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Background: Primary care for pediatric patients focuses on providing comprehensive, accessible, and coordinated healthcare from the neonatal period to adolescence. The implementation and use of electronic medical records (EMR) in pediatric primary care facilities is an efficient strategy to gather necessary information on the epidemiology of common pediatric diseases in the Philippines., Objectives: This study aimed to determine the frequency distribution of pediatric diseases in a rural primary healthcare facility in the Philippines., Methods: This cross-sectional study reviewed the EMR of all pediatric patients who consulted in a primary care facility in Samal, Bataan from April 2019 to March 2021. Data gathered include sex, age in years, chief complaint, diagnosis, and month of consultation. Data was summarized using descriptive statistics., Results: A total of 14,462 pediatric consults were recorded from April 2019 to March 2021. There were slightly more male patients (52.1%). The mean age of the patients was 6.5 years (standard deviation 5.22). The highest number of consults came from the 1- to 4-year-old age group (41.5%). The most common chief complaints were cough (45.9%), fever (25.5%), and colds (24.9%). The most frequent diagnoses were upper respiratory tract infections (47.4%), followed by lower respiratory tract infections (6.9%), and skin and soft tissue infections (5.3%). Majority of the consults for respiratory tract infections, skin and soft tissue infections, gastroenteritis, asthma, and dermatitis were in the 1- to 4-year-old age group. Urinary tract infections and otitis media or externa were recorded more frequently in the 5- to 9-year-old age group., Conclusions: Respiratory tract infections, followed by skin and soft tissue infections, were the most frequently identified diseases in children consulting a primary care facility at a rural site in the Philippines. The most common chief complaints, defined as the primary reason for seeking consult, were cough, fever, and colds. Data was gathered through EMR review, which may aid in the planning of programs and policies to improve primary care service delivery., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

Background: Turnaround time is an integral component of primary healthcare and is a key performance indicator of healthcare delivery. It is defined as the time patients spend during a healthcare facility visit. In this study, turnaround time is defined as the time elapsed from registration to the end of consultation., Objectives: This study aimed to determine the turnaround time of consults in the primary care system in a rural site in the Philippines, and compare turnaround time during the pre-pandemic and COVID-19 pandemic periods., Methods: This is a retrospective cohort study of patients seen at the primary care facility under the Philippine Primary Care Studies (PPCS) rural site from April 2019 to March 2021. Patients included in this study were chosen through random sampling. Electronic medical records (EMR) of these patients were reviewed. Turnaround time was computed electronically from time of registration to end of consultation. Descriptive statistics was used to summarize data and report turnaround time. The turnaround time before and during the pandemic was compared using an independent sample t-test (if normally distributed) or Mann Whitney U test (if not normally distributed). A p-value of <0.05 was considered statistically significant., Results: A random sample of 342 patients out of the total 45,501 patient consults seen at the rural primary healthcare facility from April 2019 to March 2021 were included in this study. The median turnaround time was 29.0 minutes (interquartile range [IQR] 68.3), with range of 0.9 to 437.2 minutes. During the pre-pandemic period, the median turnaround time of consults is 29.3 minutes (IQR 70.4) which is 1.8 minutes longer than the pandemic period which showed median turnaround time of 27.5 minutes (IQR 72.7). The difference between the two time periods was not statistically significant (P = 0.39)., Conclusion: The study showed that the median turnaround time of medical consults was 29.0 minutes, which was shorter by 80 minutes compared to other published Philippine studies. The turnaround time did not differ significantly in the pandemic and pre-pandemic period, despite new policies and systems that were implemented during the pandemic., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

Introduction: Service delivery networks, also called healthcare providers networks (HCPNs) have been used to address health inequities and promote universal healthcare (UHC). This study described the effect of instituting a mixed HCPN (partnership of public health facilities with a private pharmacy) on the provision of medications in the rural primary care pilot site of the Philippine Primary Care Studies (PPCS)., Methods: This is a case study of the mixed HCPN in the PPCS rural site. A mixed HCPN involving one private pharmacy was instituted to increase the supply of drugs. The total number of medications prescribed per month from April 2019 to October 2021, and the number of medications dispensed from the public sector (rural health unit or RHU) and from the partner private pharmacy in the same time period were obtained., Results: Of the 101 031 medications prescribed in the first year (April 2019 to March 2020), 21.7% were dispensed at the RHU and 66.7% were dispensed in the partner private pharmacy. The remaining 11.5% were unrendered or dispensed in other private pharmacies. Of the 35 408 medications prescribed in the second year (April 2020 to March 2021), 5.6% were dispensed at the RHU and 32.2% were dispensed at the partner private pharmacy. Majority (62.1%) were unrendered or dispensed in other private pharmacies. From April to October 2021, of the 6448 medications prescribed, 2.3% were dispensed at the RHU, and 47.3% were dispensed at the partner private pharmacy. Majority (50.3%) were unrendered or dispensed in other private pharmacies., Conclusion: Creation of a mixed HCPN in a rural primary care site augmented access to essential medications. The mixed HCPN model in the study showed potential in strengthening access to consultations and medications in a rural community. Improving essential primary care services can facilitate implementation of UHC in the Philippines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to describe the pattern of prescription and laboratory use in the management of infectious acute gastroenteritis (AGE) in children seen in a rural service delivery network (SDN) and to determine their adherence to the 2019 Clinical Practice Guidelines on the Management of Acute Infectious Diarrhea in Children and Adults from the Department of Health (DOH)., Methods: A descriptive retrospective study was done using the electronic medical records (EMR) of patients less than 19 years old seen by the rural SDN from April 2019-2021 and diagnosed with infectious AGE. Data were extracted on diagnostic and therapeutic management. Adherence to strong CPG recommendations focusing on rehydration, zinc supplementation, rational laboratory use, and antibiotic prescription was chosen as indicator of quality of care. Adherence of less than 70% was defined as low., Results: There were 227 infectious AGE cases, with 72% diagnosed under non-specific infectious AGE. Fifty two percent (52%) were prescribed with low-osmolarity oral rehydration solutions (ORS), while 74% were given zinc. Stool analysis was done in 25% of cases while CBC was done in 20%. Top antibiotics given were metronidazole at 44% and cotrimoxazole at 33%. There was low adherence to prescribing low-osmolarity ORS for rehydration (52%) and to deferring routine antibiotic prescription for non-specific infectious AGE cases (24%). Adherence to deferring routine stool analysis and CBC were relatively high at 73% and 70%, respectively while adherence to antibiotic use for indicated cases was high at 95%., Conclusion: Frequency of diagnostics ordered were low resulting to high adherence rates to recommendations concerning judicious laboratory use. Prescription frequency of appropriate antibiotics and interventions for AGE were low, leading to low adherence rates to recommendations concerning rational antibiotic use and prescription of cornerstone therapies for infectious AGE., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

Background and Objective: Inequity in access to healthcare continues to be a problem in the Philippines. This was further aggravated by the COVID-19 pandemic. Telemedicine is considered a potential strategy to address inequitable access to healthcare; however, it only gained popularity during the pandemic. This study aims to determine the pediatric conditions diagnosed through telemedicine consults and the platforms utilized by patients in the Philippine Primary Care Studies pilot sites during the pandemic., Methods: This is a cross-sectional study of pediatric patients below 19 years of age who sought consult using telemedicine. Using the electronic medical records (EMR) system adapted by the Philippine Primary Care Studies in UP Health Service (UPHS) Quezon City, Metro Manila (urban site), Samal, Bataan (rural site), and Bulusan, Sorsogon (remote site), pediatric conditions diagnosed through telemedicine consults and the platforms utilized by patients from September 2021 to August 2022 were extracted and summarized. Data was summarized using descriptive statistics., Results: A total of 5,388 consults involving pediatric patients were recorded from September 2021 to August 2022, of which 1,562 (29.0%) were done through telemedicine. Majority of the telemedicine consults (67.5%, n=1,055) were in the rural site. There were 274 telemedicine consults (17.6%) in the remote site, and 233 (14.9%) in the urban site. The most common diagnosis was acute upper respiratory tract infection (30.8%). Other common conditions diagnosed through telemedicine were lower respiratory tract infections, skin infections, urinary tract infections, obesity, anxiety disorders, allergic rhinitis, conditions related to pregnancy, and myalgia. The most common platforms used by patients are video calls (20.2%, n=315) and voice calls (18.4%, n=287) across all three sites. However, the most common platform differed per area-video calls for the urban site (85.8%), live chat for the rural site (76.1%), and voice calls for the remote site (60.6%)., Conclusion: The most common condition diagnosed among pediatric patients consulting through telemedicine is upper respiratory tract infection. The most common platforms used to seek consult through telemedicine are live chat, video calls, and voice calls, with differences noted per site., Competing Interests: All authors have no conflicts of interest to declare., (© 2024 Acta Medica Philippina.)

