Clinical trial NCT04033822: Fast Track Pathway to Accelerated Cholecystectomy
Official title: Fast Track Pathway to Accelerated Cholecystectomy Versus Standard of Care for Acute Cholecystitis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Cholecystitis
Cholecystectomy
Keywords: cholecystitis
cholecystectomy
accelerated surgery
feasibility study
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: St. Joseph's Health Care London
First posted: 2019-07-26
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Randomized Controlled Trial, efficacy trial
Primary purpose: TREATMENT

Brief summary: More than 10% of Canadians have gallstones, and approximately 10% of these individuals will develop gallbladder inflammation related to gallstones, which is referred to as acute cholecystitis (AC). Patients with AC who do not have their gallbladder surgically removed have a 30% risk of serious complications that can lead to death. Surgery is the only definitive treatment for AC, however, there is controversy regarding the ideal timing of surgery. The two main approaches are early surgery (typically within 7 days of diagnosis) or delayed surgery (7 days to 6 weeks after diagnosis). Although preliminary evidence suggests that early surgery is associated with shorter hospital length of stay, lower risk for complications, and lower costs, practice varies widely regarding the timing of surgery. The limitations of the existing studies include small sample sizes, varied definitions of early versus delayed surgery, and an imbalance of risk between study groups. The proposed pilot study aims to inform the design of a large clinical trial that will compare the outcomes of patients with AC who receive accelerated surgery (i.e., as soon as possible with a goal of surgery within 6 hours of diagnosis) with those who receive standard care.

Detailed description: The prevalence of gallstones is 10% and approximately 10% of patients develop acute cholecystitis (AC). AC prevalence increases with age and complications are as high as 30% in patients who do not undergo surgery, the only definitive treatment. There is controversy regarding ideal surgical timing. Previously, delayed surgery was thought to decrease bile duct injuries resulting from active inflammation. However, the state of persistent inflammation, hypercoagulability, and stress can cause medical complications such as myocardial injury. Chronic inflammation can lead to fibrosis, adhesions and higher chance of bile duct injuries during delayed surgery. There is also concern for recurrent AC episodes, recurrent pain, biliary pancreatitis, cholangitis or sepsis.

Recent studies suggest that early surgery may be associated with better outcomes, but practice remains variable, ranging anywhere from early surgery (\<7 days) to delayed surgery (\>7 days). Among \>24,000 Ontarians with AC admitted to 106 hospitals, timing of cholecystectomy varied widely across sites. Only 58% of patients underwent surgery within 7 days. High volume hospitals were more likely to perform early surgery.17

Among 14,200 Ontarians with AC, a propensity score analysis demonstrated that early surgery was associated with less bile duct injury (relative risk (RR)=0.53, 95% confidence interval (CI) 0.31-0.90) and shorter length of hospital stay (LOS) (mean 1.9 days, 95% CI 1.7-2.1). Early surgery was less costly and more effective than delayed cholecystectomy.

Trials of surgical timing in patients with AC are limited. The largest randomized controlled trial (RCT) compared early and delayed surgery for AC only included 618 patients.9 Cholecystectomy was performed a median of 1 day after randomization in the early group compared to a median of 25 days in the delayed group. Duration of surgery and conversion rate to open surgery were similar in both groups. Early surgery was associated with less morbidity (11.8% vs. 34.4%, p\<0.001), shorter LOS (5.4 vs. 10.0 days, p\<0.001), and lower cost (€2919 vs. €4262, p\<0.001).

Multiple meta-analyses have suggested that early surgery for AC is associated with fewer wound infections (RR 0.57; 95% CI 0.35-0.93) and have suggested a trend to fewer complications (RR 0.66; 95% CI 0.42-1.03). Limitations of these meta-analyses include studies with small sample sizes, few events, wide confidence intervals, and variation in the definition of early surgery. Finally, there is a lack of strong evidence to make definitive conclusions regarding impact of early surgery in AC, which has led to substantial variation in clinical practice.

