Steven Hawken

Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

BACKGROUND Although more than 80% of the global burden of cardiovascular disease occurs in low-income and middle-income countries, knowledge of the importance of risk factors is largely derived from developed countries. Therefore, the effect of such factors on risk of coronary heart disease in most regions of the world is unknown. METHODS We established a standardised case-control study of acute myocardial infarction in 52 countries, representing every inhabited continent. 15152 cases and 14820 controls were enrolled. The relation of smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins (Apo), and psychosocial factors to myocardial infarction are reported here. Odds ratios and their 99% CIs for the association of risk factors to myocardial infarction and their population attributable risks (PAR) were calculated. FINDINGS Smoking (odds ratio 2.87 for current vs never, PAR 35.7% for current and former vs never), raised ApoB/ApoA1 ratio (3.25 for top vs lowest quintile, PAR 49.2% for top four quintiles vs lowest quintile), history of hypertension (1.91, PAR 17.9%), diabetes (2.37, PAR 9.9%), abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, PAR 20.1% for top two tertiles vs lowest tertile), psychosocial factors (2.67, PAR 32.5%), daily consumption of fruits and vegetables (0.70, PAR 13.7% for lack of daily consumption), regular alcohol consumption (0.91, PAR 6.7%), and regular physical activity (0.86, PAR 12.2%), were all significantly related to acute myocardial infarction (p<0.0001 for all risk factors and p=0.03 for alcohol). These associations were noted in men and women, old and young, and in all regions of the world. Collectively, these nine risk factors accounted for 90% of the PAR in men and 94% in women. INTERPRETATION Abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, and alcohol, and regular physical activity account for most of the risk of myocardial infarction worldwide in both sexes and at all ages in all regions. This finding suggests that approaches to prevention can be based on similar principles worldwide and have the potential to prevent most premature cases of myocardial infarction.

Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study

BACKGROUND Obesity is a major risk factor for cardiovascular disease, but the most predictive measure for different ethnic populations is not clear. We aimed to assess whether markers of obesity, especially waist-to-hip ratio, would be stronger indicators of myocardial infarction than body-mass index (BMI), the conventional measure. METHODS We did a standardised case-control study of acute myocardial infarction with 27 098 participants in 52 countries (12,461 cases and 14,637 controls) representing several major ethnic groups. We assessed the relation between BMI, waist and hip circumferences, and waist-to-hip ratio to myocardial infarction overall and for each group. FINDINGS BMI showed a modest and graded association with myocardial infarction (OR 1.44, 95% CI 1.32-1.57 top quintile vs bottom quintile before adjustment), which was substantially reduced after adjustment for waist-to-hip ratio (1.12, 1.03-1.22), and non-significant after adjustment for other risk factors (0.98, 0.88-1.09). For waist-to-hip ratio, the odds ratios for every successive quintile were significantly greater than that of the previous one (2nd quintile: 1.15, 1.05-1.26; 3rd quintile: 1.39; 1.28-1.52; 4th quintile: 1.90, 1.74-2.07; and 5th quintiles: 2.52, 2.31-2.74 [adjusted for age, sex, region, and smoking]). Waist (adjusted OR 1.77; 1.59-1.97) and hip (0.73; 0.66-0.80) circumferences were both highly significant after adjustment for BMI (p<0.0001 top vs bottom quintiles). Waist-to-hip ratio and waist and hip circumferences were closely (p<0.0001) associated with risk of myocardial infarction even after adjustment for other risk factors (ORs for top quintile vs lowest quintiles were 1.75, 1.33, and 0.76, respectively). The population-attributable risks of myocardial infarction for increased waist-to-hip ratio in the top two quintiles was 24.3% (95% CI 22.5-26.2) compared with only 7.7% (6.0-10.0) for the top two quintiles of BMI. INTERPRETATION Waist-to-hip ratio shows a graded and highly significant association with myocardial infarction risk worldwide. Redefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of myocardial infarction attributable to obesity in most ethnic groups.

