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Competing Interests: Disclosures CJB reports being an advisor for AstraZeneca. RDT has nothing to disclose. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Background: Thirty-day readmission rate after heart failure (HF) hospitalization is widely used to evaluate healthcare quality. Methodology may substantially influence estimated rates. We assessed the impact of different definitions on HF and all-cause readmission rates., Methods: Readmission rates were examined in 1835 patients discharged following HF hospitalization using 64 unique definitions derived from five methodological factors: (1) International Classification of Diseases-10 codes (broad vs. narrow), (2) index admission selection (single admission only first-in-year vs. random sample; or multiple admissions in year with vs. without 30-day blanking period), (3) variable denominator (number alive at discharge vs. number alive at 30 days), (4) follow-up period start (discharge date vs. day following discharge), and (5) annual reference period (calendar vs. fiscal). The impact of different factors was assessed using linear regression., Results: The calculated 30-day readmission rate for HF varied more than two-fold depending solely on the methodological approach (6.5-15.0%). All-cause admission rates exhibited similar variation (18.8-29.9%). The highest rates included all consecutive index admissions (HF 11.1-15.0%, all-cause 24.0-29.9%), and the lowest only one index admission per patient per year (HF 6.5-11.3%, all-cause 18.8-22.7%). When including multiple index admissions and compared with blanking the 30-day post-discharge, not blanking was associated with 2.3% higher readmission rates. Selecting a single admission per year with a first-in-year approach lowered readmission rates by 1.5%, while random-sampling admissions lowered estimates further by 5.2% (P < 0.001)., Conclusion: Calculated 30-day readmission rates varied more than two-fold by altering methods. Transparent and consistent methods are needed to ensure reproducible and comparable reporting., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The optimal antithrombotic therapy to balance the risk of thrombosis and bleeding in patients who undergo transcatheter aortic valve implantation (TAVI) is unknown. This systematic review/network meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of different oral anticoagulant (OAC) and antiplatelet regimens in patients post-TAVI., Methods and Results: MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched from inception to April 2023. Co-primary outcomes were all-cause death and major bleeding. We conducted Bayesian network meta-analyses to compare all interventions simultaneously. For each outcome, we generated odds ratios (ORs) with 95% credible intervals using a random-effects model with informative priors, and ranked interventions based on mean surface under the cumulative ranking curve. We included 11 RCTs (n = 6415), including 1 unpublished RCT. Three trials enrolled patients with an indication for an OAC. Overall risk of bias was low or with some concerns. Median age was 81 years. Median follow-up was 6 months. The combination of OAC plus single antiplatelet therapy (SAPT) increased the risk of all-cause death compared with dual antiplatelet therapy (DAPT) (OR 1.78, 95% credible interval 1.15-2.77). No other comparisons for all-cause death were significantly different. For major bleeding, SAPT reduced the risk compared with DAPT, direct-acting OAC, and OAC + SAPT (OR 0.20-0.40), and DAPT reduced the risk compared with OAC + SAPT. SAPT and DAPT ranked best for all-cause death, while SAPT ranked best for major bleeding., Conclusion: In post-TAVI patients, SAPT may provide the optimal balance of reducing thrombotic events while minimizing the risk of bleeding., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Patients with atrial fibrillation (AF) often switch between oral anticoagulants (OACs). It can be hard to know why a patient has switched outside of a clinical setting. Medication attribute comparisons can suggest benefits. Consensus on terms and definitions is required for inferring OAC switch benefits. The objectives of the study were to generate consensus on a taxonomy of the potential benefits of OAC switching in patients with AF and apply the taxonomy to real-world data., Methods: Nine expert clinicians (seven clinical pharmacists, two cardiologists) with at least 3 years of clinical and research experience in AF participated in a Delphi process. The experts rated and commented on a proposed taxonomy on the potential benefits of OAC switching. After each Delphi round, ratings were analyzed with the RAND Corporation/University of California, Los Angeles (RAND/UCLA) appropriateness method. Median ratings, disagreement index, and comments were used to modify the taxonomy. The resulting taxonomy from the Delphi process was applied to a cohort of patients with AF who switched OACs in a population-based administrative health dataset from 1996 to 2019 in British Columbia, Canada., Results: The taxonomy was finalized in two Delphi rounds, reaching consensus on five switch benefit categories: safety, effectiveness, convenience, economic considerations, and drug interactions. Safety benefit (a switch that could lower the risk of adverse drug events) had three subcategories: major bleeding, intracranial hemorrhage (ICH), and gastrointestinal (GI) bleeding. Effectiveness benefit had four subcategories: stroke and systemic embolism (SSE), ischemic stroke, myocardial infarction (MI), and all-cause mortality. Real-world OAC switches revealed that more OAC switches had convenience (72.6%) and drug interaction (63.0%) benefits compared to effectiveness (SSE 22.0%, ischemic stroke 11.1%, MI 3.1%, all-cause mortality 10.1%), safety (major bleeding 24.3%, GI bleeding 10.6%, ICH 48.5%), and economic benefits (12.1%)., Conclusions: The Delphi-based taxonomy identified five criteria for the beneficial effects of OAC switching, aiding in characterizing real-world OAC switching., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Novel statistical methods have emerged in recent medical literature, which clinicians must understand to properly appraise and integrate evidence into their practice. Some of these key concepts include win ratios, restricted mean survival time, responder analyses, and standardized mean difference. This article offers guidance to busy clinicians on the comprehension and practical applicability of the results to patients. Win ratios provide an alternative method to analyze composite outcomes by prioritizing individual components of the composite; prioritization of the outcomes should be evidence-based, pre-specified, and patient-centered. Restricted mean survival time presents a method to analyze Kaplan-Meier curves when assumptions required for Cox proportional hazards analysis are not met. As it only considers outcomes that occur within a specific timeframe, the duration of follow-up must be appropriately defined and based on prior epidemiologic and mechanistic evidence. Researchers can analyze continuous outcomes with responder analyses, in which participants are dichotomized into "responders" or "non-responders." While clinicians and patients may more easily grasp outcomes analyzed in this way, they should be aware of the loss of information and resulting imprecision, as well as potential to manipulate data presentation. When meta-analyzing continuous outcomes, point estimates can be converted to standardized mean differences to facilitate the combination of data utilizing various outcome measures. However, clinicians may find it challenging to grasp the clinical meaningfulness of a standardized mean difference, and may benefit from converting it to well-known outcomes. By providing the background knowledge of these statistical methods, along with practical applicability, benefits, and inevitable limitations, this article aims to provide clinicians with an approach to appraise the literature and apply the results in clinical practice., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Objective: To provide an online interactive decision aid to facilitate shared decision making in the context of medication choices for patients with type 2 diabetes mellitus (T2DM)., Sources of Information: The best available clinical prediction model for patients with T2DM was selected based on a review of guidelines, DynaMed, and UpToDate and a search of PubMed. A list of pharmacotherapeutic options for T2DM was compiled based on a review of guidelines, narrative reviews, and expert opinion. To determine the benefits and harms of each treatment, federated search engines were searched for meta-analyses of randomized controlled trials, supplemented by individual randomized controlled trials for outcomes not reported in meta-analyses., Main Message: Approximately 2.1 million Canadians have T2DM, with a resulting increased risk of death, cardiovascular disease, and microvascular outcomes. While more than a dozen medication options are available, decisions regarding these medications are challenging, as patients vary in their preferences. Shared decision making has the potential to individualize these difficult decisions, but the number of diabetes-related outcomes and available treatment options have made this historically impractical. It is within this context that the PEER Diabetes Medication Decision Aid was developed. This decision aid provides patients with personalized 10-year risk estimates for 6 clinically important diabetes-related outcomes. The tool also allows patients to focus on the outcome that matters most to them and to compare the benefits and harms of up to 12 different treatment options. This information is displayed in personalized absolute numbers, along with practical considerations such as cost., Conclusion: The PEER Diabetes Medication Decision Aid provides a practical tool that can enable patients with T2DM to come to autonomous and well-informed medication decisions., (Copyright © 2024 the College of Family Physicians of Canada.)

