Stroke Prevention Strategies in the Developing World
2018; Lippincott Williams & Wilkins; Volume: 49; Issue: 12 Linguagem: Inglês
10.1161/strokeaha.118.017384
ISSN1524-4628
AutoresYogeshwar Kalkonde, Suvarna Alladi, Subhash Kaul, Vladimir Hachinski,
Tópico(s)Blood Pressure and Hypertension Studies
ResumoHomeStrokeVol. 49, No. 12Stroke Prevention Strategies in the Developing World Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBStroke Prevention Strategies in the Developing World Yogeshwar V. Kalkonde, MD, MSc, Suvarna Alladi, DM, Subhash Kaul, MD, DM and Vladimir Hachinski, CM, MD, DSc Yogeshwar V. KalkondeYogeshwar V. Kalkonde From the Society for Education, Action and Research in Community Health, Gadchiroli, India (Y.V.K.) Search for more papers by this author , Suvarna AlladiSuvarna Alladi Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India (S.A.) Search for more papers by this author , Subhash KaulSubhash Kaul Department of Neurology, Krishna Institute of Medical Sciences, Hyderabad, India (S.K.) Search for more papers by this author and Vladimir HachinskiVladimir Hachinski Correspondence to Vladimir Hachinski, CM, MD, DSc, Department of Clinical Neurological Sciences, University of Western Ontario, 339 Windermere Rd London, Ontario, Canada N6A5A5. Email E-mail Address: [email protected] Department of Clinical Neurological Sciences, University of Western Ontario, Canada (V.H.). Search for more papers by this author Originally published29 Oct 2018https://doi.org/10.1161/STROKEAHA.118.017384Stroke. 2018;49:3092–3097is corrected byCorrection to: Stroke Prevention Strategies in the Developing WorldOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 26, 2018: Previous Version of Record October 29, 2018: Ahead of Print Stroke is the second leading cause of death and disability in the world.1,2 During the past several decades, the burden of stroke in the world has shifted from developed to developing countries.3 Now, 75% of all stroke deaths and 81% of the total disability-adjusted life years lost because of stroke occur in developing countries.3 This shift in the burden from the developed to developing countries is thought to be driven by the aging of population, population growth, and changing patterns of diseases because of changes in risk factors and differences in socioeconomic status and health care.4,5 Stroke, therefore, has emerged as a major public health priority in developing countries.Challenges to Providing Healthcare for StrokeAlthough the burden of stroke has increased in developing countries, the health care services have not caught up. The challenges to provide health care services for stroke in developing countries include lack of awareness about stroke and its risk factors, lack of economic resources and publicly funded well functioning healthcare systems for primary and secondary prevention, lack of ambulance services and facilities for acute stroke management, unaffordable cost of tPA (tissue-type plasminogen activator), lack of rehabilitation facilities, preference for alternative and complementary medicines over modern medicines, and poor secondary prevention.6 These challenges often lead to worse outcomes after stroke, and studies in some regions of Gambia and India have reported 30-day case fatality as high as 40%.7,8 Also, a large percentage of people in developing countries live in rural areas where health care is not accessible. Authors of several studies have shown high mortality and prevalence of stroke in rural regions of developing countries.9–11 The poor population in developing countries are often affected by stroke, and stroke perpetuates poverty in these people. Attempts are being made in developing countries to improve stroke services, but these are in very early stages.12 Therefore, urgent attention is needed to reduce the burden of stroke in developing countries.Need for an Emphasis on PreventionStroke is preventable. Although attempts should be made to improve acute stroke care services in developing countries, data from the developed countries suggests that a strong emphasis on prevention would be needed to reduce the burden of stroke. From a public health point of view, preventive measures to reduce the risk of stroke would provide additional cross-cutting benefits. For example, reducing blood pressure or cholesterol using pharmacological and lifestyle interventions would also reduce mortality because of other chronic diseases, such as coronary artery disease, chronic kidney disease, and reduce the risk of dementia.Risk Factors for Stroke in Developing CountriesAre the risk factors for stroke different in developing countries than in developed countries? INTERSTROKE (A Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World), the largest international case-control study on stroke which included participants