A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

In-Hospital Macro-, Meso-, and Micro-Drivers and Interventions for Antibiotic Use and Resistance: A Rapid Evidence Synthesis of Data from Canada and Other OECD Countries.

Hospitals continue to face challenges in reducing incorrect antibiotic use due to social and cultural factors at the level of the health system, the care facility, the provider, and the patient. The objective of this paper is to highlight the social and cultural drivers of antimicrobial use and resistance and targeted interventions for secondary and tertiary care settings in Canada and other OECD countries. This paper is an extension of the synthesis conducted for the Public Health Agency of Canada's 2019 Spotlight Report: Preserving Antibiotics Now and Into the Future. We conducted a systematic review with a few modifications to meet rapid timelines. We conducted a search in Ovid MEDLINE and McMaster University's evidence databases for systematic reviews and then for individual Canadian studies. To cast a wider net, we searched OECD organization websites and screened reference lists from systematic reviews. We synthesized the evidence narratively and categorized the evidence into macro-, meso-, and microlevel. A total of 70 studies were (a) from OCED countries and summarized evidence of potential sociocultural antimicrobial resistance and use barriers or facilitators and/or interventions addressing these challenges; (b) systematic reviews with 50% of included studies that are situated in secondary and tertiary settings; and (c) published in Canada's two official languages, English and French. We found that hospital structures and policies may influence antibiotic utilization and variations in antimicrobial management. Microlevel factors may sway inappropriate prescribing among clinicians. The amount and type of antibiotics used may affect resistance rates. Interventions were mainly comprised of antibiotic stewardship and training that modify clinician behavior and that educate patients and carers. This evidence synthesis illustrates the various drivers of, and interventions for, antimicrobial use and resistance at the macro-, meso-, and microlevel in secondary and tertiary settings. We demonstrate that upstream drivers may lead to downstream events that influence antimicrobial resistance.

Coronavirus Disease 2019 and Antimicrobial Resistance: Parallel and Interacting Health Emergencies.

The coronavirus disease 2019 (COVID-19) pandemic and antimicrobial resistance (AMR) are parallel and interacting health emergencies that provide the opportunity for mutual learning. As their measures and consequences are comparable, the COVID-19 pandemic helps to illustrate the potential long-term impact of AMR, which is less acute but not less crucial. They may also impact each other as there is a push to use existing antimicrobials to treat critically ill COVID-19 patients in the absence of specific treatments. Attempts to manage the spread of COVID-19 may also lead to a slowdown in AMR. Understanding how COVID-19 affects AMR trends and what we can expect if these trends remain the same or worsen will help us to plan the next steps for tackling AMR. Researchers should start collecting data to measure the impact of current COVID-19 policies and programs on AMR.

Control of Severe, Life-Threatening External Bleeding in the Out-of-Hospital Setting: A Systematic Review.

OBJECTIVE: Trauma, with resultant bleeding, is a significant cause of morbidity and mortality throughout the world; however, the best possible method of bleeding control by immediate responders is unknown. We performed a systematic review of the effectiveness of treatment modalities for severe, life-threatening external bleeding in the out-of-hospital first aid setting. Methods: We followed the Cochrane Handbook for Systematic Reviews of Interventions methodology and report results according to PRISMA guidelines. We included randomized controlled trials, non-randomized comparative studies and case series investigating adults and children with severe, life-threatening external bleeding who were treated with therapies potentially suitable for first aid providers. We assessed the certainty of the evidence and risk of bias. Outcomes were prioritized by first aid specialists based on importance for patients and decision-makers and included mortality due to bleeding, all-cause mortality, cessation of bleeding, time to cessation of bleeding, a decrease in bleeding, and complications/adverse effects. Results were reported in Evidence Profiles. Results: Of the 1,051 full-text articles screened, 107 were included for analysis including 22,798 patients. The primary methods of bleeding control were tourniquets (n = 49), hemostatic dressings (n = 34), hemostatic devices (n = 14), pressure dressings/bandages/devices (n = 8), pressure points (n = 4), including 2 studies that reported multiple hemorrhage control methods. Overall, certainty of evidence was very low and often relied on indirect evidence and poorly controlled studies. Tourniquets were associated with a decrease in mortality when compared with direct manual pressure. Hemostatic dressings resulted in a shorter time to hemostasis than direct manual pressure using standard dressings. Direct manual compression resulted in a shorter time to hemostasis than pressure dressings/devices. Conclusion: Overall, data regarding the control of life-threatening bleeding is of very low certainty, making it difficult to draw robust conclusions for treatment by immediate responders. While more robust data is needed on first aid treatments of life-threatening bleeding, this systematic review aggregates the most comprehensive to date to help guide recommendations. Key words: bleeding; hemorrhage; tourniquet; hemostatic dressing; direct pressure.

Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19: A Living Systematic Review of Multiple Streams of Evidence.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

Development and use of health outcome descriptors: a guideline development case study.

BACKGROUND: During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed 'health outcome descriptors' for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. METHODS: We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. RESULTS: Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. CONCLUSIONS: Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.

The Canadian Community Utilization of Stroke Prevention Study in Atrial Fibrillation in the Emergency Department (C-CUSP ED).

STUDY OBJECTIVE: Lack of oral anticoagulation prescription in the emergency department (ED) has been identified as a care gap in atrial fibrillation patients. This study seeks to determine whether the use of a tool kit for emergency physicians with a follow-up community-based atrial fibrillation clinic resulted in greater oral anticoagulation prescription at ED discharge than usual care. METHODS: This was a before-after study in 5 Canadian EDs in 3 cities. Patients who presented to the ED with atrial fibrillation were eligible for inclusion. The before phase (1) was retrospective; 2 after phases (2 and 3) were prospective: phase 2 used an oral anticoagulation prescription tool for emergency physicians and patient education materials, whereas phase 3 used the same prescription tool, patient materials, atrial fibrillation educational session, and follow-up in an atrial fibrillation clinic. Each phase was 1 year long. The primary outcome was the rate of new oral anticoagulation prescription at ED discharge for patients who were oral anticoagulation eligible and not receiving oral anticoagulation at presentation. RESULTS: A total of 631 patients were included. Mean age was 69 years (SD 14 years), 47.4% were women, and 69.6% of patients had a CHADS2 score greater than or equal to 1. The rate of new oral anticoagulation prescription in phase 1 was 15.8% compared with 54.1% and 47.2%, in phases 2 and 3, respectively. After multivariable adjustment, the odds ratio for new oral anticoagulation prescription was 8.03 (95% confidence interval 3.52 to 18.29) for phase 3 versus 1. The 6-month rate of oral anticoagulation use was numerically but not significantly higher in phase 3 compared with phase 2 (71.6% versus 79.4%; adjusted odds ratio 2.30; 95% confidence interval 0.89 to 5.96). The rate of major bleeding at 6 months was 0%, 0.8%, and 1% in phases 1, 2, and 3, respectively. CONCLUSION: An oral anticoagulation prescription tool was associated with an increase in new oral anticoagulation prescription in the ED, irrespective of whether an atrial fibrillation clinic follow-up was scheduled. The use of an atrial fibrillation clinic was associated with a trend to a higher rate of oral anticoagulation at 6-month follow-up.

The influence of progression of atrial fibrillation on quality of life: a report from the Euro Heart Survey.