Objective: To provide a summary of the noteworthy medical articles published in 2023 that are relevant to family physicians., Selecting the Evidence: Articles were chosen and ranked by the PEER (Patients, Experience, Evidence, Research) team, a group of primary care health professionals focused on evidence-based medicine. The selection process involved routine surveillance of tables of contents in high-impact medical journals and continuous monitoring of EvidenceAlerts. Articles were prioritized based on their direct applicability to and potential to influence primary care practice., Main Message: Selected articles addressed various clinical areas of primary care. The topics included a comparison of a treat-to-target approach versus a high-intensity statins prescription for lipid management; semaglutide and its impact on cardiovascular outcomes; respiratory syncytial virus vaccine for older adults; chlorthalidone versus hydrochlorothiazide in preventing cardiovascular events; amitriptyline for irritable bowel syndrome; the role of opioids in acute back pain; safety of oral penicillin challenges in patients allergic to penicillin; spironolactone for facial acne; strategies to reverse frailty in older adults; and identifying the provider of chronic disease management. Two "up and coming" medications are also mentioned: retatrutide for weight loss and fezolinetant for vasomotor symptoms of menopause., Conclusion: Research published in 2023 yielded several high-quality articles with topics relevant to primary care, including cardiovascular care, irritable bowel syndrome, care of the elderly, and acne management., (Copyright © 2024 the College of Family Physicians of Canada.)

Background: The development of tools to support shared decision-making should be informed by patients' decisional needs and treatment preferences, which are largely unknown for heart failure (HF) with reduced ejection fraction (HFrEF) pharmacotherapy decisions. We aimed to identify patients' decisional needs when considering HFrEF medication options., Methods: This was a qualitative study using semi-structured interviews. We recruited patients with HFrEF from 2 Canadian ambulatory HF clinics and clinicians from Canadian HF guideline panels, HF clinics, and Canadian HF Society membership. We identified themes through inductive thematic analysis., Results: Participants included 15 patients and 12 clinicians. Six themes and associated subthemes emerged related to HFrEF pharmacotherapy decision-making: (1) patient decisional needs included lack of awareness of a choice or options, difficult decision timing and stage, information overload, and inadequate motivation, support and resources; (2) patients' decisional conflict varied substantially, driven by unclear trade-offs; (3) treatment attribute preferences-patients focused on both benefits and downsides of treatment, whereas clinicians centered discussion on benefits; (4) quality of life-patients' definition of quality of life depended on pre-HF activity, though most patients demonstrated adaptability in adjusting their daily activities to manage HF; (5) shared decision-making process-clinicians' described a process more akin to informed consent; (6) decision support-multimedia decision aids, virtual appointments, and primary-care comanagement emerged as potential enablers of shared decision-making., Conclusions: Patients with HFrEF have several decisional needs, which are consistent with those that may respond to decision aids. These findings can inform the development of HFrEF pharmacotherapy decision aids to address these decisional needs and facilitate shared decision-making., Competing Interests: Disclosures None.

