METHODS: In this large-scale prospective cohort study, we recruited adults aged between 35 years and 70 years from 367 urban and 302 rural communities in 20 countries. We collected data on families and households in two questionnaires, and data on cardiovascular risk factors in a third questionnaire, which was supplemented with physical examination. We assessed socioeconomic status using education and a household wealth index. Education was categorised as no or primary school education only, secondary school education, or higher education, defined as completion of trade school, college, or university. Household wealth, calculated at the household level and with household data, was defined by an index on the basis of ownership of assets and housing characteristics. Primary outcomes were major cardiovascular disease (a composite of cardiovascular deaths, strokes, myocardial infarction, and heart failure), cardiovascular mortality, and all-cause mortality. Information on specific events was obtained from participants or their family.
FINDINGS: Recruitment to the study began on Jan 12, 2001, with most participants enrolled between Jan 6, 2005, and Dec 4, 2014. 160 299 (87·9%) of 182 375 participants with baseline data had available follow-up event data and were eligible for inclusion. After exclusion of 6130 (3·8%) participants without complete baseline or follow-up data, 154 169 individuals remained for analysis, from five low-income, 11 middle-income, and four high-income countries. Participants were followed-up for a mean of 7·5 years. Major cardiovascular events were more common among those with low levels of education in all types of country studied, but much more so in low-income countries. After adjustment for wealth and other factors, the HR (low level of education vs high level of education) was 1·23 (95% CI 0·96-1·58) for high-income countries, 1·59 (1·42-1·78) in middle-income countries, and 2·23 (1·79-2·77) in low-income countries (pinteraction<0·0001). We observed similar results for all-cause mortality, with HRs of 1·50 (1·14-1·98) for high-income countries, 1·80 (1·58-2·06) in middle-income countries, and 2·76 (2·29-3·31) in low-income countries (pinteraction<0·0001). By contrast, we found no or weak associations between wealth and these two outcomes. Differences in outcomes between educational groups were not explained by differences in risk factors, which decreased as the level of education increased in high-income countries, but increased as the level of education increased in low-income countries (pinteraction<0·0001). Medical care (eg, management of hypertension, diabetes, and secondary prevention) seemed to play an important part in adverse cardiovascular disease outcomes because such care is likely to be poorer in people with the lowest levels of education compared to those with higher levels of education in low-income countries; however, we observed less marked differences in care based on level of education in middle-income countries and no or minor differences in high-income countries.
INTERPRETATION: Although people with a lower level of education in low-income and middle-income countries have higher incidence of and mortality from cardiovascular disease, they have better overall risk factor profiles. However, these individuals have markedly poorer health care. Policies to reduce health inequities globally must include strategies to overcome barriers to care, especially for those with lower levels of education.
FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).
METHODS: We obtained random urine samples from 9,275 cases of acute first stroke and 9,726 matched controls from 27 countries and estimated the 24-hour sodium and potassium excretion, a surrogate for intake, using the Tanaka formula. Using multivariable conditional logistic regression, we determined the associations of estimated 24-hour urinary sodium and potassium excretion with stroke and its subtypes.
RESULTS: Compared with an estimated urinary sodium excretion of 2.8-3.5 g/day (reference), higher (>4.26 g/day) (odds ratio [OR] 1.81; 95% confidence interval [CI], 1.65-2.00) and lower (<2.8 g/day) sodium excretion (OR 1.39; 95% CI, 1.26-1.53) were significantly associated with increased risk of stroke. The stroke risk associated with the highest quartile of sodium intake (sodium excretion >4.26 g/day) was significantly greater (P < 0.001) for intracerebral hemorrhage (ICH) (OR 2.38; 95% CI, 1.93-2.92) than for ischemic stroke (OR 1.67; 95% CI, 1.50-1.87). Urinary potassium was inversely and linearly associated with risk of stroke, and stronger for ischemic stroke than ICH (P = 0.026). In an analysis of combined sodium and potassium excretion, the combination of high potassium intake (>1.58 g/day) and moderate sodium intake (2.8-3.5 g/day) was associated with the lowest risk of stroke.
