Christine Ribic

The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index

OBJECTIVES A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes. STUDY DESIGN AND SETTING A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result. RESULTS The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up. CONCLUSION The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results.

Statin-associated rhabdomyolysis: is there a dose-response relationship?

BACKGROUND Statins have a well-established role in prevention of vascular events but are associated with muscle-related adverse events. The dose relationship with these adverse events is unclear. We present an original analysis of Canadian and US case reports of statin-associated rhabdomyolysis with a focus on dose response. A typical clinical case is also summarized. METHODS All cases of statin-associated rhabdomyolysis reported to Health Canadas Canadian Vigilance Program and to the US Food and Drug Administrations Adverse Event Reporting System from 2004-2008 were analyzed by severity and dose equivalence. Canadian national statin utilization data from 2002-2007 were used to estimate the dose-related incidence of rhabdomyolysis corrected for levels of utilization. RESULTS The clinical case illustrates well the potential severity of statin-induced rhabdomyolysis. Combined Canadian/US data revealed an average of 812 cases of statin-induced rhabdomyolysis reported annually with a mean patient age of 64.4 years (35.5% female). The worst outcomes reported were renal dysfunction in 17.0%, acute renal failure in 19.8%, dialysis in 5.2%, and death in 7.6%. Using 10 mg atorvastatin per day as the reference dose, the odds ratios of rhabdomyolysis were 3.8 (95% CI 2.3-6.6) for 40 mg/day atorvastatin dose equivalent and 11.3 (95% CI 6.4-20.4) for 80 mg/day atorvastatin dose equivalent. CONCLUSIONS The results of our adverse drug analysis suggest a dose-response relationship. Given the widespread use of statins, the ability to predict which patients will experience serious muscle-related harm is a research priority.

Low-molecular-weight heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review

PURPOSE The study aimed to systematically review the effect of low-molecular-weight heparin (LMWH) thromboprophylaxis in medical-surgical critically ill patients in the intensive care unit. METHODS In duplicate and independently, we searched for relevant articles using MEDLINE and EMBASE; we also contacted experts and reviewed reference lists. For included studies, we abstracted data on study and patient characteristics, LMWH use, clinical outcomes (venous thromboembolism [VTE], bleeding, and mortality), laboratory outcomes (anti-Xa levels and thrombocytopenia), and methodological quality. RESULTS We included 8 prospective cohort studies and 1 randomized trial, with a total of 629 patients. Eight studies (n = 406 patients) reported anti-Xa levels and only 3 studies (n = 240 patients) reported on at least one clinical outcome. Low-molecular-weight heparin does not appear to bioaccumulate based on repeated measurements of trough anti-Xa levels. Thrombocytopenia occurred in 9.3% of patients receiving LMWH; heparin-induced thrombocytopenia was not reported. In studies reporting clinical outcomes, the frequency of VTE in patients receiving LMWH ranged from 5.1% to 15.5%, bleeding complications ranged from 7.2% to 23.1%, and mortality ranged from 1.4% to 7.4%. CONCLUSIONS Low-molecular-weight heparin may be effective for thromboprophylaxis in medical-surgical critically ill patients, but no trials have compared LMWH against an alternative active strategy; thus, LMWH cannot be recommended routinely. Trials testing LMWH thromboprophylaxis are required, which examine patient-important end points such as the incidence and clinical consequences of VTE, bleeding, heparin-induced thrombocytopenia, and mortality.

The impact of patient preference on dialysis modality and hemodialysis vascular access