Antiplatelet therapy (APT) is the foundation of treatment and prevention of atherothrombotic events in patients with atherosclerotic cardiovascular disease. Selecting the optimal APT strategies to reduce major adverse cardiovascular events, while balancing bleeding risk, requires ongoing review of clinical trials. Appended, the focused update of the Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines for the use of APT provides recommendations on the following topics: (1) use of acetylsalicylic acid in primary prevention of atherosclerotic cardiovascular disease; (2) dual APT (DAPT) duration after percutaneous coronary intervention (PCI) in patients at high bleeding risk; (3) potent DAPT (P2Y 12 inhibitor) choice in patients who present with an acute coronary syndrome (ACS) and possible DAPT de-escalation strategies after PCI; (4) choice and duration of DAPT in ACS patients who are medically treated without revascularization; (5) pretreatment with DAPT (P2Y 12 inhibitor) before elective or nonelective coronary angiography; (6) perioperative and longer-term APT management in patients who require coronary artery bypass grafting surgery; and (7) use of APT in patients with atrial fibrillation who require oral anticoagulation after PCI or medically managed ACS. These recommendations are all on the basis of systematic reviews and meta-analyses conducted as part of the development of these guidelines, provided in the Supplementary Material., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Ongoing debate remains regarding optimal antithrombotic therapy in patients with atrial fibrillation (AF) and coronary artery disease., Methods: We performed a systematic review and meta-analysis to synthesize randomized controlled trials (RCTs) comparing the following: (i) dual-pathway therapy (DPT; oral anticoagulant [OAC] plus antiplatelet) vs triple therapy (OAC and dual-antiplatelet therapy) after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS), and (iii) OAC monotherapy vs DPT at least 1 year after PCI or ACS. Following a 2-stage process, we identified systematic reviews published between 2019 and 2022 on these 2 clinical questions, and we updated the most comprehensive search for additional RCTs published up to October 2022. Outcomes of interest were major adverse cardiovascular events (MACE), death, stent thrombosis, and major bleeding. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model., Results: Based on 6 RCTs (n = 10,435), DPT reduced major bleeding (RR 0.62, 95% CI 0.52-0.73) and increased stent thrombosis (RR 1.55, 95% CI 1.02-2.36), vs triple therapy after PCI or medically-managed ACS, with no significant differences in MACE and death. In 2 RCTs (n = 2905), OAC monotherapy reduced major bleeding (RR 0.66, 95% CI 0.49-0.91) vs DPT in AF patients with remote PCI or ACS, with no significant differences in MACE or death., Conclusions: In patients with AF and coronary artery disease, using less-aggressive antithrombotic treatment (DPT after PCI or ACS, and OAC alone after remote PCI or ACS) reduced major bleeding, with an increase in stent thrombosis with recent PCI. These results support a minimalist yet personalized antithrombotic strategy for these patients., (© 2024 The Authors.)

Background: Tachycardia-mediated cardiomyopathy (TMC) is a reversible form of heart failure with reduced ejection fraction (HFrEF), most commonly caused by atrial fibrillation or atrial flutter. Evidence for its management is scarce, and practice patterns are highly variable., Objective: To describe management patterns for HFrEF and atrial arrhythmias in patients with TMC at a specialty heart failure clinic., Methods: This retrospective cohort study involved adults with HFrEF and a physician-determined diagnosis of TMC, with an initial visit for this problem between October 2018 and October 2019. The 2 primary outcomes, evaluated at 1 year after the initial visit, were the proportion of patients receiving triple therapy (combination of angiotensin receptor-neprilysin inhibitor [or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker if ejection fraction improved to > 40% by 1 year], ß-blocker, and mineralocorticoid receptor antagonist at any dose) and the proportion receiving or with a plan to receive rhythm control., Results: A total of 59 participants met the inclusion criteria. The mean age was 73 years, 39 patients (66%) were male, and 42 (71%) had hypertension. At 1-year follow-up, 42 (71%) were receiving triple therapy, and rhythm control was attempted or planned for 20 (34%). Among the 17 patients (29%) not receiving triple therapy, a mineralocorticoid receptor antagonist was the agent most commonly omitted., Conclusions: In a specialty heart failure clinic, most patients with TMC were receiving triple therapy, with a mineralocorticoid receptor antagonist being the agent most commonly missing among those not receiving triple therapy. One-third of patients with TMC had received a rhythm-control strategy. These gaps in HFrEF therapy and rhythm control represent key areas for quality improvement initiatives in the management of patients with TMC., Competing Interests: Competing interests: None declared., (2024 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Background: Use of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces hospitalization in heart failure (HF) patients across the spectrum of ejection fraction, but no study has comprehensively explored their impact on quality of life (QoL) with respect to different subgroup populations. We aimed to explore the QoL impact of SGLT2i use in HF patients across the spectrum of ejection fraction and over time., Methods: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) covering the period from 2019 to February 2022. We included placebo-controlled randomized controlled trials (RCTs) enrolling HF patients that evaluated QoL as an outcome. Two reviewers independently assessed studies for eligibility, extracted data, and assessed risk of bias (RoB), using the Cochrane RoB2 tool, and certainty of evidence, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Primary and secondary outcomes were the mean difference in QoL, and clinically important improvement in QoL, as defined in the original study, respectively. We conducted subgroup analyses based on ejection fraction category, SGLT2i agent, and timing of QoL measurement., Results: From 1477 identified reports, we included 14 RCTs (n = 23,361). The mean age was 68 years, and 34% were female. All included RCTs reported QoL using the Kansas City Cardiomyopathy Questionnaire (KCCQ). SGLT2i use improved KCCQ-overall summary score, compared with placebo (mean difference 2.0, 95% confidence interval 1.6-2.5; high certainty). More patients receiving an SGLT2i achieved a clinically important QoL improvement (risk ratio 1.14, 95% confidence interval 1.02-1.28; moderate certainty). Similar improvements were observed in the KCCQ clinical summary and total symptom subscores, and across all subgroups and timeframes., Conclusions: Use of an SGLT2i consistently provides a clinically important improvement in QoL among patients with HF, regardless of ejection fraction, with noticeable improvements seen as early as week 2., (© 2023 The Authors.)

Competing Interests: None to declare.

Background: There is limited literature guiding the prescribing of direct oral anticoagulants (DOACs) early after cardiac surgery as this population has been excluded from landmark randomized controlled trials. This study aims to determine the rate of in-hospital DOAC use compared with warfarin early after cardiac surgery, evaluate factors associated with DOAC use, determine difference in postoperative length of stay, and characterize bleeding events., Methods: A retrospective cohort study was conducted in adult patients with indications for anticoagulation and receiving either a DOAC or warfarin after cardiac surgery during their index hospitalization. Patients were excluded if they had any contraindications to DOAC use. The primary outcome was the proportion of patients discharged on a DOAC compared with warfarin., Results: Of included 210 patients, 30% received DOACs and 70% received warfarin on discharge. The most common DOAC used was apixaban (74.6%), and median postoperative day of initiation was 5 days. Patients receiving DOACs were older (70.8 vs 68.0 years), had less valvular heart disease (38.1% vs 63.9%), were more likely to be on DOACs preoperatively (50.8% vs 31.3%), and were more likely to have undergone coronary artery bypass graft alone (54.0% vs 24.5%) compared with those on warfarin. Postoperative length of stay (7 vs 9 days; P  = 0.59) and in-hospital bleeding (1.6% vs 2.0%; P  = 1.00) did not differ between DOAC and warfarin groups., Conclusions: At a quaternary referral centre for cardiac surgery, DOACs were used in approximately one-third of patients with an indication for anticoagulation early after cardiac surgery., (© 2023 The Authors.)

