Drug-eluting stents versus bare-metal stents for stable ischaemic heart disease

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of drug‐eluting stents versus bare‐metal stents in participants with stable ischaemic heart disease

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.Fil: Korang, Steven Kwasi. Copenhagen University Hospital; DinamarcaFil: von Rohden, Elena. Copenhagen University Hospital; DinamarcaFil: Veroniki, Areti Angeliki. Imperial College London; Reino Unido. St. Michael’s Hospital; CanadáFil: Ong, Giok. John Radcliffe Hospital; Reino UnidoFil: Ngalamika, Owen. University of Zambia; ZambiaFil: Siddiqui, Faiza. Copenhagen University Hospital; DinamarcaFil: Juul, Sophie. Copenhagen University Hospital; DinamarcaFil: Nielsen, Emil Eik. Copenhagen University Hospital; DinamarcaFil: Feinberg, Joshua Buron. Copenhagen University Hospital; DinamarcaFil: Petersen, Johanne Juul. Copenhagen University Hospital; DinamarcaFil: Legart, Christian. Universidad de Copenhagen; Dinamarca. Copenhagen University Hospital; DinamarcaFil: Kokogho, Afoke. Henry M. Jackson Foundation Medical Research International; NigeriaFil: Maagaard, Mathias. Copenhagen University Hospital; Dinamarca. Zealand University Hospital; DinamarcaFil: Klingenberg, Sarah. Copenhagen University Hospital; DinamarcaFil: Thabane, Lehana. Mcmaster University; CanadáFil: Bardach, Ariel Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Ciapponi, Agustín. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Thomsen, Allan Randrup. Universidad de Copenhagen; DinamarcaFil: Jakobsen, Janus C.. University of Southern Denmark; Dinamarca. Copenhagen University Hospital; DinamarcaFil: Gluud, Christian. Copenhagen University Hospital; Dinamarca. University of Southern Denmark; Dinamarc