from developing countries in Africa, Asia, America, and the Middle East provided important insights in this regard.13 The study identified 10 modifiable risk factors for stroke and calculated their population-attributable risk which is the percentage of stroke cases that would not occur if the risk factor is eliminated (Table). The risk factors identified were hypertension, lack of physical activity, abnormal lipids, unhealthy diet, abdominal obesity, psychological factors, current smoking, cardiac causes, alcohol consumption, and diabetes mellitus. Together, these 10 risk factors accounted for close to 90% risk of stroke. Although there were geographic variations in the extent of the risk (odds ratios) because of each risk factor, the overall direction of association of risk factors with the risk of stroke was similar except for diet in south Asian countries. A recent large case-control study from Africa also confirmed the association of risk factors identified in the INTERSTROKE study with the risk of stroke.24 Therefore, by and large, the risk factors for stroke seem to be similar in the developing and developed countries. Few additional stroke risk factors were identified by the Global Burden of Disease study.25 These include low glomerular filtration rate, ambient and household air pollution, and lead exposure.Table. Stroke Risk Factors Identified in the INTERSTROKE Study,13 and the Preventive Strategies Targeting These Risk Factors in Developing CountriesRisk FactorPopulation-Attributable Risk of Stroke (%)Preventive Strategies for Stroke Being Used or Trialed in Developing CountriesHigh blood pressure47.9Mass screening and treatment of hypertension,14,15 community-based hypertension control using community health workers,16,17 polypill,18 community-based lifestyle change program,19 mass health promotion strategies19–21Physical inactivity35.8Mass health promotion strategies19–21Dyslipidemia (apolipoprotein Apo B/ApoA1 ratio)26.8Polypill,18 mass health promotion strategies19–21Diet risk score (unhealthy cardiovascular diet)23.2Mass health promotion strategies19–21Abdominal obesity18.6National program targeting obesity22Psychosocial factors17.4…Current smoking12.4Mass health promotion strategies,19–21 antitobacco measures by the state21,23Cardiac causes9.1Polypill,18 national program to control cardiac diseases22Alcohol consumption5.8Mass health promotion strategies19–21Diabetes mellitus3.9National program to control diabetes mellitus22INTERSTROKE indicates A Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World.In developing countries, the other stroke risk factors that operate include infections (eg, tuberculosis, syphilis, HIV infection, malaria, schistosomiasis, gnathostomiasis, rheumatic heart disease, infective endocarditis, mycotic aneurysms), sickle cell disease, Takayasu disease, snake bites, and scorpion sting.26 Many of these risk factors are being controlled because of gradually improving awareness, health care services, screening for those with rheumatic heart disease, and sickle cell disease in the school health programs, as well as mass infectious disease eradication programs, and likely to contribute to a smaller number of stroke cases at the population level. However, more progress needs to be made in Africa where these risk factors are still prevalent. For example, in the INTERSTROKE study, the 10 risk factors discussed above contributed to 82% of the total risk of stroke as compared to ≥90% in the other continents.13Strategies for Stroke PreventionTwo major strategies have been proposed for reducing the risk of cardiovascular diseases (CVDs). The first one is the high-risk strategy, and the other one is the mass strategy.27High-Risk StrategyThe high-risk strategy identifies those at a higher risk of developing a disease. For stroke prevention, those with modifiable risk factors (Table) can be targeted for primary prevention of stroke under the high-risk strategy. In addition, a new approach of prevention based on projected overall CVD risk has been proposed.28,29 This approach posits that an individual may not have a specific disease or a health condition, for example, hypertension or diabetes mellitus, but may have a higher overall cardiovascular risk because of presence of multiple risk factors, such as prehypertension and dysglycemia which do not meet treatment thresholds as per the current standards of care. The support for this argument comes from the observation that cardiovascular risk increases linearly above the systolic blood pressure of 115 mm Hg.30 The prevalence of individuals with higher cardiovascular risk could be high in communities. For example, in the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction), a case-control study conducted in 52 countries, which included developing countries, 99% of the control subjects had at least 1 cardiovascular risk factor.31 Based on these findings, it is proposed that preventive approach based on CVD risk needs to be applied to a larger segment of population.The interventions under the high-risk strategy can be classified as those related to changes in lifestyle and those related to pharmacological treatment.Lifestyle ChangeMost of the clinical guidelines on prevention of CVDs focus on individual patient recommendation and emphasize lifestyle change as the first line prevention strategy. Evidence from cohort and interventional studies supports the role of reduced salt intake, increased fruit and vegetable consumption, physical activity, weight loss, tobacco cessation, limited alcohol intake, and management of psychosocial stress in reducing cardiovascular risk.32 Therefore, such measures need to be emphasized to prevent stroke in developing countries as well. A recent cluster randomized controlled trial from Nepal showed that lifestyle change program implemented through community health workers successfully reduced blood pressure demonstrating the feasibility of this approach.33 However, one of the major limitations of individual-based lifestyle and behavioral change approach is that it is difficult to sustain34 and scale. The emergence of global epidemic of obesity highlights the limitations of individual-based preventive strategies.Pharmacological InterventionsHypertension is the leading risk factor for stroke (Table), and its control remains one of the most effective interventions to reduce the risk of stroke. Screening for hypertension at population level and making treatment available and affordable has resulted in reduced stroke incidence, prevalence, and mortality in Japan and Taiwan.14,15,35 Shortage of doctors in developing countries can create a barrier to screening and treatment of hypertension, but the emerging evidence from randomized controlled trials from Argentina, China, and India suggests that community-level interventions involving community health workers can lead to improved hypertension control.16,17Under the CVD risk reduction approach, use of medicines to lower blood pressure and lipids along with use of antiplatelet agents has been suggested. Several recent randomized controlled trials show evidence to support this strategy. In SPRINT (Systolic Blood Pressure Intervention Trial), targeting systolic blood pressure to a lower threshold of 120 mm Hg compared with the standard threshold of 140 mm Hg in those with increased cardiovascular risk reduced the risk of a composite primary outcome which included stroke.36 This approach also reduced the risk of death. HOPE-3 trial (Heart Outcomes Prevention Evaluation-3) also showed a beneficial effect of cholesterol lowering,37 cholesterol and blood pressure lowering,38 but not blood pressure lowering alone,39 on the risk of developing stroke in those with an intermediate risk of CVDs. Furthermore, a recent meta-analysis using individual participant data from 47 872 participants from 11 trials in the Blood Pressure Lowering Treatment Trialists’ Collaboration from 1995 to 2013 also showed that compared with treating everyone with systolic blood pressure ≥150 or ≥140 mm Hg, a CVD risk reduction strategy could prevent 16% or 3.1 % more cardiovascular events, respectively, for the same number of persons treated.40 There is some criticism of this strategy that it will medicalize prevention. Also, there could be several practical difficulties in the use of CVD risk scores in developing countries, particularly in rural areas. These include lack of risk scores which are calibrated for the local population41 and a need for laboratory tests for some risk scores. However, 1 study conducted in Bangladesh, Guatemala, Mexico, and South Africa showed that community health workers could successfully categorize cardiovascular risk using a risk score which does not need laboratory tests.42 Another potential limitation of this approach could be that people in rural areas of developing countries may find it hard to understand the concept of CVD risk as they might be more accustomed to having a disease diagnosed and treated. This may lead to resistance to the use of medications based on such a risk. Similarly, medication compliance can become a limiting factor while targeting a large segment of a population with use of multiple medications on a daily basis. A new approach of polypill, a single pill containing a combination of multiple drugs either at full or half the normal dose, can potentially address this limitation.18,28 It is proposed that a polypill can be given to a large segment of at-risk population, such as those above a specified age (eg, 55 years) to increase medication compliance and reduce CVD risk.28Population-Based StrategyThe second preventive strategy is the one where mass (population-based) approaches are used to target entire population to reduce cardiovascular risk. It is argued that even a small but population-wide reduction in the level of risk factor results in large overall beneficial effects.27 It needs health systems approach with a mass mobilization, policy, and legislative changes. Despite limited hard evidence to support such approaches, given the limitation of individual-based lifestyle change strategy, there is increasing interest in population-based strategies for cardiovascular risk reduction. A successful example of mass health promotion strategy in a developing country is from Mauritius, where an intervention involving use of mass media, legislative measures, as well as health education in community, school, and workplace was used to promote healthy nutrition, increase exercise, smoking cessation, and reduction in alcohol intake.20 The prevalence of hypertension, tobacco smoking, and heavy alcohol consumption reduced, moderate physical activity increased, and serum cholesterol levels were reduced.19 Lack of physical activity is emerging as an important cardiovascular risk factor in developing countries. Active travel, such as walking, bicycling, and using public transport has been suggested as a strategy to increase physical activity. In a cross-sectional study of a cohort in India, those bicycling to work were 50% less likely to have hypertension and 35% less likely to have diabetes mellitus indicating that promoting active travel in communities could potentially help in reducing cardiovascular risk.43 Reducing salt intake in the community is another strategy which is thought to reduce the risk of CVDs44 and the World Health Organization recommends restricting daily salt intake to <5 grams per day.45 However, a large population in developing countries lives in rural areas where the climate is hot, and loss of sodium through sweating may be high. Therefore, such recommendations for developing countries need to be backed by evidence from these countries. Tobacco control is another important way to reduce the risk of CVD. Uruguay instituted a series of comprehensive antismoking policies resulting in substantial reduction in tobacco use from 2005 to 2011.23 Other suggestions for mass approaches include use of technology. With increasing access to digital information in developing countries, such a strategy may be used to give health messages, provide information about primary and secondary prevention and sources of health care for stroke in developing countries. Innovative examples of such an approach include Stroke Riskometer, a mobile phone-based tool,46 and use of soap operas.47 The Government of India is planning to reach out to billions of people through its Digital India48 campaign, and such a platform can be potentially used to provide information about stroke prevention.Current Efforts Towards Prevention of StrokeSeveral developing countries are taking steps to reduce the risk of stroke. The Chinese Center for Disease Control and Prevention has drafted a China National Plan for Non-Communicable Diseases Prevention and Treatment to increase awareness about noncommunicable diseases, improve control of hypertension and diabetes mellitus, reduce smoking and salt consumption, and improve disease surveillance.49 Similarly, a large-scale programme called the National Program for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases, and Stroke was launched by the Government of India in 2010 for early diagnosis and treatment of these diseases, promoting lifestyle modification and capacity building at various levels, including training of manpower.22 Also, several developing countries in Latin America and the Caribbean have implemented national noncommunicable diseases programmes and have taken policy measures to reduce tobacco and alcohol use, increase physical activities, and encourage healthy dietary practices.21 More such commitments from governments of developing countries will be needed. At the same time, the impact of national programmes for CVD prevention on stroke mortality will need to be monitored so that corrective measures could be taken in time. The Sustainable Development Goals adopted in a United Nations General Assembly in 2015 calls for one-third reduction in premature mortality because of noncommunicable diseases by 2030, and this should provide impetus to developing countries to remove the barriers to CVDs prevention.50The Way ForwardThe available evidence favors use of strategies for primary and secondary prevention in developing countries to reduce the risk of stroke. Although lessons learned from developed countries would be important, developing countries would have to develop their own systems which work in the local context. In terms of achieving quick results, control of hypertension remains the most proven strategy. Lifestyle change would take longer time to implement but will bring sustainable results. Both need to be implemented simultaneously in developing countries. Use of community health workers to promote hypertension control, cardiovascular risk assessment, and polypills are interesting emerging concepts, and more evidence about acceptability and effectiveness is needed in developing countries. The risk factors identified in the INTERSTROKE study and various interventions targeting these risk factors in developing countries are listed in the Table. Several initiatives can potentially help improve stroke prevention. These include (1) national programs within health ministries for noncommunicable diseases20–22; (2) development of culturally appropriate awareness, risk factor screening, and treatment interventions with community participation20; (3) effective school health programs to educate the newer generations about the cardiovascular risks and promote healthy lifestyle at an early age20; (4) emphasis on health promoting environments, for example, availability of parks and biking or walking tracks; (5) implementation of successful governmental actions, such as tobacco control policies,21,23 banning of advertisements of alcohol,21 promoting healthy diet,21 and sin taxes (eg, sugar taxes); (6) effective delivery of primary health care to control hypertension and other risk factors for stroke21 preferably through Universal Health Coverage and inclusion of medicines for stroke prevention in essential drug lists21 to make care affordable and accessible; (7) development of evidence-based guidelines and promoting adherence to the guidelines among medical practitioners, as well as increasing awareness among people about stroke risk factors by professional medical societies; and (8) effective use of existing and emerging technologies, for example, making digital blood pressure monitors widely available to screen for hypertension, use of social media, Stroke Riskometer,43 and wearable technology (eg, pedometers) to promote lifestyle changes.Addressing Knowledge Gaps and PrioritizationSignificant knowledge gap exists on the effectiveness of various stroke prevention strategies in developing countries. For example, it is unknown as to which interventions would be acceptable and cost-effective to reduce strokes in developing countries. Therefore, more research is urgently needed in this area. One of the major limitations for making policy, allocating resources, and tracking the progress of stroke prevention in developing countries is the lack of good quality data on stroke epidemiology. Therefore, stroke surveillance needs to be significantly improved to generate high-quality data on stroke mortality, incidence, and prevalence. A recent nation-wide population-based study to estimate incidence, prevalence, and mortality in China10 and a study in India to monitor trends in stroke mortality using verbal autopsies51 are good examples of attempts to improve stroke surveillance in developing countries. Efforts through the Global Burden of Disease Study have also helped to identify countries with high stroke burden. Several countries in Africa (eg, Madagascar, Ghana, Liberia, Ivory Coast, Gabon, Republic of Congo), Asia (eg, Russia, Kazakhstan, Afghanistan, Kyrgyzstan, Bangladesh, Myanmar, Vietnam, Cambodia, Indonesia, Philippines), South America (eg, Guyana and Surinam) have higher disability-adjusted life years lost because of stroke.52 Strengthening local health systems and providing Developmental Assistance for Health, can help reduce the burden of stroke expeditiously in many of these countries.Role of the Developed WorldThe developed world needs to be part of these efforts. Global clinical trials of stroke prevention will need to include more subjects from the developing world for results to be generalizable. In addition, the genetic, ethnic, and cultural diversity of the developing world can provide explanations about stroke pathogenesis that have not been found from studies on stroke in the largely white populations. For example, studies on secondary prevention strategies for stroke subtypes more prevalent in developing countries like intracranial atherosclerosis would be more feasible in these countries.53 Also, developed countries can help build local capacity to improve research and surveillance of stroke in developing countries. Working together to prevent strokes in developing countries can help both the developing and developed countries.Sources of FundingDr Kalkonde is a Wellcome Trust/DBT (Department of Biotechnology, Government of India) India Alliance Fellow in Public Health.DisclosuresNone.FootnotesCorrespondence to Vladimir Hachinski, CM, MD, DSc, Department of Clinical Neurological Sciences, University of Western Ontario, 339 Windermere Rd London, Ontario, Canada N6A5A5. Email Vladimir.[email protected]on.caReferences1. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2017; 390:1151–1210. doi: 10.1016/S0140-6736(17)32152–9CrossrefMedlineGoogle Scholar2. GBD 2016 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the global burden of disease study 2016.Lancet. 2017; 390:1260–1344. doi: 10.1016/S0140-6736(17)32130-XCrossrefMedlineGoogle Scholar3. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, et al; GBD 2013 Writing Group; GBD 2013 Stroke Panel Experts Group. Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: The GBD 2013 study.Neuroepidemiology. 2015; 45:161–176. doi: 10.1159/000441085CrossrefMedlineGoogle Scholar4. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.Circulation. 2001; 104:2746–2753.LinkGoogle Scholar5. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality.N Engl J Med. 2015; 372:1333–1341. doi: 10.1056/NEJMoa1406656CrossrefMedlineGoogle Scholar6. Wasay M, Khatri IA, Kaul S. Stroke in South Asian countries.Nat Rev Neurol. 2014; 10:135–143. doi: 10.1038/nrneurol.2014.13CrossrefMedlineGoogle Scholar7. Ray BK, Hazra A, Ghosal M, Banerjee T, Chaudhuri A, Singh V, et al. Early and delayed fatality of stroke in Kolkata, India: results from a 7-year longitudinal population-based study.J Stroke Cerebrovasc Dis. 2013; 22:281–289. doi: 10.1016/j.jstrokecerebrovasdis.2011.09.002CrossrefMedlineGoogle Scholar8. Garbusinski JM, van der Sande MA, Bartholome EJ, Dramaix M, Gaye A, Coleman R, et al. Stroke presentation and outcome in developing countries: a prospective study in the Gambia.Stroke. 2005; 36:1388–1393. doi: 10.1161/01.STR.0000170717.91591.7dLinkGoogle Scholar9. Kalkonde YV, Deshmukh MD, Sahane V, Puthran J, Kakarmath S, Agavane V, et al. Stroke is the leading cause of death in rural Gadchiroli, India: a prospective community-based study.Stroke. 2015; 46:1764–1768. doi: 10.1161/STROKEAHA.115.008918LinkGoogle Scholar10. Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, et al; NESS-China Investigators. Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480 687 adults.Circulation. 2017; 135:759–771. doi: 10.1161/CIRCULATIONAHA.116.025250LinkGoogle Scholar11. Connor MD, Walker R, Modi G, Warlow CP. Burden of stroke in black populations in sub-Saharan Africa.Lancet Neurol. 2007; 6:269–278. doi: 10.1016/S1474-4422(07)70002-9CrossrefMedlineGoogle Scholar12. Pandian JD, William AG, Kate MP, Norrving B, Mensah GA, Davis S, et al. Strategies to improve stroke care services in low- and middle-income countries: a systematic review.Neuroepidemiology. 2017; 49:45–61. doi: 10.1159/000479518CrossrefMedlineGoogle Scholar13. O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al; INTERSTROKE Investigators. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.Lancet. 2016; 388:761–775. doi: 10.1016/S0140-6736(16)30506-2CrossrefMedlineGoogle Scholar14. Iso H, Shimamoto T, Naito Y, Sato S, Kitamura A, Iida M, et al. Effects of a long-term hypertension control program on stroke incidence and prevalence in a rural community in northeastern Japan.Stroke. 1998; 29:1510–1518.LinkGoogle Scholar15. Lin T, Chen CH, Chou P. Impact of the high-risk and mass strategies on hypertension control and stroke mortality in primary health care.J Hum Hypertens. 2004; 18:97–105. doi: 10.1038/sj.jhh.1001642CrossrefMedlineGoogle Scholar16. He J, Irazola V, Mills KT, Poggio R, Beratarrechea A, Dolan J, et al; HCPIA Investigators. Effect of a community health worker-led multicomponent intervention on blood pressure control in low-income patients in Argentina: a randomized clinical trial.JAMA. 2017; 318:1016–1025. doi: 10.1001/jama.2017.11358CrossrefMedlineGoogle Scholar17. Tian M, Ajay VS, Dunzhu D, Hameed SS, Li X, Liu Z, et al. A cluster-randomized, controlled trial of a simplified multifaceted management program for individuals at high cardiovascular risk (SimCard Trial) in rural Tibet, China, and Haryana, India.Circulation. 2015; 132:815–824. doi: 10.1161/CIRCULATIONAHA.115.015373LinkGoogle Scholar18. Elley CR, Gupta AK, Webster R, Selak V, Jun M, Patel A, et al. The efficacy and tolerability of ‘polypills’: meta-analysis of randomised controlled trials.PLoS One. 2012; 7:e52145. doi: 10.1371/journal.pone.0052145CrossrefMedlineGoogle Scholar19. Dowse GK, Gareeboo H, Alberti KG, Zimmet P, Tuomilehto J, Purran A, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after five years of the non-communicable disease intervention programme in Mauritius. Mauritius Non-communicable Disease Study Group.BMJ. 1995; 311:1255–1259.CrossrefMedlineGoogle Scholar20. Health Ministry of the Government of Mauritius. Non-Communicable Diseases and Health Promotion Division-Ministry of Health and Quality of Life, Mauritius.http://nc
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