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

BACKGROUND Psychosocial factors have been reported to be independently associated with coronary heart disease. However, previous studies have been in mainly North American or European populations. The aim of the present analysis was to investigate the relation of psychosocial factors to risk of myocardial infarction in 24767 people from 52 countries. METHODS We used a case-control design with 11119 patients with a first myocardial infarction and 13648 age-matched (up to 5 years older or younger) and sex-matched controls from 262 centres in Asia, Europe, the Middle East, Africa, Australia, and North and South America. Data for demographic factors, education, income, and cardiovascular risk factors were obtained by standardised approaches. Psychosocial stress was assessed by four simple questions about stress at work and at home, financial stress, and major life events in the past year. Additional questions assessed locus of control and presence of depression. FINDINGS People with myocardial infarction (cases) reported higher prevalence of all four stress factors (p<0.0001). Of those cases still working, 23.0% (n=1249) experienced several periods of work stress compared with 17.9% (1324) of controls, and 10.0% (540) experienced permanent work stress during the previous year versus 5.0% (372) of controls. Odds ratios were 1.38 (99% CI 1.19-1.61) for several periods of work stress and 2.14 (1.73-2.64) for permanent stress at work, adjusted for age, sex, geographic region, and smoking. 11.6% (1288) of cases had several periods of stress at home compared with 8.6% (1179) of controls (odds ratio 1.52 [99% CI 1.34-1.72]), and 3.5% (384) of cases reported permanent stress at home versus 1.9% (253) of controls (2.12 [1.68-2.65]). General stress (work, home, or both) was associated with an odds ratio of 1.45 (99% CI 1.30-1.61) for several periods and 2.17 (1.84-2.55) for permanent stress. Severe financial stress was more typical in cases than controls (14.6% [1622] vs 12.2% [1659]; odds ratio 1.33 [99% CI 1.19-1.48]). Stressful life events in the past year were also more frequent in cases than controls (16.1% [1790] vs 13.0% [1771]; 1.48 [1.33-1.64]), as was depression (24.0% [2673] vs 17.6% [2404]; odds ratio 1.55 [1.42-1.69]). These differences were consistent across regions, in different ethnic groups, and in men and women. INTERPRETATION Presence of psychosocial stressors is associated with increased risk of acute myocardial infarction, suggesting that approaches aimed at modifying these factors should be developed.

Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study.

BACKGROUND Tobacco use is one of the major avoidable causes of cardiovascular diseases. We aimed to assess the risks associated with tobacco use (both smoking and non-smoking) and second hand tobacco smoke (SHS) worldwide. METHODS We did a standardised case-control study of acute myocardial infarction (AMI) with 27,089 participants in 52 countries (12,461 cases, 14,637 controls). We assessed relation between risk of AMI and current or former smoking, type of tobacco, amount smoked, effect of smokeless tobacco, and exposure to SHS. We controlled for confounders such as differences in lifestyles between smokers and non-smokers. FINDINGS Current smoking was associated with a greater risk of non-fatal AMI (odds ratio [OR] 2.95, 95% CI 2.77-3.14, p<0.0001) compared with never smoking; risk increased by 5.6% for every additional cigarette smoked. The OR associated with former smoking fell to 1.87 (95% CI 1.55-2.24) within 3 years of quitting. A residual excess risk remained 20 or more years after quitting (1.22, 1.09-1.37). Exclusion of individuals exposed to SHS in the never smoker reference group raised the risk in former smokers by about 10%. Smoking beedies alone (indigenous to South Asia) was associated with increased risk (2.89, 2.11-3.96) similar to that associated with cigarette smoking. Chewing tobacco alone was associated with OR 2.23 (1.41-3.52), and smokers who also chewed tobacco had the highest increase in risk (4.09, 2.98-5.61). SHS was associated with a graded increase in risk related to exposure; OR was 1.24 (1.17-1.32) in individuals who were least exposed (1-7 h per week) and 1.62 (1.45-1.81) in people who were most exposed (>21 h per week). Young male current smokers had the highest population attributable risk (58.3%; 95% CI 55.0-61.6) and older women the lowest (6.2%, 4.1-9.2). Population attributable risk for exposure to SHS for more than 1 h per week in never smokers was 15.4% (12.1-19.3). CONCLUSION Tobacco use is one of the most important causes of AMI globally, especially in men. All forms of tobacco use, including different types of smoking and chewing tobacco and inhalation of SHS, should be discouraged to prevent cardiovascular diseases.

Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study

BACKGROUND Whether lipoproteins are better markers than lipids and lipoproteins for coronary heart disease is widely debated. Our aim was to compare the apolipoproteins and cholesterol as indices for risk of acute myocardial infarction. METHODS We did a large, standardised case-control study of acute myocardial infarction in 12,461 cases and 14,637 age-matched (plus or minus 5 years) and sex-matched controls in 52 countries. Non-fasting blood samples were available from 9345 cases and 12,120 controls. Concentrations of plasma lipids, lipoproteins, and apolipoproteins were measured, and cholesterol and apolipoprotein ratios were calculated. Odds ratios (OR) and 95% CI, and population-attributable risks (PARs) were calculated for each measure overall and for each ethnic group by comparison of the top four quintiles with the lowest quintile. FINDINGS The apolipoprotein B100 (ApoB)/apolipoprotein A1 (ApoA1) ratio had the highest PAR (54%) and the highest OR with each 1 SD difference (1.59, 95% CI 1.53-1.64). The PAR for ratio of LDL cholesterol/HDL cholesterol was 37%. PAR for total cholesterol/HDL cholesterol was 32%, which was substantially lower than that of the ApoB/ApoA1 ratio (p<0.0001). These results were consistent in all ethnic groups, men and women, and for all ages. INTERPRETATION The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.

Risk Factors Associated With Myocardial Infarction in Africa The INTERHEART Africa Study

Background— Cardiovascular disease (CVD) is rising in low-income countries. However, the impact of modifiable CVD risk factors on myocardial infarction (MI) has not been studied in sub-Saharan Africa (SSA). Therefore, we conducted a case-control study among patients with acute MI (AMI) in SSA to explore its association with known CVD risk factors. Methods and Results— First-time AMI patients (n=578) were matched to 785 controls by age and sex in 9 SSA countries, with South Africa contributing ≈80% of the participants. The relationships between risk factors and AMI were investigated in the African population and in 3 ethnic subgroups (black, colored, and European/other Africans) and compared with those found in the overall INTERHEART study. Relationships between common CVD risk factors and AMI were found to be similar to those in the overall INTERHEART study. Modeling of 5 risk factors (smoking history, diabetes history, hypertension history, abdominal obesity, and ratio of apolipoprotein B to apolipoprotein A-1) provided a population attributable risk of 89.2% for AMI. The risk for AMI increased with higher income and education in the black African group in contrast to findings in the other African groups. A history of hypertension revealed higher MI risk in the black African group than in the overall INTERHEART group. Conclusions— Known CVD risk factors account for ≈90% of MI observed in African populations, which is consistent with the overall INTERHEART study. Contrasting gradients found in socioeconomic class, risk factor patterns, and AMI risk in the ethnic groups suggest that they are at different stages of the epidemiological transition.

