The Global Epidemiological Transition in Cardiovascular Diseases: Unrecognised Impact of Endemic Infections on Peripheral Artery Disease.

An epidemiological transition in the prevalence of peripheral artery disease (PAD) is taking place especially in low- and middle-income countries (LMICs) where an ageing population and adoption of western lifestyles are associated with an increase in PAD. We discuss the limited evidence which suggests that infection, potentially mediated by inflammation, may be a risk factor for PAD, and show by means of an ecological analysis that country-level prevalence of the major endemic infections of HIV, tuberculosis and malaria are associated with the prevalence of PAD. While further research is required, we propose that scientists and health authorities pay more attention to the interplay between communicable and non-communicable diseases, and we suggest that limiting the occurrence of endemic infections might have some effect on slowing the epidemiological transition in PAD.

Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study.

BACKGROUND: Estimation of the epidemiological burden of carotid atherosclerosis can serve as a basis for prevention and management of cardiovascular disease. We aimed to provide the first estimation on the prevalence, number of cases, and risk factors for carotid atherosclerosis in the general population globally and regionally. METHODS: In this systematic review, meta-analysis, and modelling study, we searched PubMed, MEDLINE, Embase, Global Health, and China National Knowledge Infrastructure for articles published from database inception until May 7, 2019, with no language restrictions, for population-based studies that quantified prevalence of carotid atherosclerosis by means of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. Studies were eligible if they included bilaterally scanned carotid arteries using ultrasonography and defined increased carotid intima-media thickness as a thickness of 1·0 mm or more, carotid plaque as a focal carotid intima-media thickness of 1·5 mm or more encroaching into the lumen or at least 0·5 mm or 50% compared with the surrounding carotid intima-media thickness values, and carotid stenosis as 50% or more stenosis. Studies were excluded if the sample was not representative of the general population. We also included studies identified in our previous systematic review and meta-analysis of the prevalence of carotid atherosclerosis in China. We estimated age-specific and sex-specific prevalences of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. We used UN population data to generate the number of people affected in 2000, 2015, and 2020. We did random-effects meta-analyses to assess the effects of risk factors for increased carotid intima-media thickness and carotid plaque. We derived regional numbers of people living with increased carotid intima-media thickness and carotid plaque in 2015 using a risk factors-based model by WHO region. All analyses were done in populations aged 30-79 years due to availability of data. This systematic review and meta-analysis is registered online on PROSPERO, CRD42019134709. FINDINGS: We identified 8632 articles through our database search, of which 515 were eligible for full-text review, including 37 articles from our previous study, and 59 articles were eligible for inclusion in our systematic review and meta-analysis. Overall, in people aged 30-79 years in 2020, the global prevalence of increased carotid intima-media thickness is estimated to be 27·6% (95% CI 16·9-41·3), equivalent to 1066·70 million affected people and a percentage change of 57·46% from 2000; of carotid plaque is estimated to be 21·1% (13·2-31·5), equivalent to 815·76 million affected people and a percentage change of 58·97% from 2000; and carotid stenosis is estimated to be 1·5% (1·1-2·1), equivalent to 57·79 million affected people and a percentage change of 59·13% from 2000. The prevalence of increased carotid intima-media thickness, carotid plaque, and carotid stenosis increased consistently with age and was higher in men than in women. Current smoking, diabetes, and hypertension were common risk factors for increased carotid intima-media thickness and carotid plaque. In 2015, the Western Pacific region had the largest share of global cases of increased carotid intima-media thickness (317·62 million [33·36%] of 952·13 million affected people) and carotid plaque (240·77 million [33·20%] of 725·25 million), whereas the African region had the smallest share of cases of increased carotid intima-media thickness (59·08 million [6·21%]) and the Eastern Mediterranean region had the smallest share of carotid plaque cases (44·59 million [6·15%]). INTERPRETATION: A substantial global burden of carotid atherosclerosis exists. Effective strategies are needed for primary prevention and management of carotid atherosclerosis. High-quality epidemiological investigations on carotid atherosclerosis are needed to better address the global burden of carotid atherosclerosis at finer levels. FUNDING: None.

Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.

BACKGROUND: Peripheral artery disease is a major cardiovascular disease that affected 202 million people worldwide in 2010. In the past decade, new epidemiological data on peripheral artery disease have emerged, enabling us to provide updated estimates of the prevalence and risk factors for peripheral artery disease globally and regionally and, for the first time, nationally. METHODS: For this systematic review and analysis, we did a comprehensive literature search for studies reporting on the prevalence of peripheral artery disease in the general population that were published between Jan 1, 2011, and April 30, 2019, in PubMed, MEDLINE, Embase, the Global Health database, CINAHL, the Global Health Library, the Allied and Complementary Medicine Database, and ProQuest Dissertations and Theses Global. We also included the Global Peripheral Artery Disease Study of 2013 and the China Peripheral Artery Disease Study as sources. Peripheral artery disease had to be defined as an ankle-brachial index lower than or equal to 0·90. With a purpose-built data collection form, data on study characteristics, sample characteristics, prevalence, and risk factors were abstracted from all the included studies identified from the sources. Age-specific and sex-specific prevalence of peripheral artery disease was estimated in both high-income countries (HICs) and low-income and middle-income countries (LMICs). We also did random-effects meta-analyses to pool the odds ratios of 30 risk factors for peripheral artery disease in HICs and LMICs. UN population data were used to generate the number of people affected by the disease in 2015. Finally, we derived the regional and national numbers of people with peripheral artery disease on the basis of a risk factor-based model. FINDINGS: We included 118 articles for systematic review and analysis. The prevalence of peripheral artery disease increased consistently with age. At younger ages, prevalence was slightly higher in LMICs than HICs (4·32%, 95% CI 3·01-6·29, vs 3·54%, 1·17-10·24, at 40-44 years), but the increase with age was greater in HICs than LMICs, leading to a higher prevalence in HICs than LMICs at older ages (21·24%, 15·22-28·90, vs 12·04%, 8·67-16·60, at 80-84 years). In HICs, prevalence was slightly higher in women than in men up to age 75 years (eg, 7·81%, 3·97-14·77, vs 6·60%, 3·74-11·38, at 55-59 years), whereas in LMICs little difference was found between women and men (eg, 6·40%, 5·06-8·05, vs 6·37%, 4·74-8·49, at 55-59 years). Overall, the global prevalence of peripheral artery disease in people aged 25 years and older was 5·56%, 3·79-8·55, and the prevalence estimate was higher in HICs than that in LMICs (7·37%, 4·35-13·66, vs 5·09%, 3·64-7·24). Smoking, diabetes, hypertension, and hypercholesterolaemia were major risk factors for peripheral artery disease. Globally, a total of 236·62 million people aged 25 years and older were living with peripheral artery disease in 2015, among whom 72·91% were in LMICs. The Western Pacific Region had the most peripheral artery disease cases (74·08 million), whereas the Eastern Mediterranean Region had the least (14·67 million). More than two thirds of the global peripheral artery disease cases were concentrated in 15 individual countries in 2015. INTERPRETATION: Peripheral artery disease continues to become an increasingly serious public health problem, especially in LMICs. With the demographic trend towards ageing and projected rise in important risk factors, a larger burden of peripheral artery disease is to be expected in the foreseeable future. FUNDING: None.

Inter-arm blood pressure difference and mortality: a cohort study in an asymptomatic primary care population at elevated cardiovascular risk.

