RFA Funding Successes

Trial Summary 

Background: Globally, 2.5 million people with kidney failure receive dialysis, 6 million more would receive dialysis if it were accessible and these numbers are projected to triple over the next 15 years. Although dialysis is lifesaving, the median survival is less than 4 years. Cardiovascular disease is common and accounts for over half of deaths. Treatments to prevent cardiovascular deaths by controlling risk factors for atherosclerotic disease did not demonstrate benefits. However, antagonizing the mineralocorticoid receptor, a treatment for heart failure, appears promising in small trials. 

We are determining if spironolactone, an inexpensive, widely available mineralocorticoid receptor antagonist reduces cardiovascular deaths and heart failure hospitalizations in patients with kidney failure in an international, placebo controlled, randomized controlled trial called the Aldosterone bloCkade for Health Improvement EValuation in End-stage renal disease (ACHIEVE). 

Methods: ACHIEVE is an international, randomized, placebo-controlled trial enrolling people with kidney failure receiving dialysis (end-stage kidney disease). Eligible participants enroll in an open label run-in to assess tolerance of and adherence to spironolactone 25 mg daily. Participants that are eligible after run-in are randomly allocated to either spironolactone 25 mg daily or matching placebo. Follow-ups occur at 3 and 6 months then 6 monthly thereafter concentrating on assessing safety, encouraging study medication adherence, ascertaining outcomes and resupplying study medication with a subsample undergoing biobanking of serial blood samples from run-in to the end of the first year. 

Eligibility: Eligible participants are ≥45 years or ≥18 years with diabetes mellitus (ensures participants are at risk of cardiovascular death), have received dialysis for at least 90 days (ensures dialysis is not temporary) and receive hemodialysis at least twice weekly or peritoneal dialysis at least daily (ensures true kidney failure and risk of cardiovascular death). Participants who have recent severe hyperkalemia, develop severe hyperkalemia during run-in, are non-adherent to the run-in medication, have a scheduled kidney transplant, a sensitivity to spironolactone, an absolute indication or contraindication for spironolactone, a life expectancy less than 6 months, or are pregnant or breastfeeding are excluded from ACHIEVE (to ensure safety and the possibility of benefit). 

Intervention: Participants are randomly allocated to either spironolactone 25 mg daily or matching placebo. The dose of spironolactone is based on positive results in prior small trials in dialysis and the mean dose received in prior trials of mineralocorticoid receptor antagonist trials in heart failure trials. Participants who are unable to tolerate the full dose after randomization have the option to reduce the dose, temporarily or permanently, to 25 mg thrice weekly. 

Outcome Measures: The primary composite outcome is cardiovascular death or hospitalization for heart failure. Secondary and tertiary outcomes include, cardiovascular death, hospitalization for heart failure, all cause death, all cause hospitalization, hospitalization for hyperkalemia, health related quality of life, dialysis recovery time, new onset atrial fibrillation, stroke and myocardial infarction. 

Follow-up and Duration of Study: Participants are enrolled in 49 to 100 day active run-in period. Eligible participants are then randomly allocated and seen at 3 months, 6 months and then 6 monthly to the end of the trial (follow-up range between 1 and 7 years; median follow-up 3 years). 

Sample Size: ACHIEVE is event driven with 650 primary outcome events required to identify a hazard ratio of 0.75 with 90% power. After accounting for non-adherence, kidney transplantation, losses to 

follow-up and the length of the enrollment period, a total of 2500 participants randomized are required with a median follow-up of 3 years.

Trial Summary 

ARTESIA is a randomized-controlled, double-blind, double-dummy trial comparing Apixaban (at guideline-indicated dosing) versus Aspirin (80-100 mg/day) in patients with pacemaker or defibrillator-detected sub-clinical AF lasting between 6 minutes and 24 hours in duration 4. Eligible patients could not have a history of clinical AF or atrial flutter, or another indication for chronic anticoagulation (e.g. mechanical heart valve). Patients must also have a history of stroke, TIA or systemic embolism, OR be over the age of 75 years; aged 65-74 years with at least 2 additional stroke risk factors*; or aged 55-64 with 3 additional stroke risk factors*. (* stroke risk factors are: hypertension, heart failure, diabetes mellitus, female sex or coronary/peripheral arterial disease). Patients could not have severe kidney disease (eGFR < 25 mL/min) or serious bleeding in the prior 6 months. 

Patients are followed every 6 months for the primary efficacy outcome of stroke (all-cause) or systemic embolism. The outcome of stroke includes neurologic events lasting < 24 hours if there is evidence of stroke on brain imaging. The primary safety outcome is major bleeding (using the ISTH definition), which will also be sub-classified based on severity and outcomes. Several secondary outcomes include all-cause and cardiovascular mortality, and a 1000-patient sub-study will evaluate the effect of randomized therapy on cognitive function, using serial measures of the Montreal Cognitive Assessment (MoCA). 

ARTESIA, which is coordinated by the Population Health Research Institute in Hamilton, Ontario, and will complete its follow-up of 4012 patients by August 2023. Its principal investigator is Dr. Jeff Healey, who is a Canadian citizen from McMaster University, who is a member of CSPIN (The Canadian Stroke Prevention Intervention Network). Close-out activities, data cleaning and statistical analysis will take place in the summer/fall of 2023, with a plan to present the results at the American Heart Association Sessions in November 2023 and have a simultaneous publication in a top journal. 

The circumstances of the COVID pandemic created many hardships for ARTESIA, which have contributed to it being in a significant financial deficit despite CIHR, CSPIN and industry (BMS/Pfizer and Medtronic) funding. It is an investigator initiated and sponsored study, so no additional funds were available from industry, particularly since the study drug is now off-patent. At present, over one million dollars of deficit is being marked against budget residuals from the PIs’ other trials and salary support awards. 

Enrollment in ARTESIA slowed dramatically during the pandemic, and the completion of enrollment was delayed approximately 1 year, finishing in July 2021. This delay lead to a corresponding increase in central coordinating costs. The restrictions on in-person visits and concerns that the predominantly elderly subjects in ARTESIA had about discretionary visits to the hospital posed great challenges for study drug re-supply. However, thanks to engaged local research assistants, strong national leaders and innovative research staff at PHRI, the number of patients coming off study drug due to re-supply challenges was kept to an extremely small number. While vital to preserving the integrity of this clinical trial, these strategies (which often involved shipment of medication) were costly. Additional costs were also incurred to ascertain patient status, since many were not attending clinic or study visits.  

Funds from this ACT grant competition will close the funding shortfall due to these multiple circumstances. 

Background: Delirium is an acute disorder of cognition and attention. It affects ~15% of patients after cardiac surgery and is associated with prolonged length of stay, cognitive and functional decline, and death.1 Receiving benzodiazepines before and after cardiac surgery is associated with postoperative delirium, such that guidelines recommend avoiding their use.2,3 Benzodiazepine use during cardiac surgery remains common because of their amnestic effects and favourable hemodynamic profile.4 Randomized evidence from the intensive care unit (ICU) suggests that a benzodiazepine-free approach after cardiac surgery may reduce delirium;2 no evidence informs intraoperative benzodiazepine use. 

Objective: To evaluate whether a policy of restricted intraoperative benzodiazepine use reduces postoperative delirium when compared with a policy of liberal benzodiazepine use. 

Trial design: Multicentre, randomized, cluster crossover trial. 

Inclusion/exclusion criteria: All patients undergoing cardiac surgery at an enrolled site during the trial period are included in data collection through a waiver of individual patient consent; percutaneous procedures and secondary operations are excluded. Hospitals are included if: i) they perform ≥250 cardiac surgeries a year; ii) their cardiac anesthesia group agrees to manage patients as per both benzodiazepine policies as per their randomization schedule; and iii) if cardiac surgery patients are assessed for postoperative delirium using a validated scale ≥ 12 hours in routine clinical care. 

Trial interventions: B-Free compares 2 hospital-based cardiac anesthesia policies, both of which fall within the standard of care. Both policies allow deviations to occur when mandated by patient condition. The study expects that only 90% of patients will be treated according to the assigned policy due to appropriate deviations as described below: The “Restricted Benzodiazepine Policy” arm consists of the following: 1. No routine use of any intraoperative benzodiazepines. 2. Accepted benzodiazepine use in the case of seizure, alcohol withdrawal, severe anxiety, history of awareness during anesthesia, or known benzodiazepine dependence. 3. Accepted benzodiazepine use in patients who are hemodynamically unstable and/or have cardiac anatomy that puts them at high risk on induction of anesthesia using other agents. 

The “Liberal Benzodiazepine Policy” arm consists of the following: 1. Intraoperative administration of the equivalent of at least 0.03mg/kg midazolam equivalent. Any benzodiazepine may be used. 2. Accepted avoidance of benzodiazepine use in patients who have contraindications to the administration of these medications (e.g., documented allergy, previous adverse reaction). 

Randomization: We randomize sites to one of the two policies to be used by all anesthetists. Sites cross-over to the other policy at random. An independent statistician randomizes each site to twelve to eighteen (according to local feasibility), 4-week crossover periods, such that each policy is applied an equal number of times. 

Outcomes: The primary outcome is the incidence of delirium up to 72 hours after cardiac surgery. The secondary outcomes are ICU and hospital length-of-stay and in-hospital mortality. 

Trial status: We completed enrollment December 11/2022 and are finalizing data collection and database cleaning. Currently, 17,452 patients have complete data in the trial database and 2,248 patients still require some data entry. We have drafted a statistical analysis plan but have not yet begun undertaking analyses. 

Trial leadership: B-Free is led by a group of Canadian female early career investigators, including Principal Investigator Dr. Jessica Spence and co-Principal Investigators Drs. Emilie Belley-Côté and Shun Fu Lee, all of whom are members of the Perioperative Care Clinical Trial Network. The trial is coordinated by the Population Health Research Institute in Hamilton, Ontario, Canada. 18/20 (90%) of sites and 17489/19700 (88.8%) of patients are Canadian.

CLEAR Trial: A 2x2 factorial placebo-controlled trial of colchicine and spironolactone in patients with acute myocardial infarction (MI).

PI: Sanjit Jolly, Professor of Medicine, McMaster University, member of Canadian Association of Interventional trials network‍

Rationale: Colchicine: Inflammation is likely a key mechanism in atherosclerosis. Available randomized trials suggests that colchicine may reduce cardiovascular events but there are concerns regarding non CV mortality that need to be resolved from the largest trial. The finding of increased non-CV mortality may be spurious similar to the statin story or real and we are poised to resolve this in the CLEAR trial. Spironolactone: Similar to angiotensin receptor blockers, routine use of spironolactone in patients with acute MI (without heart failure), may be beneficial in preventing ventricular remodelling, heart failure and death.

Primary outcomes: The primary outcome for colchicine is CV death, MI or stroke and for spironolactone is CV death or new or worsening heart failure.

Power: The trial will have 80% power to detect a 25% relative risk reduction for a control event rate of 9%.

Blinding and Concealed Allocation: Patients, physicians and study staff are blinded as matching placebo is used. The Population Health Research Institute is the co-ordination site and uses computer randomization with variable block size ensuring concealed allocation.

Progress: We have recruited 7063 patients from 14 countries and completed recruitment on November 8, 2022. We expect to complete follow up in May 2024 with a median of 3 years of follow up and present in fall 2024. . There is 1.2 visits per patient left (approximately 8800 for 7062 patients) that are are due to happen before study close out.

Experience of Team and Co-ordination Centre: The group has successfully completed a number of large scale randomized trials including TOTAL, COMPLETE, OASIS 5, 6, 7 and 8 trials. Dr. Sanjit Jolly (PI), Jessica Tyrwhitt (Study manager) and Elizabeth Skuriat (Study Coordinator) are managing day to day operations of the trial. Senior clinical trialists Drs. Salim Yusuf, John Cairns, Shamir Mehta, John Eikelboom, PJ Devereaux are providing senior leadership on the steering committee of the trial. Senior statisticians Lehana Thabane and Shirikant Bangdiwala are providing biostatistical leadership for the trial. Dr. Lavi chairs the adjudication committee. Drs. Welsh, Sheth, Natarajan, Bertrand, Conen, Graham, Madan and Cantor are key recruiters. Dr. Schwalm is a KT expert and will develop strategies post trial implementation into practice.

Importance: Based on randomized trials, colchicine has a class IIB recommendation in patients with coronary artery disease. CLEAR will be the largest trial of colchicine and determine whether colchicine in acute myocardial infarction should be a class I indication. Both colchicine and spironolactone are widely available, inexpensive medications that can rapidly deployed to help the health of Canadians with acute myocardial infarction.

Trial funding: The trial was funded by 2 CIHR grants (total $5,204,224) and a grant from Boston Scientific ($7,284,00) and received in kind donation of study drugs from Tiofarma. However, due to 20% across the board cut from CIHR and delays due to COVID, we have a deficit and so this funding will be important to help us to complete the trial and allow us to complete median 3 year follow up. We confirm that we can complete the trial with this additional funding.

Will the trial be publicly reported by January 15, 2025: With recruitment complete and final visit expected in May 2024 for a median of 3 years of follow, the target would be a simultaneous publication and presentation in the fall of 2024 at major international meeting and a top tier journal (NEJM, JAMA or Lancet).

Co-ordination centre: The trial will be coordinated at the Population Health Research Institute (PHRI), McMaster University. The PHRI has coordinated large practice-changing trials in cardiology. Examples include HOPE[1] (N=9000), CURE[2] (N=12500), OASIS 5[3]and 6[4] (N=25000 & 12000, respectively), and RELY (N=18113), TOTAL[5] (N=10732) and COMPLETE[6] (N=4041). The study operations team will be supervised by Jessica Tyrhitt who has >10yrs of experience in managing large multicenter trials in ACS. All the data points required for this trial, from baseline to the follow-up visit, are being collected centrally by PHRI in electronic Case Report Forms (eCRFs), using the iDataFax database and randomization by the ROME electronic system.

Registration: ClinicalTrials.gov

Applicant / Principal investigator: David Conen MD MPH, McMaster University, Member of the perioperative network within ACT, permanent resident of Canada 

Data Coordinating Centre: Population Health Research Institute, McMaster University, Canada 

Current status: As of March 30 2023, 2,920 of 3,200 (91%) patients have been enrolled, and >2,800 of 3,200 final visits have been completed. We expect the last patient last visit around June 30, 2023. 

Study Design: Multi-centre, international, blinded, randomized controlled trial 

Primary Objectives: To determine whether the administration of colchicine compared with placebo reduces the occurrence of the co-primary outcomes 1) perioperative atrial fibrillation/atrial flutter (AF), and 2) myocardial injury after noncardiac surgery (MINS), both within 14 days of randomization. 

Secondary Objectives: The secondary trial objectives are to determine whether the administration of colchicine compared with placebo reduces the following within 14 days of randomization: 1) composite of all-cause mortality, nonfatal MINS, or nonfatal stroke; 2) composite of all-cause mortality, nonfatal myocardial infarction (MI), or nonfatal stroke; 3) MINS not fulfilling the 4th universal definition of MI; 4) MI; 5) time to chest tube removal; and 6) duration of stay in ICU, step-down, and in-hospital. 

Main Safety Outcomes: The two main COP-AF safety outcomes are 1) the occurrence of sepsis/infection; and 2) non-infectious diarrhea within 14 days of randomization 

Inclusion Criteria: Patients are eligible if they: 1) are undergoing thoracic surgery with general anesthesia; 2) are ≥55 years of age at randomization; 3) are expected to require at least an overnight hospital admission after surgery; and 4. provide written informed consent. 

Exclusion Criteria: 1) prior history of AF; 2) taking anti-arrhythmic medication; 3) undergoing minor thoracic interventions/procedures; 4) contraindications to colchicine; 5) not expected to take oral medications for >24 hours after surgery; 6) scheduled for lung transplantation; 7) currently taking non-study colchicine before surgery; 8) severe hepatic dysfunction; 9) aplastic anemia; 10) women of childbearing potential who are not taking effective contraception, pregnant or breast-feeding; 11) scheduled to take during the first 10 days after surgery clarithromycin, erythromycin, telithromycin, cyclosporine, ketoconazole or itraconazole; or 12) HIV patients treated with antiretroviral therapy. 