Background: Cardiovascular disease (CVD) continues to impart a large burden on the global population, especially in lower income countries where affordability limits the use of cardiovascular medicines. A fixed dose combination strategy of at least 2 blood pressure lowering medications and a statin with aspirin in a single pill has been shown to reduce the risk of incident CVD by 38% in primary prevention in a recent meta-analysis. We report the in-trial (median follow-up: 5 years) cost-effectiveness of a fixed dose combination (FDC) pill in different income groups based on data from that meta-analysis., Methods: Countries were categorized using World Bank economic groups: Lower Middle Income Countries (LMIC), Upper Middle Income Countries (UMIC) and High Income Countries (HIC). Country specific costs were obtained for hospitalized events, procedures, and non-study medications (2020 USD). FDC price was based on the cheapest equivalent substitute (CES) for each component., Findings: For the CES-FDC pill versus control the difference in cost was $346 (95% CI: $294-$398) per participant in Lower Middle Income Countries, $838 (95% CI: $781-$895) in Upper Middle Income Countries and $42 (95% CI: -$155 to $239) (cost-neutral) in High Income Countries. During the study period the CES-FDC pill was associated with incremental gain in quality-adjusted life years of 0.06 (95% CI: 0.04-0.08) resulting in an incremental cost-effectiveness ratio (ICER) of $5767 (95% CI: 5735-$5799), $13,937 (95% CI: $13,893-$14,041) and $700 (95% CI: $662-$738) respectively. In subgroups analyses, the highest 10 years CVD risk subgroup had ICERs of $2033, $7322 and -$6000/QALY., Interpretation: A FDC pill produced at CES costs is cost-neutral in HIC. Governments of LMI and UMI countries should assess these results based on the ICER threshold accepted in their own country and own specific health care priorities but should consider prioritizing this strategy for patients with high 10 years CVD risk as a first step., Funding: Population Health Research Institute., Competing Interests: AL, WT, PJ, PG, RM, GR, PL-J, PP, AA, AD and HG have no conflicts to declare. MDH reports Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events outside the submitted work from PwC Switzerland. Support for attending meetings and/or travel outside the submitted work from the World Heart Federation. MDH has an appointment at The George Institute for Global Health, which has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy through its social enterprise business, George Medicines and has patents pending for Heart Failure polypills. DX reports grants from Population Health Research Institute, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Coca-Cola India, the Indian Council of Medical Research, Pfizer, UK Medical Research Council, and Wellcome Trust outside the submitted work. Speaker's fees from Eli Lilly, Sanofi and Intas outside the submitted work. Support for attending meetings and/or travel outside the submitted work from the Indian Council of Medical Research, Eli Lilly, Sanofi, BIRAC and DBC. DX is an honorary VP with SOCHARA and honorary executive committee member of ISCR. SY reports grants from AstraZeneca, and Cadila Pharmaceuticals related to conducting the HOPE-3 or TIPS-3 studies and Honoraria for lectures on the Prevention of Cardiovascular Disease from diverse sources., (© 2024 The Author(s).)

Background: The Philippines has a shortage and uneven distribution of healthcare workers (HCWs). Job satisfaction is an important element to HCW retention and attracting new HCWs into the health system., Objective: This study measured HCWs' intent to stay and HCWs' satisfaction after implementation of multiple interventions intended to strengthen the primary care system, and determine factors significantly associated with HCWs' intent to stay., Methodology: This is a serial cross-sectional study in urban, rural and remote primary care sites in the Philippines. All physicians, nurses, midwives, dentists, community health workers and support staff were invited to participate. Baseline HCWs' intent to stay and satisfaction were obtained using a self-administered questionnaire prior to implementation of interventions. The same survey was again conducted in the years 2021 and 2022, corresponding to 5 and 6 years after initial implementation for the urban site, and 2 and 3 years for the rural and remote sites. We used multiple logistic regression to determine factors associated with intent to stay., Results: There were 430 survey respondents (89.4% response rate) for year 2021, and 417 survey respondents (97.4% response rate) for year 2022. The urban and rural sites had significant increase in several HCW satisfaction domains, while the remote site had significant decrease in several HCW satisfaction domains. There was no significant difference in the intent to stay in the three sites. Factors that decreased intent to stay included length of employment, job involvement and employment as a nurse, while factors that increased intent to stay included job satisfaction, enjoyment and working in the urban site., Conclusion: HCW satisfaction improved in the urban site and rural site, while HCW satisfaction declined in the remote site. Intention to stay of primary care HCWs did not significantly change., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: A thorough understanding of user needs and behavioural intent-to-use underpins the development of a responsive health information system. This study aimed to examine health workers' intent-to-use an electronic health record (EHR) system in an urban, rural and remote setting in the Philippines., Methods: Following the Unified Theory of Acceptance and Use of Technology framework, user acceptance and the factors influencing intent-to-use the EHR were examined through a self-administered questionnaire. A total of 128 EHR users, comprising physicians, nurses, midwives, barangay health workers and administrative staff, were surveyed. Median scores for each domain were compared across the sites using the Kruskal-Wallis test. Ridge regression analysis was used to identify factors associated with behavioural intent-to-use., Results: Over 94% of users across all sites reported their intent-to-use the EHR in the near future. Of the seven predictor variables examined, only self-efficacy was found to be significantly associated with behavioural intent-to-use. Intent-to-use the EHR increased by 31% (p=0.007) for each unit increase in self-efficacy score among participants., Discussion: Acceptance was high across the three sites, with self-efficacy being a predictor of intent-to-use the technology. This suggests that users are more likely to adopt an EHR if they believe they have the capacity to successfully navigate the technology and perform their designated tasks with it., Conclusion: Co-producing interventions with primary care providers is crucial in sustaining EHR systems. Rather than developing a technology based on the surveillance needs of policymakers, an EHR developed from the grassroots was shown to be well-received by end-users., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels., Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined)., Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50)., Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke., Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke., Competing Interests: We declare no competing interests. Dr. Hans-Christoph Diener has reported receiving fees from Pfizer, Abbott, and Daiichi Sankyo. Dr. Denis Xavier reported receiving grants from Population Health Research Institute, Hamilton Health Science, Boehringer Ingelheim, Bristol Myers Squibb, Coco cola India, Indian Council of Medical Research, Pfizer, United Kingdom Medical Research Council and Welcome Trust., (© 2024 The Authors.)

