Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans.

BACKGROUND: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467.).

Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

BACKGROUND: Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS: We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod-MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS: We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age-standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub-Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability-adjusted life-years due to rheumatic heart disease globally. CONCLUSIONS: We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25-year period. The health-related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.).

The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.

Exploring how a genetic attribution to disease relates to stigma experiences of Xhosa patients with schizophrenia in South Africa.

BACKGROUND: Over the past three decades, a range of international stakeholders have highlighted the possibility that genomic research may impact stigma associated with psychiatric disorders. Limited research has been conducted in Africa to investigate this relation. METHOD: In the present study, using focus group discussions, we explored the relation between genetic attribution and stigma among 36 Xhosa people with schizophrenia. We addressed three main questions: (1) What causal beliefs do Xhosa people with schizophrenia use to explain their illness and to what extent do genetic explanations play a role in these beliefs? (2) What are the internalised stigma experiences of Xhosa people with schizophrenia? (3) How do genetic explanations relate to stigma experiences, if at all? RESULTS: Most participants were able to define genetics and some linked genetics to disease causation. Despite adequate knowledge of genetics and an emphasis on genetic explanations of schizophrenia in the study, most participants held a multitude of causal explanations including: psychosocial, environmental, and cultural. Moreover, participants rarely mentioned disease cause when describing their stigma experiences. DISCUSSION: For this population group, there was no straight-forward relation between a genetic attribution and stigma. Therefore, we did not find evidence that genetic attribution may significantly increase stigma. Although North American and European literature provides conflicting evidence regarding this relation, there is increased consensus that biomedical explanations for psychiatric disorders may reduce blame. This study found evidence supporting that consensus. This study provides an empirical foundation to inform ongoing work on the psychosocial implications of psychiatric genomics research in non-Western contexts.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. METHODS: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. FINDINGS: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76). INTERPRETATION: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]. FUNDING: Boehringer Ingelheim and Canadian Institutes of Health Research.

The H3Africa policy framework: negotiating fairness in genomics.

Human Heredity and Health in Africa (H3Africa) research seeks to promote fair collaboration between scientists in Africa and those from elsewhere. Here, we outline how concerns over inequality and exploitation led to a policy framework that places a firm focus on African leadership and capacity building as guiding principles for African genomics research.

Rationale and design of the comparison of 3 combination therapies in lowering blood pressure in black Africans (CREOLE study): 2 × 3 factorial randomized single-blind multicenter trial.

BACKGROUND: Current hypertension guidelines recommend the use of combination therapy as first-line treatment or early in the management of hypertensive patients. Although there are many possible combinations of blood pressure(BP)-lowering therapies, the best combination for the black population is still a subject of debate because no large randomized controlled trials have been conducted in this group to compare the efficacy of different combination therapies to address this issue. METHODS: The comparison of 3 combination therapies in lowering BP in the black Africans (CREOLE) study is a randomized single-blind trial that will compare the efficacy of amlodipine plus hydrochlorothiazide versus amlodipine plus perindopril and versus perindopril plus hydrochlorothiazide in blacks residing in sub-Saharan Africa (SSA). Seven hundred two patients aged 30-79 years with a sitting systolic BP of 140 mm Hg and above, and less than 160 mm Hg on antihypertensive monotherapy, or sitting systolic BP of 150 mm Hg and above, and less than 180 mm Hg on no treatment, will be centrally randomized into any of the 3 arms (234 into each arm). The CREOLE study is taking place in 10 sites in SSA, and the primary outcome measure is change in ambulatory systolic BP from baseline to 6 months. The first patient was randomized in June 2017, and the trial will be concluded by 2019. CONCLUSIONS: The CREOLE trial will provide unique information as to the most efficacious 2-drug combination in blacks residing in SSA and thereby inform the development of clinical guidelines for the treatment of hypertension in this subregion.

Statistics on the use of cardiac electronic devices and interventional electrophysiological procedures in Africa from 2011 to 2016: report of the Pan African Society of Cardiology (PASCAR) Cardiac Arrhythmias and Pacing Task Forces.

Aims: To provide comprehensive information on the access and use of cardiac implantable electronic devices (CIED) and catheter ablation procedures in Africa. Methods and results: The Pan-African Society of Cardiology (PASCAR) collected data on invasive management of cardiac arrhythmias from 2011 to 2016 from 31 African countries. A specific template was completed by physicians, and additional information obtained from industry. Information on health care systems, demographics, economics, procedure rates, and specific training programs was collected. Considerable heterogeneity in the access to arrhythmia care was observed across Africa. Eight of the 31 countries surveyed (26%) did not perform pacemaker implantations. The median pacemaker implantation rate was 2.66 per million population per country (range: 0.14-233 per million population). Implantable cardioverter-defibrillator and cardiac resynchronization therapy were performed in 12/31 (39%) and 15/31 (48%) countries respectively, mostly by visiting teams. Electrophysiological studies, including complex catheter ablations were performed in all countries from Maghreb, but only one sub-Saharan African country (South Africa). Marked variation in cost (up to 1000-fold) was observed across countries with an inverse correlation between implant rates and the procedure fees standardized to the gross domestic product per capita. Lack of economic resources and facilities, high cost of procedures, deficiency of trained physicians, and non-existent fellowship programs were the main drivers of under-utilization of interventional cardiac arrhythmia care. Conclusion: There is limited access to CIED and ablation procedures in Africa. A quarter of countries did not have pacemaker implantation services, and catheter ablations were only available in one country in sub-Saharan Africa.

Prevalence of rheumatic heart disease in Zambian school children.

BACKGROUND: The large global burden of rheumatic heart disease (RHD) has come to light in recent years following robust epidemiologic studies. As an operational research component of a broad program aimed at primary and secondary prevention of RHD, we sought to determine the current prevalence of RHD in the country's capital, Lusaka, using a modern imaging-based screening methodology. In addition, we wished to evaluate the practicality of training local radiographers in echocardiography screening methods. METHODS: Echocardiography was conducted on a random sample of students in 15 schools utilizing a previously validated, abbreviated screening protocol. Through a task-shifting scheme, and in the spirit of capacity-building to enhance local diagnostic and research skills, general radiographers based at Lusaka University Teaching Hospital (UTH) were newly trained to use portable echocardiography devices. Students deemed as screen-positive were referred for comprehensive echocardiography and clinical examination at UTH. Cardiac abnormalities were classified according to standard World Heart Federation criteria. RESULTS: Of 1102 students that were consented and screened, 53 students were referred for confirmatory echocardiography. Three students had definite RHD, 10 had borderline RHD, 29 were normal, and 11 students were lost to follow-up. The rates of definite, borderline, and total RHD were 2.7 per 1000, 9.1 per 1000, and 11.8 per 1000, respectively. Anterior mitral valve leaflet thickening and chordal thickening were the most common morphological defects. The pairwise kappa test showed fair agreement between the local radiographers and an echocardiographer quality assurance specialist. CONCLUSION: The prevalence of asymptomatic RHD in urban communities in Zambia is within the range of results reported in other sub-Saharan African countries using the WHF criteria. Task-shifting local radiographers to conduct echocardiography was feasible. The results of this study will be used to inform ongoing efforts in Zambia to control and eventually eliminate RHD. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov ( #NCT02661763 ).

Endemic Cardiovascular Diseases of the Poorest Billion.

