INTERHEART: A Global Case-Control Study of Risk Factors for Acute Myocardial Infarction

Linda Brookes, MSc

Disclosures

September 24, 2004

Editorial Collaboration

Medscape &

Presenter: Salim Yusuf, MB BS, DPhil, McMaster University and Hamilton Civic Hospitals Research Centre (Hamilton, Ontario, Canada)

A major Canadian-led global study has identified 9 easily measured risk factors (smoking, lipids, hypertension, diabetes, obesity, diet, physical activity, alcohol consumption, and psychosocial factors) that account for over 90% of the risk of acute myocardial infarction (AMI). The INTERHEART investigators, led by Dr. Yusuf, found that these risk factors are the same in almost every geographic region and every racial/ethnic group worldwide and are consistent in men and women. The main results of the INTERHEART study were reported at the European Society of Cardiology (ESC) Congress and published shortly afterward in The Lancet.[1,2]

Study Rationale

Whereas cardiovascular disease-related mortality has declined in most developed countries, its known prevalence is increasing worldwide, although few data on the causes of heart disease in the developing world are available. Information about risk factors for AMI has been largely derived from studies in the developed countries, and applicability of these results to other populations was unknown. The aim of INTERHEART, a case-control study conducted in > 50 countries, was to determine the associations between a wide array of risk factors and AMI within populations defined by ethnicity and/or geographic region, and to assess the relative importance of these risk factors across these populations.

Going into the study, the investigators hypothesized (in agreement with the general consensus) that the relative impact of conventional risk factors (smoking, hypertension, elevated cholesterol, and diabetes) and emerging risk factors (glucose abnormalities, abdominal obesity, homocysteine, and other nutritional and psychosocial factors) for cardiovascular disease differ between people of varying ethnic and geographic origin. Moreover, conventional wisdom has been that, taken together, these known risk factors would explain only about 50% of cases of heart disease.

Participants

INTERHEART was a standardized case-control study that screened all patients admitted to the coronary care unit or equivalent cardiology ward for a first MI at 262 participating centers in 52 countries throughout Africa, Asia, Australia, Europe, the Middle East, and North and South America. Cases were identified using standardized definitions and enrolled within 24 hours of symptom onset. Matching controls were recruited, resulting in a total of 15,152 incident cases of AMI and 14,820 controls matched by age (± 5 years) and sex but with no history of heart disease.

Data Collection and Analysis

A study questionnaire, translated into 11 languages, was used to collect data on demographic factors (country of origin, first language), socioeconomic status (education, occupation, income), lifestyle (tobacco use, physical activity, dietary patterns), and personal and family history of cardiovascular disease and risk factors (self-reported diabetes and hypertension). These components of the questionnaire were compiled with previously validated questions included in studies of risk factors for cardiovascular disease. Questionnaires were administered by trained staff before the patients left the hospital.

Data on medications (prehospital, inhospital, and discharge) and interventions were abstracted from charts. Standard physical measurements were done in duplicate by the same examiner on each participant: height, weight, waist and hip circumference, and heart rate. A 20-mL sample of nonfasting blood was drawn from each individual and was frozen and stored for biochemical analyses, including total cholesterol, high-density lipoprotein-cholesterol, apolipoproteins B (apoB), and A1 (apoA1).

The strength of the association between various risk factors and AMI was estimated by odds ratio (OR), and the investigators calculated the variation in the association according to geographic region, ethnic origin, sex, or age in order to quantify the impact of each risk factor alone and in combination on the population risk, as calculated by the population attributable risk (PAR).

Risk Factors

Final analysis was carried out for 12,461 cases and 9459 controls. The mean age for the first presentation of AMI was 8-10 years lower in men than women worldwide and 10 years younger in Africa, the Middle East, and South Asia compared with other regions of the world.

Globally, all 9 risk factors were significantly associated with AMI (all P < .0001 except alcohol, P = .03) (Table 1). These risks were consistent in all regions, ethnic groups, and in men and women worldwide. The strongest risk predictor globally was the apoB/apoA1 ratio (a more reliable marker of cholesterol risk), followed by current smoking (associated with a 4- and 3-fold increased risk of MI, respectively). The risk associated with lipids and smoking was particularly marked in the young (< 55 in men, < 65 in women) vs the old. For all risk factors combined, the OR was 2.5-fold greater in the young vs the old.

