Association Between Dietary Factors and Mortality From Heart Disease, Stroke, and Type 2 Diabetes in the United States

Key Points

Question  What is the estimated mortality due to heart disease, stroke, or type 2 diabetes (cardiometabolic deaths) associated with suboptimal intakes of 10 dietary factors in the United States?

Findings  In 2012, suboptimal intake of dietary factors was associated with an estimated 318 656 cardiometabolic deaths, representing 45.4% of cardiometabolic deaths. The highest proportions of cardiometabolic deaths were estimated to be related to excess sodium intake, insufficient intake of nuts/seeds, high intake of processed meats, and low intake of seafood omega-3 fats.

Meaning  Suboptimal intake of specific foods and nutrients was associated with a substantial proportion of deaths due to heart disease, stroke, or type 2 diabetes.


Importance  In the United States, national associations of individual dietary factors with specific cardiometabolic diseases are not well established.

Objective  To estimate associations of intake of 10 specific dietary factors with mortality due to heart disease, stroke, and type 2 diabetes (cardiometabolic mortality) among US adults.

Design, Setting, and Participants  A comparative risk assessment model incorporated data and corresponding uncertainty on population demographics and dietary habits from National Health and Nutrition Examination Surveys (1999-2002: n = 8104; 2009-2012: n = 8516); estimated associations of diet and disease from meta-analyses of prospective studies and clinical trials with validity analyses to assess potential bias; and estimated disease-specific national mortality from the National Center for Health Statistics.

Exposures  Consumption of 10 foods/nutrients associated with cardiometabolic diseases: fruits, vegetables, nuts/seeds, whole grains, unprocessed red meats, processed meats, sugar-sweetened beverages (SSBs), polyunsaturated fats, seafood omega-3 fats, and sodium.

Main Outcomes and Measures  Estimated absolute and percentage mortality due to heart disease, stroke, and type 2 diabetes in 2012. Disease-specific and demographic-specific (age, sex, race, and education) mortality and trends between 2002 and 2012 were also evaluated.

Results  In 2012, 702 308 cardiometabolic deaths occurred in US adults, including 506 100 from heart disease (371 266 coronary heart disease, 35 019 hypertensive heart disease, and 99 815 other cardiovascular disease), 128 294 from stroke (16 125 ischemic, 32 591 hemorrhagic, and 79 578 other), and 67 914 from type 2 diabetes. Of these, an estimated 318 656 (95% uncertainty interval [UI], 306 064-329 755; 45.4%) cardiometabolic deaths per year were associated with suboptimal intakes—48.6% (95% UI, 46.2%-50.9%) of cardiometabolic deaths in men and 41.8% (95% UI, 39.3%-44.2%) in women; 64.2% (95% UI, 60.6%-67.9%) at younger ages (25-34 years) and 35.7% (95% UI, 33.1%-38.1%) at older ages (≥75 years); 53.1% (95% UI, 51.6%-54.8%) among blacks, 50.0% (95% UI, 48.2%-51.8%) among Hispanics, and 42.8% (95% UI, 40.9%-44.5%) among whites; and 46.8% (95% UI, 44.9%-48.7%) among lower-, 45.7% (95% UI, 44.2%-47.4%) among medium-, and 39.1% (95% UI, 37.2%-41.2%) among higher-educated individuals. The largest numbers of estimated diet-related cardiometabolic deaths were related to high sodium (66 508 deaths in 2012; 9.5% of all cardiometabolic deaths), low nuts/seeds (59 374; 8.5%), high processed meats (57 766; 8.2%), low seafood omega-3 fats (54 626; 7.8%), low vegetables (53 410; 7.6%), low fruits (52 547; 7.5%), and high SSBs (51 694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (−20.8% relative change [95% UI, −18.5% to −22.8%]), nuts/seeds (−18.0% [95% UI, −14.6% to −21.0%]), and excess SSBs (−14.5% [95% UI, −12.0% to −16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]).

Conclusions and Relevance  Dietary factors were estimated to be associated with a substantial proportion of deaths from heart disease, stroke, and type 2 diabetes. These results should help identify priorities, guide public health planning, and inform strategies to alter dietary habits and improve health.

JAMA. 2017;317(9):912-924.

Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study


Atrial fibrillation is an important cause of morbidity and mortality worldwide, but scant data are available for long-term outcomes in individuals outside North America or Europe, especially in primary care settings.


We did a cohort study using a prospective registry of patients in 47 countries who presented to a hospital emergency department with atrial fibrillation or atrial flutter as a primary or secondary diagnosis. 15 400 individuals were enrolled to determine the occurrence of death and strokes (the primary outcomes) in this cohort over eight geographical regions (North America, western Europe, and Australia; South America; eastern Europe; the Middle East and Mediterranean crescent; sub-Saharan Africa; India; China; and southeast Asia) 1 year after attending the emergency department. Patients from North America, western Europe, and Australia were used as the reference population, and compared with patients from the other seven regions


Between Dec 24, 2007, and Oct 21, 2011, we enrolled 15 400 individuals to the registry. Follow-up was complete for 15 361 (99·7%), of whom 1758 (11%) died within 1 year. Fewer deaths occurred among patients presenting to the emergency department with a primary diagnosis of atrial fibrillation compared with patients who had atrial fibrillation as a secondary diagnosis (377 [6%] of 6825 patients vs 1381 [16%] of 8536, p<0·0001). Twice as many patients had died by 1 year in South America (192 [17%] of 1132) and Africa (225 [20%] of 1137) compared with North America, western Europe, and Australia (366 [10%] of 3800, p<0·0001). Heart failure was the most common cause of death (519 [30%] of 1758); stroke caused 148 (8%) deaths. 604 (4%) of 15361 patients had had a stroke by 1 year; 170 (3%) of 6825 for whom atrial fibrillation was a primary diagnosis and 434 (5%) of 8536 for whom it was a secondary diagnosis (p<0·0001). The highest number of strokes occurred in patients in Africa (89 [8%] of 1137), China (143 [7%] of 2023), and southeast Asia (88 [7%] of 1331) and the lowest occurred in India (20 [<1%] of 2536). 94 (3%) of 3800 patients in North America, western Europe, and Australia had a stroke.


Marked unexplained inter-regional variations in the occurrence of stroke and mortality suggest that factors other than clinical variables might be important. Prevention of death from heart failure should be a major priority in the treatment of atrial fibrillation.


Boehringer Ingelheim.

The Lancet, Volume 388, No. 10050, p1161–1169, 17 September 2016

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study


Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke.


We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals.


Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72–3·28; PAR 47·9%, 99% CI 45·1–50·6), regular physical activity (0·60, 0·52–0·70; 35·8%, 27·7–44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65–2·06 for highest vs lowest tertile; 26·8%, 22·2–31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53–0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2–28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27–1·64 for highest vs lowest tertile; 18·6%, 13·3–25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78–2·72; 17·4%, 13·1–22·6), current smoking (1·67, 1·49–1·87; 12·4%, 10·2–14·9), cardiac causes (3·17, 2·68–3·75; 9·1%, 8·0–10·2), alcohol consumption (2·09, 1·64–2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4–9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05–1·30; 3·9%, 1·9–7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001).


Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke.


Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Volume 388, No. 10046, p761–775, 20 August 2016

Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials


Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated.


Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline.


We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32–0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20–0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02–0·31, p=0·0004; at 0–6 weeks, 14 vs 60 participants, 0·19, 0·11–0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26–0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84–1·12, p=0·67; severity mRS shift OR 1·00, 0·77–1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65–1·25, p=0·53; mRS shift OR 0·90, 0·37–1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63–0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49–0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0·37, 95% CI 0·25–0·57, p<0·0001).


Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action.


Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.

Lancet Volume 388, No. 10042, p365–375, 23 July 2016

Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study

Objective To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen.

Design Observational cohort study.

Setting Data from the French national health insurance database linked with data from the French national hospital discharge database.