The poorest billion people are distributed throughout the world, though most are concentrated in rural sub-Saharan Africa and South Asia. Cardiovascular disease (CVD) data can be sparse in low- and middle-income countries beyond urban centers. Despite this urban bias, CVD registries from the poorest countries have long revealed a predominance of nonatherosclerotic stroke, hypertensive heart disease, nonischemic and Chagas cardiomyopathies, rheumatic heart disease, and congenital heart anomalies, among others. Ischemic heart disease has been relatively uncommon. Here, we summarize what is known about the epidemiology of CVDs among the world's poorest people and evaluate the relevance of global targets for CVD control in this population. We assessed both primary data sources, and the 2013 Global Burden of Disease Study modeled estimates in the world's 16 poorest countries where 62% of the population are among the poorest billion. We found that ischemic heart disease accounted for only 12% of the combined CVD and congenital heart anomaly disability-adjusted life years (DALYs) in the poorest countries, compared with 51% of DALYs in high-income countries. We found that as little as 53% of the combined CVD and congenital heart anomaly burden (1629/3049 DALYs per 100 000) was attributed to behavioral or metabolic risk factors in the poorest countries (eg, in Niger, 82% of the population among the poorest billion) compared with 85% of the combined CVD and congenital heart anomaly burden (4439/5199 DALYs) in high-income countries. Further, of the combined CVD and congenital heart anomaly burden, 34% was accrued in people under age 30 years in the poorest countries, while only 3% is accrued under age 30 years in high-income countries. We conclude although the current global targets for noncommunicable disease and CVD control will help diminish premature CVD death in the poorest populations, they are not sufficient. Specifically, the current framework (1) excludes deaths of people <30 years of age and deaths attributable to congenital heart anomalies, and (2) emphasizes interventions to prevent and treat conditions attributed to behavioral and metabolic risks factors. We recommend a complementary strategy for the poorest populations that targets premature death at younger ages, addresses environmental and infectious risks, and introduces broader integrated health system interventions, including cardiac surgery for congenital and rheumatic heart disease.

The Heart of 25 by 25: Achieving the Goal of Reducing Global and Regional Premature Deaths From Cardiovascular Diseases and Stroke: A Modeling Study From the American Heart Association and World Heart Federation.

In 2011, the United Nations set key targets to reach by 2025 to reduce the risk of premature noncommunicable disease death by 25% by 2025. With cardiovascular disease being the largest contributor to global mortality, accounting for nearly half of the 36 million annual noncommunicable disease deaths, achieving the 2025 goal requires that cardiovascular disease and its risk factors be aggressively addressed. The Global Cardiovascular Disease Taskforce, comprising the World Heart Federation, American Heart Association, American College of Cardiology Foundation, European Heart Network, and European Society of Cardiology, with expanded representation from Asia, Africa, and Latin America, along with global cardiovascular disease experts, disseminates information and approaches to reach the United Nations 2025 targets. The writing committee, which reflects Global Cardiovascular Disease Taskforce membership, engaged the Institute for Health Metrics and Evaluation, University of Washington, to develop region-specific estimates of premature cardiovascular mortality in 2025 based on various scenarios. Results show that >5 million premature CVD deaths among men and 2.8 million among women are projected worldwide by 2025, which can be reduced to 3.5 million and 2.2 million, respectively, if risk factor targets for blood pressure, tobacco use, diabetes mellitus, and obesity are achieved. However, global risk factor targets have various effects, depending on region. For most regions, United Nations targets for reducing systolic blood pressure and tobacco use have more substantial effects on future scenarios compared with maintaining current levels of body mass index and fasting plasma glucose. However, preventing increases in body mass index has the largest effect in some high-income countries. An approach achieving reductions in multiple risk factors has the largest impact for almost all regions. Achieving these goals can be accomplished only if countries set priorities, implement cost-effective population wide strategies, and collaborate in public-private partnerships across multiple sectors.

Clinical Outcomes in 3343 Children and Adults With Rheumatic Heart Disease From 14 Low- and Middle-Income Countries: Two-Year Follow-Up of the Global Rheumatic Heart Disease Registry (the REMEDY Study).

