INTERHEART: Nine modifiable risk factors predict 90% of acute MI

September 10, 2004

Munich, Germany - Investigators conducting one of the largest case-control studies evaluating risk factors for coronary heart disease have identified nine risk factors strongly associated with an increased risk of acute MI. According to Dr Salim Yusuf (Michael DeGroote School of Medicine, Hamilton, ON), lead investigator of the INTERHEART study, more than 90% of the global risk for acute MI is predicted by these nine traditional risk factors.

Dr Salim Yusuf

"This is important, because most people believe that only half the risk of heart attacks can be predicted," said Yusuf. "This study convincingly shows that 90% of the global risk is preventable. This is good news. We can do something about it. The other good news is that the impact of these risk factors was the same in every ethnic group and in every region in the world. That means preventive messages can be simple and we can use the same strategyadjusted for economic and cultural circumstancesin every part of the world."

Evaluating more than 29000 subjects from 262 sites across 52 countries, the investigators report that the two most important risk factors worldwide for acute MI were an abnormal apolipoprotein B/apolipoprotein A-1 (ApoB/ApoA-1) ratio and cigarette smoking. Diabetes, hypertension, abdominal obesity, psychosocial variables such as stress and depression, exercise, diet, and alcohol intake were the other variables that predicted risk of acute MI.

We know most of the causes of heart disease.

"We know most of the causes of heart disease," continued Yusuf. "The key thing now is implementation of what we know to have a big impact in preventing premature heart disease."

The results of the study were presented at the 2004 European Society of Cardiology Congress and published in the September 3, 2004 issue of the Lancet[1].

Global study

During a press conference to discuss the results, Yusuf said that a majority of heart disease, nearly 80%, occurs in developing countries. Despite this, most cardiovascular research occurs in developed countries with largely white, European populations, making it difficult to say with certainty whether the findings of studies such as Framingham and other large trials apply to persons in developing nations.

Matching first-MI patients to a healthy control by age at each site, INTERHEART included 14820 healthy control subjects and 15152 first-MI patients. Approximately 25% of subjects included were from Europe, 25% were from China, 20% were from South Asia, and 13% were from the Middle East, while 12% were from South America and 5% were from Africa. Demographic as well as other information about lifestyle, health history, psychosocial factors, and use of medication were collected by questionnaire. Height, weight, waist-to-hip circumference, blood pressure, and heart rate were measured using standard methods, and a 20-mL nonfasting blood sample was collected from every subject.

The goal of the study was to evaluate the association of risk factors for MI globally, as well as in each region and among the different ethnic groups. The populationattributable risk (PAR)the relative risk associated with a given factor in the context of the prevalence of the condition within a populationwas also calculated.

Investigators report that regardless of ethnicity, region, or gender, an abnormal ApoB/ApoA-1 ratio and current smoking were the two strongest predictors of acute MI risk. Taken together, current smoking and an abnormal ApoB/ApoA-1 ratio predict 66% of global heart disease.

INTERHEART: Risk of acute MI associated with risk factors in the overall population

Risk factor Odds ratio adjusted for age, sex, and smoking (99% CI) Odds ratio adjusted for all (99% CI)
ApoB/ApoA-1 (fifth quintile compared with first) 3.87 (3.39-4.42) 3.25 (2.81-3.76)
Current smoking 2.95 (2.72-3.20) 2.87 (2.58-3.19)
Diabetes 3.08 (2.77-3.42) 2.37 (2.07-2.71)
Hypertension 2.48 (2.30-2.68) 1.91 (1.74-2.10)
Abdominal obesity 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)
Vegetable and fruits daily 0.70 (0.64-0.77) 0.70 (0.62-0.79)
Exercise 0.72 (0.65-0.79) 0.86 (0.76-0.97)
Alcohol intake 0.79 (0.73-0.86) 0.91 (0.82-1.02)
All combined 129.2 (90.2-185.0) 129.2 (90.2-185.0)

INTERHEART: Population-attributable risk of acute MI in the overall population

Risk factor PAR adjusted for age, sex, and smoking (99% CI) PAR adjusted for all (99% CI)
ApoB/ApoA-1 (fifth quintile compared with first) 54.1 (49.6-58.6) 49.2 (43.8-54.5)
Current smoking 36.4 (33.9-39.0) 35.7 (32.5-39.1)
Diabetes 12.3 (11.2-13.5) 9.9 (8.5-11.5)
Hypertension 23.4 (21.7-25.1) 17.9 (15.7-20.4)
Abdominal obesity 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)
Vegetable and fruits daily 12.9 (10.0-16.6) 13.7 (9.9-18.6)
Exercise 25.5 (20.1-31.8) 12.2 (5.5-25.1)
Alcohol intake 13.9 (9.3-20.2) 6.7 (2.0-20.2)
All combined 90.4 (88.1-92.4) 90.4 (88.1-92.4)
PAR=population-attributable risk

Yusuf said the INTERHEART investigators elected to measure the ApoB/ApoA-1 ratio as it is a more reliable measurement in nonfasting blood and provides a better index of the concentration of atherogenic proteins. When the investigators divided the ApoB/ApoA-1 values into deciles, Yusuf said that for every decile there is a stepwise increase in the risk of acute MI.

"What this means is that globally in urban populations, which is where this study was done, there is practically nobody with a level of dyslipidemia that protects against an increased risk of heart disease. That's a terrible thought," said Yusuf. "That implies that the main way to prevent heart disease is societal change, so that the population distributions of these risk factors goes down."

The main way to prevent heart disease is societal change, so that the population distributions of these risk factors goes down.

Yusuf noted that standard body mass index (BMI) was a predictor of risk, but it was very weak, while abdominal obesity was much more strongly associated with acute MI. According to Yusuf, "it is time to throw out BMI as an indicator of obesity and really focus on things like abdominal obesity."

The nine risk factors were even more predictive in younger people than in the elderly, reinforcing the belief that an overwhelming majority of heart disease can be prevented, said Yusuf. Despite his own "educated hostility" toward psychosocial variables, he noted that stress and psychosocial factors were important predictors of risk of acute MI in the young and the old and across the different regions and ethnic groups.

Psychosocial risk factors and risk of MI

A separate, more in-depth analysis, also presented at the 2004 European Society of Cardiology and published in the Lancet, investigated the relationship of psychosocial risk factors, such as stress, to risk of MI[2].

The case-control study compared 11119 first-MI patients with 13648 age- and sex-matched controls. Using a standard set of questions to assess psychosocial conditions during the past 12 months, investigators were able to assess stress levels at work and home, levels of financial stress, and major life events in the past year. The presence of depression, as well as the patient's perceived ability to control life circumstances, was also assessed.

The INTERHEART investigators found that those with MI reported a higher prevalence of stress. Of those still working, 23.0% experienced several periods of work stress compared with 17.9% of controls, and twice as many MI patients experienced permanent work stress during the previous year (odds ratio 2.14; 95% CI 1.73-2.64). Severe financial stress and stressful life events were also more common in MI patients than in controls.

The different stress levels between first-MI and control patients were consistent across regions, in different ethnic groups, and in men and women. According to first author of the paper, Dr Annika Rosengren (Sahlgrenska University Hospital, Goteborg, Sweden), the size of the effect was less than that of smoking but comparable with hypertension and abdominal obesity.

"If this effect is truly causal, the importance of psychosocial factors is much more important than commonly recognized, and might contribute to a substantial proportion of acute myocardial infarction," writes Rosenberg and colleagues.

-M O'R

The effects of smoking

During the press conference, Dr Stephanie Ounpuu (Michael DeGroote School of Medicine, Hamilton, ON) presented the cigarette-smoking data, noting the INTERHEART investigators observed a threefold increase in the risk of acute MI in those who smoked when compared with those who did not.

The negative effect of smoking was seen even at very low levels: those who smoked one to five cigarettes per day experienced a 40% increase in risk of MI compared with nonsmokers, while those who smoked six to 10 cigarettes per day had a twofold increase in risk. Those who smoked more than 20 cigarettes per day had a fourfold increase in the risk of heart disease, suggesting a very clear dose response, said Ounpuu.

"Among very heavy smokers who find it very difficult to quit, perhaps reducing the amount they smoke may be an effective way of reducing their risk," said Ounpuu.

Equally important, said Ounpuu, relative to those who never smoked, those who smoked tobacco, filtered cigarettes, nonfiltered cigarettes, bidis (a popular South Asian cigarette), pipes, and cigars all had similar risks. "No form of tobacco is safe when it comes to heart disease," said Ounpuu.

"Killing ourselves"

Yusuf concluded the press conference by saying the study was one of the most important of his career and urged clinicians to spend more time focusing on reducing traditional factors to lessen the global burden of cardiovascular disease. In the Lancet, the INTERHEART investigators write that the findings suggest "approaches to prevention can be based on similar principles worldwide and have the potential to prevent premature cases of myocardial infarction."

In an editorial accompanying the published studies, Dr Majid Ezzati (Harvard Medical School, Boston, MA) agrees that most informative results of the INTERHEART study are the consistency of results across the different populations[3].

"INTERHEART provides further confirmation that, for such factors, differences in total risk across populations are more a result of variations in exposure and background levels of disease than an outcome of different causal processes," writes Ezzati. "For these risks, in parallel to advancing our basic understanding of causative mechanisms, we can safely begin to pay attention to design of effective interventions and more importantly to programs of delivery of available interventions to those at need."

At the ESC Congress, discussant Dr Jean-Pierre Després (Laval Hospital Research Centre, St Foy, QC) said the results of INTERHEART carry an important public-health message.

"The majority of acute-MI cases can be explained by the presence of simple risk or cardioprotective factors that can be easily measured in clinical practice, " said Després. "But more important from the public-health standpoint is that they can be potentially modified. This can not be emphasized enough."

Després said the study also confirms the need to go beyond BMI as a measurement of obesity and as a risk factor for heart disease. More useful measurements, such as those that take into account abdominal obesity, represent a better index of cardiovascular risk associated with obesity and should encourage more physicians to measure waist circumference. He also praised the INTERHEART investigators for using the ApoB/ApoA-1 ratio, calling it a better index of the concentration of atherogenic lipoproteins.

Després said that it is sad to realize that an epidemic of cardiovascular disease is foreseen at a time when INTERHEART reveals that most MIs are preventable. He called for comprehensive and routine prevention strategies that will go beyond the current medical model.

"Until we reshape our living and working environments and we address social and cultural factors that favor such destructive behavior, the prevalence of cardiovascular disease is unlikely to decrease," said Després. "In essence, mankind is doing a good job of killing himself."



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