Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress.

BACKGROUND: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. OBJECTIVES: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC "Triple Pill," three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. DESIGN: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130-160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety. RESULTS: Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024. CONCLUSION: Low-dose Triple Pill BP lowering could improve long-term outcome from ICH.

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial.

AIM: To estimate the associations between risk factors and cognitive decline (CD)/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death. MATERIALS AND METHODS: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression. RESULTS: During a median 5-year follow-up, 1827 participants (43.2% women) had CD/dementia (1718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had lower odds of CD/dementia than men (odds ratio [OR] [95% confidence interval], 0.88 [0.77, 1.00]); older age, higher total cholesterol, HbA1c, waist circumference, waist-to-height ratio, moderately increased albumin-creatinine ratio, stroke/transient ischaemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women-to-men ratio of ORs [ROR], 1.05 [1.00, 1.10] per 5 cm) and presence of anxiety/depression (ROR, 1.28 [1.01, 1.63]) were associated with greater ORs for CD/dementia in women than men. CONCLUSIONS: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms that underlie these sex differences.

Obesity as a risk factor for COVID-19 mortality in women and men in the UK biobank: Comparisons with influenza/pneumonia and coronary heart disease.

Obesity is associated with severe COVID-19 outcomes, yet, it is unclear whether the risk of COVID-19 mortality associated with obesity is similar between the sexes. We used data from the UK Biobank to assess the risk of COVID-19 mortality associated with various anthropometric measures in women and men. To put these results in context, we also compared these estimates with those for mortality from influenza/pneumonia and coronary heart disease (CHD). The analyses included 502 493 individuals (54% women), of whom 410 (36% women) died from COVID-19, 549 (36% women) died from influenza/pneumonia and 3355 (19% women) died from CHD. A higher body mass index (BMI), waist circumference, waist-to-hip ratio and waist-to-height ratio were each associated with a greater risk of death from COVID-19, influenza/pneumonia and CHD in both sexes, with the exception of the association between higher BMI and the risk of influenza/pneumonia death in men. A higher BMI was associated with a stronger risk of COVID-19 mortality in women than men; the women-to-men ratio of hazard ratios was 1.20 (95% confidence interval 1.00; 1.43). This study demonstrates the role of obesity in COVID-19 mortality and shows that the relative effects of a higher BMI on COVID-19 mortality may be stronger in women than men.

SMARThealth India: A stepped-wedge, cluster randomised controlled trial of a community health worker managed mobile health intervention for people assessed at high cardiovascular disease risk in rural India.

BACKGROUND: Cardiovascular diseases (CVD) are rising in India resulting in major health system challenges. METHODS: Eighteen primary health centre (PHC) clusters in rural Andhra Pradesh were randomised over three, 6-month steps to an intervention comprising: (1) household CVD risk assessments by village-based community health workers (CHWs) using a mobile tablet device; (2) electronic referral and clinical decision support for PHC doctors; and (3) a tracking system for follow-up care. Independent data collectors screened people aged ≥ 40 years in 54 villages serviced by the PHCs to create a high CVD risk cohort (based on WHO risk charts and blood pressure thresholds). Randomly selected, independent samples, comprising 15% of this cohort, were reviewed at each 6-month step. The primary outcome was the proportion meeting systolic blood pressure (SBP) targets (<140mmHg). FINDINGS: Eight-four percent of the eligible population (n = 62,254) were assessed at baseline (18.4% at high CVD risk). Of those at high risk, 75.3% were followed up over two years. CHWs screened 85.9% of the baseline cohort and doctors followed up 70.0% of all high risk referrals. There was no difference in the proportion of people achieving SBP targets (41.2% vs 39.2%; adjusted odds ratio (OR) 1.01 95% CI 0.76-1.35) or receiving BP-lowering medications in the intervention vs control periods respectively. There was a high discordance in risk scores generated by independent data collectors and CHWs, resulting in only 37.2% of the evaluation cohort exposed to the intervention. This discordance was mainly driven by fluctuating BP values (both normal variability and marked seasonal variations). In the pre-specified high risk concordant subgroup, there was greater use of BP-lowering medications in the intervention period (54.3% vs 47.9%, OR 1.22, 95% CI 1.03-1.44) but no impact on BP control. CONCLUSIONS: The strategy was well implemented with increased treatment rates among high risk individuals assessed by CHWs, however effects on BP were not demonstrated. Use of guideline-recommended BP thresholds for identifying high risk individuals substantially affected the reproducibility of risk assessment, and thus the ability to reliably evaluate the effectiveness of the intervention. In addition, unanticipated seasonal variation in BP in the context of a stepped-wedge trial highlights the inherent risks of this study design. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2013/06/ 003753.