Aims: Progression of atrial fibrillation (AF) from paroxysmal to persistent forms is an active field of research. The influence of AF progression on health related quality of life (HRQoL) is currently unknown. We aimed to assess the influence of AF progression on HRQoL, and whether this association is mediated through symptoms, treatment, and major adverse events. Methods and results: In the Euro Heart Survey, 967 patients were included with paroxysmal AF who filled out EuroQoL-5D at baseline and at 1 year follow-up. Those who progressed (n = 132, 13.6%) developed more problems during follow-up than those who did not, on all EuroQoL-5D domains (increase in problems on mobility 20.5% vs. 11.4%; self-care 12.9% vs. 6.2%; usual activities 23.5% vs. 14.0%; pain/discomfort 20.5% vs. 13.7%; and anxiety/depression 22.7% vs. 15.7%; all P < 0.05), leading to a decrease in utility [baseline 0.744 ± 0.26, follow-up 0.674 ± 0.36; difference -0.07 (95% CI [-0.126,-0.013], P = 0.02)]. Multivariate analysis showed that the effect of progression on utility is mediated by a large effect of adverse events [stroke (-0.27 (95% CI [-0.43,-0.11]); P = 0.001], heart failure [-0.12 (95% CI [-0.20,-0.05]); P = 0.001], malignancy (-0.31 (95% CI [-0.56,-0.05]); P = 0.02] or implantation of an implantable cardiac defibrillator [-0.12 (95% CI [-0.23,-0.02]); P = 0.03)], as well as symptomatic AF [-0.04 (95% CI [-0.08,-0.01]); P = 0.008]. Conclusion: AF progression is associated with a decrease in HRQoL. However, multivariate analysis revealed that AF progression itself does not have a negative effect on HRQoL, but that this effect can be attributed to a minor effect of the associated symptoms and a major effect of associated adverse events.

Symptomatic atrial fibrillation and risk of cardiovascular events: data from the Euro Heart Survey.

AIMS: Atrial fibrillation (AF) is associated with a wide range of clinical presentations. Whether and how AF symptoms can affect prognosis is still unclear. Aims of the present analysis were to investigate potential predictors of symptomatic AF and to determine if symptoms are associated with higher incidence of cardiovascular (CV) events at 1-year follow-up. METHODS AND RESULTS: The Euro Heart Survey on Atrial Fibrillation included 3607 consecutive patients with documented AF and available follow-up regarding symptoms status. Patients found symptomatic at baseline were classified into still symptomatic (SS group; n = 896) and asymptomatic (SA; n = 1556) at 1 year. Similarly, asymptomatic patients at baseline were classified into still asymptomatic (AA group; n = 903) and symptomatic (AS group; n = 252) at 1 year. Demographics, as well as clinical variables and medical treatments, were tested as potential predictors of symptoms persistence/development at 1-year. We also compared CV events between SS and SA groups, and AS and AA groups at 1-year follow-up. Both persistence and development of AF symptoms were associated with an increased risk of CV hospitalization, stroke, heart failure worsening, and thrombo-embolism. AF type, hypothyroidism, chronic heart failure, and chronic obstructive pulmonary disease (COPD), were independently associated with an increased risk of symptomatic status at 1-year follow-up between SS and SA groups. CONCLUSION: Persistence or development of symptoms after medical treatment are associated with an increased risk of CV events during a 1-year follow-up. Type of AF, along with hypothyroidism, COPD and chronic heart failure are significantly associated with symptoms persistence despite medical treatment.

Developing consensus measures for global programs: lessons from the Global Alliance for Chronic Diseases Hypertension research program.

BACKGROUND: The imperative to improve global health has prompted transnational research partnerships to investigate common health issues on a larger scale. The Global Alliance for Chronic Diseases (GACD) is an alliance of national research funding agencies. To enhance research funded by GACD members, this study aimed to standardise data collection methods across the 15 GACD hypertension research teams and evaluate the uptake of these standardised measurements. Furthermore we describe concerns and difficulties associated with the data harmonisation process highlighted and debated during annual meetings of the GACD funded investigators. With these concerns and issues in mind, a working group comprising representatives from the 15 studies iteratively identified and proposed a set of common measures for inclusion in each of the teams' data collection plans. One year later all teams were asked which consensus measures had been implemented. RESULTS: Important issues were identified during the data harmonisation process relating to data ownership, sharing methodologies and ethical concerns. Measures were assessed across eight domains; demographic; dietary; clinical and anthropometric; medical history; hypertension knowledge; physical activity; behavioural (smoking and alcohol); and biochemical domains. Identifying validated measures relevant across a variety of settings presented some difficulties. The resulting GACD hypertension data dictionary comprises 67 consensus measures. Of the 14 responding teams, only two teams were including more than 50 consensus variables, five teams were including between 25 and 50 consensus variables and four teams were including between 6 and 24 consensus variables, one team did not provide details of the variables collected and two teams did not include any of the consensus variables as the project had already commenced or the measures were not relevant to their study. CONCLUSIONS: Deriving consensus measures across diverse research projects and contexts was challenging. The major barrier to their implementation was related to the time taken to develop and present these measures. Inclusion of consensus measures into future funding announcements would facilitate researchers integrating these measures within application protocols. We suggest that adoption of consensus measures developed here, across the field of hypertension, would help advance the science in this area, allowing for more comparable data sets and generalizable inferences.