Abdominal obesity was demonstrated to be a stronger risk factor than body mass index (BMI), suggesting that this measurement should replace BMI as an indicator of obesity, Dr. Yusuf stressed. Psychosocial stress was also found to be an important factor (see below).

Daily consumption of fruits and vegetables, moderate or strenuous exercise, and consumption of alcohol (≥ 3 times per week) were protective.

Table 1. Risk of AMI Associated With Risk Factors in the Overall Population
Risk Factor Controls (%) Cases (%) OR (99% CI)
Adjusted for
Age, Sex,
and Smoking
OR (99% CI)
Adjusted for
All Other
Risk Factors
ApoB/apoA1 (5 vs 1)* 20.0 33.5 3.87
(3.39-4.42)
3.25
(2.82-3.76)
Current smoking 26.8 45.2 2.95
(2.72-3.20)
2.87
(2.58-3.19)
Diabetes 7.5 18.5 3.08
(2.77-3.42)
2.37
(2.07-2.71)
Hypertension 21.9 39.0 2.48
(2.30-2.68)
1.91
(1.74-2.10)
Abdominal obesity (3 vs 1) 33.3 46.3 2.22
(2.03-2.42)
1.62
(1.45-1.80)
Psychosocial - - 2.51
(2.15-2.93)
2.67
(2.21-3.22)
Daily consumption of vegetables and fruit 42.2 35.8 0.70
(0.64-0.77)
0.70
(0.62-0.79)
Exercise 19.3 14.3 0.72
(0.65-0.79)
0.86
(0.76-0.97)
Alcohol intake 24.5 24.0 0.79
(0.73-0.86)
0.91
(0.82-1.02)
All combined - - 129.2 129.2
All combined (extremes) 333.7 333.7
*Fifth quintile vs lowest quintile
Top two quintiles vs lowest quintile

A strong, graded relation was seen between number of cigarettes smoked and risk of AMI, with the risk increasing at every increment. Consumption of 1-5 cigarettes daily increased AMI risk by 38%, and this increased linearly up to consumption of 40 cigarettes, which increased the risk by 900%. Reducing any cigarette consumption by half was found to reduce the risk by half. The apoB/apoA1 ratio demonstrated a similar, though less drastic, relation.

Cumulative Risks

Calculation of PAR, which takes into consideration both the OR and prevalence of a risk factor, showed that globally 50% of an AMI is predicted by apoB/apoA1 and 36% by current smoking (Table 2). These 2 risk factors together predict 66.4% of all AMIs, worldwide.

Five factors (smoking, lipids, hypertension, diabetes, and obesity) accounted for about 80% of the PAR. For all 9 risk factors combined, the PAR was significantly greater (P < .001) in younger than in older individuals, but consistent in men and women (90% and 94%, respectively).

According to Dr. Yusuf, the PAR of 90.4% for all 9 risk factors suggests that, statistically, the 9 risk factors combined accounted for basically all of the risk of AMI in this study population -- a truly startling and unanticipated result.

Table 2. Risk of AMI Associated With Risk Factors in the Overall Population
Risk Factor Controls (%) Cases (%) PAR 1
(99% CI)
PAR 2
(99% CI)
ApoB/apoA1 (5 vs 1) 20.0 33.5 54.1
(49.6-58.6)
49.2
(43.8-54.5)
Current smoking 26.8 45.2 36.4
(33.9-39.0)
35.7
(32.5-39.1)
Diabetes 7.5 18.5 12.3
(11.2-13.5)
9.9
(8.5-11.5)
Hypertension 21.9 39.0 23.4
(21.7-25.1)
17.9
(15.7-20.4)
Abdominal obesity (3 vs 1) 33.3 46.3 33.7
(30.2-37.4)
20.1
(15.3-26.0)
Psychosocial - - 28.8
(22.6-35.8)
32.5
(25.1-40.8)
Daily consumption of vegetables and fruit 42.2 35.8 12.9
(10.0-16.6)
13.7
(9.9-18.6)
Exercise 19.3 14.3 25.5
(20.1-31.8)
12.2
(5.5-25.1)
Alcohol intake 24.5 24.0 13.9
(9.3-20.2)
6.7
(2.0-20.2)
Combined - - 90.4
(88.1-92.4)
90.4
(99.1-92.4)
PAR = population-attributed risk
Psychosocial Factors

Questions about psychosocial risk factors in the INTERHEART questionnaire covered stress at work or home, financial stress, stressful life events, depression, and locus of control (the perceived ability to control life circumstances). The results indicated that psychosocial factors may contribute to a substantial proportion of the risk for AMI. The global effect was less than that for smoking, but comparable with hypertension and abdominal obesity. The PAR for each of the measures ranged from 8% to 18%, and collectively totaled 33% for all variables. The effects of stress on AMI were similar in men and women, in people of all ages, and in all geographic regions of the world studied.