BACKGROUND: There are few contemporary data on the mortality and morbidity associated with rheumatic heart disease or information on their predictors. We report the 2-year follow-up of individuals with rheumatic heart disease from 14 low- and middle-income countries in Africa and Asia. METHODS: Between January 2010 and November 2012, we enrolled 3343 patients from 25 centers in 14 countries and followed them for 2 years to assess mortality, congestive heart failure, stroke or transient ischemic attack, recurrent acute rheumatic fever, and infective endocarditis. RESULTS: Vital status at 24 months was known for 2960 (88.5%) patients. Two-thirds were female. Although patients were young (median age, 28 years; interquartile range, 18-40), the 2-year case fatality rate was high (500 deaths, 16.9%). Mortality rate was 116.3/1000 patient-years in the first year and 65.4/1000 patient-years in the second year. Median age at death was 28.7 years. Independent predictors of death were severe valve disease (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.80-3.11), congestive heart failure (HR, 2.16; 95% CI, 1.70-2.72), New York Heart Association functional class III/IV (HR, 1.67; 95% CI, 1.32-2.10), atrial fibrillation (HR, 1.40; 95% CI, 1.10-1.78), and older age (HR, 1.02; 95% CI, 1.01-1.02 per year increase) at enrollment. Postprimary education (HR, 0.67; 95% CI, 0.54-0.85) and female sex (HR, 0.65; 95% CI, 0.52-0.80) were associated with lower risk of death. Two hundred and four (6.9%) patients had new congestive heart failure (incidence, 38.42/1000 patient-years), 46 (1.6%) had a stroke or transient ischemic attack (8.45/1000 patient-years), 19 (0.6%) had recurrent acute rheumatic fever (3.49/1000 patient-years), and 20 (0.7%) had infective endocarditis (3.65/1000 patient-years). Previous stroke and older age were independent predictors of stroke/transient ischemic attack or systemic embolism. Patients from low- and lower-middle-income countries had significantly higher age- and sex-adjusted mortality than patients from upper-middle-income countries. Valve surgery was significantly more common in upper-middle-income than in lower-middle- or low-income countries. CONCLUSIONS: Patients with clinical rheumatic heart disease have high mortality and morbidity despite being young; those from low- and lower-middle-income countries had a poorer prognosis associated with advanced disease and low education. Programs focused on early detection and the treatment of clinical rheumatic heart disease are required to improve outcomes.

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Symptoms and Signs of Heart Failure at Admission and Discharge and Outcomes in the Sub-Saharan Acute Heart Failure (THESUS-HF) Registry.

BACKGROUND: Symptoms and signs of heart failure (HF) are the most common reasons for admission to hospital for acute HF (AHF) and are used routinely throughout admission to assess the severity of disease and response to therapy. METHODS AND RESULTS: The data were collected in The Sub-Saharan Africa Survey on Heart Failure (THESUS-HF) study, a prospective, multicenter, observational survey of AHF from 9 countries in sub-Saharan Africa. A total of 1006 patients, ≥12 years of age, hospitalized for AHF were recruited. Symptoms and signs of HF and changes in dyspnea and well-being, relative to admission, were assessed at entry and on days 1, 2, and 7 (or on discharge if earlier) and included oxygen saturation, degree of edema and rales, body weight, and level of orthopnea. The patient determined dyspnea and general well-being, whereas the physician determined symptoms and signs of HF, as well as improvements in vital sign measurement, throughout the admission. After multivariable adjustment, baseline rales and changes to day 7 or discharge in general well-being predicted death or HF hospitalization through day 60, and baseline orthopnea, edema, rales, oxygen saturation, and changes to day 7 or on discharge in respiratory rate and general well-being were predictive of death through day 180. CONCLUSIONS: In AHF patients in sub-Saharan Africa, symptoms and signs of HF improve throughout admission, and simple assessments, including edema, rales, oxygen saturation, respiratory rate, and asking the patient about general well-being, are valuable tools in patients' clinical assessment.

Beta-blockers for hypertension.