CONCLUSIONS: The association of sodium intake and stroke is J-shaped, with high sodium intake a stronger risk factor for ICH than ischemic stroke. Our data suggest that moderate sodium intake-rather than low sodium intake-combined with high potassium intake may be associated with the lowest risk of stroke and expected to be a more feasible combined dietary target.
METHODS: The Prospective Urban Rural Epidemiology (PURE) study is a prospective epidemiological study of individuals aged 35 and 70 years from 21 countries on five continents, with a median follow-up of 9.1 years. In the cross-sectional analyses, we assessed the association of dairy intake with prevalent MetS and its components among individuals with information on the five MetS components (n=112 922). For the prospective analyses, we examined the association of dairy with incident hypertension (in 57 547 individuals free of hypertension) and diabetes (in 131 481 individuals free of diabetes).
RESULTS: In cross-sectional analysis, higher intake of total dairy (at least two servings/day compared with zero intake; OR 0.76, 95% CI 0.71 to 0.80, p-trend<0.0001) was associated with a lower prevalence of MetS after multivariable adjustment. Higher intakes of whole fat dairy consumed alone (OR 0.72, 95% CI 0.66 to 0.78, p-trend<0.0001), or consumed jointly with low fat dairy (OR 0.89, 95% CI 0.80 to 0.98, p-trend=0.0005), were associated with a lower MetS prevalence. Low fat dairy consumed alone was not associated with MetS (OR 1.03, 95% CI 0.77 to 1.38, p-trend=0.13). In prospective analysis, 13 640 people with incident hypertension and 5351 people with incident diabetes were recorded. Higher intake of total dairy (at least two servings/day vs zero serving/day) was associated with a lower incidence of hypertension (HR 0.89, 95% CI 0.82 to 0.97, p-trend=0.02) and diabetes (HR 0.88, 95% CI 0.76 to 1.02, p-trend=0.01). Directionally similar associations were found for whole fat dairy versus each outcome.
CONCLUSIONS: Higher intake of whole fat (but not low fat) dairy was associated with a lower prevalence of MetS and most of its component factors, and with a lower incidence of hypertension and diabetes. Our findings should be evaluated in large randomized trials of the effects of whole fat dairy on the risks of MetS, hypertension, and diabetes.
METHODS: In the Prospective Urban Rural Epidemiology (PURE) study, participants aged 35-70 years (n=156 625) were recruited from 110 803 households, in 604 communities and 22 countries; availability (presence of any dose of medication in the pharmacy on the day of audit) and medicine cost data were collected from pharmacies with the Environmental Profile of a Community's Health audit tool. Our primary analysis was to describe the availability and affordability of metformin and insulin and also commonly used and prescribed combinations of two medicines for diabetes management (two oral drugs, metformin plus a sulphonylurea [either glibenclamide (also known as glyburide) or gliclazide] and one oral drug plus insulin [metformin plus insulin]). Medicines were defined as affordable if the cost of medicines was less than 20% of capacity-to-pay (the household income minus food expenditure). Our analyses included data collected in pharmacies and data from representative samples of households. Data on availability were ascertained during the pharmacy audit, as were data on cost of medications. These cost data were used to estimate the cost of a month's supply of essential medicines for diabetes. We estimated affordability of medicines using income data from household surveys.