BACKGROUND: Differences in blood pressure between arms are associated with increased cardiovascular mortality in cohorts with established vascular disease or substantially elevated cardiovascular risk. AIM: To explore the association of inter-arm difference (IAD) with mortality in a community-dwelling cohort that is free of cardiovascular disease. DESIGN AND SETTING: Cohort analysis of a randomised controlled trial in central Scotland, from April 1998 to October 2008. METHOD: Volunteers from Lanarkshire, Glasgow, and Edinburgh, free of pre-existing vascular disease and with an ankle-brachial index ≤0.95, had systolic blood pressure measured in both arms at recruitment. Inter-arm blood pressure differences were calculated and examined for cross-sectional associations and differences in prospective survival. Outcome measures were cardiovascular events and all-cause mortality during mean follow-up of 8.2 years. RESULTS: Based on a single pair of measurements, 60% of 3350 participants had a systolic IAD ≥5 mmHg and 38% ≥10 mmHg. An IAD ≥5 mmHg was associated with increased cardiovascular mortality (adjusted hazard ratio [HR] 1.91, 95% confidence interval [CI] = 1.19 to 3.07) and all-cause mortality (adjusted HR 1.44, 95% CI = 1.15 to 1.79). Within the subgroup of 764 participants who had hypertension, IADs of ≥5 mmHg or ≥10 mmHg were associated with both cardiovascular mortality (adjusted HR 2.63, 95% CI = 0.97 to 7.02, and adjusted HR 2.96, 95% CI = 1.27 to 6.88, respectively) and all-cause mortality (adjusted HR 1.67, 95% CI = 1.05 to 2.66, and adjusted HR 1.63, 95% CI = 1.06 to 2.50, respectively). IADs ≥15 mmHg were not associated with survival differences in this population. CONCLUSION: Systolic IADs in blood pressure are associated with increased risk of cardiovascular events, including mortality, in a large cohort of people free of pre-existing vascular disease.

Progression of varicose veins and chronic venous insufficiency in the general population in the Edinburgh Vein Study.

OBJECTIVE: The natural history in the general population of chronic venous disease in the legs is not well understood. This has limited our ability to predict which patients will deteriorate and to assign clinical priorities. The aims of this study were to describe the progression of trunk varicose veins and chronic venous insufficiency (CVI) in the general population, to identify important lifestyle and clinical prognostic factors, and to determine the relationship between venous reflux and progression. METHODS: The Edinburgh Vein Study is a population-based cohort study in which randomly selected adults aged 18 to 64 years had an examination at baseline. This included a questionnaire on lifestyle and clinical factors, standardized assessment and classification of venous disease in the legs, and duplex scan to detect venous reflux in eight segments of each leg. A follow-up examination 13 years later included a reclassification of venous disease to ascertain progression in the development or increase in severity of varicose veins and CVI. RESULTS: Among 1566 adults seen at baseline, 880 had a follow-up examination, of whom 334 had trunk varicose veins or CVI at baseline and composed the study sample. The mean (standard deviation) duration of follow-up was 13.4 (0.4) years. Progression was found in 193 (57.8%), equivalent to 4.3% (95% confidence interval [CI], 3.7-4.9) annually. In 270 subjects with only varicose veins at baseline, 86 (31.9%) developed CVI, with the rate increasing consistently with age (P = .04). Almost all subjects (98%) with both varicose veins and CVI at baseline deteriorated. Progression of chronic venous disease did not differ by gender or leg, but a family history of varicose veins and history of deep venous thrombosis increased risk (odds ratio [OR], 1.85 [95% CI, 1.14-1.30] and 4.10 [95% CI, 1.07-15.71], respectively). Overweight was associated with increased risk of CVI in those with varicose veins (OR, 1.85; 95% CI, 1.10-3.12). Reflux in the superficial system increased the likelihood of progression, especially in combination with deep reflux (OR, 2.57; 95% CI, 1.55-4.25) and when located in the small saphenous vein (OR, 4.73; 95% CI, 1.37-16.39). CONCLUSIONS: Nearly half of the general population with chronic venous disease deteriorated during 13 years, and almost one third with varicose veins developed skin changes of CVI, increasing their risk of ulceration. Age, family history of varicose veins, history of deep venous thrombosis, overweight, and superficial reflux, especially in the small saphenous vein and with deep reflux, might influence the risk of progression.

Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010.

