed among White women. These findings highlight racial and sex differences in PMI mortality that are more pronounced in women than men. The Black population has a higher prevalence of diabetes, hypertension, and heart failure, which contributes to the rising prevalence of premature CAD. ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ Additionally, studies continue to demonstrate lower rates of prescription for guidelines‐directed medical therapies and lower rates of angiography and stenting, with worse outcomes for AMI in the Black population compared with other races. ³³ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ Even when women present with AMI in cardiogenic shock, they are treated less aggressively than men. ⁷¹ Using the National Inpatient Sample, investigators found that for hospitalizations with STEMI and cardiogenic shock, women and minorities (Black and Hispanic population) were less likely to receive revascularization therapies, mechanical circulatory support devices, or a right heart catheterization. ⁷² Not surprisingly, women and those from diverse backgrounds had an increased odds of in‐hospital mortality compared with White men. ⁶⁷ Additionally, systemic racism and more adverse social determinants of health are frequently experienced in the Black population, and this has further widened the existing racial disparities in outcomes for AMI. ⁷³ , ⁷⁴ , ⁷⁵ The American Indian/Alaskan Native population has considerably higher AMI mortality rates compared with other races and has remained relatively unchanged, as we demonstrated in this study. This has been attributed to social determinants of health factors (such as lack of health care access/insurance, higher prevalence of comorbidities such as diabetes, smoking, obesity, etc.), reduced rates of revascularization with AMI, inadequate prevention efforts, and greater comorbidities such as diabetes. ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ Among the Asian or Pacific Islander population, there was a higher proportionate mortality of PMI in men (13%) compared with women, and it could be attributed to the higher rates of CAD risk factors in men. ⁸² Hispanic individuals also had a higher proportionate mortality of PMI compared with the White population, and this could be related to the higher burden of hypertension, obesity, and hyperlipidemia. ² , ⁸² These racial and ethnic disparities call for community‐level interventions to address this issue.

Limitations

Our study has several limitations that must be taken into consideration. This analysis of mortality was based on death certificates, and the cause of death is based on ICD‐10 coding, so there may be errors in coding, and it is subject to misclassification bias. We do not have information regarding baseline comorbidities or CVD risk factors, and we have no other medical information such as inflammatory disorders, psychosocial stressors, family history of MI, laboratory values such as lipid panel, hemoglobin A1c, echocardiogram and cardiac catheterization results or interventions, medications, or socioeconomic status. These administrative data also lack vital clinical information such as percutaneous coronary intervention, door‐to‐balloon time, door‐to‐thrombolytic time, use of fibrinolytic, mechanical complications, or other status assessments that can affect clinical outcomes in AMI.

CONCLUSIONS

We have demonstrated that despite the overall declining rates of AMI mortality, mortality due to PMI has increased in the United States. Increasing mortality from 1999 to 2020 due to PMI in the Black and White population, particularly in women, suggests a growing burden of premature CAD in these population groups. The Black female population has the highest mortality from PMI compared with any other group. Additionally, the persistently high PMI mortality in American Indian/Alaska Native people suggests the need for targeted interventions to improve the management of AMI in this population. Despite considerable advancements in therapeutic and secondary preventative measures for treating AMI, our study highlights the demographic inequities in PMI outcomes. These findings require urgent public health efforts to mitigate these differences in PMI.

Sources of Funding

None.

Disclosures

None.

Supporting information

Tables S1–S14

Figure S1