FINDINGS: Metformin was available in 113 (100%) of 113 pharmacies from high-income countries, 112 (88·2%) of 127 pharmacies in upper-middle-income countries, 179 (86·1%) of 208 pharmacies in lower-middle-income countries, 44 (64·7%) of 68 pharmacies in low-income countries (excluding India), and 88 (100%) of 88 pharmacies in India. Insulin was available in 106 (93·8%) pharmacies in high-income countries, 51 (40·2%) pharmacies in upper-middle-income countries, 61 (29·3%) pharmacies in lower-middle-income countries, seven (10·3%) pharmacies in lower-income countries, and 67 (76·1%) of 88 pharmacies in India. We estimated 0·7% of households in high-income countries and 26·9% of households in low-income countries could not afford metformin and 2·8% of households in high-income countries and 63·0% of households in low-income countries could not afford insulin. Among the 13 569 (8·6% of PURE participants) that reported a diagnosis of diabetes, 1222 (74·0%) participants reported diabetes medicine use in high-income countries compared with 143 (29·6%) participants in low-income countries. In multilevel models, availability and affordability were significantly associated with use of diabetes medicines.
INTERPRETATION: Availability and affordability of essential diabetes medicines are poor in low-income and middle-income countries. Awareness of these global differences might importantly drive change in access for patients with diabetes.
FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).
METHODS: The Prospective Urban Rural Epidemiology (PURE) study is a large multinational cohort study of individuals aged 35-70 years enrolled from 21 countries in five continents. Dietary intakes of dairy products for 136 384 individuals were recorded using country-specific validated food frequency questionnaires. Dairy products comprised milk, yoghurt, and cheese. We further grouped these foods into whole-fat and low-fat dairy. The primary outcome was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, non-fatal myocardial infarction, stroke, or heart failure). Hazard ratios (HRs) were calculated using multivariable Cox frailty models with random intercepts to account for clustering of participants by centre.
FINDINGS: Between Jan 1, 2003, and July 14, 2018, we recorded 10 567 composite events (deaths [n=6796] or major cardiovascular events [n=5855]) during the 9·1 years of follow-up. Higher intake of total dairy (>2 servings per day compared with no intake) was associated with a lower risk of the composite outcome (HR 0·84, 95% CI 0·75-0·94; ptrend=0·0004), total mortality (0·83, 0·72-0·96; ptrend=0·0052), non-cardiovascular mortality (0·86, 0·72-1·02; ptrend=0·046), cardiovascular mortality (0·77, 0·58-1·01; ptrend=0·029), major cardiovascular disease (0·78, 0·67-0·90; ptrend=0·0001), and stroke (0·66, 0·53-0·82; ptrend=0·0003). No significant association with myocardial infarction was observed (HR 0·89, 95% CI 0·71-1·11; ptrend=0·163). Higher intake (>1 serving vs no intake) of milk (HR 0·90, 95% CI 0·82-0·99; ptrend=0·0529) and yogurt (0·86, 0·75-0·99; ptrend=0·0051) was associated with lower risk of the composite outcome, whereas cheese intake was not significantly associated with the composite outcome (0·88, 0·76-1·02; ptrend=0·1399). Butter intake was low and was not significantly associated with clinical outcomes (HR 1·09, 95% CI 0·90-1·33; ptrend=0·4113).
INTERPRETATION: Dairy consumption was associated with lower risk of mortality and major cardiovascular disease events in a diverse multinational cohort.
FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).
METHODS: We did a prospective cohort study (Prospective Urban Rural Epidemiology [PURE] in 135 335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, the Middle East, south Asia, China, southeast Asia, and Africa. We documented their diet using country-specific food frequency questionnaires at baseline. Standardised questionnaires were used to collect information about demographic factors, socioeconomic status (education, income, and employment), lifestyle (smoking, physical activity, and alcohol intake), health history and medication use, and family history of cardiovascular disease. The follow-up period varied based on the date when recruitment began at each site or country. The main clinical outcomes were major cardiovascular disease (defined as death from cardiovascular causes and non-fatal myocardial infarction, stroke, and heart failure), fatal and non-fatal myocardial infarction, fatal and non-fatal strokes, cardiovascular mortality, non-cardiovascular mortality, and total mortality. Cox frailty models with random effects were used to assess associations between fruit, vegetable, and legume consumption with risk of cardiovascular disease events and mortality.
FINDINGS: Participants were enrolled into the study between Jan 1, 2003, and March 31, 2013. For the current analysis, we included all unrefuted outcome events in the PURE study database through March 31, 2017. Overall, combined mean fruit, vegetable and legume intake was 3·91 (SD 2·77) servings per day. During a median 7·4 years (5·5-9·3) of follow-up, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect). The estimates were substantially attenuated in the multivariable adjusted models for major cardiovascular disease (hazard ratio [HR] 0·90, 95% CI 0·74-1·10, ptrend=0·1301), myocardial infarction (0·99, 0·74-1·31; ptrend=0·2033), stroke (0·92, 0·67-1·25; ptrend=0·7092), cardiovascular mortality (0·73, 0·53-1·02; ptrend=0·0568), non-cardiovascular mortality (0·84, 0·68-1·04; ptrend =0·0038), and total mortality (0·81, 0·68-0·96; ptrend<0·0001). The HR for total mortality was lowest for three to four servings per day (0·78, 95% CI 0·69-0·88) compared with the reference group, with no further apparent decrease in HR with higher consumption. When examined separately, fruit intake was associated with lower risk of cardiovascular, non-cardiovascular, and total mortality, while legume intake was inversely associated with non-cardiovascular death and total mortality (in fully adjusted models). For vegetables, raw vegetable intake was strongly associated with a lower risk of total mortality, whereas cooked vegetable intake showed a modest benefit against mortality.
INTERPRETATION: Higher fruit, vegetable, and legume consumption was associated with a lower risk of non-cardiovascular, and total mortality. Benefits appear to be maximum for both non-cardiovascular mortality and total mortality at three to four servings per day (equivalent to 375-500 g/day).
FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).
METHODS: A cross-section of 163,397 adults aged 35 to 70 years were recruited from 661 urban and rural communities in selected low-, middle- and high-income countries (complete data for this analysis from 151,619 participants). Using blood pressure measurements, self-reported health and household data, concentration indices adjusted for age, sex and urban-rural location, we estimate the magnitude of wealth-related inequalities in the levels of hypertension awareness, treatment, and control in each of the 21 country samples.
RESULTS: Overall, the magnitude of wealth-related inequalities in hypertension awareness, treatment, and control was observed to be higher in poorer than in richer countries. In poorer countries, levels of hypertension awareness and treatment tended to be higher among wealthier households; while a similar pro-rich distribution was observed for hypertension control in countries at all levels of economic development. In some countries, hypertension awareness was greater among the poor (Sweden, Argentina, Poland), as was treatment (Sweden, Poland) and control (Sweden).
CONCLUSION: Inequality in hypertension management outcomes decreased as countries became richer, but the considerable variation in patterns of wealth-related inequality - even among countries at similar levels of economic development - underscores the importance of health systems in improving hypertension management for all. These findings show that some, but not all, countries, including those with limited resources, have been able to achieve more equitable management of hypertension; and strategies must be tailored to national contexts to achieve optimal impact at population level.
METHODS: Using data from the PURE Study, we estimated risk of catastrophic health spending and impoverishment among households with at least one person with NCDs (cardiovascular disease, diabetes, kidney disease, cancer and respiratory diseases; n=17 435), with hypertension only (a leading risk factor for NCDs; n=11 831) or with neither (n=22 654) by country income group: high-income countries (Canada and Sweden), upper middle income countries (UMICs: Brazil, Chile, Malaysia, Poland, South Africa and Turkey), lower middle income countries (LMICs: the Philippines, Colombia, India, Iran and the Occupied Palestinian Territory) and low-income countries (LICs: Bangladesh, Pakistan, Zimbabwe and Tanzania) and China.
RESULTS: The prevalence of catastrophic spending and impoverishment is highest among households with NCDs in LMICs and China. After adjusting for covariates that might drive health expenditure, the absolute risk of catastrophic spending is higher in households with NCDs compared with no NCDs in LMICs (risk difference=1.71%; 95% CI 0.75 to 2.67), UMICs (0.82%; 95% CI 0.37 to 1.27) and China (7.52%; 95% CI 5.88 to 9.16). A similar pattern is observed in UMICs and China for impoverishment. A high proportion of those with NCDs in LICs, especially women (38.7% compared with 12.6% in men), reported not taking medication due to costs.
CONCLUSIONS: Our findings show that financial protection from healthcare costs for people with NCDs is inadequate, particularly in LMICs and China. While the burden of NCD care may appear greatest in LMICs and China, the burden in LICs may be masked by care foregone due to costs. The high proportion of women reporting foregone care due to cost may in part explain gender inequality in treatment of NCDs.
METHODS: We assessed use of antiplatelet, cholesterol, and blood-pressure-lowering drugs in 8492 individuals with self-reported cardiovascular disease from 21 countries enrolled in the Prospective Urban Rural Epidemiology (PURE) study. Defining one or more drugs as a minimal level of secondary prevention, wealth-related inequality was measured using the Wagstaff concentration index, scaled from -1 (pro-poor) to 1 (pro-rich), standardised by age and sex. Correlations between inequalities and national health-related indicators were estimated.
FINDINGS: The proportion of patients with cardiovascular disease on three medications ranged from 0% in South Africa (95% CI 0-1·7), Tanzania (0-3·6), and Zimbabwe (0-5·1), to 49·3% in Canada (44·4-54·3). Proportions receiving at least one drug varied from 2·0% (95% CI 0·5-6·9) in Tanzania to 91·4% (86·6-94·6) in Sweden. There was significant (p<0·05) pro-rich inequality in Saudi Arabia, China, Colombia, India, Pakistan, and Zimbabwe. Pro-poor distributions were observed in Sweden, Brazil, Chile, Poland, and the occupied Palestinian territory. The strongest predictors of inequality were public expenditure on health and overall use of secondary prevention medicines.
INTERPRETATION: Use of medication for secondary prevention of cardiovascular disease is alarmingly low. In many countries with the lowest use, pro-rich inequality is greatest. Policies associated with an equal or pro-poor distribution include free medications and community health programmes to support adherence to medications.
FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).
METHODS: We undertook a standardised case-control study in 32 countries (INTERSTROKE). Cases were patients with acute first stroke (n=13 462) who were matched by age, sex and site to controls (n=13 483). We evaluated the associations of knowledge, awareness and treatment of hypertension with risk of stroke and its subtypes and whether this varied by gross national income (GNI) of country. We estimated OR and population attributable risk (PAR) associated with treated and untreated hypertension.
RESULTS: Hypertension was associated with a graded increase in OR by reducing GNI, ranging from OR 1.92 (99% CI 1.48 to 2.49) to OR 3.27 (2.72 to 3.93) for highest to lowest country-level GNI (p-heterogeneity<0.0001). Untreated hypertension was associated with a higher OR for stroke (OR 5.25; 4.53 to 6.10) than treated hypertension (OR 2.60; 2.32 to 2.91) and younger age of first stroke (61.4 vs 65.4 years; p<0.01). Untreated hypertension was associated with a greater risk of intracerebral haemorrhage (OR 6.95; 5.61 to 8.60) than ischaemic stroke (OR 4.76; 3.99 to 5.68). The PAR associated with untreated hypertension was higher in lower-income regions, PAR 36.3%, 26.3%, 19.8% to 10.4% by increasing GNI of countries. Lifetime non-measurement of blood pressure was associated with stroke (OR 1.80; 1.32 to 2.46).
CONCLUSIONS: Deficits in knowledge, detection and treatment of hypertension contribute to higher risk of stroke, younger age of onset and larger proportion of intracerebral haemorrhage in lower-income countries.
METHODS: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined).
FINDINGS: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50).
INTERPRETATION: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke.
FUNDING: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.
METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation.
RESULTS: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528).
CONCLUSIONS: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.
METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.
RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.
CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.
RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.
CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).
METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo.
RESULTS: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD.
CONCLUSIONS: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy.