Age-specific and sex-specific adult mortality risk in India in 2014: analysis of 0·27 million nationally surveyed deaths and demographic estimates from 597 districts

Background: As child mortality decreases rapidly worldwide, premature adult mortality is becoming an increasingly important contributor to global mortality. Any possible worldwide reduction of premature adult mortality before the age of 70 years will depend on progress in India. Indian districts increasingly have responsibility for implementing public health programmes. We aimed to assess age-specific and sex-specific adult mortality risks in India at the district level. Methods: We analysed data from five national surveys of 0·27 million adult deaths at an age of 15–69 years together with 2014 demographic data to estimate age-specific and sex-specific adult mortality risks for 597 districts. Cause of death data were drawn from the verbal autopsies in the Registrar General of India's ongoing Million Death Study. Findings: In 2014, about two-fifths of India's men aged 15–69 years lived in the 253 districts where the conditional probability of a man dying at these ages exceeded 50%, and more than a third of India's women aged 15–69 years lived in the 222 districts where the conditional probability of a woman dying exceeded 40%. The probabilities of a man or woman dying by the age of 70 years in high-mortality districts was 62% and 54%, respectively, whereas the probability of a man or woman dying by the age of 70 years in low-mortality districts was 40% and 30%, respectively. The roughly 10-year survival gap between high-mortality and low-mortality districts was nearly as extreme as the survival gap between the entire Indian population and people living in high-income countries. Adult mortality risks at ages 15–69 years was highest in east India and lowest in west India, by contrast with the north–south divide for child mortality. Vascular disease, tuberculosis, malaria and other infections, and respiratory diseases accounted for about 60% of the absolute gap in adult mortality risk at ages 15–69 years between high-mortality and low-mortality districts. Most of the variation in adult mortality could not be explained by known determinants or risk factors for premature mortality. Interpretation: India's large variation in adult mortality by district, notably the higher death rates in eastern India, requires further aetiological research, particularly to explore whether high levels of adult mortality risks from infections and non-communicable diseases are a result of historical childhood malnutrition and infection. Such research can be complemented by an expanded coverage of known effective interventions to reduce adult mortality, especially in high-mortality districts. Funding: National Institutes of Health, Canadian Institutes of Health Research, University of Toronto

Effects of bidi smoking on all-cause mortality and cardiorespiratory outcomes in men from south Asia: an observational community-based substudy of the Prospective Urban Rural Epidemiology Study (PURE)

Background: Bidis are minimally regulated, inexpensive, hand-rolled tobacco products smoked in south Asia. We examined the effects of bidi smoking on baseline respiratory impairment, and prospectively collected data for all-cause mortality and cardiorespiratory events in men from this region. Methods: This substudy of the international, community-based Prospective Urban Rural Epidemiology (PURE) study was done in seven centres in India, Pakistan, and Bangladesh. Men aged 35–70 years completed spirometry testing and standardised questionnaires at baseline and were followed up yearly. We used multilevel regression to compare cross-sectional baseline cardiorespiratory symptoms, spirometry measurements, and follow-up events (all-cause mortality, cardiovascular events, respiratory events) adjusted for socioeconomic status and baseline risk factors between non-smokers, light smokers of bidis or cigarettes (≤10 pack-years), heavy smokers of cigarettes only (>10 pack-years), and heavy smokers of bidis (>10 pack-years). Findings: 14 919 men from 158 communities were included in this substudy (8438 non-smokers, 3321 light smokers, 959 heavy cigarette smokers, and 2201 heavy bidi smokers). Mean duration of follow-up was 5·6 years (range 1–13). The adjusted prevalence of self-reported chronic wheeze, cough or sputum, dyspnoea, and chest pain at baseline increased across the categories of non-smokers, light smokers, heavy cigarette smokers, and heavy bidi smokers (p<0·0001 for association). Adjusted cross-sectional age-related changes in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) ratio were larger for heavy bidi smokers than for the other smoking categories. Hazard ratios (relative to non-smokers) showed increasing hazards for all-cause mortality (light smokers 1·28 [95% CI 1·02–1·62], heavy cigarette smokers 1·59 [1·13–2·24], heavy bidi smokers 1·56 [1·22–1·98]), cardiovascular events (1·45 [1·13–1·84], 1·47 [1·05–2·06], 1·55 [1·17–2·06], respectively) and respiratory events (1·30 [0·91–1·85], 1·21 [0·70–2·07], 1·73 [1·23–2·45], respectively) across the smoking categories. Interpretation: Bidi smoking is associated with severe baseline respiratory impairment, all-cause mortality, and cardiorespiratory outcomes. Stricter controls and regulation of bidis are needed to reduce the tobacco-related disease burden in south Asia. Funding: Population Health Research Institute, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Ontario

Availability, affordability, and consumption of fruits and vegetables in 18 countries across income levels: findings from the Prospective Urban Rural Epidemiology (PURE) study

Background: Several international guidelines recommend the consumption of two servings of fruits and three servings of vegetables per day, but their intake is thought to be low worldwide. We aimed to determine the extent to which such low intake is related to availability and affordability. Methods: We assessed fruit and vegetable consumption using data from country-specific, validated semi-quantitative food frequency questionnaires in the Prospective Urban Rural Epidemiology (PURE) study, which enrolled participants from communities in 18 countries between Jan 1, 2003, and Dec 31, 2013. We documented household income data from participants in these communities; we also recorded the diversity and non-sale prices of fruits and vegetables from grocery stores and market places between Jan 1, 2009, and Dec 31, 2013. We determined the cost of fruits and vegetables relative to income per household member. Linear random effects models, adjusting for the clustering of households within communities, were used to assess mean fruit and vegetable intake by their relative cost. Findings: Of 143 305 participants who reported plausible energy intake in the food frequency questionnaire, mean fruit and vegetable intake was 3·76 servings (95% CI 3·66–3·86) per day. Mean daily consumption was 2·14 servings (1·93–2·36) in low-income countries (LICs), 3·17 servings (2·99–3·35) in lower-middle-income countries (LMICs), 4·31 servings (4·09–4·53) in upper-middle-income countries (UMICs), and 5·42 servings (5·13–5·71) in high-income countries (HICs). In 130 402 participants who had household income data available, the cost of two servings of fruits and three servings of vegetables per day per individual accounted for 51·97% (95% CI 46·06–57·88) of household income in LICs, 18·10% (14·53–21·68) in LMICs, 15·87% (11·51–20·23) in UMICs, and 1·85% (−3·90 to 7·59) in HICs (ptrend=0·0001). In all regions, a higher percentage of income to meet the guidelines was required in rural areas than in urban areas (p<0·0001 for each pairwise comparison). Fruit and vegetable consumption among individuals decreased as the relative cost increased (ptrend=0·00040). Interpretation: The consumption of fruit and vegetables is low worldwide, particularly in LICs, and this is associated with low affordability. Policies worldwide should enhance the availability and affordability of fruits and vegetables. Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries

Real-World Evidence of EGFR Targeted Therapy in NSCLC– A Brief Report of Decade Long Single Center Experience

The significance of EGFR targeted therapy in the lung adenocarcinoma is paramount. Several controlled clinical trials have reported considerable survival of EGFR mutation positive patients on receiving the EGFR tyrosine kinase inhibitor (TKI). However, the real-world evidence of benefits of EGFR TKI would be further useful to understand how the designated therapeutic regimen benefits the patients. In this study, we report a decade long real-world evidence of EGFR molecular testing in lung cancer at Tata Memorial Hospital (Mumbai, India). Laboratory and hospital records containing basic demographic details, clinical characteristics, treatment regimen, survival outcome were collected retrospectively. Statistical association and survival analysis were performed using the R programming. The cohort includes 9,053 lung cancer patients tested for EGFR mutations during 2011 to 2019. Baseline T790M and compound mutations were the only mutations observed co-occurring while all other EGFR mutations were mutually exclusive. Furthermore, the baseline T790M were also observed to be associated with TTF1 positivity, smoking and local metastasis. Overall survival of the patients harboring co-occurring compound mutations was significantly lesser than the other EGFR positive patients. Overall, our study suggests that EGFR TKI may provide real-world benefit to the lung cancer patients harboring mutually exclusive EGFR mutations. On the other hand, further systematic study is essential to develop better therapeutic regimen for co-occurring baseline EGFR T790M and other compound mutations

Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): an international, community-based cohort study