Importance: Shared decision-making (SDM) is a key component of the provision of ethical care, but prior reviews have indicated that clinical practice guidelines seldom promote or facilitate SDM. It is currently unknown whether these findings extend to contemporary cardiovascular guidelines., Objective: To identify and characterize integration of SDM in contemporary cardiovascular guideline recommendations using a systematic classification system., Design, Setting, and Participants: This cross-sectional study assessed the latest guidelines or subsequent updates that included pharmacotherapy recommendations and were published between January 2012 and December 2022 by the American College of Cardiology (ACC), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC). Data were analyzed from February 21 to July 21, 2023., Main Outcomes and Measures: All pharmacotherapy recommendations were identified within each guideline. Recommendations that incorporated SDM were rated according to a systematic rating framework to evaluate the quality of SDM incorporation based on directness (range, 1-3; assessing whether SDM was incorporated directly and impartially into the recommendation's text, with 1 indicating direct and impartial incorporation of SDM into the recommendation's text) and facilitation (range, A-D; assessing whether decision aids or quantified benefits and harms were provided, with A indicating that a decision aid quantifying benefits and harms was provided). The proportion of recommendations incorporating SDM was also analyzed according to guideline society and category (eg, general cardiology, heart failure)., Results: Analyses included 65 guideline documents, and 33 documents (51%) incorporated SDM either in a general statement or within specific recommendations. Of 7499 recommendations, 2655 (35%) recommendations addressed pharmacotherapy, and of these, 170 (6%) incorporated SDM. By category, general cardiology guidelines contained the highest proportion of pharmacotherapy recommendations incorporating SDM (86 of 865 recommendations [10%]), whereas heart failure and myocardial disease contained the least (9 of 315 recommendations [3%]). The proportion of pharmacotherapy recommendations incorporating SDM was comparable across societies (ACC: 75 of 978 recommendations [8%]; CCS: 29 of 333 recommendations [9%]; ESC: 67 of 1344 recommendations [5%]), with no trend for change over time. Only 5 of 170 SDM recommendations (3%) were classified as grade 1A (impartial recommendations for SDM supported by a decision aid), whereas 114 of 170 recommendations (67%) were grade 3D (SDM mentioned only in supporting text and without any tools or information to facilitate SDM)., Conclusions and Relevance: In this cross-sectional study across guidelines published by 3 major cardiovascular societies over the last decade, 51% of guidelines mentioned the importance of SDM, yet only 6% of recommendations incorporated SDM in any form, and fewer adequately facilitated SDM.

Introduction: Dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) reduces major adverse cardiovascular events (MACE) and stent thrombosis. However, DAPT duration is a concern in high bleeding risk (HBR) patients. We evaluated the effect of short DAPT (1-3 months) compared to standard DAPT (6-12 months) on bleeding and ischemic events in HBR PCI., Methods: We searched MEDLINE, Embase and CENTRAL up to August 18, 2022. Randomized controlled trials (RCTs) comparing short DAPT (1-3 months) versus standard DAPT in HBR PCI were included. We assessed risk of bias (RoB) using the Cochrane RoB2 tool, and certainty of evidence using GRADE criteria. Outcomes included MACE, all-cause death, stent thrombosis, major bleeding, and the composite of major or clinically-relevant non-major bleeding. We estimated risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model., Results: From 503 articles, we included five RCTs (n = 7,242) at overall low risk of bias with median follow-up of 12-months. Compared to standard DAPT, short DAPT did not increase MACE (RR 1.02, 95% CI 0.84-1.23), all-cause death (RR 0.92, 95% CI 0.71-1.20) or stent thrombosis (RR 1.47, 95% CI 0.73-2.93). Short DAPT reduced major bleeding (RR 0.34, 95% CI 0.13-0.90) and the composite of major or clinically-relevant non-major bleeding (RR 0.60, 95% CI 0.44-0.81), translating to 21 and 34 fewer events, respectively, per 1000 patients., Conclusions: In HBR PCI, DAPT for 1-3 months compared to 6-12 months reduced clinically-relevant bleeding events without jeopardizing ischemic risk. Short DAPT should be considered in HBR patients receiving PCI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bainey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Oral anticoagulants (OACs) prevent stroke in patients with atrial fibrillation (AF). Several factors may cause OAC switching., Objectives: To examine the phenomenon of OAC switching in patients with AF, including all available evidence; frequency and patterns of switch, clinical outcomes, adherence, patient-reported outcomes, reasons for switch, factors associated with switch and evidence gaps., Design: Scoping review., Data Sources: MEDLINE, Embase and Web of Science, up to January 2022., Results: Of the 116 included studies, 2/3 examined vitamin K antagonist (VKA) to direct-acting OAC (DOAC) switching. Overall, OAC switching was common and the definition of an OAC switch varied across. Switching from VKA to dabigatran was the most prevalent switch type, but VKA to apixaban has increased in recent years. Patients on DOAC switched more to warfarin than to other DOACs. OAC doses involved in the switches were hardly reported and patients were often censored after the first switch. Switching back to a previously taken OAC (frequently warfarin) occurred in 5%-21% of switchers.The risk of ischaemic stroke and gastrointestinal bleeding in VKA to DOAC switchers compared with non-switchers was conflicting, while there was no difference in the risk of other types of bleeding. The risk of ischaemic stroke in switchers from DOAC versus non-switchers was conflicting. Studies evaluating adherence found no significant changes in adherence after switching from VKA to DOAC, however, an increase in satisfaction with therapy were reported. Reasons for OAC switch, and factors associated with OAC switch were mostly risk factors for stroke and bleeding. Clinical outcomes, adherence and patient-reported outcomes were sparse for switches from DOACs., Conclusions: OAC switching is common in patients with AF and patients often switch back to an OAC they have previously been on. There are aspects of OAC switching that have received little study, especially in switches from DOACs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Vancouver Coastal Health (VCH) ST-elevation myocardial infarction (STEMI) program aimed to increase access to primary percutaneous coronary intervention (PPCI) and reduce first-medical-contact-to-device times (FMC-DTs). We evaluated the long-term program impact on PPCI access and FMC-DT, and overall and reperfusion-specific in-hospital mortality., Methods: We analyzed all VCH STEMI patients between June 2007 and November 2019. The primary outcome was the proportion of patients receiving PPCI over 4 program implementation phases over 12 years. We also evaluated overall changes in median FMC-DT and the proportion of patients achieving guideline-mandated FMC-DT, in addition to overall and reperfusion-specific in-hospital mortality., Results: A total of 3138 of 4305 VCH STEMI patients were treated with PPCI. PPCI rates increased from 40.2% to 78.7% from 2007 to 2019 ( P < 0.001). From phase 1 to 4, median FMC-DT improved from 118 to 93 minutes (percutaneous coronary intervention [PCI]-capable hospitals, P < 0.001) and from 174 to 118 minutes (non-PCI-capable hospitals, P < 0.001), with a concomitant increase in those achieving guideline-mandated FMC-DT (35.5% to 66.1%, P < 0.001). Overall in-hospital mortality was 9.0% ( P  = 0.20 across phases), with mortality differing significantly by reperfusion strategy (4.0% fibrinolysis, 5.7% PPCI, 30.6% no reperfusion therapy, P < 0.001). Mortality significantly decreased from phase 1 to phase 4 at non-PCI-capable centres (9.6% to 3.9%, P  = 0.022) but not at PCI-capable centres (8.7% vs 9.9%, P  = 0.27)., Conclusions: A regional STEMI program increased the proportion of patients who received PPCI and improved reperfusion times over 12 years. Although no statistically significant decrease occurred in overall regional mortality incidence, mortality incidence was decreased for patients presenting to non-PCI-capable centres., (© 2022 The Authors.)

Background: Pharmacologic management of heart failure with reduced ejection fraction (HFrEF) involves several medications. Decision aids informed by patient decisional needs and treatment preferences could assist in making HFrEF medication choices; however, these are largely unknown., Methods: We searched MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), without language restriction, for qualitative, quantitative, and mixed-method studies that included patients with HFrEF or clinicians providing HFrEF care, and reported data on decisional needs or treatment preferences applicable to HFrEF medications. We classified decisional needs using a modified version of the Ottawa Decision Support Framework (ODSF)., Results: From 3996 records, we included 16 reports describing 13 studies (n = 854). No study explicitly assessed ODSF decisional needs; however, 11 studies reported ODSF-classifiable data. Patients commonly reported having inadequate knowledge or information, and difficult decisional roles. No study systematically assessed treatment preferences, but 6 studies reported on attribute preferences. Reducing mortality and improving symptoms frequently were ranked as being important, whereas cost importance rankings varied, and adverse events generally were ranked as being less important., Conclusion: This scoping review identified key decisional needs regarding HFrEF medications, notably inadequate knowledge or information, and difficult decisional roles, which can readily be addressed by decision aids. Future studies should systematically explore the full scope of ODSF-based decisional needs in patients with HFrEF, along with relative preferences among treatment attributes to further inform development of individualized decision aids., (© 2022 The Authors.)

Background: The suboptimal implementation of guideline-directed medical therapy (GDMT) for heart failure (HF) patients has been linked with poor clinical outcomes. Little is known about the potential role of cardiology residency training programs in improving trainees' (ie, future cardiologists') ability to utilize GDMT., Methods: In this survey-based study, we examined the degree of exposure to ambulatory HF patient management among cardiology trainees in Canada. All cardiology residency program directors (n = 15; 100% response rate) completed our survey., Results: Although 9 programs (60%) mandated ≥ 3 ambulatory cardiology rotations, only 3 (20%) required ≥ 2 ambulatory HF rotations. When HF rotations were provided, only 7 programs (47%) offered moderate or higher exposure to ambulatory nontransplant HF patients (defined as ≥ 5 clinics/rotations). This element was independent of program- and institution-specific characteristics. All institutions had a multidisciplinary HF clinic, and the majority (13 [87%]) had access to an inpatient HF service, a consultative HF service, and/or a specialist pharmacist. Furthermore, 13 program directors (87%) agreed on the importance of adopting HF training curriculum and their program's readiness to implement such a module., Conclusions: The current state of HF training among cardiology residencies is suboptimal and in need of improvement. Most programs have access to a HF clinic, a specialist pharmacist, or an inpatient consultative service, which would facilitate adoption of a HF management curriculum that focuses on practical and experiential aspects of GDMT optimization. This program, which is under development, will be offered to training programs nationwide, to enable trainees to manage this growing and increasingly complex patient population., (© 2022 The Authors.)