Drug-eluting stents versus bare-metal stents for acute coronary syndrome

Background Approximately 3.7 million people died from acute coronary syndrome worldwide in 2012. Acute coronary syndrome, also known as myocardial infarction or unstable angina pectoris, is caused by a sudden blockage of the blood supplied to the heart muscle. Percutaneous coronary intervention is often used for acute coronary syndrome, but previous systematic reviews on the effects of drug‐eluting stents compared with bare‐metal stents have shown conflicting results with regard to myocardial infarction; have not fully taken account of the risk of random and systematic errors; and have not included all relevant randomised clinical trials. Objectives To assess the benefits and harms of drug‐eluting stents versus bare‐metal stents in people with acute coronary syndrome. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, SCI‐EXPANDED, and BIOSIS from their inception to January 2017. We also searched two clinical trials registers, the European Medicines Agency and the US Food and Drug Administration databases, and pharmaceutical company websites. In addition, we searched the reference lists of review articles and relevant trials. Selection criteria Randomised clinical trials assessing the effects of drug‐eluting stents versus bare‐metal stents for acute coronary syndrome. We included trials irrespective of publication type, status, date, or language. Data collection and analysis We followed our published protocol and the methodological recommendations of Cochrane. Two review authors independently extracted data. We assessed the risks of systematic error by bias domains. We conducted Trial Sequential Analyses to control the risks of random errors. Our primary outcomes were all‐cause mortality, major cardiovascular events, serious adverse events, and quality of life. Our secondary outcomes were angina, cardiovascular mortality, and myocardial infarction. Our primary assessment time point was at maximum follow‐up. We assessed the quality of the evidence by the GRADE approach. Main results We included 25 trials randomising a total of 12,503 participants. All trials were at high risk of bias, and the quality of evidence according to GRADE was low to very low. We included 22 trials where the participants presented with ST‐elevation myocardial infarction, 1 trial where participants presented with non‐ST‐elevation myocardial infarction, and 2 trials where participants presented with a mix of acute coronary syndromes. Meta‐analyses at maximum follow‐up showed no evidence of a difference when comparing drug‐eluting stents with bare‐metal stents on the risk of all‐cause mortality or major cardiovascular events. The absolute risk of death was 6.97% in the drug‐eluting stents group compared with 7.74% in the bare‐metal stents group based on the risk ratio (RR) of 0.90 (95% confidence interval (CI) 0.78 to 1.03, 11,250 participants, 21 trials/22 comparisons, low‐quality evidence). The absolute risk of a major cardiovascular event was 6.36% in the drug‐eluting stents group compared with 6.63% in the bare‐metal stents group based on the RR of 0.96 (95% CI 0.83 to 1.11, 10,939 participants, 19 trials/20 comparisons, very low‐quality evidence). The results of Trial Sequential Analysis showed that we did not have sufficient information to confirm or reject our anticipated risk ratio reduction of 10% on either all‐cause mortality or major cardiovascular events at maximum follow‐up. Meta‐analyses at maximum follow‐up showed evidence of a benefit when comparing drug‐eluting stents with bare‐metal stents on the risk of a serious adverse event. The absolute risk of a serious adverse event was 18.04% in the drug‐eluting stents group compared with 23.01% in the bare‐metal stents group based on the RR of 0.80 (95% CI 0.74 to 0.86, 11,724 participants, 22 trials/23 comparisons, low‐quality evidence), and Trial Sequential Analysis confirmed this result. When assessing each specific type of adverse event included in the serious adverse event outcome separately, the majority of the events were target vessel revascularisation. When target vessel revascularisation was analysed separately, meta‐analysis showed evidence of a benefit of drug‐eluting stents, and Trial Sequential Analysis confirmed this result. Meta‐analyses at maximum follow‐up showed no evidence of a difference when comparing drug‐eluting stents with bare‐metal stents on the risk of cardiovascular mortality (RR 0.91, 95% CI 0.76 to 1.09, 9248 participants, 14 trials/15 comparisons, very low‐quality evidence) or myocardial infarction (RR 0.98, 95% CI 0.82 to 1.18, 10,217 participants, 18 trials/19 comparisons, very low‐quality evidence). The results of the Trial Sequential Analysis showed that we had insufficient information to confirm or reject our anticipated risk ratio reduction of 10% on cardiovascular mortality and myocardial infarction. No trials reported results on quality of life or angina. Authors' conclusions The current evidence suggests that drug‐eluting stents may lead to fewer serious adverse events compared with bare‐metal stents without increasing the risk of all‐cause mortality or major cardiovascular events. However, our Trial Sequential Analysis showed that there currently was not enough information to assess a risk ratio reduction of 10% for all‐cause mortality, major cardiovascular events, cardiovascular mortality, or myocardial infarction, and there were no data on quality of life or angina. The evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review. More randomised clinical trials with low risk of bias and low risks of random errors are needed if the benefits and harms of drug‐eluting stents for acute coronary syndrome are to be assessed properly. More data are needed on the outcomes all‐cause mortality, major cardiovascular events, quality of life, and angina to reduce the risk of random error

Drug-eluting stents versus bare-metal stents for non-acute ischaemic heart disease

The editorial team of Cochrane Heart made the decision to withdraw this protocol for a Cochrane Review as the question is no longer pertinent to current clinical practice.

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

Abstract 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

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

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 (&lt;110 beats per minute (bpm) at rest) compared with strict rate control strategy (&lt;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 (&lt;110 bpm at rest) or a strict medical rate control strategy (&lt;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).

BackgroundCOVID-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 findingsWe 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 ConclusionsNo 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 registrationPROSPERO CRD42020178787

Additional file 1 of 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

Additional file 1: Text S1. Detail Search strategy. Text S2. Other functional capacity Berg Balance Scal. Table S1. Characteristics of included studies. Text S3. Sensitivity Analysis (Fixed Model; Inverse Variance). Table S2. Subgroup analysis for VO2 max for age and baseline BMI. Table S4. Subgroup analysis for 10MWT for age, baseline BMI and size of trials. Table S5. Subgroup analysis for body weight for age and baseline BMI. Table S6. Meta-regression on effect of exercise on VO2max. Table S7. Meta-regression on effect of exercise on 6MWT. Table S8. Meta-regression on effect of exercise on 10MWT. Table S9. Meta-regression on effect of exercise on body weight