A comprehensive and systematic assessment of disability and mortality due to lower extremity peripheral artery disease (PAD) is lacking. Therefore, we estimated PAD deaths, disability-adjusted life years (DALYs), and years of life lost in 21 regions worldwide for 1990 and 2010. We used the GBD (Global Burden of Diseases 2010) study causes of death database, and the cause of death ensemble modeling approach to assess levels and trends of PAD deaths and years of life lost over time, by age, sex, and region. Assessment of DALYs employed estimates of PAD prevalence from systematic reviews of epidemiologic data using a Bayesian meta-regression method. In 1990, the age-specific PAD death rate per 100,000 population ranged from 0.05 (95% confidence interval [CI]: 0.03 to 0.09) among those 40 to 44 years old to 16.63 (95% CI: 10.47 to 25.31) among the 80+ years group. In 2010, the corresponding estimates were 0.07 (95% CI: 0.04 to 0.13) and 28.71 (95% CI: 18.3 to 43.06). Death rates increased consistently with age in 1990 and 2010, and the rates in 2010 were higher than they were in 1990 in all age categories. The largest relative change in median death rate of +6.03 per 100,000 (95% CI: 1.50 to 11.85) was noted in the Asia Pacific-High Income region and was largely driven by higher rates in women: +17.36 (95% CI: 1.79 to 32.01) versus +1.25 (95% CI: 0.13 to 2.39) in men. The overall relative change in median DALYs was larger in developing nations than in developed nations: 1.15 (95% CI: 0.80 to 1.66) versus 0.77 (95% CI: 0.55 to 1.08). Of note, the overall relative change in median DALYs was higher among both men and women in developing versus developed countries: men: 1.18 (95% CI: 0.82 to 1.65) versus 0.51 (95% CI: 0.30 to 0.81), and women: 1.11 (95% CI: 0.58 to 2.02) versus 1 (95% CI: 0.67 to 1.47). Within developed nations, the overall relative change in median DALY rates was larger in women than in men: +1.00 (95% CI: 0.67 to 1.47) versus +0.51 (95% CI: 0.3 to 0.81). Similarly, the overall relative change in median years of life lost rate in developed countries was larger in women than in men: +1.64 (95% CI: 1.17 to 2.34) versus +0.53 (95% CI: 0.24 to 0.94). The relative increases in median years lived with nonfatal disease disability (YLD) rates in men and women were larger in developing versus developed nations: men: 0.87 (95% CI: 0.59 to 1.2) versus 0.49 (95% CI: 0.29 to 0.73), and women: 0.75 (95% CI: 0.46 to 1.09) versus 0.49 (95% CI: 0.29 to 0.73). Disability and mortality associated with PAD has increased over the last 20 years, and this increase in burden has been greater among women than among men. In addition, the burden of PAD is no longer confined to the elderly population, but now involves young adults. Furthermore, the relative increase in PAD burden in developing regions of the world is striking and exceeds the increases in developed nations.

Global and regional burden of aortic dissection and aneurysms: mortality trends in 21 world regions, 1990 to 2010.

A comprehensive and systematic assessment of the global burden of aortic aneurysms (AA) has been lacking. Therefore, we estimated AA regional deaths and years of life lost (YLL) in 21 regions worldwide for 1990 and 2010. We used the GBD (Global Burden of Disease) 2010 study causes of death database and the cause of death ensemble modeling approach to assess levels and trends of AA deaths by age, sex, and GBD region. The global AA death rate per 100,000 population was 2.49 (95% CI: 1.78 to 3.27) in 1990 and 2.78 (95% CI: 2.04 to 3.62) in 2010. In 1990 and 2010, the highest mean death rates were in Australasia and Western Europe: 8.82 (95% CI: 6.96 to 10.79) and 7.69 (95% CI: 6.11 to 9.57) in 1990 and 8.38 (95% CI: 6.48 to 10.86) and 7.68 (95% CI: 6.13 to 9.54) in 2010. YLL rates by GBD region mirrored the mortality rate pattern. Overall, men had higher AA death rates than women: 2.86 (95% CI: 1.90 to 4.22) versus 2.12 (95% CI: 1.33 to 3.00) in 1990 and 3.40 (95% CI: 2.26 to 5.01) versus 2.15 (95% CI: 1.44 to 2.89) in 2010. The relative change in median death rate was +0.22 (95% CI: 0.10 to 0.33) in developed nations versus +0.71 (95% CI: 0.28 to 1.40) in developing nations. The smallest relative changes in median death rate were noted in North America high income, Central Europe, Western Europe, and Australasia, with estimates of +0.07 (95% CI: -0.26 to 0.37), +0.08 (95% CI: -0.02 to 0.23), +0.09 (95% CI: -0.02 to 0.21), and +0.22 (95% CI: -0.08 to 0.46), respectively. The largest increases were in Asia Pacific high income, Southeast Asia, Latin America tropical, Oceania, South Asia, and Central Sub-Saharan Africa. Women rather than men drove the increase in the Asia Pacific high-income region: the relative change in median rates was +2.92 (95% CI: 0.6 to 4.35) versus +1.05 (95% CI: 0.61 to 2.42). In contrast to high-income regions, the observed pattern in developing regions suggests increasing AA burden, which portends future health system challenges in these regions.

Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010.

The global burden of abdominal aortic aneurysm (AAA) has not been studied previously. Such information is important given the emergence of cardiovascular diseases in developing countries. We conducted a systematic literature review and estimated the global and regional incidence and prevalence of AAA in 21 world regions by age and sex. The search for prevalence and incidence of AAA using standard clinical and epidemiological terms was conducted using MEDLINE (1950 to 2010), EMBASE (1980 to 2010), AMED (1985 to 2010), CINAHL (1982 to 2010), and LILACS (2008 to 2010). Data abstracted from the systematic review served as priors for Bayesian meta-regression analyses. The analysis drew from 26 high-quality studies to estimate AAA prevalence and incidence. In 1990, the global age-specific prevalence rate per 100,000 ranged from 8.43 (95% CI: 7.03 to 10.14) in the 40 to 44 years age group to 2,422.53 (95% CI: 2,298.63 to 2,562.25) in the 75 to 79 years age group; the corresponding range in 2010 was 7.88 (95% CI: 6.54 to 9.59) to 2,274.82 (95% CI: 2,149.77 to 2,410.17). Prevalence was higher in developed versus developing nations, and the rates within each development stratum decreased between 1990 and 2010. Globally, the age-specific annual incidence rate per 100,000 in 1990 ranged from 0.89 (95% CI: 0.66 to 1.17) in 40 to 44 years age group to 176.08 (95% CI: 162.72 to 190.28) in the 75 to 79 years age group. In 2010, this range was 0.83 (95% CI: 0.61 to 1.11) to 164.57 (95% CI: 152.20 to 178.78). The highest prevalence in 1990 was in Australasia and North America high income regions: 382.65 (95% CI: 356.27 to 410.88) and 300.59 (95% CI: 280.93 to 321.54), respectively. Australasia had the highest prevalence in 2010, although the prevalence decreased to 310.27 (95% CI: 289.01 to 332.94). Regional prevalence increased in Oceania, tropical Latin America, Asia Pacific high income, Southern Sub-Saharan Africa (SSA), Central SSA, South Asia, Western SSA, and Central Asia. AAA global prevalence and incidence rates have decreased over the last 20 years. However, rising rates in some regions highlight the need for policies to enhance global disease surveillance and prevention.

Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.

BACKGROUND: Lower extremity peripheral artery disease is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke. This study provides the first comparison of the prevalence of peripheral artery disease between high-income countries (HIC) and low-income or middle-income countries (LMIC), establishes the primary risk factors for peripheral artery disease in these settings, and estimates the number of people living with peripheral artery disease regionally and globally. METHODS: We did a systematic review of the literature on the prevalence of peripheral artery disease in which we searched for community-based studies since 1997 that defined peripheral artery disease as an ankle brachial index (ABI) lower than or equal to 0·90. We used epidemiological modelling to define age-specific and sex-specific prevalence rates in HIC and in LMIC and combined them with UN population numbers for 2000 and 2010 to estimate the global prevalence of peripheral artery disease. Within a subset of studies, we did meta-analyses of odds ratios (ORs) associated with 15 putative risk factors for peripheral artery disease to estimate their effect size in HIC and LMIC. We then used the risk factors to predict peripheral artery disease numbers in eight WHO regions (three HIC and five LMIC). FINDINGS: 34 studies satisfied the inclusion criteria, 22 from HIC and 12 from LMIC, including 112,027 participants, of which 9347 had peripheral artery disease. Sex-specific prevalence rates increased with age and were broadly similar in HIC and LMIC and in men and women. The prevalence in HIC at age 45-49 years was 5·28% (95% CI 3·38-8·17%) in women and 5·41% (3·41-8·49%) in men, and at age 85-89 years, it was 18·38% (11·16-28·76%) in women and 18·83% (12·03-28·25%) in men. Prevalence in men was lower in LMIC than in HIC (2·89% [2·04-4·07%] at 45-49 years and 14·94% [9·58-22·56%] at 85-89 years). In LMIC, rates were higher in women than in men, especially at younger ages (6·31% [4·86-8·15%] of women aged 45-49 years). Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72 (95% CI 2·39-3·09) in HIC and 1·42 (1·25-1·62) in LMIC, followed by diabetes (1·88 [1·66-2·14] vs 1·47 [1·29-1·68]), hypertension (1·55 [1·42-1·71] vs 1·36 [1·24-1·50]), and hypercholesterolaemia (1·19 [1·07-1·33] vs 1·14 [1·03-1·25]). Globally, 202 million people were living with peripheral artery disease in 2010, 69·7% of them in LMIC, including 54·8 million in southeast Asia and 45·9 million in the western Pacific Region. During the preceding decade the number of individuals with peripheral artery disease increased by 28·7% in LMIC and 13·1% in HIC. INTERPRETATION: In the 21st century, peripheral artery disease has become a global problem. Governments, non-governmental organisations, and the private sector in LMIC need to address the social and economic consequences, and assess the best strategies for optimum treatment and prevention of this disease. FUNDING: Peripheral Arterial Disease Research Coalition (Europe).

Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.

BACKGROUND: Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS: We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS: Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009). INTERPRETATION: Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING: None.

Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.

BACKGROUND: The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. METHODS: We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks). FINDINGS: The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 µmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 µmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. INTERPRETATION: In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

BACKGROUND: Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. METHODS: We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. RESULTS: In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older. INTERPRETATION: Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention. FUNDING: None.

Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: Cerebral microvascular disease associated with type 2 diabetes may exacerbate the effects of aging on cognitive function. A considerable homology exists between the retinal and cerebral microcirculations; a hypothesized association between diabetic retinopathy (DR) and cognitive decline was examined in older people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In the population-based Edinburgh Type 2 Diabetes Study, 1,046 men and women aged 60-75 years with type 2 diabetes underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. DR was graded using a modification of the Early Treatment of Diabetic Retinopathy Scale. RESULTS: After age and sex adjustment, a significant relationship was observed with increasing severity of DR (none, mild, and moderate to severe) for most cognitive measures. Participants with moderate-to-severe retinopathy had the worst g and the worst performances on the individual tests. There was a significant interaction between sex and retinopathy for g. In male subjects, the associations of retinopathy with g (and with tests of verbal fluency, mental flexibility, and processing speed but not memory and nonverbal reasoning) persisted (P < 0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, sociodemographic characteristics, cardiovascular risk factors, and macrovascular disease. CONCLUSIONS: DR was independently associated with estimated lifetime cognitive decline in older men with type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A sex interaction with stronger findings in men requires further confirmation.

Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.

CONTEXT: A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments. OBJECTIVE: To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population. DESIGN, SETTING, AND PARTICIPANTS: The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events. INTERVENTIONS: Once daily 100 mg aspirin (enteric coated) or placebo. MAIN OUTCOME MEASURES: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality. RESULTS: After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97). CONCLUSION: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN66587262.

Ankle--brachial index predicts level of, but not change in, cognitive function: the Edinburgh Artery Study at the 15-year follow-up.

The ankle-brachial index (ABI), a marker of generalized atherosclerosis, is related to cognitive impairment in older adults. We investigated whether ABI is associated specifically with age-related cognitive decline. We measured ABI at recruitment and 5 and 12 years later in a sample of individuals aged 55-74 years. Cognition was measured in 717 of these participants 10 years after recruitment and 5 years later. It was found that ABI was associated with the level of cognitive function, even after adjustment for estimated premorbid function and concurrently measured anxiety and depression (standardized coefficient of 0.07), but this was attenuated by anxiety and depression. ABI was not associated with change in cognitive function. In conclusion, over long time periods, low ABI may be associated with reduced cognitive function in older adults, at least partly because the associated poor health creates anxiety and depression.

Intelligence and persisting with medication for two years: Analysis in a randomised controlled trial.

The study examined whether verbal intelligence is associated with persisting to take medication for up to two years. The design is a prospective follow-up of compliance with taking medication in high-risk individuals participating in a randomised, placebo-controlled trial set in Central Scotland. Participants were 1993 people aged between 50 and 77 years with an ankle brachial index

Metabolic syndrome, haemostatic and inflammatory markers, cerebrovascular and peripheral arterial disease: The Edinburgh Artery Study.

The role of metabolic syndrome and associated haemostatic and inflammatory markers in risk of atherosclerosis in different vascular beds is controversial. We used modified National Cholesterol Education Program criteria to define metabolic syndrome in a population-based cohort of men and women aged 55-74 years with up to 15 years of follow-up to investigate whether metabolic syndrome is associated with risk of cerebrovascular and peripheral arterial disease and the role of inflammatory and haemostatic factors in these relationships. Data were available for 762 participants, of whom 267 (35%) had metabolic syndrome at baseline and 69 (9.0%) and 108 (14%) had cerebrovascular and peripheral arterial disease events, respectively, during follow-up. We used Cox proportional hazards modelling to estimate hazard ratios (HRs). Metabolic syndrome was associated with several haemostatic and inflammatory variables and with cerebrovascular disease both after adjusting for age and sex (HR 2.12 (1.31-3.41) and after further adjustment for conventional cardiovascular risk factors and inflammatory and haemostatic markers (HR 1.77 (1.05-2.96). The association between metabolic syndrome and peripheral arterial disease was not statistically significant either with adjustment for age and sex (HR 1.33 (0.90-1.96) or after full adjustment (HR 0.89 (0.57-1.38). We conclude that metabolic syndrome was more strongly related to risk of atherosclerosis in the cerebrovascular than the peripheral circulation and the association was independent of conventional risk factors, haemostatic and inflammatory markers in this population. Improving insulin sensitivity may reduce cerebrovascular disease risk.

Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts.

BACKGROUND: Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events. METHODS: We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship. RESULTS: NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and -0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of <5, 5-10 and >10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0-0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP. CONCLUSIONS: CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent. Guidance on the clinical use of CRP measurement in the prediction of coronary events may require updating in light of this large comparative analysis.

The Edinburgh Type 2 Diabetes Study: study protocol.

BACKGROUND: Risk factors underlying the development and progression of some of the less well-recognised complications of type 2 diabetes, including cognitive impairment and non-alcoholic fatty liver disease, are poorly understood. The Edinburgh Type 2 Diabetes Study was established in 2006 in order to investigate the role of potential risk factors in these complications, as well as to further investigate mechanisms underlying the development and progression of micro and macrovascular disease in type 2 diabetes. METHODS AND DESIGN: The study is designed as a prospective cohort study. Participants recruited at baseline (2006-2007) constitute 1066 men and women aged 60 to 75 years with established type 2 diabetes, living in the Lothian region of central Scotland. Subjects underwent detailed cognitive and physical examination, the latter including measures of micro- and macro-vascular disease, glycaemic control, body fat composition and plasma inflammatory markers, cortisol, lipids and liver function tests. Participants were re-examined after one year with hepatic ultrasonography and additional measures of vascular disease. This paper reports the methods of recruitment to the study and examinations performed at baseline and one year. Follow-up cognitive, vascular and liver assessments are scheduled for 2010-2011 when subjects will have been in the study for 4 years. DISCUSSION: This study will provide a wealth of epidemiological and biomarker data that should be invaluable in the identification of potentially modifiable, causal risk factors for diabetes-related cognitive impairment, liver dysfunction and vascular disease, which can be targeted for the development of preventive and therapeutic interventions.