Participants 4 945 088 women aged 15-49 years, living in France, with at least one reimbursement for oral contraceptives and no previous hospital admission for cancer, pulmonary embolism, ischaemic stroke, or myocardial infarction, between July 2010 and September 2012.

Main outcome measures Relative and absolute risks of first pulmonary embolism, ischaemic stroke, and myocardial infarction.

Results The cohort generated 5 443 916 women years of oral contraceptive use, and 3253 events were observed: 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years). After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% confidence interval 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel. Levonorgestrel combined with 20 µg oestrogen was associated with a statistically significantly lower risk than levonorgestrel with 30-40 µg oestrogen for each of the three serious adverse events.

Conclusions For the same dose of oestrogen, desogestrel and gestodene were associated with statistically significantly higher risks of pulmonary embolism but not arterial thromboembolism compared with levonorgestrel. For the same type of progestogen, an oestrogen dose of 20 µg versus 30-40 µg was associated with lower risks of pulmonary embolism, ischaemic stroke, and myocardial infarction.

BMJ 2016;353:i2002

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals


Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke.


We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data.


We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35–40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02–1·26; p=0·02) and incident stroke (1·33, 1·11–1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30–1·42). We recorded a dose–response association for stroke, with RR estimates of 1·10 (95% CI 0·94–1·28; p=0·24) for 41–48 working hours, 1·27 (1·03–1·56; p=0·03) for 49–54 working hours, and 1·33 (1·11–1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (ptrend<0·0001).


Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours.


Medical Research Council, Economic and Social Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), US National Institutes of Health, British Heart Foundation.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals by Mika Kivimäki et al.

Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation

Importance The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is used clinically for stroke risk stratification in atrial fibrillation (AF). Its usefulness in a population of patients with heart failure (HF) is unclear.

Objective To investigate whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in a cohort of patients with HF with and without AF.

Design, Setting, and Population Nationwide prospective cohort study using Danish registries, including 42,987 patients (21.9% with concomitant AF) not receiving anticoagulation who were diagnosed as having incident HF during 2000-2012. End of follow-up was December 31, 2012. Exposures Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk), stratified by concomitant AF at baseline. Analyses took into account the competing risk of death.

Main Outcomes and Measures Ischemic stroke, thromboembolism, and death within 1 year after HF diagnosis.

Results In patients without AF, the risks of ischemic stroke, thromboembolism, and death were 3.1% (n=977), 9.9% (n=3187), and 21.8% (n=6956), respectively; risks were greater with increasing CHA2DS2-VASc scores as follows, for scores of 1 through 6, respectively: (1) ischemic stroke with concomitant AF: 4.5%, 3.7%, 3.2%, 4.3%, 5.6%, and 8.4%; without concomitant AF: 1.5%, 1.5%, 2.0%, 3.0%, 3.7%, and 7% and (2) all-cause death with concomitant AF: 19.8%, 19.5%, 26.1%, 35.1%, 37.7%, and 45.5%; without concomitant AF: 7.6%, 8.3%, 17.8%, 25.6%, 27.9%, and 35.0%. At high CHA2DS2-VASc scores (≥4), the absolute risk of thromboembolism was high regardless of presence of AF (for a score of 4, 9.7% vs 8.2% for patients without and with concomitant AF, respectively; overall P<.001 for interaction). C statistics and negative predictive values indicate that the CHA2DS2-VASc score performed modestly in this HF population with and without AF (for ischemic stroke, 1-year C statistics, 0.67 [95% CI, 0.65-0.68] and 0.64 [95% CI, 0.61-0.67], respectively; 1-year negative predictive values, 92% [95% CI, 91%-93%] and 91% [95% CI, 88%-95%], respectively).

Conclusions and Relevance Among patients with incident HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke, thromboembolism, and death. The absolute risk of thromboembolic complications was higher among patients without AF compared with patients with concomitant AF at high CHA2DS2-VASc scores. However, predictive accuracy was modest, and the clinical utility of the CHA2DS2-VASc score in patients with HF remains to be determined.

Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation by Line Melgaard, et al. JAMA. 2015;314(10):1030-1038