Renal function and outcomes in acute coronary syndrome: Impact of clopidogrel

Introduction Patients with renal dysfunction are more prone to bleeding when receiving antithrombotic drugs. The aim of the study was to assess the impact of clopidogrel on safety and efficacy in patients with renal dysfunction in non-ST elevation acute coronary syndromes. Methods and results Patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial were analysed to assess the relationship of chronic kidney disease to cardiovascular outcomes. Renal function was estimated by the glomerular filtration rate computed from the baseline serum creatinine measurements in 12253 (97.5%) patients enrolled in the trial. Patients were grouped into tertiles of glomerular filtration rate. The primary outcome (cardiovascular death, myocardial infarction, stroke combined) occurred more frequently in the lowest glomerular filtration rate tertile. The bleeding risk was also significantly increased in patients in this tertile, compared with the other two. The beneficial effect of adding clopidogrel to standard treatment in non-ST elevation acute coronary syndrome was observed in all three tertiles of renal function {(lower third relative risk (RR) = 0.89 [95% confidence interval (CI) 0.76–1.05]; medium third RR = 0.68 (95% CI 0.56–0.84); upper third RR = 0.74 (95% CI 0.60–0.93) (P for heterogeneity = 0.11)}. Clopidogrel treatment significantly increased the risk of minor bleeding in all tertiles of renal function. The risk of major or life-threatening bleeding increased moderately with the addition of clopidogrel to standard treatment [lower third RR = 1.12 (95% CI 0.83–1.51); medium third RR = 1.4 (95% CI 0.97–2.02); upper third RR = 1.83 (95% CI 1.23–2.73)], but this did not appear to be greatest in those with the lowest renal function. Conclusions Even mild chronic kidney disease worsens the prognosis in patients with non-ST elevation acute coronary syndromes. Clopidogrel was beneficial and safe in patients with and without chronic kidney disease.

CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration

OBJECTIVE The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. DESIGN Genetic analysis of a randomized, prospective clinical trial. PARTICIPANTS White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995). METHODS Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. MAIN OUTCOME MEASURES The effect of inherited gene polymorphisms on treatment group-specific rate of progression to advanced AMD. RESULTS Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. CONCLUSIONS Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy.

Systematic Meta-Analyses and Field Synopsis of Genetic Association Studies in Colorectal Cancer

BACKGROUND Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/). METHODS We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. RESULTS We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. CONCLUSION The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.

Treatment Response to Antioxidants and Zinc Based on CFH and ARMS2 Genetic Risk Allele Number in the Age-Related Eye Disease Study

OBJECTIVE To evaluate the impact of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk alleles on the observed response to components of the Age-Related Eye Disease Study (AREDS) formulation. DESIGN Genetic and statistical subgroup analysis of a randomized, prospective clinical trial. PARTICIPANTS White patients from the AREDS with category 3 or 4 age-related macular degeneration (AMD) with available DNA (n = 989). METHODS Four genotype groups based on CFH and ARMS2 risk allele number were defined. Progression to advanced AMD was analyzed by genotype and treatment using Cox proportionate hazards estimates and 7-year events. MAIN OUTCOME MEASURES The effect of predefined genotype group on treatment-specific progression to advanced AMD. RESULTS Patients with 2 CFH risk alleles and no ARMS2 risk alleles progressed more with zinc-containing treatment compared with placebo, with a hazard ratio (HR) of 3.07 (P = 0.0196) for zinc and 2.73 (P = 0.0418) for AREDS formulation (AF). Seven-year treatment-specific progression rates were: placebo, 17.0%; zinc, 43.2% (P = 0.023); and AF, 40.2% (P = 0.039). Patients with 0 or 1 CFH risk alleles and 1 or 2 ARMS2 risk alleles benefited from zinc-containing treatment compared with placebo, with an HR of 0.514 for zinc (P = 0.012) and 0.569 for AF (P = 0.0254). Seven-year treatment-specific AMD progression rates were as follows: placebo, 43.3%; zinc, 25.2% (P = 0.020); and AF, 27.3% (P = 0.011). Zinc and AF treatment each interacted statistically with these 2 genotype groups under a Cox model, with P values of 0.000999 and 0.00366, respectively. For patients with 0 or 1 CFH risk alleles and no ARMS2 risk alleles, neither zinc-containing treatment altered progression compared with placebo, but treatment with antioxidants decreased progression (HR, 0.380; P = 0.034). Seven-year progression with placebo was 22.6% and with antioxidants was 9.17% (P = 0.033). For patients with 2 CFH risk alleles and 1 or 2 ARMS2 risk alleles, no treatment was better than placebo (48.4%). CONCLUSIONS The benefit of the AREDS formulation seems the result of a favorable response by patients in only 1 genotype group, balanced by neutral or unfavorable responses in 3 genotype groups.