Summary: Background: The associations between the extent of forced expiratory volume in 1 s (FEV1) impairment and mortality, incident cardiovascular disease, and respiratory hospitalisations are unclear, and how these associations might vary across populations is unknown. Methods: In this international, community-based cohort study, we prospectively enrolled adults aged 35–70 years who had no intention of moving residences for 4 years from rural and urban communities across 17 countries. A portable spirometer was used to assess FEV1. FEV1 values were standardised within countries for height, age, and sex, and expressed as a percentage of the country-specific predicted FEV1 value (FEV1%). FEV1% was categorised as no impairment (FEV1% ≥0 SD from country-specific mean), mild impairment (FEV1% <0 SD to −1 SD), moderate impairment (FEV1% <–1 SD to −2 SDs), and severe impairment (FEV1% <–2 SDs [ie, clinically abnormal range]). Follow-up was done every 3 years to collect information on mortality, cardiovascular disease outcomes (including myocardial infarction, stroke, sudden death, or congestive heart failure), and respiratory hospitalisations (from chronic obstructive pulmonary disease, asthma, pneumonia, tuberculosis, or other pulmonary conditions). Fully adjusted hazard ratios (HRs) were calculated by multilevel Cox regression. Findings: Among 126 359 adults with acceptable spirometry data available, during a median 7·8 years (IQR 5·6–9·5) of follow-up, 5488 (4·3%) deaths, 5734 (4·5%) cardiovascular disease events, and 1948 (1·5%) respiratory hospitalisation events occurred. Relative to the no impairment group, mild to severe FEV1% impairments were associated with graded increases in mortality (HR 1·27 [95% CI 1·18–1·36] for mild, 1·74 [1·60–1·90] for moderate, and 2·54 [2·26–2·86] for severe impairment), cardiovascular disease (1·18 [1·10–1·26], 1·39 [1·28–1·51], 2·02 [1·75–2·32]), and respiratory hospitalisation (1·39 [1·24–1·56], 2·02 [1·75–2·32], 2·97 [2·45–3·60]), and this pattern persisted in subgroup analyses considering country income level and various baseline risk factors. Population-attributable risk for mortality (adjusted for age, sex, and country income) from mildly to moderately reduced FEV1% (24·7% [22·2–27·2]) was larger than that from severely reduced FEV1% (3·7% [2·1–5·2]) and from tobacco use (19·7% [17·2–22·3]), previous cardiovascular disease (5·5% [4·5–6·5]), and hypertension (17·1% [14·6–19·6]). Population-attributable risk for cardiovascular disease from mildly to moderately reduced FEV1 was 17·3% (14·8–19·7), second only to the contribution of hypertension (30·1% [27·6–32·5]). Interpretation: FEV1 is an independent and generalisable predictor of mortality, cardiovascular disease, and respiratory hospitalisation, even across the clinically normal range (mild to moderate impairment). Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Ontario Ministry of Health and Long-Term Care, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Servier, and GlaxoSmithKline, Novartis, and King Pharma. Additional funders are listed in the appendix

Divergent trends in ischaemic heart disease and stroke mortality in India from 2000 to 2015: a nationally representative mortality study

Summary: Introduction: India accounts for about a fifth of cardiovascular deaths globally, but nationally representative data on mortality trends are not yet available. In this nationwide mortality study, we aimed to assess the trends in ischaemic heart disease and stroke mortality over 15 years using the Million Death Study. Methods: We determined national and subnational cardiovascular mortality rates and trends by sex and birth cohort using cause of death ascertained by verbal autopsy from 2001 to 2013 among 2·4 million households. We derived mortality rates for ischaemic heart disease and stroke by applying mortality proportions to UN mortality estimates for India and projected the rates from 2000 to 2015. Findings: Cardiovascular disease caused more than 2·1 million deaths in India in 2015 at all ages, or more than a quarter of all deaths. At ages 30–69 years, of 1·3 million cardiovascular deaths, 0·9 million (68·4%) were caused by ischaemic heart disease and 0·4 million (28·0%) by stroke. At these ages, the probability of dying from ischaemic heart disease increased during 2000–15, from 10·4% to 13·1% in men and 4·8% to 6·6% in women. Ischaemic heart disease mortality rates in rural areas increased rapidly and surpassed those in urban areas. By contrast, the probability of dying from stroke decreased from 5·7% to 5·0% in men and 5·0% to 3·9% in women. A third of premature stroke deaths occurred in the northeastern states, inhabited by a sixth of India's population, where rates increased significantly and were three times higher than the national average. The increased mortality rates of ischaemic heart disease nationally and stroke in the northeastern states were higher in the cohorts of adults born in the 1970s onwards, than in earlier decades. A large and growing proportion of the ischaemic heart disease nationally and stroke deaths in high-burden states reported earlier diagnosis of cardiovascular disease, but low medication use. Interpretation: The unexpectedly diverse patterns of cardiovascular mortality require investigation to identify the role of established and new cardiovascular risk factors. Secondary prevention with effective and inexpensive long-term treatment and adult smoking cessation could prevent substantial numbers of premature deaths. Without progress against the control of cardiovascular disease in India, global goals to reduce non-communicable diseases by 2030 will be difficult to achieve. Funding: Fogarty International Center of the US National Institutes of Health, Dalla Lana School of Public Health, University of Toronto, Indian Council of Medical Research, and the Disease Control Priorities

Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data

Background: Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. Methods: We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. Findings: The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59–3·12); p<0·0001), combination therapy (1·53, 1·13–2·07; p=0·054), and have their blood pressure controlled (2·06, 1·69–2·50; p<0·0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1·42, 95% CI 1·25–1·62; p<0·0001), combination therapy (1·26, 1·08–1·47; p=0·0038), and have their blood pressure controlled (1·13, 1·00–1·28; p=0·0562) than were those unable to afford the medicines. Interpretation: A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries