Effect of exercise on functional capacity and body weight for people with hypertension, type 2 diabetes, or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Hypertension, type 2 diabetes, and cardiovascular disease affect the activities of daily living at varying degree. While the effects of aerobic exercise on functional capacity are well-documented, the extent of change for different types of exercise in these chronic conditions remains unexplored. Additionally, there is conflicting evidence regarding the role of exercise in reducing body weight. METHODS: We conducted systematic review with meta-analysis and trial sequential analysis and searched various databases from inception to July 2020. We included randomised clinical trials adding any form of trialist defined exercise to usual care versus usual care in people with either hypertension, type 2 diabetes, and/or cardiovascular disease irrespective of setting, publication status, year, and language. The outcomes assessed were i) functional capacity assessed through different scales separately i.e., Maximal Oxygen Uptake (VO2max), 6-min walk test (6MWT), 10-m walk test (10MWT), and ii) body weight. RESULTS: We included 950 studies out of which 444 trials randomising 20,098 participants reported on various functional outcomes (355 trials) and body weight (169 trials). The median follow-up was 3 months (Interquartile ranges (IQR): 2.25 to 6). Exercise added to the usual care, improved VO2max (Mean Difference (MD):2.72 ml/kg/min; 95% Confidence Interval (CI) 2.38 to 3.06; p < 0.01; I2 = 96%), 6MWT (MD: 42.5 m; 95%CI 34.95 to 50.06; p < 0.01; I2 = 96%), and 10MWT (MD: 0.06 m/s; 95%CI 0.03 to 0.10; p < 0.01; I2 = 93%). Dynamic aerobic and resistance exercise showed a consistent improvement across various functional outcomes, whereas body-mind therapies (MD: 3.23 ml/kg/min; 95%CI 1.97 to 4.49, p < 0.01) seemed especially beneficial for VO2max and inspiratory muscle training (MD: 59.32 m; 95%CI 33.84 to 84.80; p < 0.01) for 6MWT. Exercise yielded significant reduction in body weight for people with hypertension (MD: -1.45 kg; 95%CI -2.47 to -0.43; p < 0.01), and type 2 diabetes (MD: -1.53 kg; 95%CI -2.19 to -0.87; p < 0.01) but not for cardiovascular disease with most pronounced for combined exercise (MD: -1.73 kg; 95%CI -3.08 to -0.39; p < 0.05). The very low certainty of evidence warrants cautious interpretations of the results. CONCLUSION: Exercise seemed to improve functional capacity for people with hypertension, type 2 diabetes, and/or cardiovascular disease but the effectiveness seems to vary with different forms of exercise. The potentially superior improvement in VO2max and 6MWT by body-mind therapies and inspiratory muscle training calls for further exploration. Additionally, prescribing exercise for the sole purpose of losing weight may be a potential strategy for people with hypertension and type 2 diabetes. The extent of improvement in functional capacity and body weight reduction differed with different exercise regimens hence personalised exercise prescriptions tailored to individual needs may be of importance. PROSPERO REGISTRATION: PROSPERO registration number: CRD42019142313.

A multidisciplinary, shared care clinic using personalized medicine and coordinated care in patients with concomitant type 2 diabetes and cardiovascular disease. Protocol and baseline characteristics.

Background: Concomitant type 2 diabetes (T2DM) and cardiovascular disease (CVD) is frequent with a poor prognosis with high risk of comorbidities. Strict risk factor control reduces the risk for complications - yet many people do not achieve treatment targets. The complexity and fragmentation of the healthcare system may, together with the vulnerability of these patients, be a reason. Objective: The purpose of this paper is to describe the protocol of a non-randomized interventional pilot study testing the feasibility and effect of a multidisciplinary, shared care clinic using personalized medicine and coordinated care in people living with concomitant T2D and CVD. Methods: Participants were included from the Holbaek area in Denmark. People suffered from T2DM and CVD and were dysregulated regarding to HbA1c, cholesterol, micro/macroalbuminuaria or blood pressure. Participants went through a thorough evaluation to identify their needs and resources and received consultations every three months for one year. Results: A total of 63 participants with T2DM and CVD were enrolled in the clinic. The participants had a mean age of 69 years and a BMI of 30.9 kg/m2. Almost 50 % had heart failure, 95 % dyslipidemia and 91 % hypertension. Around 54 % received GLP-1 agonists and 39 % received SGLT-2-inhibitors. Perspectives: To our knowledge, a similar study with a multidisciplinary, shared care, outpatient clinic treating people living with concomitant T2DM and CVD, has not been performed previously. This study will provide information about the feasibility and efficacy of a multidisciplinary clinic based on changes in cardiovascular risk factors and medication.

