Quality of stroke guidelines in low- and middle-income countries: a systematic review

Abstract Objective To identify gaps in national stroke guidelines that could be bridged to enhance the quality of stroke care services in low- and middle-income countries. Methods We systematically searched medical databases and websites of medical societies and contacted international organizations. Country-specific guidelines on care and control of stroke in any language published from 2010 to 2020 were eligible for inclusion. We reviewed each included guideline for coverage of four key components of stroke services (surveillance, prevention, acute care and rehabilitation). We also assessed compliance with the eight Institute of Medicine standards for clinical practice guidelines, the ease of implementation of guidelines and plans for dissemination to target audiences. Findings We reviewed 108 eligible guidelines from 47 countries, including four low-income, 24 middle-income and 19 high-income countries. Globally, fewer of the guidelines covered primary stroke prevention compared with other components of care, with none recommending surveillance. Guidelines on stroke in low- and middle-income countries fell short of the required standards for guideline development; breadth of target audience; coverage of the four components of stroke services; and adaptation to socioeconomic context. Fewer low- and middle-income country guidelines demonstrated transparency than those from high-income countries. Less than a quarter of guidelines encompassed detailed implementation plans and socioeconomic considerations. Conclusion Guidelines on stroke in low- and middle-income countries need to be developed in conjunction with a wider category of health-care providers and stakeholders, with a full spectrum of translatable, context-appropriate interventions.


Introduction
Stroke is the second leading cause of death and disability globally, with evidence of an increasing incidence of stroke among young adults. 1-3 The burden of stroke is increasing in low-and middle-income countries. 4 Studies have shown a 37% increase in the number of deaths among younger adults aged 20-64 years in low-and middle-income countries, from 942 921 to 1 292 347, versus a 20% decline in high-income countries over the period 1990-2013, from 236 566 to 191 359. 4 Improvements in the prevention and management of stroke after implementation of evidence-based guidelines in routine medical practice have substantially lowered the incidence and mortality rates of stroke in high-income countries over the past 30 years. 1,3,5-8 In contrast, low-and middle-income countries present wide differences in the quality of stroke prevention and care, with gaps identified in the knowledge and skills of health professionals, the resources available within health systems and the components of stroke care available locally. 6,9 Addressing these gaps could be aided by guidelines with pragmatic evidence-based recommendations and implementation action plans for individuals and health systems. 10 However, successful implementation of guidelines depends on having locally developed content in which region-specific barriers and local sociocultural characteristics are considered. [11][12][13] We conducted a systematic review to compare recent clinical guidelines on stroke in low-and middle-income countries with those of high-income countries. We aimed to characterize specific gaps in guideline development, target audiences and content in relation to the spectrum of stroke care covered 14 and the features that promote implementation. Our review was informed by the view that the content of guidelines for low-and middle-income countries should be adapted with solutions that are pragmatic for these countries and perhaps graded according to ease of implementation. 15 Periodic review of published stroke guidelines is also important to improve their impact on stroke prevention and outcomes.

Methods
We pre-registered the proposed methods for this systematic review on the International Prospective Register of Systematic Reviews (CRD42018112620). The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines 16 as well as procedures used by the Global Alliance for Chronic Diseases group for the systematic review of guidelines for hypertension and diabetes mellitus. 14,17,18

Search strategy
We searched the following electronic medical databases for published guidelines on management and prevention of stroke: PubMed®, African Journals Online, Directory of Open Access Journals, Google Scholar, SciELO and Excerpta Medica Database (EMBASE). We based our search strategy on the PICO strategy 19 of evidence-based models (population: stroke guidelines; intervention: not applicable; comparison: guidelines from high-income countries versus those from low-and middle-income countries; outcome: spectrum of stroke care). We used medical subject headings and titles containing the following search terms: "country name" AND "guideline" OR "consensus" OR "clinical protocols" OR "standards" OR "recommendations" AND "stroke OR cerebrovascular disorder/disease OR intracranial haemorrhage OR cerebrovascular accident". We also used the Google search engine to identify stroke guidelines published on the websites of medical societies. To identify additional guidelines, we contacted country representatives on the Lancet Neurology Commission on Stroke (listed in the authors' data repository), 20 members of the World Stroke Organization and the Global Alliance of Health Research Funders. 15 Three of the authors independently screened the titles of records from the above-mentioned sources. Three authors independently reviewed the title, year of publication, publication type and author. This information was collated by one author and duplicates and irrelevant records based on the reviewers' decisions were removed. Abstracts of each relevant title were independently reviewed for eligibility by three authors and the relevant publications were obtained for review. Additional publications obtained were screened by one author to determine their eligibility before inclusion. Reviewers with experience in stroke care in each participating country assisted in reviewing guidelines that were not published in English language.
We included all country-specific stroke guidelines published from 2010 to 2020 regardless of the language. To avoid duplication, we selected the most recent guidelines where there were two or more guidelines. We excluded guidelines if they were designed exclusively for management of stroke in younger people (age < 45 years). However, we included guidelines concerning the management of stroke in the young among other age groups.

Data extraction
Relevant data from each guideline were extracted independently by at least two researchers into a pre-designed structured evaluation form (available in the data repository). 20 The extracted data were reassessed for consistency by a different reviewer and in the event of contradictory entries, the publications were cross-checked by an independent reviewer. Non-English language guidelines were reviewed independently by at least two researchers fluent in the language. In the event of differing opinions between reviewers, we carried out a joint review to arrive at a consensus.
The design of the proforma allowed us to assess each guideline's coverage of the four key components of stroke services: (i) epidemiological surveillance; (ii) stroke prevention (primary and secondary); (iii) acute care; and (iv) rehabilitation. 14 Primary and secondary stroke prevention and treatment covered stroke risk factors such as hypertension, smoking, diabetes, dyslipidaemia and atrial fibrillation. We assessed acute stroke care in the following categories: pre-hospital care; management of blood pressure, fever, glucose, oedema and seizures; ischaemic stroke care (including thrombolysis); intracerebral haemorrhage care; and subarachnoid haemorrhage care. Rehabilitation covered: dysphagia care; prophylaxis of deep venous thrombosis; depression care; education; physiotherapy nursing; and speech and cognition therapy.
We determined if a guideline was published by a stroke-related organization (such as a professional medical society) or government health ministry. Also, each guideline was assessed based on the Institute of Medicine eight quality standards for the development of trustworthy clinical practice guidelines: (i) transparency; (ii) management of conflict of interest; (iii) composition of guideline development group; (iv) use of systematic review; (v) grading rated by strength of recommendations; (vi) articulation of recommendations; (vii) external review; and (viii) proposed date for future review. 21 We categorized the target audience for guidelines into health-care providers, patients, general population, policy-makers, payers (health-care funders) or implementation partners. 14 We determined the guideline content by assessing which services were covered on the spectrum of stroke care and the characteristics that promote guideline implementation -contextualization (translatability); a clear implementation plan or dissemination plan; economic considerations; social considerations; legal considerations; and ethical considerations. A guideline was deemed to have considered ethical, legal, social and economic issues if it included information about ethical dilemmas, stroke-related legal issues, social issues and stroke financing. If the required information was not stated by the guidelines, we scored the guideline as not having addressed them. A guideline was deemed to be translatable if locally sourced interventions were stated Systematic reviews Systematic review of stroke guidelines Joseph Yaria et al.
or the recommendations were graded according to the resources required for implementation.

Data analysis
We analysed the data collected using Stata statistical software, version 12 (StataCorp, College Station, United States of America). We report the frequencies and percentage of guidelines by country income group using the 2020 World Bank classification. 22 We used the total number of countries or total number of guidelines as denominators.

Results
After screening 4356 records from the literature search, we included 108 national guidelines from 47 countries in the final analysis ( Fig. 1

Guideline development
Of the included guidelines, 72 (67%) were published by stroke-related organizations, 25 (23%) by government health ministries and 7 (6%) by both strokerelated organizations and health ministries. The publisher was not specified for four guidelines. A higher proportion of the guidelines from high-income countries (54 out of 67; 81%) were published by a stroke-related organization than were guidelines from countries in other income groups (18 of 41; 44%). Fig. 2 shows the profile of the included guidelines based on the eight Institute of Medicine standards. Just one (25%) of the low-income country guidelines established transparency in guideline development compared with 21 (60%) of the guidelines from middle-income countries and 46 (74%) of the guidelines from highincome countries. Similarly, one (25%) low-income country guideline was based on systematic reviews compared with 19 (54%) guidelines from middle-income countries and 42 (68%) guidelines from high-income countries. None of the low-income country guidelines graded the strength of their recommendations.

Target audience
Of the 81 guidelines that stated their target audience, all but one were directed towards health-care providers. None of the low-or middle-income country guidelines and four (8%) of the highincome country guidelines were directed at payers (health-care funders). Three (11%) of the middle-income country and eight (15%) of high-income country guidelines were directed at policy-makers. One (4%) guideline from middleincome countries and four (8%) from high-income countries targeted patients. Two (8%) of the middle-income country guidelines and one (2%) of the highincome country guidelines were targeted at the general population.

Guideline content
On the spectrum of stroke interventions covered in each country (Fig. 3), we found 19 (40%) out of 47 countries had guidelines that covered primary prevention, 27 (57%) had guidelines addressing secondary prevention, 43 (91%) had guidelines covering acute care and 28 (60%) had guidelines addressing stroke rehabilitation. Of the guidelines assessed, a few documented stroke epidemiology in their various locales, but none specifically recommended epidemiological surveillance.
Only one (25%) of the low-income countries had a guideline that covered secondary stroke prevention in detail, while none dealt with diagnoses of cardiovascular risks or the use of anti-platelet therapy in detail ( Fig. 3; see further details in the data repository). 20 Globally, few guidelines considered implementation during the development process. One (25%) of the guidelines from low-income countries and seven guidelines (10%) from high-income countries ordered their recommendations by ease of implementation or gave locally sourced alternatives (Fig. 4). Similarly, economic implications were considered in seven (10%) and three (8%) guidelines from high-income countries and middle-income countries, respectively. Twenty-eight (42%) highincome country guidelines and five (14%) middle-income country guidelines gave research recommendations.