Cardiovascular disease risk and comparison of different strategies for blood pressure management in rural India.

BACKGROUND: Non-optimal blood pressure (BP) levels are a major cause of disease burden globally. We describe current BP and treatment patterns in rural India and compare different approaches to BP lowering in this setting. METHODS: All individuals aged ≥40 years from 54 villages in a South Indian district were invited and 62,194 individuals (84%) participated in a cross-sectional study. Individual 10-year absolute cardiovascular disease (CVD) risk was estimated using WHO/ISH charts. Using known effects of treatment, proportions of events that would be averted under different paradigms of BP lowering therapy were estimated. RESULTS: After imputation of pre-treatment BP levels for participants on existing treatment, 76·9% (95% confidence interval, 75.7-78.0%), 5·3% (4.9-5.6%), and 17·8% (16.9-18.8%) of individuals had a 10-year CVD risk defined as low (< 20%), intermediate (20-29%), and high (≥30%, established CVD, or BP > 160/100 mmHg), respectively. Compared to the 19.6% (18.4-20.9%) of adults treated with current practice, a slightly higher or similar proportion would be treated using an intermediate (23·2% (22.0-24.3%)) or high (17·9% (16.9-18.8%) risk threshold for instituting BP lowering therapy and this would avert 87·2% (85.8-88.5%) and 62·7% (60.7-64.6%) more CVD events over ten years, respectively. These strategies were highly cost-effective relative to the current practice. CONCLUSION: In a rural Indian community, a substantial proportion of the population has elevated CVD risk. The more efficient and cost-effective clinical approach to BP lowering is to base treatment decisions on an estimate of an individual's short-term absolute CVD risk rather than with BP based strategy. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2013/06/003753 , 14 June 2013.

Elevated blood pressure and risk of aortic valve disease: a cohort analysis of 5.4 million UK adults.

Aims: To test two related hypotheses that elevated blood pressure (BP) is a risk factor for aortic valve stenosis (AS) or regurgitation (AR). Methods and results: In this cohort study of 5.4 million UK patients with no known cardiovascular disease or aortic valve disease at baseline, we investigated the relationship between BP and risk of incident AS and AR using multivariable-adjusted Cox regression models. Over a median follow-up of 9.2 years, 20 680 patients (0.38%) were diagnosed with AS and 6440 (0.12%) patients with AR. Systolic BP (SBP) was continuously related to the risk of AS and AR with no evidence of a nadir down to 115 mmHg. Each 20 mmHg increment in SBP was associated with a 41% higher risk of AS (hazard ratio 1.41, 95% confidence interval 1.38-1.45) and a 38% higher risk of AR (1.38, 1.31-1.45). Associations were stronger in younger patients but with no strong evidence for interaction by gender or body mass index. Each 10 mmHg increment in diastolic BP was associated with a 24% higher risk of AS (1.24, 1.19-1.29) but not AR (1.04, 0.97-1.11). Each 15 mmHg increment in pulse pressure was associated with a 46% greater risk of AS (1.46, 1.42-1.50) and a 53% higher risk of AR (1.53, 1.45-1.62). Conclusion: Long-term exposure to elevated BP across its whole spectrum was associated with increased risk of AS and AR. The possible causal nature of the observed associations warrants further investigation.

Elevated blood pressure and risk of mitral regurgitation: A longitudinal cohort study of 5.5 million United Kingdom adults.

