Burden, determinants, consequences and care of multimorbidity in rural and urbanising Telangana, India: protocol for a mixed-methods study within the APCAPS cohort.

INTRODUCTION: The epidemiological and demographic transitions are leading to a rising burden of multimorbidity (co-occurrence of two or more chronic conditions) worldwide. Evidence on the burden, determinants, consequences and care of multimorbidity in rural and urbanising India is limited, partly due to a lack of longitudinal and objectively measured data on chronic health conditions. We will conduct a mixed-methods study nested in the prospective Andhra Pradesh Children and Parents' Study (APCAPS) cohort to develop a data resource for understanding the epidemiology of multimorbidity in rural and urbanising India and developing interventions to improve the prevention and care of multimorbidity. METHODS AND ANALYSIS: We aim to recruit 2100 APCAPS cohort members aged 45+ who have clinical and lifestyle data collected during a previous cohort follow-up (2010-2012). We will screen for locally prevalent non-communicable, infectious and mental health conditions, alongside cognitive impairments, disabilities and frailty, using a combination of self-reported clinical diagnosis, symptom-based questionnaires, physical examinations and biochemical assays. We will conduct in-depth interviews with people with varying multimorbidity clusters, their informal carers and local healthcare providers. Deidentified data will be made available to external researchers. ETHICS AND DISSEMINATION: The study has received approval from the ethics committees of the National Institute of Nutrition and Indian Institute of Public Health Hyderabad, India and the London School of Hygiene and Tropical Medicine, UK. Meta-data and data collection instruments will be published on the APCAPS website alongside details of existing APCAPS data and the data access process (www.lshtm.ac.uk/research/centres-projects-groups/apcaps).

Treatment effect modification due to comorbidity: Individual participant data meta-analyses of 120 randomised controlled trials.

BACKGROUND: People with comorbidities are underrepresented in clinical trials. Empirical estimates of treatment effect modification by comorbidity are lacking, leading to uncertainty in treatment recommendations. We aimed to produce estimates of treatment effect modification by comorbidity using individual participant data (IPD). METHODS AND FINDINGS: We obtained IPD for 120 industry-sponsored phase 3/4 trials across 22 index conditions (n = 128,331). Trials had to be registered between 1990 and 2017 and have recruited ≥300 people. Included trials were multicentre and international. For each index condition, we analysed the outcome most frequently reported in the included trials. We performed a two-stage IPD meta-analysis to estimate modification of treatment effect by comorbidity. First, for each trial, we modelled the interaction between comorbidity and treatment arm adjusted for age and sex. Second, for each treatment within each index condition, we meta-analysed the comorbidity-treatment interaction terms from each trial. We estimated the effect of comorbidity measured in 3 ways: (i) the number of comorbidities (in addition to the index condition); (ii) presence or absence of the 6 commonest comorbid diseases for each index condition; and (iii) using continuous markers of underlying conditions (e.g., estimated glomerular filtration rate (eGFR)). Treatment effects were modelled on the usual scale for the type of outcome (absolute scale for numerical outcomes, relative scale for binary outcomes). Mean age in the trials ranged from 37.1 (allergic rhinitis trials) to 73.0 (dementia trials) and percentage of male participants range from 4.4% (osteoporosis trials) to 100% (benign prostatic hypertrophy trials). The percentage of participants with 3 or more comorbidities ranged from 2.3% (allergic rhinitis trials) to 57% (systemic lupus erythematosus trials). We found no evidence of modification of treatment efficacy by comorbidity, for any of the 3 measures of comorbidity. This was the case for 20 conditions for which the outcome variable was continuous (e.g., change in glycosylated haemoglobin in diabetes) and for 3 conditions in which the outcomes were discrete events (e.g., number of headaches in migraine). Although all were null, estimates of treatment effect modification were more precise in some cases (e.g., sodium-glucose co-transporter-2 (SGLT2) inhibitors for type 2 diabetes-interaction term for comorbidity count 0.004, 95% CI -0.01 to 0.02) while for others credible intervals were wide (e.g., corticosteroids for asthma-interaction term -0.22, 95% CI -1.07 to 0.54). The main limitation is that these trials were not designed or powered to assess variation in treatment effect by comorbidity, and relatively few trial participants had >3 comorbidities. CONCLUSIONS: Assessments of treatment effect modification rarely consider comorbidity. Our findings demonstrate that for trials included in this analysis, there was no empirical evidence of treatment effect modification by comorbidity. The standard assumption used in evidence syntheses is that efficacy is constant across subgroups, although this is often criticised. Our findings suggest that for modest levels of comorbidities, this assumption is reasonable. Thus, trial efficacy findings can be combined with data on natural history and competing risks to assess the likely overall benefit of treatments in the context of comorbidity.

Determining the optimal diagnostic and risk stratification approaches for people with hypertension in two rural populations in Kenya and The Gambia: a study protocol for IHCoR-Africa Work Package 2.

Background: Sub-Saharan Africa (SSA) has one of the highest prevalences of hypertension worldwide. The impact of hypertension is of particular concern in rural SSA, where access to clinics and hospitals is limited. Improvements in the management of people with hypertension in rural SSA could be achieved by sharing diagnosis and care tasks between the clinic and the community. To develop such a community-centred programme we need optimal approaches to identify and risk stratify patients with elevated blood pressure. The aim of the study is to improve the evidence base for diagnosis and risk estimation for a community-centred hypertension programme in two rural settings in SSA. Methods: We will conduct a cross-sectional study of 1250 adult participants in Kilifi, Kenya and Kiang West, The Gambia. The study has five objectives which will determine the: (1) accuracy of three blood pressure (BP) measurement methods performed by community health workers in identifying people with hypertension in rural SSA, compared to the reference standard method; (2) relationship between systolic BP and cardiovascular risk factors; (3) prevalence of hypertension-mediated organ damage (HMOD); (4) accuracy of innovative point-of-care (POC) technologies to identify patients with HMOD; and (5) cost-effectiveness of different combinations of BP and HMOD measurements for directing hypertension treatment initiation. Expected findings: This study will determine the accuracy of three methods for community BP measurement and POC technologies for HMOD assessment. Using the optimal methods in this setting it will estimate the prevalence of hypertension and provide the best estimate to date of HMOD prevalence in SSA populations. The cost-effectiveness of decision-making approaches for initiating treatment of hypertension will be modelled. These results will inform the development of a community-centred programme to improve care for hypertensive patients living in rural SSA. Existing community engagement networks will be used to disseminated within the research setting.

Many people live with high blood pressure in sub-Saharan Africa. In this region, the proportion of people with high blood pressure is one of the highest in the world. However, few people with high blood pressure are treated and this can lead to serious medical issues and even death. This is particularly true in rural areas where treatment and understanding of blood pressure is lower than in cities. There are many reasons why high blood pressure is a major health problem in rural sub-Saharan Africa, such as a lack of clear symptoms; less access to healthcare; and limited time to travel to clinics for care. One option for improving the management of blood pressure is to use a community-centred approach, where care is brought into the community making it easier to access. To bring care into the community, we need to find out what is the best way for community health workers to identify who needs to be treated. Standard techniques may not be useful in a rural community and could require too many resources to make them practical. This study aims to determine what is the best way to identify high blood pressure and related health complications in a community setting. The study will take place across two sites: one in Kilifi, Kenya and the other in Kiang West, The Gambia. We will enrol 1250 participants, with 625 in each country. The people living in these areas have been involved in the design of this study through community engagement and have helped identify the need for improving how blood pressure is treated in a rural areas. Throughout this study, we will continue to meet with the communities. Once the study is completed, we will use our strong links with the communities, healthcare providers and policymakers to share the results.

Cardiovascular risk factors and markers of myocardial injury and inflammation in people living with HIV in Nairobi, Kenya: a pilot cross-sectional study.

OBJECTIVES: To determine the prevalence of cardiovascular disease (CVD) risk factors and explore associations with high-sensitivity cardiac troponin I (hscTnI) and high-sensitivity C-reactive protein (hsCRP) in people living with HIV (PLHIV) in Kenya. DESIGN: Pilot cross-sectional study. SETTING: Data were collected from community HIV clinics across two sites in Nairobi, Kenya, from July 2019 to May 2020. PARTICIPANTS: Convenience sample of 200 PLHIV (≥30 years with no prior history of CVD). OUTCOME MEASURES: Prevalence of cardiovascular risk factors and its association with hsTnI and hsCRP levels. RESULTS: Across 200 PLHIV (median age 46 years, IQR 38-53; 61% women), the prevalence of hypercholesterolaemia (total cholesterol >6.1 mmol/L) and hypertension were 19% (n=30/199) and 30% (n=60/200), respectively. Smoking and diabetes prevalence was 3% (n=5/200) and 4% (n=7/200). HscTnI was below the limit of quantification (<2.5 ng/L) in 65% (n=109/169). High (>3 mg/L), intermediate (1-3 mg/L) and low (<1 mg/L) hsCRP levels were found in 38% (n=75/198), 33% (n=65/198) and 29% (n=58/198), respectively. Framingham laboratory-based risk scores classified 83% of PLHIV at low risk with 12% and 5% at intermediate and high risk, respectively. Older age (adjusted OR (aOR) per year increase 1.05, 95% CI 1.01 to 1.08) and systolic blood pressure (140-159 mm Hg (aOR 2.96; 95% CI 1.09 to 7.90) and >160 mm Hg (aOR 4.68, 95% CI 1.55 to 14) compared with <140 mm Hg) were associated with hscTnI levels. No associations were observed between hsCRP and CVD risk factors. CONCLUSION: The majority of PLHIV-using traditional risk estimation systems-have a low estimated CVD risk likely reflecting a younger aged population predominantly consisting of women. Hypertension and hypercholesterolaemia were common while smoking and diabetes rates remained low. While hscTnI values were associated with increasing age and raised blood pressure, no associations between hsCRP levels and traditional cardiovascular risk factors were observed.

Clinical outcomes following balloon aortic valvuloplasty.