Effects of adding exercise to usual care on blood pressure in patients with hypertension, type 2 diabetes, or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Exercise is the most recommended lifestyle intervention in managing hypertension, type 2 diabetes, and/or cardiovascular disease; however, evidence in lowering blood pressure is still inconsistent and often underpowered. METHOD: We conducted a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials adding any form of trialist defined exercise to usual care versus usual care and its effect on systolic blood pressure (SBP) or diastolic blood pressure (DBP) in participants with hypertension, type 2 diabetes, or cardiovascular disease searched in different databases from inception to July 2020. Our methodology was based on PRISMA and Cochrane Risk of Bias-version1. Five independent reviewers extracted data and assessed risk of bias in pairs. RESULTS: Two hundred sixty-nine trials randomizing 15 023 participants reported our predefined outcomes. The majority of exercise reported in the review was dynamic aerobic exercise (61%), dynamic resistance (11%), and combined aerobic and resistance exercise (15%). The trials included participants with hypertension (33%), type 2 diabetes (28%), or cardiovascular disease (37%). Meta-analyses and trial sequential analyses reported that adding exercise to usual care reduced SBP [mean difference (MD) MD: -4.1 mmHg; 95% confidence interval (95% CI) -4.99 to -3.14; P  < 0.01; I2  = 95.3%] and DBP (MD: -2.6 mmHg; 95% CI -3.22 to -2.07, P  < 0.01; I2  = 94%). Test of interaction showed that the reduction of SBP and DBP was almost two times higher among trials from low-and middle-income countries (LMICs) as compared to high-income countries (HICs). The exercise induced SBP reduction was also higher among participants with hypertension and type 2 diabetes compared to participants with cardiovascular disease. The very low certainty of evidence warrants a cautious interpretation of the present results. CONCLUSION: Adding any type of exercise to usual care may be a potential complementary strategy for optimal management of blood pressure for patients with hypertension, type 2 diabetes, or cardiovascular disease, especially, in LMICs.PROSPERO registration number CRD42019142313.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

Effects of adding exercise to usual care in patients with either hypertension, type 2 diabetes or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: To assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. DESIGN: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. DATA SOURCES: The CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science and BIOSIS searched from inception to July 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included all randomised clinical trials adding any form of trialist defined exercise to usual care versus usual care in participants with either hypertension, type 2 diabetes or cardiovascular disease irrespective of setting, publication status, year and language. OUTCOME AND MEASURES: The primary outcomes were all-cause mortality, serious adverse events and quality of life. DATA EXTRACTION AND SYNTHESIS: Five independent reviewers extracted data and assessed risk of bias in pairs. Our methodology was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Grading of Recommendations Assessment, Development and Evaluation and Cochrane Risk of Bias-version 1. RESULTS: We included 950 trials, of which 248 trials randomising 21 633 participants reported on our predefined outcomes. All included trials were at high risk of bias. The major types of exercise reported were dynamic aerobic exercise (126/248 trials), dynamic resistance exercise (25/248 trials), and combined aerobic and resistance exercise (58/248 trials). The study participants were included due to cardiovascular diseases (189/248 trials), type 2 diabetes (41/248 trials) or hypertension (16/248 trials). The median intervention period was 3 months (IQR: 2-4 months) and the median follow-up period was 6 months (IQR: 3-8 months) after randomisation. Meta-analyses and trial sequential analyses showed evidence of a beneficial effect of adding exercise to usual care when assessing all-cause mortality (risk ratio (RR) 0.82; 95% CI 0.73 to 0.93; I2=0%, moderate certainty of evidence) and serious adverse events (RR 0.79; 95% CI 0.71 to 0.88; I2=0%, moderate certainty of evidence). We did not find evidence of a difference between trials from different economic regions, type of participants, type of exercise or duration of follow-up. Quality of life was assessed using several different tools, but the results generally showed that exercise improved quality of life, but the effect sizes were below our predefined minimal important difference. CONCLUSIONS: A short duration of any type of exercise seems to reduce the risk of all-cause mortality and serious adverse events in patients with either hypertension, type 2 diabetes or cardiovascular diseases. Exercise seems to have statistically significant effects on quality of life, but the effect sizes seem minimal. PROSPERO REGISTRATION NUMBER: CRD42019142313.

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Ivabradine added to usual care in patients with heart failure: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVES: To assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure. DESIGN: A systematic review with meta-analysis and trial sequential analysis. ELIGIBILITY CRITERIA: Randomised clinical trials comparing ivabradine and usual care with usual care (with or without) placebo in participants with heart failure. INFORMATION SOURCES: Medline, Embase, CENTRAL, LILACS, CNKI, VIP and other databases and trial registries up until 31 May 2021. DATA EXTRACTION: Primary outcomes were all-cause mortality, serious adverse events and quality of life. Secondary outcomes were cardiovascular mortality, myocardial infarction and non-serious adverse events. We performed meta-analysis of all outcomes. We used trial sequential analysis to control risks of random errors, the Cochrane risk of bias tool to assess the risks of systematic errors and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence. RESULTS: We included 109 randomised clinical trials with 26 567 participants. Two trials were at low risk of bias, although both trials were sponsored by the company that developed ivabradine. All other trials were at high risk of bias. Meta-analyses and trial sequential analyses showed that we could reject that ivabradine versus control reduced all-cause mortality (risk ratio (RR)=0.94; 95% CI 0.88 to 1.01; p=0.09; high certainty of evidence). Meta-analysis and trial sequential analysis showed that ivabradine seemed to reduce the risk of serious adverse events (RR=0.90; 95% CI 0.87 to 0.94; p<0.00001; number needed to treat (NNT)=26.2; low certainty of evidence). This was primarily due to a decrease in the risk of 'cardiac failure' (RR=0.83; 95% CI 0.71 to 0.97; p=0.02; NNT=43.9), 'hospitalisations' (RR=0.89; 95% CI 0.85 to 0.94; p<0.0001; NNT=36.4) and 'ventricular tachycardia' (RR=0.59; 95% CI 0.43 to 0.82; p=0.001; NNT=212.8). However, the trials did not describe how these outcomes were defined and assessed during follow-up. Meta-analyses showed that ivabradine increased the risk of atrial fibrillation (RR=1.19; 95% CI 1.04 to 1.35; p=0.008; number needed to harm (NNH)=116.3) and bradycardia (RR=3.95; 95% CI 1.88 to 8.29; p=0.0003; NNH=303). Ivabradine seemed to increase quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference (MD)=2.92; 95% CI 1.34 to 4.50; p=0.0003; low certainty of evidence), but the effect size was small and possibly without relevance to patients, and on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) (MD=-5.28; 95% CI -6.60 to -3.96; p<0.00001; very low certainty of evidence), but the effects were uncertain. Meta-analysis showed no evidence of a difference between ivabradine and control when assessing cardiovascular mortality and myocardial infarction. Ivabradine seemed to increase the risk of non-serious adverse events. CONCLUSION AND RELEVANCE: High certainty evidence shows that ivabradine does not seem to affect the risks of all-cause mortality and cardiovascular mortality. The effects on quality of life were small and possibly without relevance to patients on the KCCQ and were very uncertain for the MLWHFQ. The effects on serious adverse events, myocardial infarction and hospitalisation are uncertain. Ivabradine seems to increase the risk of atrial fibrillation, bradycardia and non-serious adverse events.PROSPERO registration number: CRD42018112082.

Beta-blockers in patients without heart failure after myocardial infarction.

BACKGROUND: Cardiovascular disease is the number one cause of death globally. According to the World Health Organization (WHO), 7.4 million people died from ischaemic heart disease in 2012, constituting 15% of all deaths. Beta-blockers are recommended and are often used in patients with heart failure after acute myocardial infarction. However, it is currently unclear whether beta-blockers should be used in patients without heart failure after acute myocardial infarction. Previous meta-analyses on the topic have shown conflicting results. No previous systematic review using Cochrane methods has assessed the effects of beta-blockers in patients without heart failure after acute myocardial infarction. OBJECTIVES: To assess the benefits and harms of beta-blockers compared with placebo or no treatment in patients without heart failure and with left ventricular ejection fraction (LVEF) greater than 40% in the non-acute phase after myocardial infarction. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index - Expanded, BIOSIS Citation Index, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, European Medicines Agency, Food and Drug Administration, Turning Research Into Practice, Google Scholar, and SciSearch from their inception to February 2021. SELECTION CRITERIA: We included all randomised clinical trials assessing effects of beta-blockers versus control (placebo or no treatment) in patients without heart failure after myocardial infarction, irrespective of publication type and status, date, and language. We excluded trials randomising participants with diagnosed heart failure at the time of randomisation. DATA COLLECTION AND ANALYSIS: We followed our published protocol, with a few changes made, and methodological recommendations provided by Cochrane and Jakobsen and colleagues. Two review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse events, and major cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial reinfarction). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow-up. We assessed all outcomes at maximum follow-up. We systematically assessed risks of bias using seven bias domains and we assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 25 trials randomising a total of 22,423 participants (mean age 56.9 years). All trials and outcomes were at high risk of bias. In all, 24 of 25 trials included a mixed group of participants with ST-elevation myocardial infarction and non-ST myocardial infarction, and no trials provided separate results for each type of infarction. One trial included participants with only ST-elevation myocardial infarction. All trials except one included participants younger than 75 years of age. Methods used to exclude heart failure were various and were likely insufficient. A total of 21 trials used placebo, and four trials used no intervention, as the comparator. All patients received usual care; 24 of 25 trials were from the pre-reperfusion era (published from 1974 to 1999), and only one trial was from the reperfusion era (published in 2018). The certainty of evidence was moderate to low for all outcomes. Our meta-analyses show that beta-blockers compared with placebo or no intervention probably reduce the risks of all-cause mortality (risk ratio (RR) 0.81, 97.5% confidence interval (CI) 0.73 to 0.90; I² = 15%; 22,085 participants, 21 trials; moderate-certainty evidence) and myocardial reinfarction (RR 0.76, 98% CI 0.69 to 0.88; I² = 0%; 19,606 participants, 19 trials; moderate-certainty evidence). Our meta-analyses show that beta-blockers compared with placebo or no intervention may reduce the risks of major cardiovascular events (RR 0.72, 97.5% CI 0.69 to 0.84; 14,994 participants, 15 trials; low-certainty evidence) and cardiovascular mortality (RR 0.73, 98% CI 0.68 to 0.85; I² = 47%; 21,763 participants, 19 trials; low-certainty evidence). Hence, evidence seems to suggest that beta-blockers versus placebo or no treatment may result in a minimum reduction of 10% in RR for risks of all-cause mortality, major cardiovascular events, cardiovascular mortality, and myocardial infarction. However, beta-blockers compared with placebo or no intervention may not affect the risk of angina (RR 1.04, 98% CI 0.93 to 1.13; I² = 0%; 7115 participants, 5 trials; low-certainty evidence). No trials provided data on serious adverse events according to good clinical practice from the International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP), nor on quality of life. AUTHORS' CONCLUSIONS: Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction in patients younger than 75 years of age without heart failure following acute myocardial infarction. Beta-blockers may further reduce the risks of major cardiovascular events and cardiovascular mortality compared with placebo or no intervention in patients younger than 75 years of age without heart failure following acute myocardial infarction. These effects could, however, be driven by patients with unrecognised heart failure. The effects of beta-blockers on serious adverse events, angina, and quality of life are unclear due to sparse data or no data at all. All trials and outcomes were at high risk of bias, and incomplete outcome data bias alone could account for the effect seen when major cardiovascular events, angina, and myocardial infarction are assessed. The evidence in this review is of moderate to low certainty, and the true result may depart substantially from the results presented here. Future trials should particularly focus on patients 75 years of age and older, and on assessment of serious adverse events according to ICH-GCP and quality of life. Newer randomised clinical trials at low risk of bias and at low risk of random errors are needed if the benefits and harms of beta-blockers in contemporary patients without heart failure following acute myocardial infarction are to be assessed properly. Such trials ought to be designed according to the SPIRIT statement and reported according to the CONSORT statement.

Lenient rate control versus strict rate control for atrial fibrillation: a protocol for the Danish Atrial Fibrillation (DanAF) randomised clinical trial.

INTRODUCTION: Atrial fibrillation is the most common heart arrhythmia with a prevalence of approximately 2% in the western world. Atrial fibrillation is associated with an increased risk of death and morbidity. In many patients, a rate control strategy is recommended. The optimal heart rate target is disputed despite the results of the the RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient vs strict rate control II (RACE II) trial.Our primary objective will be to investigate the effect of lenient rate control strategy (<110 beats per minute (bpm) at rest) compared with strict rate control strategy (<80 bpm at rest) on quality of life in patients with persistent or permanent atrial fibrillation. METHODS AND ANALYSIS: We plan a two-group, superiority randomised clinical trial. 350 outpatients with persistent or permanent atrial fibrillation will be recruited from four hospitals, across three regions in Denmark. Participants will be randomised 1:1 to a lenient medical rate control strategy (<110 bpm at rest) or a strict medical rate control strategy (<80 bpm at rest). The recruitment phase is planned to be 2 years with 3 years of follow-up. Recruitment is expected to start in January 2021. The primary outcome will be quality of life using the Short Form-36 (SF-36) questionnaire (physical component score). Secondary outcomes will be days alive outside hospital, symptom control using the Atrial Fibrillation Effect on Quality of Life, quality of life using the SF-36 questionnaire (mental component score) and serious adverse events. The primary assessment time point for all outcomes will be 1 year after randomisation. ETHICS AND DISSEMINATION: Ethics approval was obtained through the ethics committee in Region Zealand. The design and findings will be published in peer-reviewed journals as well as be made available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04542785.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.

Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how.

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.

Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

Current guidelines recommend angiotensin receptor blocker neprilysin inhibitors (ARNI) (sacubitril/valsartan) as a replacement for angiotensin-converting-enzymeinhibitor (ACE-I) in heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy. The effects of ARNIs have not previously been assessed in a systematic review. We searched for relevant trials until October 2019 in CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, CNKI, VIP, WanFang and CBM. Our primary outcomes were all-cause mortality and serious adverse events. We systematically assessed the risks of random errors and systematic errors. PROSPERO registration: CRD42019129336. 48 trials randomising 19 086 participants were included. The ARNI assessed in all trials was sacubitril/valsartan. ACE-I or ARB were used as control interventions. Trials randomising HFrEF participants (27 trials) and heart failure with preserved ejection fraction (HFpEF) participants (four trials) were analysed separately. In HFrEF participants, meta-analyses and Trial Sequential Analyses showed evidence of a beneficial effect of sacubitril/valsartan when assessing all-cause mortality (risk ratio (RR), 0.86; 95% CI, 0.79 to 0.94) and serious adverse events (RR, 0.89; 95% CI, 0.86 to 0.93); and the results did not differ between the guideline recommended target population and HFrEF participants in general. We found no evidence of an effect of sacubitril/valsartan in HFpEF participants. Sacubitril/valsartan compared with either ACE-I or ARB seems to have a beneficial effect in patients with HFrEF. Our results indicate that sacubitril/valsartan might be beneficial in a wider population of patients with heart failure than the guideline recommended target population. Sacubitril/valsartan does not seem to show evidence of a difference compared with valsartan in patients with HFpEF.

Vaccines to prevent COVID-19: a protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING VACCINE Project).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. METHODS/DESIGN: We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; "active placebo;" no intervention; standard care; an "active" intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. DISCUSSION: COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020196492.

Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis.

OBJECTIVE: To determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease. METHODS: We conducted a systematic review. We included randomised clinical trials comparing ivabradine versus placebo or no intervention for patients with angina pectoris due to coronary artery disease published prior to June 2020. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Cochrane methodology, Trial Sequential Analysis, Grading of Recommendations Assessment, Development, and Evaluation, and our eight-step procedure. Primary outcomes were all-cause mortality, serious adverse events and quality of life. RESULTS: We included 47 randomised clinical trials enrolling 35 797 participants. All trials and outcomes were at high risk of bias. Ivabradine compared with control did not have effects when assessing all-cause mortality (risk ratio [RR] 1.04; 95% CI 0.96 to 1.13), quality of life (standardised mean differences -0.05; 95% CI -0.11 to 0.01), cardiovascular mortality (RR 1.07; 95% CI 0.97 to 1.18) and myocardial infarction (RR 1.03; 95% CI 0.91 to 1.16). Ivabradine seemed to increase the risk of serious adverse events after removal of outliers (RR 1.07; 95% CI 1.03 to 1.11) as well as the following adverse events classified as serious: bradycardia, prolonged QT interval, photopsia, atrial fibrillation and hypertension. Ivabradine also increased the risk of non-serious adverse events (RR 1.13; 95% CI 1.11 to 1.16). Ivabradine might have a statistically significant effect when assessing angina frequency (mean difference (MD) 2.06; 95% CI 0.82 to 3.30) and stability (MD 1.48; 95% CI 0.07 to 2.89), but the effect sizes seemed minimal and possibly without any relevance to patients, and we identified several methodological limitations, questioning the validity of these results. CONCLUSION: Our findings do not support that ivabradine offers significant benefits on patient important outcomes, but rather seems to increase the risk of serious adverse events such as atrial fibrillation and non-serious adverse events. Based on current evidence, guidelines need reassessment and the use of ivabradine for angina pectoris should be reconsidered. PROSPERO REGISTRATION NUMBER: CRD42018112082.

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. METHODS AND FINDINGS: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62-0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40-1.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80-1.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63-0.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97-1.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96-1.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01-2.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33-1.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors. CONCLUSIONS: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.

Beta-blockers for suspected or diagnosed acute myocardial infarction.

BACKGROUND: Cardiovascular disease is the number one cause of death globally. According to the World Health Organization, 7.4 million people died from ischaemic heart diseases in 2012, constituting 15% of all deaths. Acute myocardial infarction is caused by blockage of the blood supplied to the heart muscle. Beta-blockers are often used in patients with acute myocardial infarction. Previous meta-analyses on the topic have shown conflicting results ranging from harms, neutral effects, to benefits. No previous systematic review using Cochrane methodology has assessed the effects of beta-blockers for acute myocardial infarction. OBJECTIVES: To assess the benefits and harms of beta-blockers compared with placebo or no intervention in people with suspected or diagnosed acute myocardial infarction. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded and BIOSIS Citation Index in June 2019. We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, Turning Research into Practice, Google Scholar, SciSearch, and the reference lists of included trials and previous reviews in August 2019. SELECTION CRITERIA: We included all randomised clinical trials assessing the effects of beta-blockers versus placebo or no intervention in people with suspected or diagnosed acute myocardial infarction. Trials were included irrespective of trial design, setting, blinding, publication status, publication year, language, and reporting of our outcomes. DATA COLLECTION AND ANALYSIS: We followed the Cochrane methodological recommendations. Four review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse events according to the International Conference on Harmonization - Good Clinical Practice (ICH-GCP), and major adverse cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial infarction during follow-up). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow-up. Our primary time point of interest was less than three months after randomisation. We also assessed the outcomes at maximum follow-up beyond three months. Due to risk of multiplicity, we calculated a 97.5% confidence interval (CI) for the primary outcomes and a 98% CI for the secondary outcomes. We assessed the risks of systematic errors through seven bias domains in accordance to the instructions given in the Cochrane Handbook. The quality of the body of evidence was assessed by GRADE. MAIN RESULTS: We included 63 trials randomising a total of 85,550 participants (mean age 57.4 years). Only one trial was at low risk of bias. The remaining trials were at high risk of bias. The quality of the evidence according to GRADE ranged from very low to high. Fifty-six trials commenced beta-blockers during the acute phase of acute myocardial infarction and seven trials during the subacute phase. At our primary time point 'less than three months follow-up', meta-analysis showed that beta-blockers versus placebo or no intervention probably reduce the risk of a reinfarction during follow-up (risk ratio (RR) 0.82, 98% confidence interval (CI) 0.73 to 0.91; 67,562 participants; 18 trials; moderate-quality evidence) with an absolute risk reduction of 0.5% and a number needed to treat for an additional beneficial outcome (NNTB) of 196 participants. However, we found little or no effect of beta-blockers when assessing all-cause mortality (RR 0.94, 97.5% CI 0.90 to 1.00; 80,452 participants; 46 trials/47 comparisons; high-quality evidence) with an absolute risk reduction of 0.4% and cardiovascular mortality (RR 0.99, 95% CI 0.91 to 1.08; 45,852 participants; 1 trial; moderate-quality evidence) with an absolute risk reduction of 0.4%. Regarding angina, it is uncertain whether beta-blockers have a beneficial or harmful effect (RR 0.70, 98% CI 0.25 to 1.84; 98 participants; 3 trials; very low-quality evidence) with an absolute risk reduction of 7.1%. None of the trials specifically assessed nor reported serious adverse events according to ICH-GCP. Only two trials specifically assessed major adverse cardiovascular events, however, no major adverse cardiovascular events occurred in either trial. At maximum follow-up beyond three months, meta-analyses showed that beta-blockers versus placebo or no intervention probably reduce the risk of all-cause mortality (RR 0.93, 97.5% CI 0.86 to 0.99; 25,210 participants; 21 trials/22 comparisons; moderate-quality evidence) with an absolute risk reduction of 1.1% and a NNTB of 91 participants, and cardiovascular mortality (RR 0.90, 98% CI 0.83 to 0.98; 22,457 participants; 14 trials/15 comparisons; moderate-quality evidence) with an absolute risk reduction of 1.2% and a NNTB of 83 participants. However, it is uncertain whether beta-blockers have a beneficial or harmful effect when assessing major adverse cardiovascular events (RR 0.81, 97.5% CI 0.40 to 1.66; 475 participants; 4 trials; very low-quality evidence) with an absolute risk reduction of 1.7%; reinfarction (RR 0.89, 98% CI 0.75 to 1.08; 6825 participants; 14 trials; low-quality evidence) with an absolute risk reduction of 0.9%; and angina (RR 0.64, 98% CI 0.18 to 2.0; 844 participants; 2 trials; very low-quality evidence). None of the trials specifically assessed nor reported serious adverse events according to ICH-GCP. None of the trials assessed quality of life. We identified two ongoing randomised clinical trials investigating the effect of early administration of beta-blockers after percutaneous coronary intervention or thrombolysis to patients with an acute myocardial infarction and one ongoing trial investigating the effect of long-term beta-blocker therapy. AUTHORS' CONCLUSIONS: Our present review indicates that beta-blockers for suspected or diagnosed acute myocardial infarction probably reduce the short-term risk of a reinfarction and the long-term risk of all-cause mortality and cardiovascular mortality. Nevertheless, it is most likely that beta-blockers have little or no effect on the short-term risk of all-cause mortality and cardiovascular mortality. Regarding all remaining outcomes (serious adverse events according to ICH-GCP, major adverse cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial infarction during follow-up), the long-term risk of a reinfarction during follow-up, quality of life, and angina), further information is needed to confirm or reject the clinical effects of beta-blockers on these outcomes for people with or suspected of acute myocardial infarction.

Adding exercise to usual care in patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Hypertension, type 2 diabetes mellitus and cardiovascular disease are among the leading causes of mortality globally. Exercise is one of the commonly recommended interventions/preventions for hypertension, type 2 diabetes mellitus and cardiovascular disease. However, the previous reviews have shown conflicting evidence on the effects of exercise. Our objective is to assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and the eight-step assessment procedure suggested by Jakobsen et al. We plan to include all relevant randomised clinical trials and cluster-randomised trials assessing the effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP) and BIOSIS. We will systematically assess the risks of random errors using Trial Sequential Analysis as well as risks of bias of all included trials. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: The present systematic review will have the potential to aid patients, clinicians and decision-makers recommending exercise and thereby, benefit patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019142313.

The effects of adding angiotensin receptor neprilysin inhibitors to usual care in patients with heart failure: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment. DISCUSSION: The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019129336.

Coronary artery bypass surgery plus medical therapy versus medical therapy alone for ischaemic heart disease: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Despite increasing survival, cardiovascular disease remains the primary cause of death worldwide with an estimated 7.4 million annual deaths. The main symptom of ischaemic heart disease is chest pain (angina pectoris) most often caused by blockage of a coronary artery. The aim of coronary artery bypass surgery is revascularisation achieved by surgically grafting harvested arteries or veins distal to the coronary lesion restoring blood flow to the heart muscle. Older evidence suggested a clear survival benefit of coronary artery bypass graft surgery, but more recent trials yield less clear evidence. We want to assess the benefits and harms of coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease. METHODS: This protocol for a systematic review follows the recommendations of Cochrane and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all randomised clinical trials assessing coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed as high risk or low risk of bias, and our conclusions will primarily be based on trials at low risk of bias. The analyses of the extracted data will be performed using Review Manager 5, STATA 16 and trial sequential analysis. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table and use GRADE to assess the certainty of the evidence. DISCUSSION: Coronary artery bypass surgery is invasive and can cause death, which is why its use must be thoroughly studied to determine if it yields a large enough long-term benefit for the thousands of patients receiving it every year. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID 131924.