Objectives: This study measured changes in patient satisfaction levels before and after the introduction of primary care system strengthening interventions in urban, rural, and remote sites in the Philippines., Methods: A previously validated 16-item questionnaire was distributed to 200 patients per site before implementation of interventions and to a different set of 200 patients 1 year after implementation. We compared the percentage change in highly satisfied patients per site before and after implementing interventions using a two-proportion Z-test., Results: The urban site had a significant increase in patient satisfaction in 13 survey items, which corresponded to the domains of healthcare availability, service efficiency, technical competency and health communication. The rural site had a significant increase in six survey items, which corresponded to the domains of service efficiency, environment, location, health communication and handling. The remote site had a decrease in patient satisfaction in 10 survey items, with a significant increase in only 4 items under the domains of healthcare availability and handling., Conclusion: Our findings support the 'inverse equity hypothesis', where well-resourced urban communities quickly adopt complex health interventions while rural and remote settings experience delays in effectively meeting patient needs and system demands. Extended intervention periods and targeted strategies may be necessary to impact patient satisfaction in underserved areas considerably., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Strengthening primary care helps address health inequities that continue to persist in the Philippines. The Philippine Primary Care Studies pilot-tested interventions to improve the primary care system. One intervention was the provision of a free subscription to an electronic decision support application called UpToDate (UTD) for primary care providers (PCPs), including doctors, nurses, midwives and community health workers (CHWs). This study aimed to (1) assess the feasibility of using UTD as information source for PCPs in urban, rural and remote settings, (2) determine the acceptability of UTD as an information source for PCPs and (3) examine the impact of UTD access on PCP clinical decision-making., Methods: Four focus group discussions (FGDs) and two key informant interviews (KII) were conducted to gather insights from 30 PCPs. Thematic analysis through coding in NVivo V.12 was done using the technology acceptance model (TAM) as a guiding framework., Results: All PCPs had positive feedback regarding UTD use because of its comprehensiveness, accessibility, mobility and general design. The participants relayed UTD's benefit for point-of-contact use, capacity-building and continuing professional development. PCPs across the three sites, including CHWs with no formal medical education, were able to provide evidence-based medical advice to patients through UTD. However, external factors in these settings impeded the full integration of UTD in the PCPs' workflow, including poor internet access, unstable sources of electricity, lack of compatible mobile devices and the need for translation to the local language., Conclusion: UTD was a feasible and acceptable clinical decision support tool for the PCPs. Factors affecting the feasibility of using UTD include technological and environmental factors (ie, internet access and the lack of translation to the local language), as well as the organisational structure of the primary care facility which determines the roles of the PCPs. Despite the difference in roles and responsibilities of the PCPs, UTD positively impacted decision-making and patient education for all PCPs through its use as a point-of-contact tool and a tool for capacity-building., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Information on the magnitude and durability of humoral immunity against COVID-19 among specific populations can guide policies on vaccination, return from isolation and physical distancing measures. The study determined the durability of SARS-CoV-2 antibodies after an initial infection among Filipinos in Metro Manila, Philippines, and the extent of protection SARS-CoV-2 antibodies confer against reinfection., Methods: We conducted a cohort study to monitor the antibody levels of patients diagnosed with COVID-19. Receptor-binding domain (RBD)-specific antibodies were measured at Days 21, 90, 180, 270 and 360. Antibody levels were reported as geometric mean titers (GMT) with geometric standard deviation (GSD). Differences in GMT were tested using Friedman test and Kruskal Wallis test, with Bonferroni multiple comparisons procedure. Adjusted hazard ratios on the development of probable reinfection were estimated using Cox proportional models., Results: There were 307 study participants included in the study, with 13 dropouts. Study participants received SARS-CoV-2 vaccines at varying times, with 278 participants (90.5%) fully vaccinated by the end of study. The GMT of the study cohort increased over time, from 19.7 U/mL (GSD 11) at Day 21; to 284.5 U/mL (GSD 9.6) at Day 90; 1,061 U/mL (GSD 5.3) at Day 180; 2,003 U/mL (GSD 6.7) at Day 270; and 8,403 U/mL (GSD 3.1) at Day 360. The increase was statistically significant from Day 21 to Day 90 (p<0.0001), Day 90 to Day 180 (p=0.0005), and Day 270 to Day 360 (p<0.0001). Participants with more severe initial infection demonstrated significantly higher antibody levels compared to those with milder infection at Day 21. Sixty-four patients had probable COVID-19 reinfection (incidence of 20.8%, 95% CI 16.4, 25.8%). The GMT of these 64 patients was 411.8 U/mL (GSD 6.9) prior to the occurrence of the probable reinfection. Majority (87.5%) were fully vaccinated. Antibody titers significantly affected the risk of developing reinfection, with adjusted hazard ratio of 0.994, 95% CI 0.992-0.996, p<0.001., Conclusion: Antibody levels against SARS-CoV-2 increased over a one-year follow-up. Higher antibody levels were observed among those with more severe initial infection and those vaccinated. Higher antibody levels are associated with a lower risk of probable reinfection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gonzales, Dans, Tan-Lim, Uy, Cutiongco-dela Paz, Sulit, Alejandria, Lansang, Dans, Dator, Cordero and Pardilla.)

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries., Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development., Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years., Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death., Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies., Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Aims: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE)., Methods and Results: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination., Conclusion: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19., Methods: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing., Findings: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions., Interpretation: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19., Funding: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation., Translations: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests JWE reports grants or in-kind support from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Glaxo-Smith-Kline, Pfizer, Janssen, and Sanofi-Aventis and honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli-Lilly, Glaxo-Smith-Kline, Merck, Pfizer, Janssen, Sanofi-Aventis, and Servier. SSJ reports grant support from Boston Scientific and consulting fees from Medtronic and Boston Scientific. EPB-C reports grant support from Bayer, Roche, BMS–Pfizer. RPW reports grant support from Bayer, Roche, and BMS-Pfizer, grant and honorarium from Boehringer-Ingelheim, and consultancy fees from Atricure and Phasebio. LMP-V reports ACT study support from Unilab, RiteMed Phils, Philippine Council for Health Research and Development, grant support from Wellcome Trust and Sanofi. AA reports institutional grant support from Bayer and EMS, lecture fees from Bayer, Sanofi-Aventis. DX reports ACT study funding from CIHR, grant support from PHRI, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Coco Cola India, Indian Council of Medical Research, Pfizer, UK Medical Research Council, and Wellcome Trust, speaker fees from Eli Lilly and Sanofi, meeting support from the Indian Council of Medical Research, Eli Lilly, and Sanofi, and leadership roles in SOCHARA and ISCR. RDL reports institutional grant support from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi, consulting fees from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Portola, honoraria from Pfizer and meeting travel support from IQVIA. OB reports grant support from Astra Zeneca, Bayer, Amgen, Novartis, Servier, and Pfizer. SW reports grant support from NIH, honoraria from Pfizer, and safety monitoring committee of an AIDS Clinical Trial. SSA reports grants from CIHR and PHAC, honoraria or consulting fees from Bayer, Janssen Pharma, meeting support from Heart and Stroke Canada, committee member at American Heart Association, Canadian Cardiovascular Society, Heart and Stroke Canada. JB reports consulting fees from Bayer. SC reports ACT study funding from Bayer, owns Bayer stock, is a board member of Canadian Arrhythmia Network, is an institutional advisory board member at the Institute of Circulatory and Respiratory Health, Canadian Institutes for Health Research. MEF reports institutional grants from Amgen, Astra Zeneca, Novartis, and Novo Nordisk and consulting fees from Otitopic. ML reports participation in vaccine advisory boards for Medicago, Pfizer, Sanofi, and is on the data safety and monitoring board for CanSino Biologics. SY reports institutional grant support from Bayer and honoraria and travel costs for lectures from Bayer. SR, LX, LH, SIB, WMT, MH, AK, WH, SKS, PL-J, ALD, PP, CF, AY, and ZA have no disclosures to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: The International Polycap Study 3 (TIPS-3) trial demonstrated that a polypill containing cholesterol- and multiple blood-pressure-lowering drugs reduces cardiovascular events by 20% compared with placebo in people without cardiovascular disease. The polypill plus aspirin led to a 31% relative risk reduction in cardiovascular disease events compared with double placebo. We report regional variations in costs and affordability of a polypill based on the TIPS-3 trial., Methods and Results: Countries were categorized using World Bank economic groups: lower-middle-income, upper-middle-income, and high-income countries. Country-specific costs were obtained for hospitalization events, procedures, and non-study medications (2019 US dollars). Polypill price was based on the cheapest equivalent substitute (CES) for each component. For the polypill vs. placebo, the difference in cost over the 4.6 years of the trial was $291 [95% confidence interval (CI): $243-339] per participant in lower-middle-income countries, $1068 (95% CI: $992-1144) in upper-middle-income countries, and $48 (95% CI: -$271 to $367) in high-income countries. Results were similar for the polypill plus aspirin vs. a double placebo. In both cases, the polypill was affordable in all groups using monthly household capacity to pay or a threshold of 4% of the gross national income per capita., Conclusion: The use of a polypill (CES) in TIPS-3 increases costs in lower-middle-income countries and upper-middle-income countries but is affordable in countries at various economic levels and is cost neutral (dominant) in high-income countries., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Elevated body mass index (BMI) is an important cause of cardiovascular disease (CVD). The population-level impact of pharmacologic strategies to mitigate the risk of CVD conferred by the metabolic consequences of an elevated BMI is not well described., Methods and Results: We conducted an analysis of 145 986 participants (mean age 50 years, 58% women) from 21 high-, middle-, and low-income countries in the Prospective Urban and Rural Epidemiology study who had no history of cancer, ischaemic heart disease, heart failure, or stroke. We evaluated whether the hazards of CVD (myocardial infarction, stroke, heart failure, or cardiovascular death) differed among those taking a cardiovascular medication (n = 29 174; including blood pressure-lowering, blood glucose-lowering, cholesterol-lowering, or anti-thrombotic medications) vs. those not taking a cardiovascular medication (n = 116 812) during 10.2 years of follow-up. Cox proportional hazard models with the community as a shared frailty were constructed by adjusting age, sex, education, geographic region, physical activity, tobacco, and alcohol use. We observed 7928 (5.4%) CVD events and 9863 (6.8%) deaths. Cardiovascular medication use was associated with different hazards of CVD (interaction P &lt; 0.0001) and death (interaction P = 0.0020) as compared with no cardiovascular medication use. Among those not taking a cardiovascular medication, as compared with those with BMI 20 to &lt;25 kg/m2, the hazard ratio (HR) [95% confidence interval (95% CI)] for CVD were, respectively, 1.14 (1.06-1.23); 1.45 (1.30-1.61); and 1.53 (1.28-1.82) among those with BMI 25 to &lt;30 kg/m2; 30 to &lt;35 kg/m2; and ≥35 kg/m2. However, among those taking a cardiovascular medication, the HR (95% CI) for CVD were, respectively, 0.79 (0.72-0.87); 0.90 (0.79-1.01); and 1.14 (0.98-1.33). Among those not taking a cardiovascular medication, the respective HR (95% CI) for death were 0.93 (0.87-1.00); 1.03 (0.93-1.15); and 1.44 (1.24-1.67) among those with BMI 25 to &lt;30 kg/m2; 30 to &lt;35 kg/m2; and ≥35 kg/m2. However, among those taking a cardiovascular medication, the respective HR (95% CI) for death were 0.77 (0.69-0.84); 0.88 (0.78-0.99); and 1.12 (0.96-1.30). Blood pressure-lowering medications accounted for the largest population attributable benefit of cardiovascular medications., Conclusion: To the extent that CVD risk among those with an elevated BMI is related to hypertension, diabetes, and an elevated thrombotic milieu, targeting these pathways pharmacologically may represent an important complementary means of reducing the CVD burden caused by an elevated BMI., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Traditional, complementary and alternative medicine (TCAM) is used to treat a broad range of conditions. In low- and middle-income countries (LMICs), TCAM use is particularly common among those with low socio-economic status. To better understand the patterns and impact of TCAM use on the management of non-communicable diseases in these populations, this study examines the prevalence and characteristics of TCAM use for hypertension, its determinants, and its association with hypertension management outcomes and wellbeing among low-income adults in two Southeast Asian countries at different levels of economic and health system development, Malaysia and the Philippines., Methods: We analysed cross-sectional data from 946 randomly selected adults diagnosed with hypertension from low-income rural and urban communities in Malaysia (n = 495) and the Philippines (n = 451). We compared the prevalence, characteristics and household expenditure on TCAM use between countries and used multi-level, mixed-effects regression to estimate associations between TCAM use and its determinants, and five hypertension management outcomes and wellbeing., Results: The prevalence of TCAM use to manage hypertension was higher in the Philippines than in Malaysia (18.8% vs 8.8%, p < 0.001). Biologically-based modalities, e.g. herbal remedies, were the most common type of TCAM used in both countries, mainly as a complement, rather than an alternative to conventional treatment. Households allocated around 10% of health spending to TCAM in both countries. Belief that TCAM is effective for hypertension was a positive predictor of TCAM use, while belief in conventional medicine was a negative predictor. TCAM use was not strongly associated with current use of medications for hypertension, self-reported medication adherence, blood pressure level and control, or wellbeing in either country., Conclusions: A small, but significant, proportion of individuals living in low-income communities in Malaysia and the Philippines use TCAM to manage their hypertension, despite a general lack of evidence on efficacy and safety of commonly used TCAM modalities. Recognising that their patients may be using TCAM to manage hypertension will enable health care providers to deliver safer, more patient-centred care., (© 2022. The Author(s).)

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging., Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death., Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic., Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials., (© 2022 The Authors.)

Background and Purpose: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes., Methods: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH)., Results: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001)., Conclusions: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Background: Separate studies suggest that the risks from smoking might vary between high-income (HICs), middle-income (MICs), and low-income (LICs) countries, but this has not yet been systematically examined within a single study using standardised approaches. We examined the variations in risks from smoking across different country income groups and some of their potential reasons., Methods: We analysed data from 134 909 participants from 21 countries followed up for a median of 11·3 years in the Prospective Urban Rural Epidemiology (PURE) cohort study; 9711 participants with myocardial infarction and 11 362 controls from 52 countries in the INTERHEART case-control study; and 11 580 participants with stroke and 11 331 controls from 32 countries in the INTERSTROKE case-control study. In PURE, all-cause mortality, major cardiovascular disease, cancers, respiratory diseases, and their composite were the primary outcomes for this analysis. Biochemical verification of urinary total nicotine equivalent was done in a substudy of 1000 participants in PURE., Findings: In PURE, the adjusted hazard ratio (HR) for the composite outcome in current smokers (vs never smokers) was higher in HICs (HR 1·87, 95% CI 1·65-2·12) than in MICs (1·41, 1·34-1·49) and LICs (1·35, 1·25-1·46; interaction p<0·0001). Similar patterns were observed for each component of the composite outcome in PURE, myocardial infarction in INTERHEART, and stroke in INTERSTROKE. The median levels of tar, nicotine, and carbon monoxide displayed on the cigarette packs from PURE HICs were higher than those on the packs from MICs. In PURE, the proportion of never smokers reporting high second-hand smoke exposure (≥1 times/day) was 6·3% in HICs, 23·2% in MICs, and 14·0% in LICs. The adjusted geometric mean total nicotine equivalent was higher among current smokers in HICs (47·2 μM) than in MICs (31·1 μM) and LICs (25·2 μM; ANCOVA p<0·0001). By contrast, it was higher among never smokers in LICs (18·8 μM) and MICs (11·3 μM) than in HICs (5·0 μM; ANCOVA p=0·0001)., Interpretation: The variations in risks from smoking between country income groups are probably related to the higher exposure of tobacco-derived toxicants among smokers in HICs and higher rates of high second-hand smoke exposure among never smokers in MICs and LICs., Funding: Full funding sources are listed at the end of the paper (see Acknowledgments)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background/aims: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period., Methods: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks., Results: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p < 0.001)., Conclusions: Three and seven-week run-in periods and both self-reported and pill count assessments performed similarly., Trial