Understanding the modifiable health systems barriers to hypertension management in Malaysia: a multi-method health systems appraisal approach.

BACKGROUND: The growing burden of non-communicable diseases in middle-income countries demands models of care that are appropriate to local contexts and acceptable to patients in order to be effective. We describe a multi-method health system appraisal to inform the design of an intervention that will be used in a cluster randomized controlled trial to improve hypertension control in Malaysia. METHODS: A health systems appraisal was undertaken in the capital, Kuala Lumpur, and poorer-resourced rural sites in Peninsular Malaysia and Sabah. Building on two systematic reviews of barriers to hypertension control, a conceptual framework was developed that guided analysis of survey data, documentary review and semi-structured interviews with key informants, health professionals and patients. The analysis followed the patients as they move through the health system, exploring the main modifiable system-level barriers to effective hypertension management, and seeking to explain obstacles to improved access and health outcomes. RESULTS: The study highlighted the need for the proposed intervention to take account of how Malaysian patients seek treatment in both the public and private sectors, and from western and various traditional practitioners, with many patients choosing to seek care across different services. Patients typically choose private care if they can afford to, while others attend heavily subsidised public clinics. Public hypertension clinics are often overwhelmed by numbers of patients attending, so health workers have little time to engage effectively with patients. Treatment adherence is poor, with a widespread belief, stemming from concepts of traditional medicine, that hypertension is a transient disturbance rather than a permanent asymptomatic condition. Drug supplies can be erratic in rural areas. Hypertension awareness and education material are limited, and what exist are poorly developed and ineffective. CONCLUSION: Despite having a relatively well funded health system offering good access to care, Malaysia's health system still has significant barriers to effective hypertension management. DISCUSSION: The study uncovered major patient-related barriers to the detection and control of hypertension which will have an impact on the design and implementation of any hypertension intervention. Appropriate models of care must take account of the patient modifiable health systems barriers if they are to have any realistic chance of success; these findings are relevant to many countries seeking to effectively control hypertension despite resource constraints.

Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges.

Combination pills containing aspirin, multiple blood pressure (BP) lowering drugs, and a statin have demonstrated safety, substantial risk factor reductions, and improved medication adherence in the prevention of cardiovascular disease (CVD). The individual medications in combination pills are already recommended for use together in secondary CVD prevention. Therefore, current information on their pharmacokinetics, impact on the risk factors, and tolerability should be sufficient to persuade regulators and clinicians to use fixed-dose combination pills in high-risk individuals, such as in secondary prevention. Long-term use of these medicines, in a polypill or otherwise, is expected to reduce CVD risk by at least 50-60% in such groups. This risk reduction needs confirmation in prospective randomized trials for populations for whom concomitant use of the medications is not currently recommended (e.g. primary prevention). Given their additive benefits, the combined estimated relative risk reduction (RRR) in CVD from both lifestyle modification and a combination pill is expected to be 70-80%. The first of several barriers to the widespread use of combination therapy in CVD prevention is physician reluctance to use combination pills. This reluctance may originate from the belief that lifestyle modification should take precedence, and that medications should be introduced one drug at a time, instead of regarding combination pills and lifestyle modification as complementary and additive. Second, widespread availability of combination pills is also impeded by the reluctance of large pharmaceutical companies to invest in development of novel co-formulations of generic (or 'mature') drugs. A business model based on 'mass approaches' to drug production, packaging, marketing, and distribution could make the combination pill available at an affordable price, while at the same time providing a viable profit for the manufacturers. A third barrier is regulatory approval for novel multidrug combination pills, as there are few precedents for the approval of combination products with four or more components for CVD. Acceptance of combination therapy in other settings suggests that with concerted efforts by academics, international health agencies, research funding bodies, governments, regulators, and pharmaceutical manufacturers, combination pills for prevention of CVD in those with disease or at high risk (e.g. those with multiple risk factors) can be made available worldwide at affordable prices. It is anticipated that widespread use of combination pills with lifestyle modifications can lead to substantial risk reductions (as much as an 80% estimated RRR) in CVD. Heath care systems need to deploy these strategies widely, effectively, and efficiently. If implemented, these strategies could avoid several millions of fatal and non-fatal CVD events every year worldwide.