Implications
  • With the documentation that these 9 risk factors account for > 90% of the risk for AMI, it is probable that all of the significant risk factors for heart disease in the world today have been identified.

  • Although INTERHEART found that 90.4% of AMIs can be predicted by the 9 global risk factors, the impact of diabetes and hypertension may have been underestimated, since these 2 factors were self reported.

  • Abdominal obesity is a greater risk factor than BMI, indicating that measurement of waist-to-hip ratio should replace BMI as an indicator of obesity.

  • The 10-year younger mean age for the first presentation of AMI in Africa, the Middle East, and South Asia compared with other regions of the world implies the onset of an oncoming epidemic and predicts a large increase in cardiovascular disease in these regions in the coming years.

  • Globally, practically no one in an urban population has a level of dyslipidemia that avoids an increased risk of heart disease.

  • A protective effect was seen for moderate alcohol consumption (PAR 7%). Advice about this should take into account possible social, cultural, or religious constraints, as well as the potential health risks of excessive alcohol consumption.

  • Implementing preventive strategies based on current knowledge would avert the majority of premature coronary heart disease worldwide.

Role of Smoking

INTERHEART showed that smoking 1-5 cigarettes daily increases the risk of an AMI by 40%. This could cancel the beneficial effects of secondary prevention, such as aspirin, which reduces risk by 20%; it could also eliminate as much as 75% of the benefit of taking a statin. The risk increased with the amount of tobacco smoked per day (OR 9.2 in those who smoke > 40 cigarettes per day). All forms of tobacco, including filtered and nonfiltered cigarettes, pipes and cigars, and chewing tobacco, are harmful. Dr. Yusuf strongly advocates, in congruence with the official position of the ESC, that global policies for tobacco control should be implemented.

"Landmark Study"

Referring to the INTER-HEART study as a "landmark study" and a "monumental achievement," ESC Congress-designated discussant Jean-Pierre Després, PhD (Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Quebec, Canada), re-emphasized that the results of INTERHEART carry an important public health message, ie, that the majority of AMI cases can be explained by the presence of simple risk or cardioprotective factors that can easily be assessed in clinical practice, and importantly, can be modified.

Dr. Després also supported the call for assessing the waist-to-hip ratio, rather than BMI, as the simplest index of diabetogenic and atherogenic abdominal fat. He also noted the "consistent and independent" relation between elevated ApoB/apoA and risk, as opposed to serum lipid levels such as triglycerides and HDL cholesterol, which are affected by food intake, noting that ApoB/apoA1 can be measured in nonfasting plasma, a clear advantage in clinical practice.

It is disheartening to realize that there is such a pandemic of cardiovascular disease worldwide when most MIs are preventable, Dr. Després lamented. "We have to reshape our working and living environments and address cultural and social factors favoring destructive behaviors," he said, warning that "mankind is doing a good job of killing itself."

Focus for Future Research

In a comment accompanying the INTERHEART reports in The Lancet,Majid Ezzati, MD (Harvard School of Public Health, Boston, Massachusetts), says that INTERHEART "takes an important step towards identifying current intervention options and subsequent research for some of the most important global health risks."[3] The INTERHEART results "should motivate future research to focus on unexplored areas, especially how exposure to each risk is distributed across and within populations in relation to other risk factors and to socioeconomic factors such as income, education, and rural-urban life." Dr. Ezzati predicts that such studies "would provide invaluable evidence for assessing the role of multiple risks in health equalities and for delivering interventions for multiple risks."

References
  1. Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952.

  2. Rosengren A, Hawken S, Ounpuu S, et al, for the INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:953-962.

  3. Ezzati M. How can cross-country research on health risks strengthen interventions? Lessons from INTERHEART. Lancet. 2004;364:912-914.

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