Treatment: Oral colchicine (0.5 mg) or matching placebo is given within 4 hours before surgery. Thereafter, patients will receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. 

Follow-up: Patients will be followed while in hospital and at 14 days after randomization.

Trial Summary: CYCLE - Critical Care Cycling to Improve Lower Extremity Strength

Survivors of critical illness may face physical disability up to 5 years following their discharge from the intensive care unit (ICU).1 Muscle mass decreases within the first 72 hours of a patient’s ICU stay.2 Leg muscles account for 75% of total skeletal muscle mass3 and are most vulnerable to weakness from immobility.4 Therefore, addressing immobility while patients are in the ICU is an important opportunity to optimize physical function.4 The Society of Critical Care Medicine guidelines recommend rehabilitation or mobilization in the ICU for critically ill adults, as the benefits likely outweigh the risks.5 However, the guidelines did not recommend specific types or timing of rehabilitation activities due to heterogeneous evidence. Further, two recent prominent randomized controlled trials (RCTs)6,7 and a systematic review8 raised concerns for an increased risk of safety events in patients randomized to early rehabilitation interventions, prompting discussion within the critical care and rehabilitation communities. Data from high-quality, rigorous clinical trials, performed in the Canadian context are urgently needed.

CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) is a Canadian, physiotherapist-led, CIHR-funded research program started in 2013. In-bed cycling is an underused, promising intervention aimed at minimizing immobility and improving physical function post-ICU discharge. The CYCLE research program has culminated in an international RCT with the following objectives: 1) to determine if early in-bed cycling and usual care physiotherapy (PT) compared to usual care PT alone in critically ill, mechanically ventilated adults improves the primary outcome of physical function, and 2) to conduct an economic evaluation of the CYCLE RCT.

Characteristics of CYCLE RCT:

Study design: 360-patient, 17 site (14 Canada, 1 Australia, 2 United States), concealed, open-label, parallel-group.

‍Population: Adults (³18 years old) within the first 7 days of ICU admission, first 4 days of mechanical ventilation, and who could ambulate independently before their critical illness (with or without a gait aid). Intervention: 30 minutes per day of cycling, 5 days per week in addition to usual care PT activities. A specialized in-bed cycle ergometer provides passive (no patient induced muscular contribution), active-assisted (partial patient), or active cycling (full patient). Starting at enrollment, individual participants receive in-bed cycling for the duration of their index ICU admission, or until the patient can march on the spot for two consecutive days, or to a maximum of 28 days, whichever occurs first. ICU physiotherapists deliver the intervention as part of their usual clinical role.

‍Comparison: Patients allocated to the control arm receive usual care PT activities per current institutional practice.

Outcomes: Primary: Physical Function ICU Test-Scored,9 a reliable and valid measure in critically ill patients, 3-days post ICU discharge completed by assessors blinded to treatment allocation. Secondary: Safety, muscle strength, physical function, frailty, psychological distress, quality of life (EQ-5D),10-12 mortality, and healthcare utilization (ICU and hospital length of stay). Follow-up: 90-days post-randomization.

Meaningful impact: CYCLE is the largest study of critical care in-bed cycling rehabilitation in the world. Results of the CYCLE RCT will provide Canadian efficacy and safety evidence to determine whether inbed cycling during critical illness improves short-term physical and functional outcomes and accelerates recovery in ICU survivors.

‍Given recent concerns raised regarding the safety of ICU rehabilitation, additional data are urgently needed to inform contemporary clinical practice.

Trial Summary 

Importance: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant.

Objective: To evaluate the effect of a multi-component quality improvement intervention designed to help eligible patients complete key steps toward receiving a kidney transplant.

Design, setting, and participants: A pragmatic, two-arm, parallel-group, open-label, registry-based, superiority, cluster-randomized trial (November 1, 2017, to December 31, 2021). The trial included all 26 CKD programs in Ontario. These programs care for patients approaching the need for or receiving maintenance dialysis.

Intervention: Using stratified, covariate-constrained randomization, we allocated the CKD programs (1:1) to provide the intervention or usual care for 4.2 years. The intervention had 4 main components: (1) administrative support to establish local teams to drive performance; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders.

Primary outcome: Total steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant centre for evaluation; step 2, had a potential living donor contact a transplant centre for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor.

Results to date: The 26 CKD programs (13 intervention, 13 usual care) cared for 20,375 potentially transplant-eligible patients with advanced CKD (intervention [n=9780 patients], usual care [n=10 595 patients]). The provincial core operations group met over 100 times during the trial. Each of the 13 CKD programs established a local quality improvement team, developed a charter with their goals and activities, and indicated that team members met regularly to review and improve transplant performance. Together, the programs reported that 1740 patients completed the educational program Explore Transplant Ontario (etontario.org). Transplant ambassadors (prior kidney transplant recipients and living kidney donors) recorded 5471 meaningful interactions with patients with advanced CKD and 719 meaningful interactions with potential living kidney donors (transplantambassadors.ca). Each CKD program received regular performance reports and had annual performance meetings with the provincial renal agency. We are currently analyzing and preparing the results for publication.

HEMOTION Trial: HEMOglobin transfusion threshold in Traumatic brain Injury OptimizatioN

The problem: In Canada, trauma causes more than 15,000 deaths every year. Most deaths are related to traumatic brain injury (TBI). Although the management of TBI patients has improved, mortality remains unacceptably high (20 to 50%), and half of survivors are left with major functional impairment. Current guidelines for the management of TBI are based on limited evidence and practice is highly variable, including strategies to improve brain oxygen delivery such as blood transfusion. Most critically ill patients with TBI will develop anemia, which may decrease oxygen delivered to a fragile traumatized brain. While clinical practice is moving towards transfusing patients at low hemoglobin (Hgb) levels, experts have expressed concerns regarding restrictive strategies and the low level of evidence on which they are based. Indeed, there is concern that anemia might adversely affect clinical outcomes in TBI.

Study hypothesis: We hypothesize that, among critically ill adult patients with TBI, a liberal RBC transfusion strategy (triggered by Hgb ≤100g/L) improves long-term functional outcomes compared to a restrictive strategy (triggered by Hgb ≤70g/L).

Trial design: We are conducting a multicenter international pragmatic open blinded-endpoint (PROBE) randomized trial in critically ill patients with TBI.

Eligibility criteria: We enroll adult patients (≥18 years old) admitted to the ICU with an acute (hospital admission within 24 hours of injury) moderate or severe (Glasgow Coma Score (GCS) ≤12) blunt TBI and a Hb level ≤100 g/L. We exclude patients who receive transfusion after ICU admission, have contraindications or known objection to transfusions or have no fixed address.

Interventions: Experimental intervention: liberal transfusion strategy: patients in the liberal transfusion strategy group receive an RBC transfusion if their Hgb is ≤100 g/L. Control intervention: restrictive transfusion strategy: patients in the restrictive transfusion strategy group receive an RBC transfusion only if their Hgb is ≤70 g/L. The trial intervention is initiated within 3 hours in patients meeting the threshold for transfusion in their respective group to avoid prolonged exposure to Hgb levels below this threshold. The allocated transfusion strategy is applied from the time of randomization to death or discharge from the ICU. Methods to minimize biases and ensure feasibility have been put in place.

Primary outcome: We are using the Glasgow Outcome Scale extended (GOSe) to assess neurological outcome at 6 months.1,2 The GOSe scale comprises eight ranking levels from 1 (death, least favorable outcome) to 8 (upper good recovery, most favorable outcome) and is the gold standard outcome measure in TBI.

Secondary outcomes: We are assessing ICU, hospital and 6-month mortality. At 6 months, we measure the Functional Independence Measure (FIM), the quality of life using the EuroQoL 5-Dimension 5-Level (EQ- 5D-5L) (generic scale) and the Quality of Life after Brain Injury (QOLIBRI) (TBI-specific scale), and the self-reported Patient Health Questionnaire (PHQ-9) to evaluate depression.

Tertiary outcomes: We are capturing the number of RBC units transfused in the ICU, lowest daily Hb, infections, duration of mechanical ventilation and ICU and hospital length of stay. We are also assessing complications related to transfusion.

Sample size: We will include 742 adult patients at 34 sites in 4 countries (Canada, UK, France, Brazil).

SUMMARY 

ClinicalTrials.gov Identifier: NCT04485195 

Our study question, comparing IV vernakalant to IV procainamide, has equipoise amongst Canadian ED physicians and has never been directly studied. Background: Atrial fibrillation (AF) causes a rapid, irregular heart rate and is the most common arrhythmia seen in the emergency department (ED). We will focus on acute-onset episodes of AF, which usually have onset <48 hours and are highly symptomatic. Most Canadian ED physicians attempt cardioversion (CV) to sinus rhythm, either with drugs or electrically. If drug CV fails, then patients usually undergo electrical CV which is effective but is often associated with significant delays and adverse events (13.9%; Stiell CJC 2022). The most commonly used drug is the older intravenous (IV) procainamide which has a conversion rate of 52.2%, median time to conversion 55 minutes, and incidence adverse events 9.8%. The newer IV vernakalant reportedly has a conversion rate of 65%, median time to conversion 12 minutes, and adverse events <1%; it was approved in Canada in 2017 but has seen modest uptake. 

Most acute AF patients occupy valuable ED cardiac monitors for a prolonged period. Our hope is that IV vernakalant will result in more rapid cardioversions in our extremely crowded Canadian EDs. We hypothesize that our study will reveal that IV vernakalant is superior with a higher conversion rate, faster conversion times, and far fewer adverse events. RAFF4 is an open-label pragmatic trial so that we can see the actual performance of these drugs in real clinical circumstances. 

Recruitment has been delayed over the past year due to the pandemic but we have enrolled 190 patients, 75% in Ottawa. We have funded the RAFF4 study using funds from a CIHR Foundation award held by the PI (IGS) - this expires in early 2023, hence the current application is essential to ensure trial completion. Cipher Pharmaceuticals Inc. (Canada) offers unrestricted support by providing vernakalant at no cost for all study sites but gives no money. 

Study Objective: To compare IV vernakalant to IV procainamide for acute AF patients. 

Primary Outcomes: conversion to and maintenance of sinus rhythm for at least 30 minutes after the drug infusion. Other: length of stay in the ED, adverse events, and 30-day follow-up status. 

Primary Analysis: on an intention-to-treat basis, using multiple logistic regression controlling for the following variables: age, sex, first or repeat episode, time from onset, and history of heart failure. 

Methods: Design: Pragmatic comparative effectiveness trial with an open label, randomized (1:1) comparison of drug CV with: i) IV vernakalant, and ii) IV procainamide. Stratified by site. 

Interventions: a) IV Vernakalant. Given as an initial infusion of 3 mg/kg over 10 minutes, followed if necessary by a second infusion of 2 mg/kg. b) IV Procainamide. Given as an infusion of 15 mg/kg, over 60 minutes. If patients have not converted to sinus rhythm by 30 minutes after the end of either drug infusion, they will be offered electrical CV. 

Setting: 12 tertiary care EDs in 5 provinces. 

Subjects: 340 patients with acute AF where acute rhythm control is a safe option.

Importance: If IV vernakalant proves to be more effective, faster, and safer than IV procainamide, this will give clinicians an important alternative for drug cardioversion of acute AF. The study results should lead to higher rhythm conversion rates and more rapid discharges from our crowded EDs and should change clinical practice worldwide.

REVISE is a global Canadian-led randomized clinical trial [NCT03374800] conducted by the Canadian Critical Care Trials Group, an ACT Partner. The Global Principal Investigator (Dr. D Cook) and Canadian Principal Investigator (Dr. G Guyatt) are Canadian. The Global Methods Center is in Hamilton, Canada. Randomization is ongoing. As of March 29, 2023, 3,992 of 4,800 patients have been recruited in 63 international centers; 808 patients remain to enrol. The manuscript submission is anticipated in September 2024. 

Structured Abstract Summary 

Background: For 40 years, pharmacologic prevention of stress ulcer-related gastrointestinal (GI) bleeding with acid suppression has been the standard of care for mechanically ventilated patients in the intensive care unit (ICU) [1]. Proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists (H2RAs). Observational studies and our recent networkmeta-analysis suggest that PPIs may increase the risk of ventilator-associated pneumonia (VAP) and Clostridioides difficile infection (CDI) [2,3]. Moreover, a recent large trial raised concerns about an increased risk of death associated with pantoprazole in the most severely ill patients [4]. Although in this trial GI bleeding events were less frequent in the pantoprazole group, the bleeds may not have been patient-important, and investigators identified no other benefits. Moreover, a cluster-crossover trial of 26,771 patients evaluating PPIs versus H2RAs also suggested an increased risk of death in the most severely ill patients receiving PPIs, raising further misgivings about PPIs in the ICU setting [5]. Given that the widespread use of PPIs may not be in the best interest of critically ill patients, successfully completing the REVISE trial is crucial from a clinical, ethical and policy perspective. 

Objectives: To determine, in mechanically ventilated patients, the effect of pantoprazole versus placebo on the primary efficacy outcome of clinically important upper GI bleeding, and the primary safety outcome of 90-day mortality. Secondary outcomes are patient-important GI bleeding, VAP and CDI, treatment with renal replacement therapy and hospital mortality. Tertiary outcomes are red blood cell transfusions, serum creatinine, duration of mechanical ventilation, duration of ICU stay and duration of hospital stay. 

Methods: REVISE is a high-impact global randomized trial of 4,800 ICU patients >18 years old who have an anticipated duration of mechanical ventilation of ≥48 hours. Exclusion criteria are acute or recent GI bleeding, dual antiplatelet therapy, combined antiplatelet and anticoagulant therapy, intent to withdraw advanced life support or hopeless prognosis, and previous enrolment in this or a confounding trial. The protocol allows either a priori informed consent or informed consent to continue with study drug. Patients are randomized in a fixed 1:1 allocation, stratified by center and whether or not they were using acid suppression prior to hospitalization. Stratification by pre-hospital acid suppression will allow evaluation of possible rebound gastric acid hypersecretion upon acid suppression termination [6] and possible microbiome and infection risk modification by long-term acid suppression [7]. Study Pharmacists obtain concealed allocation from a password-protected website; all researchers and clinicians, patients and families are blinded. With a priori or deferred consent, patients are randomized to pantoprazole 40 mg or placebo intravenously daily while in ICU up to 90days or until successful discontinuation of mechanical ventilation for >48 hours; development of clinically important GI bleeding; or 3) death in ICU. 

International Collaboration: REVISE is conducted under the auspices of the International Forum for Acute Care Trialists in collaboration with the Canadian Critical Care Trials Group [www.ccctg.ca], the Australian and New Zealand Critical Care Trials Group [www.anzicsctg.com].

Trial Synopsis REFINE ICD is testing whether an implantable cardioverter defibrillator (ICD), in addition to usual care, will alter mortality as compared to usual care alone. A total of 700 patients with an LVEF 36% to 50% plus impaired HRT and abnormal TWA, measured at least 2 months after MI, are being randomized. Patients with normal HRT +/- TWA are not eligible for randomization but are followed in a registry. 

Primary hypothesis. An ICD in addition to usual care will increase the probability of survival in subjects with LVEF values of 36% to 50%, impaired HRT and abnormal TWA measured at least 2 months after the index MI. 

Outcome. Mortality is the standard by which most cardiac interventions are judged since it is unbiased and unambiguous. In the event of a positive outcome, quality of life should be assessed to aid in the overall interpretation of the results. As such, these outcomes comprise secondary outcomes and will only be assessed if the primary outcome is positive. 

Inclusion Criteria: 18-80 years old, clinically appropriate ICD candidate, LVEF 36% to 50% measured 2 months post-MI and at least 3 months after angioplasty or bypass surgery, revascularization where clinically indicated, appropriate medical therapy, sinus rhythm in the 8 weeks prior to the Holter assessment, and abnormal HRT and TWA on the Holter assessment performed 2 months after MI (core lab with expert over-read). The trial is registered at clinicaltrials.gov (NCT00673842)