BACKGROUND: Mitral regurgitation in people without prior cardiac disease is considered a degenerative disease with no established risk factors for its prevention. We aimed to test the hypothesis that elevated systolic blood pressure (SBP) across its usual spectrum is associated with higher risk of mitral regurgitation. METHODS AND FINDINGS: We used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) from 1 January 1990 to 31 December 2015. CPRD covers approximately 7% of the current UK population and is broadly representative of the population by age, sex, and ethnicity. About 5.5 million UK patients with no known cardiovascular or valve disease at baseline were included in this cohort study. We investigated the relationship between blood pressure (BP) and risk of mitral regurgitation using Cox regression models. Our primary exposure variable was SBP and our primary outcome was incident reports of mitral regurgitation, which were identified from hospital discharge reports or primary care records. Of the 5,553,984 patients in the CPRD that met our inclusion criteria, during the 10-year follow-up period, 28,655 (0.52%) were diagnosed with mitral regurgitation and a further 1,262 (0.02%) were diagnosed with mitral stenosis. SBP was continuously related to the risk of mitral regurgitation with no evidence of a nadir down to 115 mmHg (p < 0.001). Each 20 mmHg increment in SBP was associated with a 26% higher risk of mitral regurgitation (hazard ratio [HR] 1.26; CI 1.23, 1.29). The observed association was partially mediated by diseases affecting the left ventricle during follow-up (myocardial infarction [MI], ischaemic heart disease [IHD], cardiomyopathy, and heart failure). However, the percentage of excess risk mediated (PERM) by these proximate causes of secondary mitral regurgitation was only 13% (CI 6.1%, 20%), and accounting for them had little effect on the long-term association between SBP and mitral regurgitation (mediator-adjusted HR 1.22; CI 1.20, 1.25; p < 0.001). Associations were similar for each 10 mmHg increment in diastolic blood pressure (DBP) (p < 0.001) or each 15 mmHg increment in pulse pressure (PP) (p < 0.001). By contrast, there was no association between SBP and risk of mitral stenosis (HR per 20 mmHg higher SBP 1.03; CI 0.93, 1.14; p = 0.58). These analyses are based on routinely collected data from health records which may be sensitive to measurement errors, and the observed associations may not be generalizable to less severe and subclinical cases of mitral regurgitation. CONCLUSIONS: Long-term exposure to elevated BP across its whole spectrum is associated with an increased risk of primary and secondary mitral regurgitation. These findings suggest that BP control may be of importance in the prevention of mitral regurgitation.

Gender inequalities in cardiovascular risk factor assessment and management in primary healthcare.

OBJECTIVES: To quantify contemporary differences in cardiovascular disease (CVD) risk factor assessment and management between women and men in Australian primary healthcare services. METHODS: Records of routinely attending patients were sampled from 60 Australian primary healthcare services in 2012 for the Treatment of Cardiovascular Risk using Electronic Decision Support study. Multivariable logistic regression models were used to compare the rate of CVD risk factor assessment and recommended medication prescriptions, by gender. RESULTS: Of 53 085 patients, 58% were female. Adjusting for demographic and clinical characteristics, women were less likely to have sufficient risk factors measured for CVD risk assessment (OR (95% CI): 0.88 (0.81 to 0.96)). Among 13 294 patients (47% women) in the CVD/high CVD risk subgroup, the adjusted odds of prescription of guideline-recommended medications were greater for women than men: 1.12 (1.01 to 1.23). However, there was heterogeneity by age (p <0.001), women in the CVD/high CVD risk subgroup aged 35-54 years were less likely to be prescribed the medications (0.63 (0.52 to 0.77)), and women in the CVD/high CVD risk subgroup aged ≥65 years were more likely to be prescribed the medications (1.34 (1.17 to 1.54)) than their male counterparts. CONCLUSIONS: Women attending primary healthcare services in Australia were less likely than men to have risk factors measured and recorded such that absolute CVD risk can be assessed. For those with, or at high risk of, CVD, the prescription of appropriate preventive medications was more frequent in older women, but less frequent in younger women, compared with their male counterparts. TRIAL REGISTRATION NUMBER: 12611000478910, Pre-results.

Usual blood pressure, atrial fibrillation and vascular risk: evidence from 4.3 million adults.

Background: Although elevated blood pressure is associated with an increased risk of atrial fibrillation (AF), it is unclear if this association varies by individual characteristics. Furthermore, the associations between AF and a range of different vascular events are yet to be reliably quantified. Methods: Using linked electronic health records, we examined the time to first diagnosis of AF and time to first diagnosis of nine vascular events in a cohort of 4.3 million adults, aged 30 to 90 years, in the UK. Results: : A 20-mmHg higher usual systolic blood pressure was associated with a higher risk of AF [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.19, 1.22]. The strength of the association declined with increasing age, from an HR of 1.91 (CI 1.75, 2.09) at age 30-40 to an HR of 1.01 (CI 0.97, 1.04) at age 80-90 years. AF without antithrombotic use at baseline was associated with a greater risk of any vascular event than AF with antithrombotic usage ( P interaction < 0.0001). AF without baseline antithrombotic usage was associated with an increased risk of ischaemic heart disease (HR 2.52, CI 2.23, 2.84), heart failure (HR 3.80, CI 3.50, 4.12), ischaemic stroke (HR 2.72, CI 2.19, 3.38), unspecified stroke (HR 2.59, CI 2.25, 2.99), haemorrhagic stroke, chronic kidney disease, peripheral arterial disease and vascular dementia, but not aortic aneurysm. Conclusions: The association between elevated blood pressure and AF attenuates with increasing age. AF without antithrombotic usage is associated with an increased risk of eight vascular events.