BACKGROUND: Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties. They have shown long-term beneficial effects on mortality and cardiovascular disease (CVD) when used in people with heart failure or acute myocardial infarction. Beta-blockers were thought to have similar beneficial effects when used as first-line therapy for hypertension. However, the benefit of beta-blockers as first-line therapy for hypertension without compelling indications is controversial. This review is an update of a Cochrane Review initially published in 2007 and updated in 2012. OBJECTIVES: To assess the effects of beta-blockers on morbidity and mortality endpoints in adults with hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to June 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 6), MEDLINE (from 1946), Embase (from 1974), and ClinicalTrials.gov. We checked reference lists of relevant reviews, and reference lists of studies potentially eligible for inclusion in this review, and also searched the the World Health Organization International Clinical Trials Registry Platform on 06 July 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of at least one year of duration, which assessed the effects of beta-blockers compared to placebo or other drugs, as first-line therapy for hypertension, on mortality and morbidity in adults. DATA COLLECTION AND ANALYSIS: We selected studies and extracted data in duplicate, resolving discrepancies by consensus. We expressed study results as risk ratios (RR) with 95% confidence intervals (CI) and conducted fixed-effect or random-effects meta-analyses, as appropriate. We also used GRADE to assess the certainty of the evidence. GRADE classifies the certainty of evidence as high (if we are confident that the true effect lies close to that of the estimate of effect), moderate (if the true effect is likely to be close to the estimate of effect), low (if the true effect may be substantially different from the estimate of effect), and very low (if we are very uncertain about the estimate of effect). MAIN RESULTS: Thirteen RCTs met inclusion criteria. They compared beta-blockers to placebo (4 RCTs, 23,613 participants), diuretics (5 RCTs, 18,241 participants), calcium-channel blockers (CCBs: 4 RCTs, 44,825 participants), and renin-angiotensin system (RAS) inhibitors (3 RCTs, 10,828 participants). These RCTs were conducted between the 1970s and 2000s and most of them had a high risk of bias resulting from limitations in study design, conduct, and data analysis. There were 40,245 participants taking beta-blockers, three-quarters of them taking atenolol. We found no outcome trials involving the newer vasodilating beta-blockers (e.g. nebivolol).There was no difference in all-cause mortality between beta-blockers and placebo (RR 0.99, 95% CI 0.88 to 1.11), diuretics or RAS inhibitors, but it was higher for beta-blockers compared to CCBs (RR 1.07, 95% CI 1.00 to 1.14). The evidence on mortality was of moderate-certainty for all comparisons.Total CVD was lower for beta-blockers compared to placebo (RR 0.88, 95% CI 0.79 to 0.97; low-certainty evidence), a reflection of the decrease in stroke (RR 0.80, 95% CI 0.66 to 0.96; low-certainty evidence) since there was no difference in coronary heart disease (CHD: RR 0.93, 95% CI 0.81 to 1.07; moderate-certainty evidence). The effect of beta-blockers on CVD was worse than that of CCBs (RR 1.18, 95% CI 1.08 to 1.29; moderate-certainty evidence), but was not different from that of diuretics (moderate-certainty) or RAS inhibitors (low-certainty). In addition, there was an increase in stroke in beta-blockers compared to CCBs (RR 1.24, 95% CI 1.11 to 1.40; moderate-certainty evidence) and RAS inhibitors (RR 1.30, 95% CI 1.11 to 1.53; moderate-certainty evidence). However, there was little or no difference in CHD between beta-blockers and diuretics (low-certainty evidence), CCBs (moderate-certainty evidence) or RAS inhibitors (low-certainty evidence). In the single trial involving participants aged 65 years and older, atenolol was associated with an increased CHD incidence compared to diuretics (RR 1.63, 95% CI 1.15 to 2.32). Participants taking beta-blockers were more likely to discontinue treatment due to adverse events than participants taking RAS inhibitors (RR 1.41, 95% CI 1.29 to 1.54; moderate-certainty evidence), but there was little or no difference with placebo, diuretics or CCBs (low-certainty evidence). AUTHORS' CONCLUSIONS: Most outcome RCTs on beta-blockers as initial therapy for hypertension have high risk of bias. Atenolol was the beta-blocker most used. Current evidence suggests that initiating treatment of hypertension with beta-blockers leads to modest CVD reductions and little or no effects on mortality. These beta-blocker effects are inferior to those of other antihypertensive drugs. Further research should be of high quality and should explore whether there are differences between different subtypes of beta-blockers or whether beta-blockers have differential effects on younger and older people.

Interventions for treating tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis can impair the heart's function and cause death; long term, it can cause the membrane to fibrose and constrict causing heart failure. In addition to antituberculous chemotherapy, treatments include corticosteroids, drainage, and surgery. OBJECTIVES: To assess the effects of treatments for tuberculous pericarditis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (27 March 2017); the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2017, Issue 2); MEDLINE (1966 to 27 March 2017); Embase (1974 to 27 March 2017); and LILACS (1982 to 27 March 2017). In addition we searched the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal using 'tuberculosis' and 'pericard*' as search terms on 27 March 2017. We searched ClinicalTrials.gov and contacted researchers in the field of tuberculous pericarditis. This is a new version of the original 2002 review. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search outputs, evaluated study eligibility, assessed risk of bias, and extracted data; and we resolved any discrepancies by discussion and consensus. One trial assessed the effects of both corticosteroid and Mycobacterium indicus pranii treatment in a two-by-two factorial design; we excluded data from the group that received both interventions. We conducted fixed-effect meta-analysis and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Seven trials met the inclusion criteria; all were from sub-Saharan Africa and included 1959 participants, with 1051/1959 (54%) HIV-positive. All trials evaluated corticosteroids and one each evaluated colchicine, M. indicus pranii immunotherapy, and open surgical drainage. Four trials (1841 participants) were at low risk of bias, and three trials (118 participants) were at high risk of bias.In people who are not infected with HIV, corticosteroids may reduce deaths from all causes (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.09; 660 participants, 4 trials, low certainty evidence) and the need for repeat pericardiocentesis (RR 0.85, 95% CI 0.70 to 1.04; 492 participants, 2 trials, low certainty evidence). Corticosteroids probably reduce deaths from pericarditis (RR 0.39, 95% CI 0.19 to 0.80; 660 participants, 4 trials, moderate certainty evidence). However, we do not know whether or not corticosteroids have an effect on constriction or cancer among HIV-negative people (very low certainty evidence).In people living with HIV, only 19.9% (203/1959) were on antiretroviral drugs. Corticosteroids may reduce constriction (RR 0.55, 0.26 to 1.16; 575 participants, 3 trials, low certainty evidence). It is uncertain whether corticosteroids have an effect on all-cause death or cancer (very low certainty evidence); and may have little or no effect on repeat pericardiocentesis (RR 1.02, 0.89 to 1.18; 517 participants, 2 trials, low certainty evidence).For colchicine among people living with HIV, we found one small trial (33 participants) which had insufficient data to make any conclusions about any effects on death or constrictive pericarditis.Irrespective of HIV status, due to very low certainty evidence from one trial, it is uncertain whether adding M. indicus pranii immunotherapy to antituberculous drugs has an effect on any outcome.Open surgical drainage for effusion may reduce repeat pericardiocentesis In HIV-negative people (RR 0.23, 95% CI 0.07 to 0.76; 122 participants, 1 trial, low certainty evidence) but may make little or no difference to other outcomes. We did not find an eligible trial that assessed the effects of open surgical drainage in people living with HIV.The review authors found no eligible trials that examined the length of antituberculous treatment needed nor the effects of other adjunctive treatments for tuberculous pericarditis. AUTHORS' CONCLUSIONS: For HIV-negative patients, corticosteroids may reduce death. For HIV-positive patients not on antiretroviral drugs, corticosteroids may reduce constriction. For HIV-positive patients with good antiretroviral drug viral suppression, clinicians may consider the results from HIV-negative patients more relevant.Further research may help evaluate percutaneous drainage of the pericardium under local anaesthesia, the timing of pericardiectomy in tuberculous constrictive pericarditis, and new antibiotic regimens.

The association between HIV and atherosclerotic cardiovascular disease in sub-Saharan Africa: a systematic review.