BACKGROUND: Balloon aortic valvuloplasty (BAV) remains a treatment option for the selected patients with severe aortic stenosis. We examined clinical outcomes and predictors of prognosis in patients undergoing BAV for severe aortic stenosis. METHODS: We identified all patients undergoing BAV from January 2010 to March 2018 (n=167) at a single transcatheter aortic valve implantation (TAVI) centre. Patient demographics, investigations, subsequent interventions and clinical outcomes were obtained from electronic health records. RESULTS: Patients undergoing BAV were elderly (median age 80, IQR 73-86 years) and half (n=87, 52%) were male. All-cause mortality at 30 days and 12 months was 11% and 43%, respectively. Reduce ejection fraction (EF 30%-50%: HR 1.76, 95% CI 1.05 to 2.94; EF <30%: HR 1.90, 95% CI 1.12 to 3.20) was the only independent predictor at baseline of overall mortality. Median survival was 212 (IQR 54-490) days from the index procedure. Mortality at 1 year was lowest in patients who subsequently underwent TAVI or SAVR but high among those who had no further interventions or those who had a repeat BAV (14%, 19%, 60%, 89% respectively, log-rank p<0.001). CONCLUSION: BAV as a bridge to definitive aortic valve intervention in carefully selected patients offers acceptable outcomes. These contemporary observational findings demonstrate the ongoing potential utility of BAV in the TAVI era.

Determinants and prognostic value of echocardiographic first-phase ejection fraction in aortic stenosis.

OBJECTIVE: First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis. METHODS: EF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death. RESULTS: Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m2 vs 20.6 (16.8-24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR. CONCLUSION: EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.

High-sensitivity troponin and novel biomarkers for the early diagnosis of non-ST-segment elevation myocardial infarction in patients with atrial fibrillation.

AIMS: To evaluate the diagnostic performance of high-sensitivity troponin I (hsTnI) and other novel biomarkers for diagnosing non-ST-segment elevation myocardial infarction (NSTEMI) in patients with atrial fibrillation. METHODS: In an acute chest pain cohort (N=1673), mean age 61.4±13.6 (34% female), we measured hsTnI and 13 established and novel biomarkers reflecting ischaemia, necrosis, inflammation, myocardial stress, angiogenesis on admission and after three hours in order to investigate their diagnostic accuracy for NSTEMI. RESULTS: In atrial fibrillation patients (N=299) hsTnI on admission had the best discriminatory ability for NSTEMI (area under the curve 0.97) with only two novel biomarkers, copeptin and heart-type fatty acid binding protein, having area under the curve >0.70. Measured biomarkers showed comparable discriminatory ability in atrial fibrillation and non-atrial fibrillation patients. The combination of hsTnI on admission with additional biomarkers did not clinically significantly improve diagnostic performance. In atrial fibrillation patients, hsTnI concentrations ⩽21.7 ng/L (99th percentile in a healthy German cohort) on admission gave a negative predictive value of ~100% (95% confidence interval 97-100%). The combination of hsTnI on admission and absolute change of hsTnI concentration after three hours of ⩾40 ng/L resulted in a positive predictive value of 81.2% and sensitivity of 88.6%. Diagnostic accuracy was validated in an independent cohort (N=1076). CONCLUSION: The diagnostic accuracy of hsTnI in patients with acute chest pain and atrial fibrillation is high and comparable to those without atrial fibrillation. Absolute change in hsTnI concentration enhanced diagnostic performance. No clinically relevant improvement was achieved by adding other biomarkers.

Impaired vascular function and repair in patients with premature coronary artery disease.

BACKGROUND: Endothelial dysfunction is central to the pathogenesis of coronary artery disease, but the role of local and circulating endothelial progenitor cells in maintaining vascular health is poorly understood. We hypothesised that impaired local and circulating vascular repair mechanisms predispose to endothelial dysfunction and the premature onset of coronary artery disease. METHODS AND RESULTS: Patients with premature coronary artery disease (n = 16) and healthy age- and sex-matched controls (n = 16) underwent venous occlusion plethysmography with intra-arterial infusion of acetylcholine and sodium nitroprusside. Numbers of circulating endothelial progenitor cells were directly quantified in whole blood by flow cytometry. Endothelial cells were isolated from the blood vessel wall and from peripheral blood mononuclear cells, and expanded in vitro for phenotypic and functional characterisation and analysis of microRNA expression levels. A dose-dependent increase in forearm blood flow (p < 0.001) was attenuated in response to the endothelial-dependent vasodilator acetylcholine in patients compared with controls (p = 0.03). No differences in the number of circulating endothelial progenitor cells or in the phenotype, function or microRNA expression levels of endothelial outgrowth cells isolated from blood were observed in patients and controls. Conversely, local vessel wall endothelial cells from patients had significant impairments in proliferation, adhesion and migration, and significantly reduced expression levels of microRNAs known to regulate endothelial function (miRs -10 a, -let7b, -126 and -181 b) (p < 0.05 for all). CONCLUSION: Local vessel wall derived endothelial cells, rather than circulating endothelial progenitor cells and their progeny, are impaired in patients with vascular dysfunction and premature coronary artery disease.