The Effects of a Community-Based Sodium Reduction Program in Rural China - A Cluster-Randomized Trial.

BACKGROUND: Average sodium intake and stroke mortality in northern China are both among the highest in the world. An effective, low-cost strategy to reduce sodium intake in this population is urgently needed. OBJECTIVE: We sought to determine the effects of a community-based sodium reduction program on salt consumption in rural northern China. DESIGN: This study was a cluster-randomized trial done over 18 months in 120 townships (one village from each township) from five provinces. Sixty control villages were compared to 60 intervention villages that were given access to a reduced-sodium, added-potassium salt substitute in conjunction with a community-based health education program focusing on sodium reduction. The primary outcome was the difference in 24-hour urinary sodium excretion between randomized groups. RESULTS: Among 1,903 people with valid 24-hour urine collections, mean urinary sodium excretion in intervention compared with control villages was reduced by 5.5% (-14mmol/day, 95% confidence interval -26 to -1; p = 0.03), potassium excretion was increased by 16% (+7mmol/day, +4 to +10; p<0.001), and sodium to potassium ratio declined by 15% (-0.9, -1.2 to -0.5; p<0.001). Mean blood pressure differences were -1.1 mm Hg systolic (-3.3 to +1.1; p = 0.33) and -0.7 mm Hg diastolic (-2.2 to +0.8, p = 0.35) and the difference in the proportion with hypertension was -1.3% (-5.1 to 2.5, p = 0.56). CONCLUSION: There were clear differences in population sodium and potassium intake between villages that were most likely a consequence of increased use of salt substitute. The absence of effects on blood pressure reflects the moderate changes in sodium and potassium intake achieved. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01259700.

Interpretation of the evidence for the efficacy and safety of statin therapy.

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

Prevention and Control of Cardiovascular Disease in the Rapidly Changing Economy of China.

With one-fifth of the world's total population, China's prevention and control of cardiovascular disease (CVD) may affect the success of worldwide efforts to achieve sustainable CVD reduction. Understanding China's current cardiovascular epidemic requires awareness of the economic development in the past decades. The rapid economic transformations (industrialization, marketization, urbanization, globalization, and informationalization) contributed to the aging demography, unhealthy lifestyles, and environmental changes. The latter have predisposed to increasing cardiovascular risk factors and the CVD pandemic. Rising CVD rates have had a major economic impact, which has challenged the healthcare system and the whole society. With recognition of the importance of health, initial political steps and national actions have been taken to address the CVD epidemic. Looking to the future, we recommend that 4 priorities should be taken: pursue multisectorial government and nongovernment strategies targeting the underlying causes of CVD (the whole-of-government and whole-of-society policy); give priority to prevention; reform the healthcare system to fit the nature of noncommunicable diseases; and conduct research for evidence-based, low-cost, simple, sustainable, and scalable interventions. By pursuing the 4 priorities, the pandemic of CVD and other major noncommunicable diseases in China will be reversed and the global sustainable development goal achieved.

Long-term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON.

OBJECTIVE: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes. RESEARCH DESIGN AND METHODS: Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes. RESULTS: A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26). CONCLUSIONS: Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure.

Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.

BACKGROUND: Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. METHODS: For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. FINDINGS: We identified 19 trials including 44,989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3·8 years of follow-up (range 1·0-8·4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]), albuminuria (10% [3-16]), and retinopathy progression (19% [0-34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI -11 to 34]), cardiovascular death (9% [-11 to 26]), total mortality (9% [-3 to 19]), or end-stage kidney disease (10% [-6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group participants, compared with 0·9% in the less intensive treatment group (RR 1·35 [95% CI 0·93-1·97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2·68 [1·21-5·89], p=0·015), but the absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up). INTERPRETATION: Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. FUNDING: National Health and Medical Research Council of Australia.

Major surgery in south India: a retrospective audit of hospital claim data from a large community health insurance programme.

BACKGROUND: Information about use of major surgery in India is scarce. This study aims to bridge this gap by auditing hospital claims from the Rajiv Aarogyasri Community Health Insurance Scheme (RACHIS) that provides access to free tertiary care for major surgery through state-funded insurance to 68 million beneficiaries with limited household incomes-81% of population in states of Telangana and Andhra Pradesh (combined Human Development Index 0·485). Beneficiary households receive an annual coverage of INR 200 000 (US$3333) for admissions to any empanelled public or private hospital. METHODS: Publicly available deidentified hospital claim data for all surgical procedures conducted between mid-2008 and mid-2012 were compiled across all 23 districts in Telangana and Andhra Pradesh. FINDINGS: 677 332 surgical admissions (80% at private hospitals) were recorded at a mean annual rate of 259 per 100 000 beneficiaries (95% CI 235-283), excluding cataract and caesarean sections as these were not covered under the insurance programme. Men accounted for 56% of admissions. Injury was the most common cause for surgical admission (185 733; 27%) with surgical correction of long bone fractures being the most common procedure (144 997; 20%) identified in the audit. Diseases of digestive (110 922; 16%), genitourinary (82 505; 12%), and musculoskeletal system (70 053; 10%) were other leading causes for surgical admissions. Most hospital bed-days were used for injuries (584 days per 100 000 person years; 31%), digestive diseases (314 days; 17%), and musculoskeletal system (207 days; 11%), costing 19% (INR 4·4 billion), 13% (3·03 billion), and 11% (2·5 billion) of claims, respectively. Cardiovascular surgeries (53 023; 8%) alone accounted for 21% (INR 4·9 billion) of cost. Annual per capita cost of surgical claims was US$1·49 (95% CI 1·32-1·65). INTERPRETATION: Our findings are limited to a population socioeconomically representative of India and other countries with low-income and middle-income. Despite near universal access for major surgery, use continues to remain low, at levels expected in countries with per capita health expenditure below US$100, and lower than a tenth of rates estimated at spending (US$400-1000) comparable with financial access provided. Hence, strategies beyond traditional financing for care are required to improve use of surgery in LMICs. FUNDING: The George Institute for Global Health.

Use of major surgery in south India: A retrospective audit of hospital claim data from a large, community health insurance program.

BACKGROUND: Information on the use of major surgery in India is scarce. In this study we aimed to bridge this gap by auditing hospital claims from Rajiv Aarogyasri Community Health Insurance Scheme, which provides access to free hospital care through state-funded insurance to 68 million beneficiaries, an estimated 81% of population in the states of Telangana and Andhra Pradesh. METHODS: Publicly available deidentified hospital claim data for all surgery procedures conducted between mid-2008 and mid-2012 were compiled across all 23 districts in Telangana and Andhra Pradesh. RESULTS: A total of 677,332 operative admissions (80% at private hospitals) were recorded at an annual rate of 259 per 100,000 beneficiaries, with male subjects accounting for 56% of admissions. Injury was the most common cause for operative admission (27%) with operative correction of long bone fractures being the most common procedure (20%) identified in the audit. Diseases of the digestive (16%), genitourinary (12%), and musculoskeletal (10%) systems were other leading causes for operative admissions. Most hospital bed-days were used by admissions for injuries (31%) and diseases of the digestive (17%) and musculoskeletal system (11%) costing 19%, 13%, and 11% of reimbursement. Operations on the circulatory system (8%) accounted for 21% of reimbursements. Annual per capita cost of operative claims was US$1.48. CONCLUSION: The use of surgery by an insured population in India continued to be low despite access to financing comparable with greater spending countries, highlighting need for strategies, beyond traditional health financing, that prioritize improvement in access, delivery, and use of operative care.

The epidemiology of blood pressure and its worldwide management.

Despite the vast amount of evidence on the benefits of blood pressure lowering accumulated to date, elevated blood pressure is still the leading risk factor for disease and disability worldwide. The purpose of this review is to summarize the epidemiological evidence underpinning the association between blood pressure and a range of conditions. This review focuses on the association between systolic and diastolic blood pressures and the risk of cardiovascular and renal disease. Evidence for and against the existence of a J-shaped curve association between blood pressure and cardiovascular risk, and differences in the predictive power of systolic, diastolic, and pulse pressure, are described. In addition, global and regional trends in blood pressure levels and management of hypertension are reviewed.