BACKGROUND: Sub-Saharan Africa (SSA) has confronted decades of the HIV epidemic with substantial improvements in access to life-saving antiretroviral therapy (ART). Now, with improved survival, people living with HIV (PLWH) are at increased risk for non-communicable diseases (NCDs), including atherosclerotic cardiovascular disease (CVD). We assessed the existing literature regarding the association of CVD outcomes and HIV in SSA. METHODS: We used the PRISMA guidelines to perform a systematic review of the published literature regarding the association of CVD and HIV in SSA with a focus on CVD surrogate and clinical outcomes in PLWH. RESULTS: From January 2000 until March 2017, 31 articles were published regarding CVD outcomes among PLWH in SSA. Data from surrogate CVD outcomes (n = 13) suggest an increased risk of CVD events among PLWH in SSA. Although acute coronary syndrome is reported infrequently in SSA among PLWH, limited data from five studies suggest extensive thrombus and hypercoagulability as contributing factors. Additional studies suggest an increased risk of stroke among PLWH (n = 13); however, most data are from immunosuppressed ART-naïve PLWH and thus are potentially confounded by the possibility of central nervous system infections. CONCLUSIONS: Given ongoing gaps in our current understanding of CVD and other NCDs in PLWH in SSA, it is imperative to ascertain the burden of CVD outcomes, and to examine strategies for intervention and best practices to enhance the health of this vulnerable population.

"I passed the test!" Evidence of diagnostic misconception in the recruitment of population controls for an H3Africa genomic study in Cape Town, South Africa.

BACKGROUND: Advances in genetic and genomic research have introduced challenges in obtaining informed consent for research in low and middle-income settings. However, there are only few studies that have explored challenges in obtaining informed consent in genetic and genomic research in Africa and none in South Africa. To start filling this gap, we conducted an empirical study to investigate the efficacy of informed consent procedures for an H3Africa genomic study on Rheumatic Heart Disease (RHDGen) at the University of Cape Town in South Africa. The main aim of the study was to understand ethical challenges in obtaining informed consent in the RHDGen study. METHODS: We used a qualitative study methodology involving in-depth interviews and participant observations. Our study participants were RHDGen cases (patients), healthy controls and research staff involved in the recruitment of RHDGen cases and controls. In total, we conducted 32 in-depth interviews with RHDGen cases and controls, 2 in-depth interviews with research staff and 57 direct observations of the consent procedures of RHDGen cases and controls. The interviews were conducted in English, audio-recorded and transcribed verbatim. Data were analyzed using thematic content analysis. The study was conducted in 3 sites within Cape Town, South Africa. RESULTS: Most healthy controls joined the RHDGen study in order to be screened for rheumatic heart disease (diagnostic misconception). A majority of RHDGen cases decided to join the RHDGen study because of therapeutic misconception. CONCLUSION: The ethical challenges that impacted on obtaining informed consent in the RHDGen study were complex. In this study, the main challenges were diagnostic misconception among RHDGen controls and therapeutic misconception among RHDGen cases.

Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association.

BACKGROUND: Acute rheumatic fever remains a serious healthcare concern for the majority of the world's population despite its decline in incidence in Europe and North America. The goal of this statement was to review the historic Jones criteria used to diagnose acute rheumatic fever in the context of the current epidemiology of the disease and to update those criteria to also take into account recent evidence supporting the use of Doppler echocardiography in the diagnosis of carditis as a major manifestation of acute rheumatic fever. METHODS AND RESULTS: To achieve this goal, the American Heart Association's Council on Cardiovascular Disease in the Young and its Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee organized a writing group to comprehensively review and evaluate the impact of population-specific differences in acute rheumatic fever presentation and changes in presentation that can result from the now worldwide availability of nonsteroidal anti-inflammatory drugs. In addition, a methodological assessment of the numerous published studies that support the use of Doppler echocardiography as a means to diagnose cardiac involvement in acute rheumatic fever, even when overt clinical findings are not apparent, was undertaken to determine the evidence basis for defining subclinical carditis and including it as a major criterion of the Jones criteria. This effort has resulted in the first substantial revision to the Jones criteria by the American Heart Association since 1992 and the first application of the Classification of Recommendations and Levels of Evidence categories developed by the American College of Cardiology/American Heart Association to the Jones criteria. CONCLUSIONS: This revision of the Jones criteria now brings them into closer alignment with other international guidelines for the diagnosis of acute rheumatic fever by defining high-risk populations, recognizing variability in clinical presentation in these high-risk populations, and including Doppler echocardiography as a tool to diagnose cardiac involvement.