Cluster randomized controlled trial of a simple warfarin maintenance dosing algorithm versus usual care among primary care practices.

Many patients using warfarin are being managed in primary care and typically achieve a lower time in therapeutic range (TTR) for the international normalized ratio (INR) than patients in specialized care. A simple warfarin maintenance dosing tool could assist primary care physicians with improving TTR. We tested whether a simple warfarin maintenance dosing algorithm can improve TTR compared with usual care among Canadian primary care physicians. Primary care practices managing warfarin therapy without an anticoagulation clinic, computer decision support system or patient self-management tools enrolled 10-30 patients with target INR range 2-3. Practices were randomized to manage warfarin maintenance with the algorithm, or as usual in 2009-2010. Primary outcome was the mean individual patient TTR, and was compared between groups with adjustment for clustering within practices. There were 13 practices randomized to the Algorithm and 15 practices to Control, enrolling 240 and 297 patients respectively, with a mean follow-up of 280 days. Mean (standard deviation; SD) TTR before the study was comparable between groups [68 % (SD 26) for usual care vs. 70 % (SD 27) for the algorithm; p = 0.49]. Dosing decisions during the study in the algorithm group were more often in agreement with the algorithm's recommendations than with usual care (81 vs. 91 %; p < 0.0001). Mean study TTR of the algorithm group was not superior to usual care: [72.1 (SE 1.7) vs. 71.4 % (SE 1.5) respectively; p = 0.73]. The simple warfarin maintenance dosing algorithm did not improve TTR compared with usual care among Canadian primary care practices.

Interventions for enhancing medication adherence.

BACKGROUND: People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications. OBJECTIVES: The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes. SEARCH METHODS: We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles. SELECTION CRITERIA: We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive findings at earlier time points. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta-analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome. MAIN RESULTS: The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub-analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes. AUTHORS' CONCLUSIONS: Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements in patient-important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.

Why are we failing to implement effective therapies in cardiovascular disease?

Worldwide, there are ~18 million deaths each year from cardiovascular disease and at least 2-3 times as many experience non-fatal cardiovascular events. Numerous evidence-based prevention and management guideline recommendations for cardiovascular disease are available. However, significant gaps between the evidence and its implementation persist ('evidence-practice gap'). There exist 'under-use' gaps with lack of implementation of proven effective strategies and 'over-use' gaps with inappropriate use of strategies with strong evidence against, or insufficient evidence for their effectiveness and safety. To better tackle the global burden of cardiovascular disease (CVD), more effective strategies are needed. We discuss three selected areas where advances in implementation research for CVD could provide improvements. First, a better assessment and understanding of the most important modifiable context-specific barriers to evidence-based care will allow optimal tailoring of interventions to overcome them. Second, novel community intervention strategies from outside current CVD research should be considered, especially for CVD areas where major barriers exist and little progress has been made. Examples of such interventions include cell phone text messaging, non-physician health workers for the delivery community CVD care in areas of need, and low-cost single-pill combination CVD therapy. Third, increasing our understanding of successful implementation and sustainability of improvements is essential for CVD as a widespread chronic disease. Learning how to better implement effective therapies for CVD will have a larger effect on patient outcomes than most single new drugs and is a priority for tackling the global burden of CVD.

Representation of published core outcome sets in practice guidelines.

OBJECTIVES: A core outcome set (COS) is an agreed standardized set of outcomes that should be measured and reported, as a minimum, in specific areas of health or health care. A COS is developed through a consensus process to ensure health care outcomes to be measured are relevant to decision-makers, including patients and health-care professionals. Use of COS in guideline development is likely to increase the relevance of the guideline to those decision-makers. Previous work has looked at the uptake of COS in trials, systematic reviews, health technology assessments and regulatory guidance but to date there has been no evaluation of the use of COS in practice guideline development. The objective of this study was to investigate the representation of core outcomes in a set of international practice guidelines. STUDY DESIGN AND SETTING: We searched for clinical guidelines relevant to ten high-quality COS (with focus on the United Kingdom, Germany, China, India, Canada, Denmark, United States and World Health Organisation). We matched scope between COS and guideline in terms of condition, population and outcome. We calculated the proportion of guidelines mentioning or referencing COS and the proportion of COS domains specifically, or generally, matching to outcomes specified in each guideline populations, interventions, comparators and outcome (PICO) statement. RESULTS: We found 38 guidelines that contained 170 PICO statements matching the scope of the ten COS and of sufficient quality to allow data extraction. None of the guidelines reviewed explicitly mentioned or referenced the relevant COS. The median (range) of the proportion of core outcomes covered either specifically or generally by the guideline PICO was 30% (0%-100%). CONCLUSION: There is no evidence that COS are being used routinely to inform the guideline development process, and concordance between outcomes in published guidelines and those in COS is limited. Further work is warranted to explore barriers and facilitators in the use of COS when developing clinical guidelines.

Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial.

BACKGROUND: The outcome of atrial fibrillation patients on warfarin partially depends on maintaining adequate time in therapeutic International Normalized Ratio range (TTR). Large differences in TTR have been reported between centers and countries. The association between warfarin dosing practice, TTR, and clinical outcomes was evaluated in Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial patients receiving warfarin. METHODS AND RESULTS: RE-LY provided an algorithm for warfarin dosing, recommending no change for in-range, and 10% to 15% weekly dose changes for out-of-range International Normalized Ratio values. We determined whether dose adjustments were consistent with algorithm recommendations but could not verify whether providers used the algorithm. Using multilevel regression models to adjust for patient, center, and country characteristics, we assessed whether algorithm-consistent warfarin dosing could predict patient TTR and the composite outcome of stroke, systemic embolism, or major hemorrhage. We included 6022 nonvalvular atrial fibrillation patients from 912 centers in 44 countries. We found a strong association between the proportion of algorithm-consistent warfarin doses and mean country TTR (R(2)=0.65). The degree of algorithm-consistency accounted for 87% of the between-center and 55% of the between-country TTR variation. Each 10% increase in center algorithm-consistent dosing independently predicted a 6.12% increase in TTR (95% confidence interval, 5.65-6.59) and an 8% decrease in rate of the composite clinical outcome (hazard ratio, 0.92; 95% confidence interval, 0.85-1.00). CONCLUSIONS: Adherence, intentional or not, to a simple warfarin dosing algorithm predicts improved TTR and accounts for considerable TTR variation between centers and countries. Systems facilitating algorithm-based warfarin dosing could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation on a global scale. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

The influence of health systems on hypertension awareness, treatment, and control: a systematic literature review.

BACKGROUND: Hypertension (HT) affects an estimated one billion people worldwide, nearly three-quarters of whom live in low- or middle-income countries (LMICs). In both developed and developing countries, only a minority of individuals with HT are adequately treated. The reasons are many but, as with other chronic diseases, they include weaknesses in health systems. We conducted a systematic review of the influence of national or regional health systems on HT awareness, treatment, and control. METHODS AND FINDINGS: Eligible studies were those that analyzed the impact of health systems arrangements at the regional or national level on HT awareness, treatment, control, or antihypertensive medication adherence. The following databases were searched on 13th May 2013: Medline, Embase, Global Health, LILACS, Africa-Wide Information, IMSEAR, IMEMR, and WPRIM. There were no date or language restrictions. Two authors independently assessed papers for inclusion, extracted data, and assessed risk of bias. A narrative synthesis of the findings was conducted. Meta-analysis was not conducted due to substantial methodological heterogeneity in included studies. 53 studies were included, 11 of which were carried out in LMICs. Most studies evaluated health system financing and only four evaluated the effect of either human, physical, social, or intellectual resources on HT outcomes. Reduced medication co-payments were associated with improved HT control and treatment adherence, mainly evaluated in US settings. On balance, health insurance coverage was associated with improved outcomes of HT care in US settings. Having a routine place of care or physician was associated with improved HT care. CONCLUSIONS: This review supports the minimization of medication co-payments in health insurance plans, and although studies were largely conducted in the US, the principle is likely to apply more generally. Studies that identify and analyze complexities and links between health systems arrangements and their effects on HT management are required, particularly in LMICs. Please see later in the article for the Editors' Summary.