AC initiates inflammatory, hypercoagulable, and stress states that can cause medical complications. Early surgical treatment will reduce the time patients are exposed to these harmful states and therefore may reduce the risk of complications. Furthermore, rapid surgery results in a shorter period of AC, which may impact hospital costs. The goal is to undertake a large multicentre RCT of the impact of accelerated surgery (goal within 6 hours of diagnosis) vs. usual timing of surgery in patients with AC on a composite outcome of major clinical and surgical complications at 90 days. "Standard of care", as described, is highly variable and depends on the surgeon and hospital practice patterns.

The main objective of this pilot study is to assess the feasibility of a large trial. The team hypothesizes that accelerated surgery for AC will improve clinical and surgical outcomes. A large RCT on this topic is needed for the following reasons: 1) time to surgery is a modifiable factor; 2) available data are encouraging, but not definitive; 3) there is variation in clinical practice across Ontario and internationally 4) the definition of early surgery has varied substantially across studies; 5) available data may be substantially underestimating the effect of timing of surgery because no trial has evaluated surgery within 6 hours of diagnosis; 6) high-quality evidence will modify clinical practice; and 7) implementation of accelerated surgery could save millions of healthcare dollars annually.

Eligibility criteria: Inclusion Criteria:

1. Age ≥45 years; or age ≥18 years and \<45 years with at least one of the following co-morbidities: diabetes or chronic respiratory, cardiovascular, or renal disease;
2. Diagnosis of acute cholecystitis defined by the presence of at least 2 of the following:

   1. Abdominal pain in upper right quadrant,
   2. Murphy's sign,
   3. Leukocytosis \>10 × 103/μl, or
   4. Oral temperature \<36.5°C or \>38°C;
3. Cholelithiasis (stones/sludge);
4. Ultrasound signs of cholecystitis;
5. Acute cholecystitis that requires surgery and is diagnosed during working hours;
6. Expected to require at least an overnight hospital admission after surgery; and
7. Provide written informed consent to participate in FAST.

Exclusion Criteria

1. Patients requiring emergent surgery or emergent interventions for another reason;
2. Patients whose therapeutic anticoagulation is not reversible;
3. Patients with a history of heparin-induced thrombocytopenia and current use of warfarin with an INR ≥1.5;
4. Pregnant patients;
5. Previous participation in the trial.

Primary outcomes:
measure: Feasibility (pertaining to patient recruitment)
timeFrame: 1 year
measure: Feasibility (pertaining to adherence to follow-up assessment)
timeFrame: 90 days post-randomization
measure: Feasibility (pertaining to patients who are randomized to Accelerated Care)
timeFrame: Within 6 hours after diagnosis of acute cholecystitis
Secondary outcomes:
measure: Hospital Length of Stay
timeFrame: 2 weeks
measure: Proportion of patients who experience e a composite of Clinical Outcomes
timeFrame: 90 days after randomization
measure: Length of surgical procedure
timeFrame: 1 week
measure: Proportion of patients who experience acute kidney injury
timeFrame: 90 days after randomization
measure: Proportion of patients who are admitted to ICU within 90 days of randomization
timeFrame: 90 days after randomization
measure: Number of hospital readmissions within 90 days of randomization
timeFrame: 90 days after randomization
measure: Proportion of patients who experience peripheral arterial thrombosis within 90 days of randomization
timeFrame: 90 days after randomization
measure: Proportion of patients who experience intra-operative cholangiogram
timeFrame: 1 day
measure: Subtotal cholecystectomy rate
timeFrame: 1 year
measure: Proportion of postoperative ileus
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: London
country: Canada
facility: Lawson Health Research Institute, London Health Sciences Centre
state: Ontario
Study officials:
affiliation: Population Health Research Institute
name: Flavia Kessler Borges PhD, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Joseph's Health Care London
name: Rahima Nenshi Msc, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Hamilton Health Sciences Corporation
name: PJ Devereaux PhD, M.D
role: PRINCIPAL_INVESTIGATOR
References: