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Participants without cardiovascular disease who were at increased risk were randomly assigned to receive a polypill (containing a statin and three blood-pressure–lowering drugs) or placebo and to receive aspirin or placebo. At 4.6 years, the incidence of cardiovascular events was lower among participants receiving both the polypill and aspirin than among those receiving both placebos.

Low-Dose Aspirin and Recurrent Thromboembolism Results from the ASPIRE trial add evidence supporting the use of low-dose daily aspirin for preventing recurrent venous thromboembolism in patients who have had an initial unprovoked clotting episode. Patients who have had a first episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued. 1 – 4 Long-term treatment with a vitamin K antagonist is very effective in preventing a recurrence of venous thromboembolism while treatment continues 5 but has not been shown to improve survival, is associated with a substantially increased risk of bleeding, and is inconvenient for patients. 6 – 10 Consequently, many patients who have had a first episode of unprovoked venous thromboembolism discontinue anticoagulant therapy after 3 to 6 months despite recommendations to prolong therapy. 5 Low-dose aspirin is a simple, inexpensive, and widely . . .

Polypills have been approved in more than 30 countries, but worldwide experience with and availability of polypills remain limited, unlike fixed-dose combinations in other diseases such as HIV, tuberculosis, and malaria. In this Series review, we aim to propose a guide for the use of polypills in future research and clinical activities and to synthesise contemporary evidence supporting the use of polypills for prevention of atherosclerosis. Polypill uses can be categorised by population and indication, both of which influence the balance between benefits and risks. Populations include secondary prevention, high-risk primary prevention based on formal risk assessment, and primary prevention based on single risk factor measurement, such as age, also known as mass treatment. For each population, potential indications are initiation, step-up of current drug therapy, and straight substitution of individual drug components. We summarise efficacy and safety results from 13 polypill trials (9059 participants) done in 32 countries. Polypills improve adherence, are generally well tolerated, and reduce risk factor levels, although heterogeneity limits the certainty of the effect on risk factors. Trials published to date have not been designed to detect differences in clinical outcomes, and thus no significant differences between polypill and comparator groups have been reported. Polypill therapy could be one of the most scalable strategies to reduce the risk of premature mortality from atherosclerosis by 25% by 2025 by improving medication adherence and access, but further trial data and clinical experience will be useful to determine how polypills can best be implemented to achieve this goal.

Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services. Bill & Melinda Gates Foundation.

Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1–5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85–1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79–0·95; p=0·0018). Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. Eli Lilly and Company.

Tranexamic acid is an antifibrinolytic drug that reduces bleeding in patients undergoing cesarean section or cardiac surgery. In this randomized trial involving patients undergoing noncardiac surgery, the risk of bleeding was lower with tranexamic acid than with placebo, but noninferiority with respect to cardiovascular complications was not established.

In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown. We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies. Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53–0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38–0·70), revascularisation (0·54, 0·36–0·80), stroke (0·59, 0·45–0·78), and cardiovascular death (0·65, 0·52–0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001). Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors. Population Health Research Institute.

The role of low grade systemic inflammation as evidenced by elevated high sensitivity C-reactive protein (hsCRP) levels in the pathogenesis of atherosclerotic vascular disease has been intensely investigated through observational studies and clinical trials in the past two decades. On the basis of evidence that has accrued, hsCRP measurement has been integrated into the Reynolds risk scoring system to predict cardiovascular risk. The JUPITER trial proved the benefit of statins in cardiovascular risk reduction in patients with low grades of systemic inflammation and 'normal' cholesterol levels. However, substantial evidence has been generated from western studies. We, therefore, conducted a scoping review for studies done in India with a view to identify gaps in evidence and make further recommendations. Most Indian studies had small sample sizes and short term follow ups. There were no large population based prospective studies where patients were followed up for long periods of time for major cardiovascular end points. An analysis of the hsCRP level from the control arms of case-control studies derived a mean hsCRP value of 1.88 mg/l, which is higher than the western population where values < 1 mg/l are classified as low cardiovascular risk. Further large prospective cohort studies with longer term follow ups are essential before we can make further recommendations to integrate hsCRP into risk prediction models for cardiovascular disease prevention.

In one comparison from a 2-by-2 factorial trial, over 12,000 participants with a mean baseline blood pressure of 138/82 mm Hg were assigned to candesartan plus hydrochlorothiazide or to placebo. At 5.6 years, there was no between-group difference in the rates of cardiovascular events. High blood pressure is the leading risk factor for cardiovascular disease globally 1 and affects more than 1 billion adults worldwide. 2 Observational studies involving persons without cardiovascular disease show a graded increase in risk at systolic blood-pressure levels above 115 mm Hg. 3 It has been suggested that lowering blood pressure at any level above this value will reduce the risk of cardiovascular events. 4 Antihypertensive therapy has been clearly shown to reduce the risk of cardiovascular disease among people with vascular or renal disease, diabetes, or hypertension with end-organ damage or, in the absence of these conditions, among persons with a systolic . . .

In a 2-by-2 factorial trial, 12,705 persons at intermediate risk were assigned to candesartan plus hydrochlorothiazide or placebo and to rosuvastatin or placebo. At 5.6 years, combination therapy resulted in a significantly lower risk of cardiovascular events than dual placebo. Cardiovascular diseases are major causes of death and illness worldwide. 1 Both systolic blood pressure and low-density lipoprotein (LDL) cholesterol show graded associations with cardiovascular disease and together account for two thirds of the population-attributable risk of cardiovascular disease. 2 – 4 Therefore, combined lowering of LDL cholesterol and blood pressure can potentially have a bigger effect in reducing cardiovascular events than either intervention alone. Because the majority of cardiovascular events occur in persons at average risk with no previous cardiovascular disease, a strategy of broad population-based treatment of LDL cholesterol and blood pressure could be more effective than targeting only high-risk persons. . . .