Discussion
Our study showed that national stroke guidelines from low-and middleincome countries, especially those from low-income countries, fell short in terms of quality, coverage and content. The implementation of recommended interventions in these countries may be hampered by factors such as shortages of health-care providers, 132 limited access to health care, 133 deficient infrastructure and ineffective health policies. Poor transportation and infrastructure and shortages of skilled personnel are the main factors responsible for suboptimal or unavailable pre-hospital stroke care. 134 Acute stroke care is also affected by numerous factors including financial constraints, inadequate facili-  ties and sociocultural practices. 135 The health promotion strategies required for improved stroke prevention and stroke rehabilitation are also hampered by limited finances and lack of required resources. These constraints -rarely considered in the development of stroke guidelines for low-and middle-income countries -need to be addressed with pragmatic recommendations. Previous studies have evaluated stroke guidelines, but have rarely investigated country-specific guidelines with regards to their development and ease of implementation in various settings. Each low-and middle-income country may need to analyse the capacity of its health system and identify weaknesses and barriers to the implementation of stroke guidelines. Such information is key to developing guidelines that would be relevant to the country context and hence more effective. Based on this information, recommendations should then be graded according to ease of implementation, 14 with clear dissemination and implementation plans adapted to the country's health system. We aimed to address these issues and offer pragmatic solutions for low-and middle-income countries.
In Latin America, countries such as Colombia and Mexico have made efforts towards building capacity for developing clinical guidelines to improve guidelines implementation. State agencies were involved in the development of national clinical guidelines, with open-access resources explaining the methods for the development of guidelines. 136 These types of initiatives and resources could also assist in developing a translatability index for prioritizing or grading recommendations according to ease, cost and simplicity of implementation. 14 However, funding is needed for guideline development and implementation. Availability of funds may explain the higher frequency of guidelines published by funded stroke-related organizations among high-income countries. Increasing the target audience for stroke guidelines to include policy-makers, health payers and implementation partners should stimulate collaboration in financing and sustaining pragmatic interventions.
Crucially, low-and middle-income countries should stop regarding guidelines as a tool solely for complex care at the hospital level, a bias suggested by our results. Guidelines should be designed as not only a tool for primary and specialized clinical care, but also as a guide for health planning and implementation, to enable better resource allocation and increased efficiency in stroke prevention and treatment. Expanding the target audience in future guidelines to include policy-makers, health payers and implementation partners is therefore an important step as most interventions require funding, policy initiatives and population buy-in. As shown in our review, none of the low-or middle-income country guidelines targeted payers, policy-makers, patients or the general population.
Pragmatic solutions in low-and middle-income countries require a wider reach of stroke guidelines through task-sharing, including the services of community health extension workers. A structured guideline-based programme involving health extension workers and other allied health professionals, possibly with supervision from stroke physicians, is worth exploring for rural communities and areas where health facilities are poorer quality or harder to access. 137 Therefore, stroke guidelines could include clear instructions for immediate recognition of symptomswho is responsible for care, what is to be done, when action or intervention should be taken, how this intervention is to be done and assessed, and a standard to guide referral practices. Simple measures to identify early stroke complications, prevention of stroke complications and necessary treatment (such as the Glasgow Coma Scale, the National Early Warning Score or limb girth), should be included in low-and middle-income country guidelines. Sim- ilarly, the resources and skills required at each hospital level can be stated, as listed for example in the guideline from Mongolia. 46 This pragmatic approach is important, to improve implementation of guidelines from low-and middleincome countries towards addressing acute care, both for basic interventions and more advanced care. Reperfusion therapy, for example, is an effective intervention with cost-effectiveness analysis of more than 100 international dollars per disability-adjusted life years averted in low-and middle-income countries. 138 Similarly, guideline recommendations need to reflect the sociocultural characteristics of each country, as cultural perspectives on diseases and care-seeking behaviour differ among countries. 139 Notably, we found that stroke guidelines in low-and middle-income countries were not only deficient in quality but also in the spectrum of stroke prevention and care covered. None of the guidelines recommended stroke surveillance, a crucial component for monitoring, planning and evaluation of stroke burden and interventions. 140 Primary and secondary stroke prevention also required improvement. 141 For example, only one of the low-income countries had guidelines that covered secondary stroke prevention, while none had an independent stroke guideline that dealt with diagnoses of cardiovascular risks or the use of anti-platelet agents for secondary stroke prevention. The need for low-and middle-income countries to focus on stroke prevention is further strengthened by the success of high-income countries that has been rooted in primary and secondary prevention. 3 In contrast, stroke guidelines from low-and middle-income countries had inadequate or no information on stroke prevention. A few of the low-and middle-income countries guidelines addressed major stroke risk factors, such as hypertension and diabetes, as well as feasible and effective population-wide strategies for primary stroke prevention. Nevertheless, these guidelines fell short of Institute of Medicine standards for trustworthiness and showed implementation gaps. 17,18 In post-stroke care, where standard rehabilitation services may be lacking, stroke guidelines could indicate procedures for implementation of home-based or community-based reha-bilitation care. Rehabilitation, nursing care, speech therapy and post-stroke cognition were not addressed in any of the low-income country guidelines, and less often in middle-than high-income country guidelines. In addition, including instructions for managing the unmet needs of caregivers who bear most of the burden of post-stroke care in low-and middle-income countries is needed. 142 A comprehensive guideline-based programme with supervision is worth exploring for rural communities and areas with poor health facilities or access to care. 137 Recommendations for community-or family-based rehabilitation, and the appropriate time to start them in the trajectory of stroke care, should be further explored as pragmatic interventions 143 both in low-and middle-income countries and rural settings of highincome countries. 144,145 Stroke care in low-and middle-income countries presents both challenges and opportunities for improvement. Guidelines in these countries may be more effective if properly adapted to the local context and disseminated for implementation by all stakeholders. 14 It is important to address all the steps in the implementation cycle of guidelines for stroke care which includes content development, contextualization, dissemination to all stakeholders and evaluation. 14 In countries that suffer from poor implementation of policies, addition of necessary details into national stroke guidelines may be a way of bringing the information directly to health-care providers and the general public. These cost-effective interventions can easily be adapted from already proven policyrelated publications such as the World Health Organization recommended "best buys", 138 the health interventions for universal health coverage 146 and other cost-effective interventions.
This review is not without its limitations as guidelines published online stood a higher chance of being included in the review. Also, guidelines available online but not published on any of the databases searched were unlikely to be included in the review as not every national association or official body could be individually contacted. However, to reduce this bias, we contacted stroke experts to determine the availability of additional guidelines that were not available online. Also, involving the World Health Organization more in the review process might have helped us to obtain more guidelines.
In conclusion, the quality and implementation strategies of stroke guidelines need to be improved and adapted to the health-system context in low-and middle-income countries. To achieve this, the governments of these countries need to develop new guidelines or adapt existing guidelines in conjunction with a wider range of health-care providers and stakeholders.