BackgroundHome-based dialysis, including peritoneal dialysis (PD) and home hemodialysis (HHD), is associated with improved health related quality of life and reduced health resource costs. It is uncertain to what extent initial preferences for dialysis modality influence the first dialysis therapy actually utilized. We examined the relationship between initial dialysis modality choice and first dialysis therapy used.MethodsPatients with chronic kidney disease (CKD) from a single centre who started dialysis after receiving modality education were included in this study. Multivariable logistic regression models were constructed to assess the independent association of patient characteristics and initial dialysis modality choice with actual dialysis therapy used and starting hemodialysis (HD) with a central venous catheter (CVC).ResultsOf 299 eligible patients, 175 (58.5%) initially chose a home-based therapy and 102 (58.3%) of these patients’ first actual dialysis was a home-based therapy. Of the 89 patients that initially chose facility-based HD, 84 (94.4%) first actual dialysis was facility-based HD. The adjusted odds ratio (OR) for first actual dialysis as a home-based therapy was 29.0 for patients intending to perform PD (95% confidence interval [CI] 10.7-78.8; p < 0.001) and 12.4 for patients intending to perform HHD (95% CI 3.29-46.6; p < 0.001). Amongst patients whose first actual dialysis was HD, an initial choice of PD or not choosing a modality was associated with an increased risk of starting dialysis with a CVC (adjusted OR 3.73, 95% CI 1.51-9.21; p = 0.004 and 4.58, 95% CI 1.53-13.7; p = 0.007, respectively).ConclusionsAlthough initially choosing a home-based therapy substantially increases the probability of the first actual dialysis being home-based, many patients who initially prefer a home-based therapy start with facility-based HD. Programs that continually re-evaluate patient preferences and reinforce the values of home based therapies that led to the initial preference may improve home-based therapy uptake and improve preparedness for starting HD.

Study of Cardiovascular Outcomes in Renal Transplantation: A Prospective, Multicenter Study to Determine the Incidence of Cardiovascular Events in Renal Transplant Recipients in Ontario, Canada:

Background: Renal transplant recipients (RTRs) are at significantly higher risk for morbidity and mortality compared with the general population, largely attributed to cardiovascular disease (CVD). Previous estimates of CVD events have come from health care databases and retrospective studies. Objective: The objective of this study was to prospectively determine the prevalence of risk factors and incidence of CVD events in a Canadian cohort of RTRs. Design: Study of Cardiovascular Outcomes in Renal Transplantation (SCORe) was a prospective, longitudinal, multicenter observational study. Setting: Adult RTRs were recruited from 6 participating transplant sites in Ontario, Canada. Patients: Eligible patients were those receiving a living or deceased donor renal transplant. Patients who received simultaneous transplant of any other organ were excluded. Measurements: Primary outcomes included myocardial infarction (MI) defined by American College of Cardiology (ACC-MI) criteria, and major adverse cardiac events (MACE), defined as cardiovascular (CV) death, ACC-MI, coronary revascularization, and nonhemorrhagic stroke. CV events were adjudicated by a single, independent cardiologist. Methods: CV and transplant-specific risk factors that predict MACE and ACC-MI were identified by stepwise regression analysis using the Cox proportional hazards model. Results: A total of 1303 patients enrolled across 6 transplant centers were followed for 4.5 ± 1.6 years (mean ± SD). Incidence of MACE was 7.0%, with significant independent predictors/risk factors including age, diabetes, coronary revascularization, nonhemorrhagic stroke, and renal replacement therapy (RRT). ACC-MI incidence was 4.0%, with significant independent predictors/risk factors including age, coronary revascularization, and duration of RRT in excess of the median value (2.91 years). Limitations: Patients were recruited from a single province, so may not reflect the experience of RTRs in other areas of Canada. Conclusions: Using a prospective design and rigorous methodology, this study found that the incidence of CV events after renal transplantation was elevated relative to the general Canadian population and was comparable with that reported in patient registries, thus helping validate the utility of retrospective analysis in this field. SCORe highlights the importance of monitoring RTRs for traditional cardiac and transplant-specific CV risk factors to help prevent CV morbidity and mortality. Further research is needed to investigate a broader range of potential risk factors and their combined effects on incident CV events.

Assessment of Postresuscitation Volume Status by Bioimpedance Analysis in Patients with Sepsis in the Intensive Care Unit: A Pilot Observational Study.

Background. Bioimpedance analysis (BIA) is a novel method of assessing a patients volume status. Objective. We sought to determine the feasibility of using vector length (VL), derived from bioimpedance analysis (BIA), in the assessment of postresuscitation volume status in intensive care unit (ICU) patients with sepsis. Method. This was a prospective observational single-center study. Our primary outcome was feasibility. Secondary clinical outcomes included ventilator status and acute kidney injury. Proof of concept was sought by correlating baseline VL measurements with other known measures of volume status. Results. BIA was feasible to perform in the ICU. We screened 655 patients, identified 78 eligible patients, and approached 64 for consent. We enrolled 60 patients (consent rate of 93.8%) over 12 months. For each 50-unit increase in VL, there was an associated 22% increase in the probability of not requiring invasive mechanical ventilation (IMV) (p = 0.13). Baseline VL correlated with other measures of volume expansion including serum pro-BNP levels, peripheral edema, and central venous pressure (CVP). Conclusion. It is feasible to use BIA to predict postresuscitation volume status and patient-important outcomes in septic ICU patients. Trial Registration. This trial is registered with clinicaltrials.gov NCT01379404 registered on June 7, 2011.

Transfusion Management of Incident Dialysis Patients in Canada: A Prospective Observational Study:

Background: Several studies have demonstrated harm associated with using erythropoiesis-stimulating agents (ESA) to achieve higher hemoglobin (Hb) levels. Subsequently, more conservative use of ESAs has changed anemia therapy in patients with chronic renal failure. Objective: The objectives were to identify transfusion rates in hemodialysis (HD) patients during the first year of therapy, to identify factors associated with the probability of transfusion, describe reasons for the transfusions, and identify the Hb values associated with each transfusion. An exploratory objective was to describe the age of red blood cell transfusions. Design: This was a multicenter prospective observational cohort study. Setting: There were 12 study sites in 5 Canadian provinces. The study was performed from 2012 to 2014. Methods: The study patients were adult incident chronic HD patients in these centers. Patients with acute kidney injury, peritoneal dialysis, and planned transfer to satellite units were excluded. Patients had to receive at least 1 month of chronic HD to be eligible. Data for 3 months prior to HD were obtained by retrospective chart review. Prospectively, charts were reviewed monthly for 12 months for data abstraction. Results: There were 314 patients enrolled and 79.9% completed 12 month follow-up. Ninety-four (29.9%) patients received at least 1 unit of blood. During the first 90 days, the transfusion episode rate was 148.4 per 100 patient-years compared with 62.6 per 100 patient-years post 90 days. The most frequent indication was a low Hb value (92%) with gastrointestinal bleeding, surgical blood loss, and fatigue accounting for 9.9%, 8.6%, and 4.5%, respectively. Some patients had >1 indication. The mean Hb values prior to transfusion episodes ranged from 75.3 to 78.6 g/L. Cox regression analysis on time to first transfusion and time to first hospitalization/death both showed an association with inpatient initiation of HD. Some 37.5% initiated HD as an inpatient and differed from those starting as an outpatient. They had less predialysis care and laboratory data suggested more inflammation. The mean and median ages of the blood units transfused were 24.9 (SD = 10.0) and 23 days (interquartile range = 17-33). Conclusions: This work reported the blood transfusion rate in incident HD patients in Canada during a period associated with conservative ESA prescription. The major indication for transfusion was a low Hb rather than clinical symptoms. Initiation of HD as an inpatient was independently associated with the probability of receiving a blood transfusion. These findings require further investigation.

Canada-DONATE study protocol: a prospective national observational study of the medical management of deceased organ donors

Introduction Research on the management of deceased organ donors aims to improve the number and quality of transplants and recipient outcomes. In Canada, this research is challenged by regionalisation of donation services within provinces and the geographical, clinical and administrative separation of donation from transplantation services. This study aims to build a national platform for future clinical trials in donor management. Objectives are to engage collaborators at donation hospitals and organ donation organisations (ODOs) across Canada, describe current practices, evaluate the effectiveness of donation-specific interventions and assess the feasibility of future clinical trials. Methods and analysis This ongoing prospective observational study of the medical management of deceased organ donors will enrol more than 650 consented potential donors from adult intensive care units at 33 hospital sites across Canada, each participating for 12 months. ODOs ensure enrolment of consecutive eligible participants. Research staff record detailed data about participants, therapies, organ assessments, death declaration procedures and adverse clinical exposures from the time of donation consent to organ recovery. ODOs provide reasons that organs are declined, dates and places of transplantation, and recipient age and sex. Descriptive analyses will summarise current practices. Effectiveness analyses will examine donation-specific interventions with respect to the number of transplants, using multilevel regression models to account for clustering by donor, hospitals and ODOs. Feasibility analyses will focus on acceptance of the research consent model; participation of academic and community hospitals as well as ODOs; and accessibility of recipient data. Ethics and dissemination This study uses a waiver of research consent. Hospitals will receive reports on local practices benchmarked to (1) national practices and (2) national donor management guidelines. We will report findings to donation and transplant collaborators (ie, clinicians, researchers, ODOs) and publish in peer-reviewed journals. Trial registration number NCT03114436.