Registration: ClinicalTrials.gov Identifier: NCT03020303., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To compare the prevalence of electrocardiogram (ECG)-documented atrial fibrillation (or flutter) (AF) across eight regions of the world, and to examine antithrombotic use and clinical outcomes., Methods and Results: Baseline ECGs were collected in 153 152 middle-aged participants (ages 35-70 years) to document AF in two community-based studies, spanning 20 countries. Medication use and clinical outcome data (mean follow-up of 7.4 years) were available in one cohort. Cross-sectional analyses were performed to document the prevalence of AF and medication use, and associations between AF and clinical events were examined prospectively. Mean age of participants was 52.1 years, and 57.7% were female. Age and sex-standardized prevalence of AF varied 12-fold between regions; with the highest in North America, Europe, China, and Southeast Asia (270-360 cases per 100 000 persons); and lowest in the Middle East, Africa, and South Asia (30-60 cases per 100 000 persons) (P < 0.001). Compared with low-income countries (LICs), AF prevalence was 7-fold higher in middle-income countries (MICs) and 11-fold higher in high-income countries (HICs) (P < 0.001). Differences in AF prevalence remained significant after adjusting for traditional AF risk factors. In LICs/MICs, 24% of participants with AF and a CHADS2 score ≥1 received antithrombotic therapy, compared with 85% in HICs. AF was associated with an increased risk of stroke [hazard ratio (HR) 2.29; 95% confidence interval (CI) 1.49-3.52] and death (HR 2.97; 95% CI 2.25-3.93); with similar rates in different countries grouped by income level., Conclusions: Large variations in AF prevalence occur in different regions and countries grouped by income level, but this is only partially explained by traditional AF risk factors. Antithrombotic therapy is infrequently used in poorer countries despite the high risk of stroke associated with AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Although low sodium intake (<2 g/day) and high potassium intake (>3.5 g/day) are proposed as public health interventions to reduce stroke risk, there is uncertainty about the benefit and feasibility of this combined recommendation on prevention of stroke., Methods: We obtained random urine samples from 9,275 cases of acute first stroke and 9,726 matched controls from 27 countries and estimated the 24-hour sodium and potassium excretion, a surrogate for intake, using the Tanaka formula. Using multivariable conditional logistic regression, we determined the associations of estimated 24-hour urinary sodium and potassium excretion with stroke and its subtypes., Results: Compared with an estimated urinary sodium excretion of 2.8-3.5 g/day (reference), higher (>4.26 g/day) (odds ratio [OR] 1.81; 95% confidence interval [CI], 1.65-2.00) and lower (<2.8 g/day) sodium excretion (OR 1.39; 95% CI, 1.26-1.53) were significantly associated with increased risk of stroke. The stroke risk associated with the highest quartile of sodium intake (sodium excretion >4.26 g/day) was significantly greater (P < 0.001) for intracerebral hemorrhage (ICH) (OR 2.38; 95% CI, 1.93-2.92) than for ischemic stroke (OR 1.67; 95% CI, 1.50-1.87). Urinary potassium was inversely and linearly associated with risk of stroke, and stronger for ischemic stroke than ICH (P = 0.026). In an analysis of combined sodium and potassium excretion, the combination of high potassium intake (>1.58 g/day) and moderate sodium intake (2.8-3.5 g/day) was associated with the lowest risk of stroke., Conclusions: The association of sodium intake and stroke is J-shaped, with high sodium intake a stronger risk factor for ICH than ischemic stroke. Our data suggest that moderate sodium intake-rather than low sodium intake-combined with high potassium intake may be associated with the lowest risk of stroke and expected to be a more feasible combined dietary target., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Objective: To examine the association between social isolation and mortality and incident diseases in middle-aged adults in urban and rural communities from high-income, middle-income and low-income countries., Design: Population-based prospective observational study., Setting: Urban and rural communities in 20 high income, middle income and low income., Participants: 119 894 community-dwelling middle-aged adults., Main Outcome Measures: Associations of social isolation with mortality, cardiovascular death, non-cardiovascular death and incident diseases., Results: Social isolation was more common in middle-income and high-income countries compared with low-income countries, in urban areas than rural areas, in older individuals and among women, those with less education and the unemployed. It was more frequent among smokers and those with a poorer diet. Social isolation was associated with greater risk of mortality (HR of 1.26, 95% CI: 1.17 to 1.36), incident stroke (HR: 1.23, 95% CI: 1.07 to 1.40), cardiovascular disease (HR: 1.15, 95% CI: 1.05 to 1.25) and pneumonia (HR: 1.22, 95% CI: 1.09 to 1.37), but not cancer. The associations between social isolation and mortality were observed in populations in high-income, middle-income and low-income countries (HR (95% CI): 1.69 (1.32 to 2.17), 1.27 (1.15 to 1.40) and 1.47 (1.25 to 1.73), respectively, interaction p=0.02). The HR associated with social isolation was greater in men than women and in younger than older individuals. Mediation analyses for the association between social isolation and mortality showed that unhealthy behaviours and comorbidities may account for about one-fifth of the association., Conclusion: Social isolation is associated with increased risk of mortality in countries at different economic levels. The increasing share of older people in populations in many countries argues for targeted strategies to mitigate its adverse effects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In a meta-analysis, a question always arises. Is it worthwhile to combine estimates from studies of different populations using various formulations of an intervention, evaluating outcomes measured differently? Sometimes even study designs differ. Differences are expected in a meta-analysis. These may be negligible, and a pooled estimate of effect can guide the clinical decision. However, when the differences are large, this estimate may mislead. Effect estimates from study to study differ because of real differences (between-study variability) and because of chance (within-study variability). To combine estimates when there is heterogeneity (between-study differences are large) may not be sensible. Two complementary methods may be used to detect heterogeneity: visual inspection of the forest plot and calculating numerical measures of heterogeneity (I 2 and Q). Visual inspection can show effects that are different from the rest. A large I 2 (proportion of overall variability attributed to between-study variation) or a small P-value associated with Q may suggest heterogeneity. Large P-values, however, do not mean the absence of heterogeneity. It is more informative to report the confidence interval of the I 2 . If there is no heterogeneity, a pooled estimate of the true effect may be generated using only within-study variation (fixed-effect model). If there is substantial heterogeneity, reasons should be sought. Subgroup analysis or meta-regression using study-level characteristics may be done. Although more involved and potentially challenging, individual-level data (Individual Participant Data, IPD) may also be used. In the case of unexplained heterogeneity, both within- and between-study variation should be used to generate a pooled estimate (random-effects model). This estimate does not estimate a single true effect but estimates the average of a range of effects of the intervention on populations represented by the studies. If precise enough (narrow confidence interval), this estimate, together with the prediction interval (a measure of uncertainty in the effect one might see in a particular context), can guide clinical and policy decisions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Previous studies reported an association of renal impairment with stroke, but there are uncertainties underpinning this association., Aims: We explored if the association is explained by shared risk factors or is independent and whether there are regional or stroke subtype variations., Methods: INTERSTROKE is a case-control study and the largest international study of risk factors for first acute stroke, completed in 27 countries. We included individuals with available serum creatinine values and calculated estimated glomerular filtration rate (eGFR). Renal impairment was defined as eGFR <60 mL/min/1.73 m2. Multivariable conditional logistic regression was used to determine the association of renal function with stroke., Results: Of 21,127 participants, 41.0% were female, the mean age was 62.3 ± 13.4 years, and the mean eGFR was 79.9 ± 23.5 mL/min/1.73 m2. The prevalence of renal impairment was higher in cases (22.9% vs. 17.7%, p < 0.001) and differed by region (p < 0.001). After adjustment, lower eGFR was associated with increased odds of stroke. Renal impairment was associated with increased odds of all stroke (OR 1.35; 95% CI: 1.24-1.47), with higher odds for intracerebral hemorrhage (OR 1.60; 95% CI: 1.35-1.89) than ischemic stroke (OR 1.29; 95% CI: 1.17-1.42) (pinteraction 0.12). The largest magnitudes of association were seen in younger participants and those living in Africa, South Asia, or South America (pinteraction < 0.001 for all stroke). Renal impairment was also associated with poorer clinical outcome (RRR 2.97; 95% CI: 2.50-3.54 for death within 1 month)., Conclusion: Renal impairment is an important risk factor for stroke, particularly in younger patients, and is associated with more severe stroke and worse outcomes., (© 2021 S. Karger AG, Basel.)

Objective: Hypertension is the most important modifiable risk factor for stroke globally. We hypothesised that country-income level variations in knowledge, detection and treatment of hypertension may contribute to variations in the association of blood pressure with stroke., Methods: We undertook a standardised case-control study in 32 countries (INTERSTROKE). Cases were patients with acute first stroke (n=13 462) who were matched by age, sex and site to controls (n=13 483). We evaluated the associations of knowledge, awareness and treatment of hypertension with risk of stroke and its subtypes and whether this varied by gross national income (GNI) of country. We estimated OR and population attributable risk (PAR) associated with treated and untreated hypertension., Results: Hypertension was associated with a graded increase in OR by reducing GNI, ranging from OR 1.92 (99% CI 1.48 to 2.49) to OR 3.27 (2.72 to 3.93) for highest to lowest country-level GNI (p-heterogeneity<0.0001). Untreated hypertension was associated with a higher OR for stroke (OR 5.25; 4.53 to 6.10) than treated hypertension (OR 2.60; 2.32 to 2.91) and younger age of first stroke (61.4 vs 65.4 years; p<0.01). Untreated hypertension was associated with a greater risk of intracerebral haemorrhage (OR 6.95; 5.61 to 8.60) than ischaemic stroke (OR 4.76; 3.99 to 5.68). The PAR associated with untreated hypertension was higher in lower-income regions, PAR 36.3%, 26.3%, 19.8% to 10.4% by increasing GNI of countries. Lifetime non-measurement of blood pressure was associated with stroke (OR 1.80; 1.32 to 2.46)., Conclusions: Deficits in knowledge, detection and treatment of hypertension contribute to higher risk of stroke, younger age of onset and larger proportion of intracerebral haemorrhage in lower-income countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Studies often combine several events, for example, death or myocardial infarction or stroke, into a single study outcome. This is called a composite endpoint. Composite endpoints make doing trials easier by reducing the sample size or follow-up period required to demonstrate the effectiveness of an intervention. However, interpreting the results of composite endpoints can be confusing. To avoid misleading conclusions about the effectiveness of an intervention, it is important for readers of studies reporting a composite endpoint to ascertain that the clinical importance, the frequency of events, and the effect of the intervention on each component of the composite endpoint are similar., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Previous prospective studies on the association of white rice intake with incident diabetes have shown contradictory results but were conducted in single countries and predominantly in Asia. We report on the association of white rice with risk of diabetes in the multinational Prospective Urban Rural Epidemiology (PURE) study., Research Design and Methods: Data on 132,373 individuals aged 35-70 years from 21 countries were analyzed. White rice consumption (cooked) was categorized as <150, ≥150 to <300, ≥300 to <450, and ≥450 g/day, based on one cup of cooked rice = 150 g. The primary outcome was incident diabetes. Hazard ratios (HRs) were calculated using a multivariable Cox frailty model., Results: During a mean follow-up period of 9.5 years, 6,129 individuals without baseline diabetes developed incident diabetes. In the overall cohort, higher intake of white rice (≥450 g/day compared with <150 g/day) was associated with increased risk of diabetes (HR 1.20; 95% CI 1.02-1.40; P for trend = 0.003). However, the highest risk was seen in South Asia (HR 1.61; 95% CI 1.13-2.30; P for trend = 0.02), followed by other regions of the world (which included South East Asia, Middle East, South America, North America, Europe, and Africa) (HR 1.41; 95% CI 1.08-1.86; P for trend = 0.01), while in China there was no significant association (HR 1.04; 95% CI 0.77-1.40; P for trend = 0.38)., Conclusions: Higher consumption of white rice is associated with an increased risk of incident diabetes with the strongest association being observed in South Asia, while in other regions, a modest, nonsignificant association was seen., (© 2020 by the American Diabetes Association.)

Objectives: We aimed to examine the relationship between access to medicine for cardiovascular disease (CVD) and major adverse cardiovascular events (MACEs) among people at high risk of CVD in high-income countries (HICs), upper and lower middle-income countries (UMICs, LMICs) and low-income countries (LICs) participating in the Prospective Urban Rural Epidemiology (PURE) study., Methods: We defined high CVD risk as the presence of any of the following: hypertension, coronary artery disease, stroke, smoker, diabetes or age >55 years. Availability and affordability of blood pressure lowering drugs, antiplatelets and statins were obtained from pharmacies. Participants were categorised: group 1-all three drug types were available and affordable, group 2-all three drugs were available but not affordable and group 3-all three drugs were not available. We used multivariable Cox proportional hazard models with nested clustering at country and community levels, adjusting for comorbidities, sociodemographic and economic factors., Results: Of 163 466 participants, there were 93 200 with high CVD risk from 21 countries (mean age 54.7, 49% female). Of these, 44.9% were from group 1, 29.4% from group 2 and 25.7% from group 3. Compared with participants from group 1, the risk of MACEs was higher among participants in group 2 (HR 1.19, 95% CI 1.07 to 1.31), and among participants from group 3 (HR 1.25, 95% CI 1.08 to 1.50)., Conclusion: Lower availability and affordability of essential CVD medicines were associated with higher risk of MACEs and mortality. Improving access to CVD medicines should be a key part of the strategy to lower CVD globally., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine developed by SanofiPasteur is widely licensed in dengue-endemic countries. In a large cohort study Dengvaxia was found to partially protect children who had prior dengue virus (DENV) infections but sensitized seronegative children to breakthrough DENV disease of enhanced severity. In 2019, the European Medicines Agency and the US FDA issued licenses that reconciled safety issues by restricting vaccine to individuals with prior dengue infections. Using revised Dengvaxia efficacy and safety data we sought to estimate hospitalized and severe dengue cases among the more than 800,000 9 year-old children vaccinated in the Philippines. Despite an overall vaccine efficacy of 69% during 4 years post-vaccination we project there will be more than one thousand vaccinated seronegative and seropositive children hospitalized for severe dengue. Assisting these children through a program of enhanced surveillance leading to improved care deserves widespread support. Clinical responses observed during breakthrough dengue infections in vaccinated individuals counsel prudence in design of vaccine policies. Recommendations concerning continued use of this dengue vaccine are: (1) obtain a better definition of vaccine efficacy and safety through enhanced phase 4 surveillance, (2) obtain a valid, accessible, sensitive, specific and affordable serological test that identifies past wild-type dengue virus infection and (3) clarify safety and efficacy of Dengvaxia in flavivirus immunes. In the absence of an acceptable serological screening test these unresolved ethical issues suggest Dengvaxia be given only to those signing informed consent., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SBH: Sanofipasteur, Takeda, GlaxoSmithKline and Merck within past 3 years. PKR: Inviragen, (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Understanding explanatory models is important for hypertension, a leading risk factor for cardiovascular disease and stroke. This article aims to determine what adult patients with hypertension in the Philippines attribute their condition to, how these views might be explained and what the implications are for hypertension management., Methods: This is a qualitative study drawing on 71 semistructured interviews (40 initial and 31 follow-up) and four focus group discussions with patients diagnosed with hypertension. The setting was urban and rural low-income communities in the Philippines., Results: Four prominent perceived causes were identified-genetics, heat, stress and diet-for what patients refer to as 'high blood'. We propose a 'folk physiology' that rests on local understandings of blood and blood flow, draws from broader cultural notions of illness causation and accounts for a dynamic, non-chronic view of hypertension that in turn informs the health behaviours of those affected., Conclusions: By understanding that hypertension is frequently seen not as a chronic constant condition but rather as an episodic one triggered by external influences, although in those genetically predisposed to it, it may be possible to address patient's beliefs and thus adherence to treatment., Competing Interests: Competing interests: ALD and LMP-V have been and/or are currently involved in clinical trials of antihypertensive medications that receive some funding from industry., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Chelation therapy is promoted and practiced around the world as a form of alternative medicine in the treatment of atherosclerotic cardiovascular disease. It has been suggested as a safe, relatively inexpensive, non-surgical method of restoring blood flow in atherosclerotic vessels. However, there is currently limited high-quality, adequately-powered research informing evidence-based medicine on the topic, specifically regarding clinical outcomes. Due to this limited evidence, the benefit of chelation therapy remains controversial at present. This is an update of a review first published in 2002., Objectives: To assess the effects of ethylene diamine tetra-acetic acid (EDTA) chelation therapy versus placebo or no treatment on clinical outcomes among people with atherosclerotic cardiovascular disease., Search Methods: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 6 August 2019. We searched the bibliographies of the studies retrieved by the literature searches for further trials., Selection Criteria: We included studies if they were randomised controlled trials of EDTA chelation therapy versus placebo or no treatment in participants with atherosclerotic cardiovascular disease. The main outcome measures we considered include all-cause or cause-specific mortality, non-fatal cardiovascular events, direct or indirect measurement of disease severity, and subjective measures of improvement or adverse events., Data Collection and Analysis: Two review authors independently extracted data and assessed trial quality using standard Cochrane procedures. A third author considered any unresolved issues, and we discussed any discrepancies until a consensus was reached. We contacted study authors for additional information., Main Results: We included five studies with a total of 1993 randomised participants. Three studies enrolled participants with peripheral vascular disease and two studies included participants with coronary artery disease, one of which specifically recruited people who had had a myocardial infarction. The number of participants in each study varied widely (from 10 to 1708 participants), but all studies compared EDTA chelation to a placebo. Risk of bias for the included studies was generally moderate to low, but one study had high risk of bias because the study investigators broke their randomisation code halfway through the study and rolled the placebo participants over to active treatment. Certainty of the evidence, as assessed by GRADE, was generally low to very low, which was mostly due to a paucity of data in each outcome's meta-analysis. This limited our ability to draw any strong conclusions. We also had concerns about one study's risk of bias regarding blinding and outcome assessment that may have biased the results. Two studies with coronary artery disease participants reported no evidence of a difference in all-cause mortality between chelation therapy and placebo (risk ratio (RR) 0.97, 95% CI 0.73 to 1.28; 1792 participants; low-certainty). One study with coronary artery disease participants reported no evidence of a difference in coronary heart disease deaths between chelation therapy and placebo (RR 1.02, 95% CI 0.70 to 1.48; 1708 participants; very low-certainty). Two studies with coronary artery disease participants reported no evidence of a difference in myocardial infarction (RR 0.81, 95% CI 0.57 to 1.14; 1792 participants; moderate-certainty), angina (RR 0.95, 95% CI 0.55 to 1.67; 1792 participants; very low-certainty), and coronary revascularisation (RR 0.46, 95% CI 0.07 to 3.25; 1792 participants). Two studies (one with coronary artery disease participants and one with peripheral vascular disease participants) reported no evidence of a difference in stroke (RR 0.88, 95% CI 0.40 to 1.92; 1867 participants; low-certainty). Ankle-brachial pressure index (ABPI; also known as ankle brachial index) was measured in three studies, all including participants with peripheral vascular disease; two studies found no evidence of a difference in the treatment groups after three months after treatment (mean difference (MD) 0.02, 95% CI -0.03 to 0.06; 181 participants; low-certainty). A third study reported an improvement in ABPI in the EDTA chelation group, but this study was at high risk of bias. Meta-analysis of maximum and pain-free walking distances three months after treatment included participants with peripheral vascular disease and showed no evidence of a difference between the treatment groups (MD -31.46, 95% CI -87.63 to 24.71; 165 participants; 2 studies; low-certainty). Quality of life outcomes were reported by two studies that included participants with coronary artery disease, but we were unable to pool the data due to different methods of reporting and varied criteria. However, there did not appear to be any major differences between the treatment groups. None of the included studies reported on vascular deaths. Overall, there was no evidence of major or minor adverse events associated with EDTA chelation treatment., Authors' Conclusions: There is currently insufficient evidence to determine the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of people with atherosclerotic cardiovascular disease. More high-quality, randomised controlled trials are needed that assess the effects of chelation therapy on longevity and quality of life among people with atherosclerotic cardiovascular disease., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Non-communicable diseases (NCDs) are the leading cause of death globally. In 2014, the United Nations committed to reducing premature mortality from NCDs, including by reducing the burden of healthcare costs. Since 2014, the Prospective Urban and Rural Epidemiology (PURE) Study has been collecting health expenditure data from households with NCDs in 18 countries., Methods: Using data from the PURE Study, we estimated risk of catastrophic health spending and impoverishment among households with at least one person with NCDs (cardiovascular disease, diabetes, kidney disease, cancer and respiratory diseases; n=17 435), with hypertension only (a leading risk factor for NCDs; n=11 831) or with neither (n=22 654) by country income group: high-income countries (Canada and Sweden), upper middle income countries (UMICs: Brazil, Chile, Malaysia, Poland, South Africa and Turkey), lower middle income countries (LMICs: the Philippines, Colombia, India, Iran and the Occupied Palestinian Territory) and low-income countries (LICs: Bangladesh, Pakistan, Zimbabwe and Tanzania) and China., Results: The prevalence of catastrophic spending and impoverishment is highest among households with NCDs in LMICs and China. After adjusting for covariates that might drive health expenditure, the absolute risk of catastrophic spending is higher in households with NCDs compared with no NCDs in LMICs (risk difference=1.71%; 95% CI 0.75 to 2.67), UMICs (0.82%; 95% CI 0.37 to 1.27) and China (7.52%; 95% CI 5.88 to 9.16). A similar pattern is observed in UMICs and China for impoverishment. A high proportion of those with NCDs in LICs, especially women (38.7% compared with 12.6% in men), reported not taking medication due to costs., Conclusions: Our findings show that financial protection from healthcare costs for people with NCDs is inadequate, particularly in LMICs and China. While the burden of NCD care may appear greatest in LMICs and China, the burden in LICs may be masked by care foregone due to costs. The high proportion of women reporting foregone care due to cost may in part explain gender inequality in treatment of NCDs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background & Aims: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial., Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up., Results: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant., Conclusions: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the association of estimated total daily sleep duration and daytime nap duration with deaths and major cardiovascular events., Methods and Results: We estimated the durations of total daily sleep and daytime naps based on the amount of time in bed and self-reported napping time and examined the associations between them and the composite outcome of deaths and major cardiovascular events in 116 632 participants from seven regions. After a median follow-up of 7.8 years, we recorded 4381 deaths and 4365 major cardiovascular events. It showed both shorter (≤6 h/day) and longer (>8 h/day) estimated total sleep durations were associated with an increased risk of the composite outcome when adjusted for age and sex. After adjustment for demographic characteristics, lifestyle behaviours and health status, a J-shaped association was observed. Compared with sleeping 6-8 h/day, those who slept ≤6 h/day had a non-significant trend for increased risk of the composite outcome [hazard ratio (HR), 1.09; 95% confidence interval, 0.99-1.20]. As estimated sleep duration increased, we also noticed a significant trend for a greater risk of the composite outcome [HR of 1.05 (0.99-1.12), 1.17 (1.09-1.25), and 1.41 (1.30-1.53) for 8-9 h/day, 9-10 h/day, and >10 h/day, Ptrend < 0.0001, respectively]. The results were similar for each of all-cause mortality and major cardiovascular events. Daytime nap duration was associated with an increased risk of the composite events in those with over 6 h of nocturnal sleep duration, but not in shorter nocturnal sleepers (≤6 h)., Conclusion: Estimated total sleep duration of 6-8 h per day is associated with the lowest risk of deaths and major cardiovascular events. Daytime napping is associated with increased risks of major cardiovascular events and deaths in those with >6 h of nighttime sleep but not in those sleeping ≤6 h/night., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: Cardiovascular disease risk assessment tools help identify individuals likely to benefit from preventative therapies. In this study we compared outcomes using the American College of Cardiology/American Heart Association (ACC/AHA) risk algorithm and the Framingham Risk Score (FRS) tool in the Heart Outcomes Prevention Evaluation (HOPE)-3 study., Methods: We compared outcomes using the ACC/AHA algorithm and the FRS with those seen in HOPE-3, which randomized participants to 10 mg rosuvastatin or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; second coprimary outcome additionally included heart failure, cardiac arrest, and revascularization., Results: Relative risks using risk scores were similar to those observed in the HOPE-3. Hazards ratios for the first coprimary outcome according to risk categories of ≤ 10%, 10%-20%, and ≥ 20% using the ACC/AHA algorithm were 0.82 (95% confidence interval [CI], 0.53-1.28), 0.72 (95% CI, 0.53-0.96), and 0.72 (95% CI, 0.55-0.93), and absolute risk reduction (ARR) of 0.18%, 1.33%, and 1.85%, respectively, over a median of 5.6 years. Corresponding results using the FRS were 0.69 (95% CI, 0.36-1.35), 0.73 (95% CI, 0.52-1.01), and 0.75 (95% CI, 0.60- 0.94); and ARR of 1.32%, 0.61%, and 1.43%. Hazard ratios for the second coprimary outcome were 0.77 (95% CI, 0.51-1.14), 0.73 (95% CI, 0.56-0.95), and 0.74 (95% CI, 0.58-0.94); and ARR of 0.36%, 1.49%, and 1.85%, using the ACC/AHA algorithm and 0.76 (95% CI, 0.41-1.41), 0.70 (95% CI, 0.52-0.95), and 0.76 (95% CI, 0.62-0.94); and ARR of 1.08%, 0.83%, and 1.56% using the FRS., Conclusions: The pragmatic HOPE-3 trial approach identifies in an ethnically diverse primary prevention population individuals at intermediate risk who benefit from statin therapy using simple clinical characteristics without the need for complex, currently used risk assessment tools., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial., Methods: TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events., Results: The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk., Conclusion: Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Hypertension is a leading contributor to the global burden of disease. While safe and effective treatment exists, blood pressure control is poor in many countries, often reflecting barriers at the levels of health systems and services as well as at the broader level of patients' sociocultural contexts. This study examines how these interact to facilitate or hinder hypertension control, taking into account characteristics of service provision components and social contexts., Methods and Analysis: The study, set in Malaysia and the Philippines, builds on two systematic reviews of barriers to effective hypertension management. People with hypertension (pre-existing and newly diagnosed) will be identified in poor households in 24-30 communities per country. Quantitative and qualitative methods will be used to examine their experiences of and pathways into seeking and obtaining care. These include two waves of household surveys of 20-25 participants per community 12-18 months apart, microcosting exercises to assess the cost of illness (including costs due to health seeking activities and inability to work (5 per community)), preliminary and follow-up in-depth interviews and digital diaries with hypertensive adults over the course of a year (40 per country, employing an innovative mobile phone technology), focus group discussions with study participants and structured assessments of health facilities (including formal and informal providers)., Ethics and Dissemination: Ethical approval has been granted by the Observational Research Ethics Committee at the London School of Hygiene and Tropical Medicine and the Research Ethics Boards at the Universiti Putra Malaysia and the University of the Philippines Manila. The project team will disseminate findings and engage with a wide range of stakeholders to promote uptake and impact. Alongside publications in high-impact journals, dissemination activities include a comprehensive stakeholder analysis, engagement with traditional and social media and 'digital stories' coproduced with research participants., Competing Interests: Competing interests: ALD, KY, JRI, FAM and LMP-V have been and/or are currently involved in clinical trials of antihypertensive medications that receive some funding from industry., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels., Methods: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month., Findings: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p<0·0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1·29; 95% CI 1·14-1·44; all p<0·0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1·39; 1·12-1·72) irrespective of other patient and service characteristics., Interpretation: Evidence-based treatments, diagnostics, and stroke units were less commonly available or used in low and middle-income countries. Access to stroke units and appropriate use of antiplatelet treatment were associated with improved recovery. Improved care and facilities in low-income and middle-income countries are essential to improve outcomes., Funding: Chest, Heart and Stroke Scotland., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Severe life-threatening dengue fever usually occurs when a child is infected by dengue virus a second time. This is caused by a phenomenon called antibody-dependent enhancement (ADE). Since dengue vaccines can mimic a first infection in seronegative children (those with no previous infection), a natural infection later in life could lead to severe disease. The possibility that dengue vaccines can cause severe dengue through ADE has led to serious concern regarding the safety of mass vaccination programs. A published meta-analysis addressed this safety issue for a new vaccine against dengue fever-Dengvaxia. The trials in this meta-analysis have been used to campaign for mass vaccination programs in developing countries. We discuss the results of this paper and point out problems in the analyses. Reporting the findings in an Asian trial (CYD14), the authors show a sevenfold rise in one outcome-hospitalization for dengue fever in children <5 years old. However, they fail to point out two signals of harm for another outcome-hospitalization for severe dengue fever (as confirmed by an independent data monitoring committee): 1. In children younger than 9 years, the relative risk was 8.5 (95% confidence interval [CI]: 0.5, 146.8), and 2. In the overall study group, the relative risk was 5.5 (95% CI: 0.9, 33). The authors conduct a subgroup analysis to support claims that the vaccine is probably safe among children aged 9 years or more. This subgroup analysis has limited credibility because: (1) it was a post hoc analysis; (2) it was one of a large number of subgroup analyses; (3) the test of interaction was not reported, but was insignificant (P = 0.14); and (4) there is no biological basis for a threshold age of 9 years. The more likely explanation for the higher risk in younger children is ADE, that is, more frequent seronegativity, rather than age itself. The selective reporting and inappropriate subgroup claims mask the potential harm of dengue mass vaccination programs. Countries planning public use of the vaccine must conduct diligent postmarketing surveillance, secure informed consent from parents of potential recipients, and closely monitor the results of ongoing long-term follow-up of clinical trial participants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: There is little evidence on the use of secondary prevention medicines for cardiovascular disease by socioeconomic groups in countries at different levels of economic development., Methods: We assessed use of antiplatelet, cholesterol, and blood-pressure-lowering drugs in 8492 individuals with self-reported cardiovascular disease from 21 countries enrolled in the Prospective Urban Rural Epidemiology (PURE) study. Defining one or more drugs as a minimal level of secondary prevention, wealth-related inequality was measured using the Wagstaff concentration index, scaled from -1 (pro-poor) to 1 (pro-rich), standardised by age and sex. Correlations between inequalities and national health-related indicators were estimated., Findings: The proportion of patients with cardiovascular disease on three medications ranged from 0% in South Africa (95% CI 0-1·7), Tanzania (0-3·6), and Zimbabwe (0-5·1), to 49·3% in Canada (44·4-54·3). Proportions receiving at least one drug varied from 2·0% (95% CI 0·5-6·9) in Tanzania to 91·4% (86·6-94·6) in Sweden. There was significant (p<0·05) pro-rich inequality in Saudi Arabia, China, Colombia, India, Pakistan, and Zimbabwe. Pro-poor distributions were observed in Sweden, Brazil, Chile, Poland, and the occupied Palestinian territory. The strongest predictors of inequality were public expenditure on health and overall use of secondary prevention medicines., Interpretation: Use of medication for secondary prevention of cardiovascular disease is alarmingly low. In many countries with the lowest use, pro-rich inequality is greatest. Policies associated with an equal or pro-poor distribution include free medications and community health programmes to support adherence to medications., Funding: Full funding sources listed at the end of the paper (see Acknowledgments)., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0. license. Published by Elsevier Ltd.. All rights reserved.)

Background: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease., Methods: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants., Findings: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012)., Interpretation: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide., Funding: Bayer AG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)