Proposed triggers for retiring a living systematic review.

Living systematic reviews (LSRs) are systematic reviews that are continually updated, incorporating relevant new evidence as it becomes available. LSRs are critical for decision-making in topics where the evidence continues to evolve. It is not feasible to continue to update LSRs indefinitely; however, guidance on when to retire LSRs from the living mode is not clear. We propose triggers for making such a decision. The first trigger is to retire LSRs when the evidence becomes conclusive for the outcomes that are required for decision-making. Conclusiveness of evidence is best determined based on the GRADE certainty of evidence construct, which is more comprehensive than solely relying on statistical considerations. The second trigger to retire LSRs is when the question becomes less pertinent for decision-making as determined by relevant stakeholders, including people affected by the problem, healthcare professionals, policymakers and researchers. LSRs can also be retired from a living mode when new studies are not anticipated to be published on the topic and when resources become unavailable to continue updating. We describe examples of retired LSRs and apply the proposed approach using one LSR about adjuvant tyrosine kinase inhibitors in high-risk renal cell carcinoma that we retired from a living mode and published its last update.

Antibiotic prescribing guideline recommendations in COVID-19: a systematic survey.

Background: COVID-19 and antimicrobial resistance (AMR) are two intersecting public health crises. Antimicrobial overuse in patients with COVID-19 threatens to worsen AMR. Guidelines are fundamental in encouraging antimicrobial stewardship. We sought to assess the quality of antibiotic prescribing guidelines and recommendations in the context of COVID-19, and whether they incorporate principles of antimicrobial stewardship. Methods: We performed a systematic survey which included a search using the concepts "antibiotic/antimicrobial" up to November 15, 2022 of the eCOVID-19 living map of recommendations (RecMap) which aggregates guidelines across a range of international sources and all languages. Guidelines providing explicit recommendations regarding antibacterial use in COVID-19 were eligible for inclusion. Guideline and recommendation quality were assessed using the AGREE II and AGREE-REX instruments, respectively. We extracted guideline characteristics including panel representation and the presence or absence of explicit statements related to antimicrobial stewardship (i.e., judicious antibiotic use, antimicrobial resistance or adverse effects as a consequence of antibiotic use). We used logistic regression to evaluate the relationship between guideline characteristics including quality and incorporation of antimicrobial stewardship principles. Protocol registration (OSF): https://osf.io/4pgtc. Findings: Twenty-eight guidelines with 63 antibiotic prescribing recommendations were included. Recommendations focused on antibiotic initiation (n = 52, 83%) and less commonly antibiotic selection (n = 13, 21%), and duration of therapy (n = 15, 24%). Guideline and recommendation quality varied widely. Twenty (71%) guidelines incorporated at least one concept relating to antimicrobial stewardship. Including infectious diseases expertise on the guideline panel (OR 9.44, 97.5% CI: 1.09-81.59) and AGREE-REX score (OR 3.26, 97.5% CI: 1.14-9.31 per 10% increase in overall score) were associated with a higher odds of guidelines addressing antimicrobial stewardship. Interpretation: There is an opportunity to improve antibiotic prescribing guidelines in terms of both quality and incorporation of antimicrobial stewardship principles. These findings can help guideline developers better address antibiotic stewardship in future recommendations beyond COVID-19. Funding: This project was funded by Michael G. DeGroote Cochrane Canada and McMaster GRADE centres.