Aims: Post-acute coronary syndrome (ACS) P2Y12 inhibitor non-adherence is common and associated with greater risk of major adverse cardiovascular events (MACEs). Non-adherence can follow different trajectories from an inability to initiate, implement, or continue therapy for the intended duration. We aimed to evaluate P2Y12 inhibitor adherence trajectories among ACS patients treated with percutaneous coronary intervention (PCI), their frequency, and association with MACE., Methods and Results: We conducted a cohort study of adults discharged alive after PCI for ACS (2012-16) using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry linked with administrative data. The primary outcome was P2Y12 inhibitor adherence trajectory in the year after PCI assessed using group-based trajectory modelling. We used logistic regression and Cox proportional-hazards regression to assess associations of trajectories with risk factors and MACE, respectively. We included 12 844 patients (mean age 62.4 years, 23.6% female). Five trajectories were identified: early consistent non-adherence (11.0%), rapid decline (7.7%), delayed initiation (6.0%), gradual decline (20.5%), and persistent adherence (54.8%). Compared with persistent adherence, rapid decline [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01-1.49] and delayed initiation (HR 1.41, 95% CI 1.12-1.78) were associated with higher MACE in the overall cohort, whereas early consistent non-adherence was associated with higher MACE only in the subgroup receiving a drug-eluting stent (HR 2.44, 95% CI 1.60-3.71)., Conclusion: After PCI for ACS, patients followed one of five distinct P2Y12 inhibitor adherence trajectories. Rapid decline and delayed initiation were associated with a higher risk of MACE, whereas early consistent non-adherence was only associated with higher MACE risk in patients with a drug-eluting stent., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There are concerns of delays in ST-segment elevation myocardial infarction (STEMI) care during the COVID-19 pandemic. It is unclear whether the care and outcomes of STEMI patients differ between COVID-19 waves and compared with historical periods., Methods: Consecutive patients in the Vancouver Coastal Health Authority STEMI database were included to compare care during 3 distinct waves of the COVID-19 pandemic (9 months; March 2020 to January 2021) with an historical non-COVID-19 cohort. We compared STEMI incidence, baseline characteristics, and outcomes between groups. We also examined time from first medical contact (FMC) to reperfusion, symptom to FMC, and FMC to STEMI diagnosis, as well as predictors of delays., Results: The incidence of STEMI was similar during COVID-19 (n = 305; mean 0.93/day) and before COVID-19 (n = 949; 0.97/day; P = 0.80). The COVID-19 cohort showed significant delay in FMC-to-reperfusion (median 116 min vs 102 min; P < 0.001) and FMC-to-STEMI diagnosis (median 17 mins vs 11 min; P < 0.001). Delays in FMC-to-device times worsened across the 3 COVID-19 waves (FMC-to-device time ≤ 90 min in wave 1: 32.9%; in wave 2: 25.6%; in wave 3: 16.3%; P = 0.045 [47.5% before COVID-19; P < 0.001]). There were no significant predictors of delay were unique to the COVID-19 cohort., Conclusions: This study demonstrates delays in reperfusion during the COVID-19 pandemic compared with the historical control, with delays increasing during subsequent waves within the pandemic. It is critical to further understand these care gaps to improve STEMI care for future waves of the current and future pandemics., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Objective: To summarize 10 high-quality studies or guidelines from 2021 that have strong relevance to physicians in comprehensive family practice., Selecting the Evidence: Routine literature surveillance of abstracts in high-impact journals and EvidenceAlerts was completed by the PEER (Patients, Experience, Evidence, Research) team, a group of health care professionals with a research interest in evidence-based medicine and primary care. Abstracts were screened, selected, and ranked by the PEER team., Main Message: The articles from 2021 that are most likely to impact primary care practice discuss the following topics: empagliflozin for heart failure with preserved ejection fraction; semaglutide for weight loss; stopping antidepressants in primary care; inhaled budesonide for COVID-19; acetylsalicylic acid for preeclampsia prevention; quarter-dose blood pressure medications for hypertension; aggressive blood pressure control for elderly patients; kangaroo care for low-birth-weight infants; footwear for knee osteoarthritis; and delayed antibiotics for pediatric respiratory infections. Two "honourable mention" studies are also briefly reviewed., Conclusion: Research from 2021 produced several high-quality studies in cardiovascular care but also addressed a variety of conditions relevant to primary care including weight loss, depression, and COVID-19., (Copyright © 2022 the College of Family Physicians of Canada.)

AF is a common chronic and progressive disorder. Without treatment, AF will recur in up to 75% of patients within a year of their index diagnosis. Antiarrhythmic drugs (AADs) have been proven to be more effective than placebo at maintaining sinus rhythm and remain the recommended initial therapeutic option for AF. However, the emergence of 'single-shot' AF ablation toolsets, which have enabled enhanced procedural standardisation and consistent outcomes with low rates of complications, has led to renewed interest in determining whether first-line catheter ablation may improve outcomes. The recently published EARLY-AF trial evaluated the role of initial cryoballoon ablation versus guideline-directed AAD therapy. Compared to AADs, an initial treatment cryoballoon ablation strategy resulted in greater freedom from atrial tachyarrhythmia, superior reduction in AF burden, greater improvement in quality of life and lower healthcare resource utilisation. These findings are relevant to patients, providers and healthcare systems when considering the initial treatment choice for rhythm-control therapy., Competing Interests: Disclosure: JGA reports grants and personal fees from Medtronic, grants from Baylis and personal fees from Biosense Webster. MWD reports grants and personal fees from Biosense Webster and personal fees from Medtronic, Abbott and Boston Scientific. LM reports grants and personal fees from Biosense Webster, Abbott, Medtronic, Servier and BMS-Pfizer. RDT has no conflicts of interest to declare., (Copyright © 2022, Radcliffe Cardiology.)

Objective: To develop a clinical practice guideline to support the management of chronic pain, including low back, osteoarthritic, and neuropathic pain in primary care., Methods: The guideline was developed with an emphasis on best available evidence and shared decision-making principles. Ten health professionals (4 generalist family physicians, 1 pain management-focused family physician, 1 anesthesiologist, 1 physical therapist, 1 pharmacist, 1 nurse practitioner, and 1 psychologist), a patient representative, and a nonvoting pharmacist and guideline methodologist comprised the Guideline Committee. Member selection was based on profession, practice setting, and lack of financial conflicts of interest. The guideline process was iterative in identification of key questions, evidence review, and development of guideline recommendations. Three systematic reviews, including a total of 285 randomized controlled trials, were completed. Randomized controlled trials were included only if they reported a responder analysis (eg, how many patients achieved a 30% or greater reduction in pain). The committee directed an Evidence Team (composed of evidence experts) to address an additional 11 complementary questions. Key recommendations were derived through committee consensus. The guideline and shared decision-making tools underwent extensive review by clinicians and patients before publication., Recommendations: Physical activity is recommended as the foundation for managing osteoarthritis and chronic low back pain; evidence of benefit is unclear for neuropathic pain. Cognitive-behavioural therapy or mindfulness-based stress reduction are also suggested as options for managing chronic pain. Treatments for which there is clear, unclear, or no benefit are outlined for each condition. Treatments for which harms likely outweigh benefits for all or most conditions studied include opioids and cannabinoids., Conclusion: This guideline for the management of chronic pain, including osteoarthritis, low back pain, and neuropathic pain, highlights best available evidence including both benefits and harms for a number of treatment interventions. A strong recommendation for exercise as the primary treatment for chronic osteoarthritic and low back pain is made based on demonstrated long-term evidence of benefit. This information is intended to assist with, not dictate, shared decision making with patients., (Copyright© 2022 the College of Family Physicians of Canada.)

Atrial fibrillation (AF), the most common sustained arrhythmia observed in clinical practice, is a chronic and progressive disorder characterized by exacerbations and remissions. Guidelines recommend antiarrhythmic drugs as the initial therapy for the maintenance of sinus rhythm; however, antiarrhythmic drugs have modest efficacy to maintain sinus rhythm and can be associated with significant adverse effects. An initial treatment strategy of cryoballoon catheter ablation in patients with treatment-naïve AF has been shown to significantly improve arrhythmia outcomes (freedom from any, or symptomatic atrial tachyarrhythmia), produce clinically meaningful improvements in patient-reported outcomes (symptoms and quality of life), and significantly reduce subsequent health care resource use (hospitalization), and it does not increase the risk of serious or any adverse events compared with initial antiarrhythmic drug therapy. These findings are relevant to inform patients, providers, and health care systems regarding the initial choice of rhythm-control therapy in patients with treatment-naïve AF., Competing Interests: Funding Support and Author Disclosures The EARLY-AF Trial was funded by a peer-reviewed grant from the Cardiac Arrhythmia Network of Canada (grant number SRG-15-P15-001), with additional unrestricted support from Medtronic and Baylis Medical. The STOP-AF First trial and the Cryo-FIRST trial were supported by Medtronic. Dr Andrade has received grants and personal fees from Medtronic; has received grants from Baylis; and has received personal fees from Biosense Webster. Dr Wazni has received grants from Medtronic; and has received personal fees from Biosense Webster and Boston Scientific. Dr Kuniss has received speaker fees from Abbott and Medtronic; has provided proctoring, consultancy, and advisory board services for Medtronic; and has received research grants from Medtronic and Biosense Webster. Dr Deyell has received grants and personal fees from Biosense Webster; and has received personal fees from Medtronic and Abbott. Dr Chierchia has received speaker fees from Medtronic, Biotronik, Biosense Webster, and Abbott. Dr Nissen has received grants from Medtronic. Dr Verma has received grant support from Biotronik, Bristol Myers Squibb, and Boehringer Ingelheim; has received grant support, advisory board fees, and lecture fees from Bayer and Biosense Webster; has received advisory board fees and lecture fees from and served as principal investigator (PULSED AF and DIAMOND II trial) for Medtronic; has received consulting fees from and served on steering committees for Boston Scientific, Kardium, Medlumics, and Thermedical; and has received lecture fees from Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Guidelines recommend mineralocorticoid receptor antagonist (MRA) use in patients with left ventricular ejection fraction ≤40% following a myocardial infarction plus heart failure or diabetes mellitus, based on mortality benefit in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial. The objective of this study was to evaluate the real-world utilization of MRAs for patients with ST-segment-elevation myocardial infarction (STEMI) with left ventricular dysfunction. Methods and Results The prospective, population-based, Vancouver Coastal Health Authority STEMI database was linked with local outpatient cardiology records from 2007 to 2018. EPHESUS criteria were used to define post-STEMI MRA eligibility (left ventricular ejection fraction ≤40% plus clinical heart failure or diabetes mellitus, and no dialysis-dependent renal dysfunction). The primary outcome was MRA prescription among eligible patients at discharge and the secondary outcome was MRA prescription within 3 months postdischarge. Of 2691 patients with STEMI, 317 (12%) were MRA eligible, and 70 (22%) eligible patients were prescribed an MRA at discharge. Among eligible patients with no MRA at discharge, 12/126 (9.5%) with documented postdischarge follow-up were prescribed an MRA within 3 months. In multivariable analysis, left ventricular ejection fraction (odds ratio [OR], 1.55 per 5% left ventricular ejection fraction decrease; 95% CI, 1.26-1.90) and calendar year (OR, 1.23 per year, 95% CI, 1.11-1.37) were associated with MRA prescription at discharge. Other prespecified variables were not associated with MRA prescription. Conclusions In this contemporary STEMI cohort, only 1 in 4 MRA-eligible patients were prescribed an MRA within 3 months following hospitalization despite high-quality evidence for use. Novel decision-support tools are required to optimize pharmacotherapy decisions during hospitalization and follow-up to target this gap in post-STEMI care.

Aims: The aim of this study was to synthesize the evidence on the effect of heart failure with reduced ejection fraction (HFrEF) pharmacotherapy on health-related quality of life (HRQoL)., Methods and Results: We searched MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform in June 2020. Randomized placebo-controlled trials evaluating contemporary HFrEF pharmacotherapy and reporting HRQoL as an outcome were included. Two reviewers independently assessed studies for eligibility, extracted data, and assessed risk of bias and GRADE certainty of evidence. The primary outcome was HRQoL at last available follow-up analysed using a random-effects model. We included 37 studies from 5770 identified articles. Risk of bias was low in 10 trials and high/unclear in 27 trials. High certainty evidence from meta-analyses demonstrated improved HRQoL over placebo with sodium-glucose co-transporter 2 (SGLT2) inhibitors [standardized mean difference (SMD) 0.16, 95% confidence interval (CI) 0.08-0.23] and intravenous iron (SMD 0.52, 95% CI 0.04-1.00). Furthermore, high certainty evidence from ≥1 landmark trial further supported improved HRQoL with angiotensin receptor blockers (ARBs) (SMD 0.09, 95% CI 0.02-0.17), ivabradine (SMD 0.14, 95% CI 0.04-0.23), hydralazine-nitrate (SMD 0.24, 95% CI 0.04-0.44) vs. placebo, and for angiotensin receptor-neprilysin inhibitor (ARNI) compared with an angiotensin-converting enzyme (ACE) inhibitor (SMD 0.09, 95% CI 0.02-0.17). Findings were inconclusive for ACE inhibitors, beta-blockers, digoxin, and oral iron based on low-to-moderate certainty evidence., Conclusion: ARBs, ARNIs, SGLT2 inhibitors, ivabradine, hydralazine-nitrate, and intravenous iron improved HRQoL in patients with HFrEF. These findings can be incorporated into discussions with patients to enable shared decision-making., (© 2021 European Society of Cardiology.)

Background: Major bleeding (MB) is an independent predictor of mortality among ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). Prevention of access-site MB has received significant attention. However, limited data have been obtained on the influence of access-site MB vs non-access-site MB and association with subsequent adverse in-hospital outcomes in the STEMI population undergoing pPCI., Methods: We identified 1494 STEMI patients who underwent pPCI between 2012 and 2018. Unadjusted and adjusted differences among patients with no MB, access-site MB, non-access-site MB, and in-hospital clinical outcomes were assessed. The use of bleeding-avoidance strategies and their effects on MB were also evaluated., Results: MB occurred in 121 (8.1%) patients. Access-site MB occurred in 34 (2.3%) patients, and non-access-site MB occurred in 87 (5.8%). The median reduction in hemoglobin was 31 g/L (interquartile range: 19-43) with access-site MB, and 44 g/L (interquartile range: 29-62) with non-access-site MB. After multivariable adjustment, non-access-site MB was independently associated with in-hospital death (adjusted odds ratio [aOR] 4.21; 95% confidence interval [CI] 2.04-8.68), cardiogenic shock (aOR 10.91; 95% CI 5.67-20.98), and cardiac arrest (aOR 5.63; 95% CI 2.88-11.01). Conversely, access-site MB was not associated with adverse in-hospital outcomes. Bleeding-avoidance strategies were used frequently; however, after multivariable adjustment, no single bleeding-avoidance strategy was significantly associated with reduced MB., Conclusions: In STEMI patients undergoing pPCI, non-access-site MB was independently associated with adverse in-hospital outcomes, whereas access-site MB was not. Additional study of strategies to reduce the incidence and impact of non-access-site MB appears to be warranted., (© 2021 The Authors.)

Competing Interests: Statement of Conflicting Interests:The authors have no conflict of interest to declare.

Background: Acute liver failure is a rare and serious disease. Acute liver failure may be paracetamol-induced or non-paracetamol-induced. Acute liver failure not caused by paracetamol (acetaminophen) has a poor prognosis with limited treatment options. N-acetylcysteine has been successful in treating paracetamol-induced acute liver failure and reduces the risk of needing to undergo liver transplantation. Recent randomised clinical trials have explored whether the benefit can be extrapolated to treat non-paracetamol-related acute liver failure. The American Association for the Study of Liver Diseases (AASLD) 2011 guideline suggested that N-acetylcysteine could improve spontaneous survival when given during early encephalopathy stages for patients with non-paracetamol-related acute liver failure., Objectives: To assess the benefits and harms of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, in people with non-paracetamol-related acute liver failure., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (searched 25 June 2020), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 6) in The Cochrane Library, MEDLINE Ovid (1946 to 25 June 2020), Embase Ovid (1974 to 25 June 2020), Latin American and Caribbean Health Science Information database (LILACS) (1982 to 25 June 2020), Science Citation Index Expanded (1900 to 25 June 2020), and Conference Proceedings Citation Index - Science (1990 to 25 June 2020)., Selection Criteria: We included randomised clinical trials that compared N-acetylcysteine at any dose or route with placebo or no intervention in participants with non-paracetamol-induced acute liver failure., Data Collection and Analysis: We used standard methodological procedures as described in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CIs). We quantified statistical heterogeneity by calculating I 2 . We assessed bias using the Cochrane risk of bias tool and determined the certainty of the evidence using the GRADE approach., Main Results: We included two randomised clinical trials: one with 183 adults and one with 174 children (birth through age 17 years). We classified both trials at overall high risk of bias. One unregistered study in adults is awaiting classification while we are awaiting responses from study authors for details on trial methodology (e.g. randomisation processes). We did not meta-analyse all-cause mortality because of significant clinical heterogeneity in the two trials. For all-cause mortality at 21 days between adults receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (N-acetylcysteine 24/81 (29.6%) versus placebo 31/92 (33.7%); RR 0.88, 95% CI 0.57 to 1.37; low certainty evidence). The certainty of the evidence was low due to risk of bias and imprecision. Similarly, for all-cause mortality at one year between children receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (25/92 (27.2%) versus 17/92 (18.5%); RR 1.47, 95% CI 0.85 to 2.53; low certainty evidence). We downgraded the certainty of evidence due to very serious imprecision.  We did not meta-analyse serious adverse events and liver transplantation at one year due to incomplete reporting and clinical heterogeneity. For liver transplantation at 21 days in the trial with adults, there was inconclusive evidence of effect (RR 0.72, 95% CI 0.49 to 1.06; low certainty evidence). We downgraded the certainty of the evidence due to serious risk of bias and imprecision. For liver transplantation at one year in the trial with children, there was inconclusive evidence of effect (RR 1.23, 95% CI 0.84 to 1.81; low certainty of evidence). We downgraded the certainty of the evidence due to very serious imprecision.   There was inconclusive evidence of effect on serious adverse events in the trial with children (RR 1.25, 95% CI 0.35 to 4.51; low certainty evidence). We downgraded the certainty of the evidence due to very serious imprecision.  We did not meta-analyse non-serious adverse events due to clinical heterogeneity. There was inconclusive evidence of effect on non-serious adverse events in adults (RR 1.07, 95% CI 0.79 to 1.45; 173 participants; low certainty of evidence) and children (RR 1.19, 95% CI 0.62 to 2.16; 184 participants; low certainty of evidence). None of the trials reported outcomes of proportion of participants with resolution of encephalopathy and coagulopathy or health-related quality of life. The National Institute of Health in the United States funded both trials through grants. One of the trials received additional funding from two hospital foundations' grants. Pharmaceutical companies provided the study drug and matching placebo, but they did not have input into study design nor involvement in analysis., Authors' Conclusions: The available evidence is inconclusive regarding the effect of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, on mortality or transplant rate in non-paracetamol-induced acute liver failure. Current evidence does not support the guideline suggestion to use N-acetylcysteine in adults with non-paracetamol-related acute liver failure, nor the rising use observed in clinical practice. The uncertainty based on current scanty evidence warrants additional randomised clinical trials with non-paracetamol-related acute liver failure evaluating N-acetylcysteine versus placebo, as well as investigations to identify predictors of response and the optimal N-acetylcysteine dose and duration., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)