Stephanie N. Dixon

Impact of CONSORT extension for cluster randomised trials on quality of reporting and study methodology: review of random sample of 300 trials, 2000-8

Objective To assess the impact of the 2004 extension of the CONSORT guidelines on the reporting and methodological quality of cluster randomised trials. Design Methodological review of 300 randomly sampled cluster randomised trials. Two reviewers independently abstracted 14 criteria related to quality of reporting and four methodological criteria specific to cluster randomised trials. We compared manuscripts published before CONSORT (2000-4) with those published after CONSORT (2005-8). We also investigated differences by journal impact factor, type of journal, and trial setting. Data sources A validated Medline search strategy. Eligibility criteria for selecting studies Cluster randomised trials published in English language journals, 2000-8. Results There were significant improvements in five of 14 reporting criteria: identification as cluster randomised; justification for cluster randomisation; reporting whether outcome assessments were blind; reporting the number of clusters randomised; and reporting the number of clusters lost to follow-up. No significant improvements were found in adherence to methodological criteria. Trials conducted in clinical rather than non-clinical settings and studies published in medical journals with higher impact factor or general medical journals were more likely to adhere to recommended reporting and methodological criteria overall, but there was no evidence that improvements after publication of the CONSORT extension for cluster trials were more likely in trials conducted in clinical settings nor in trials published in either general medical journals or in higher impact factor journals. Conclusion The quality of reporting of cluster randomised trials improved in only a few aspects since the publication of the extension of CONSORT for cluster randomised trials, and no improvements at all were observed in essential methodological features. Overall, the adherence to reporting and methodological guidelines for cluster randomised trials remains suboptimal, and further efforts are needed to improve both reporting and methodology.

Association between water intake, chronic kidney disease, and cardiovascular disease: a cross-sectional analysis of NHANES data.

Background: Evidence from animal and human studies suggests a protective effect of higher water intake on kidney function and cardiovascular disease (CVD). Here the associations between water intake, chronic kidney disease (CKD) and CVD were examined in the general population. Methods: We conducted a cross-sectional analysis of the 2005-2006 National Health and Nutrition Examination Survey. Non-pregnant adults with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2 who were not taking diuretics were included. Total water intake from foods and beverages was categorized as low (<2.0 l/day), moderate (2.0-4.3 l/day) and high (>4.3 l/day). We examined associations between low total water intake and CKD (eGFR 30-60 ml/min/1.73 m2) and self-reported CVD. Results: Of 3,427 adults (mean age 46 (range 20-84); mean eGFR 95 ml/min/1.73 m2 (range 30-161)), 13% had CKD and 18% had CVD. CKD was higher among those with the lowest (<2.0 l/day) vs. highest total water intake (>4.3 l/day) (adjusted odds ratio (OR) 2.52; 95% confidence interval (CI) 0.91-6.96). When stratified by intake of (1) plain water and (2) other beverages, CKD was associated with low intake of plain water: adjusted OR 2.36 (95% CI 1.10-5.06), but not other beverages: adjusted OR 0.87 (95% CI 0.30-2.50). There was no association between low water intake and CVD (adjusted OR 0.76; 95% CI 0.37-1.59). Conclusions: Our results provide additional evidence suggesting a potentially protective effect of higher total water intake, particularly plain water, on the kidney.

Detecting chronic kidney disease in population-based administrative databases using an algorithm of hospital encounter and physician claim codes

BackgroundLarge, population-based administrative healthcare databases can be used to identify patients with chronic kidney disease (CKD) when serum creatinine laboratory results are unavailable. We examined the validity of algorithms that used combined hospital encounter and physician claims database codes for the detection of CKD in Ontario, Canada.MethodsWe accrued 123,499 patients over the age of 65 from 2007 to 2010. All patients had a baseline serum creatinine value to estimate glomerular filtration rate (eGFR). We developed an algorithm of physician claims and hospital encounter codes to search administrative databases for the presence of CKD. We determined the sensitivity, specificity, positive and negative predictive values of this algorithm to detect our primary threshold of CKD, an eGFR <45 mL/min per 1.73 m2 (15.4% of patients). We also assessed serum creatinine and eGFR values in patients with and without CKD codes (algorithm positive and negative, respectively).ResultsOur algorithm required evidence of at least one of eleven CKD codes and 7.7% of patients were algorithm positive. The sensitivity was 32.7% [95% confidence interval: (95% CI): 32.0 to 33.3%]. Sensitivity was lower in women compared to men (25.7 vs. 43.7%; p <0.001) and in the oldest age category (over 80 vs. 66 to 80; 28.4 vs. 37.6 %; p < 0.001). All specificities were over 94%. The positive and negative predictive values were 65.4% (95% CI: 64.4 to 66.3%) and 88.8% (95% CI: 88.6 to 89.0%), respectively. In algorithm positive patients, the median [interquartile range (IQR)] baseline serum creatinine value was 135 μmol/L (106 to 179 μmol/L) compared to 82 μmol/L (69 to 98 μmol/L) for algorithm negative patients. Corresponding eGFR values were 38 mL/min per 1.73 m2 (26 to 51 mL/min per 1.73 m2) vs. 69 mL/min per 1.73 m2 (56 to 82 mL/min per 1.73 m2), respectively.ConclusionsPatients with CKD as identified by our database algorithm had distinctly higher baseline serum creatinine values and lower eGFR values than those without such codes. However, because of limited sensitivity, the prevalence of CKD was underestimated.

Atypical Antipsychotic Drugs and the Risk for Acute Kidney Injury and Other Adverse Outcomes in Older Adults: A Population-Based Cohort Study

Context Acute kidney injury (AKI) is reportedly associated with atypical antipsychotic drugs, although the risk has not been quantified. Contribution This population-based cohort study found that persons who had received a prescription for any of 3 atypical antipsychotic drugs in the previous 90 days had an elevated risk for hospitalization with AKI. These drugs were also associated with increased risk for hypotension, acute urinary retention, and death. Caution Only older adults and 3 antipsychotic agents were studied. Implication An association with specific adverse events may explain the increased risk for AKI observed with certain atypical antipsychotic drugs. The Editors Each year, millions of older adults worldwide are prescribed atypical antipsychotic drugs (quetiapine, risperidone, and olanzapine). These drugs are frequently used to manage behavioral symptoms of dementia, which is not an approved indication, and such use has raised safety concerns (1, 2). These drugs antagonize -adrenergic, muscarinic, serotonin, and dopamine receptors (3). Acute kidney injury (AKI) (defined as a sudden loss of kidney function) from atypical antipsychotic drugs is described in several case reports (48). Adverse outcomes potentially attributable to these drugs, such as hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis, are known to cause AKI (411). Moreover, pneumonia, acute myocardial infarction, and ventricular arrhythmia have been associated with these drugs in previous population-based studies and AKI may also co-occur with these events (1214). However, no clinical or epidemiologic studies have quantified the risk for AKI from atypical antipsychotic drugs and information on outcomes of hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis is limited. Such information would contribute to growing knowledge of potential adverse events from this drug class. The U.S. Food and Drug Administration warns of an increased risk for death in older patients treated with these drugs based on analyses of randomized, placebo-controlled trials (averaging 10 weeks in duration) (1). For these reasons, we did this population-based study of older adults to investigate the 90-day risk for hospitalization with AKI and other adverse outcomes from new use of an oral atypical antipsychotic drug initiated in the nonhospital setting. Methods Design and Setting We conducted this study at the Institute for Clinical Evaluative Sciences according to a prespecified protocol that was approved by the research ethics board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Patient informed consent was not required. We did a population-based, retrospective cohort study of older adults using linked health care databases in Ontario, Canada. Ontario residents have universal access to hospital care and physician services, and those aged 65 years or older have universal prescription drug coverage. The reporting of this study followed guidelines for observational studies (Table 1 of the Supplement) (15). Supplement. Supplementary material Data Sources We ascertained patient characteristics, drug use, covariate information, and outcome data using records from 5 databases. We obtained vital statistics from the Registered Persons Database of Ontario, which contains demographic information on all Ontario residents who have ever been issued a health card. We used the Ontario Drug Benefit database to identify prescription drug use. This database contains highly accurate recordsthe error rate is less than 1%of all outpatient prescriptions dispensed to patients aged 65 years or older (16). We identified diagnostic and procedural information on all hospitalizations from the Canadian Institute for Health Information Discharge Abstract Database. We obtained covariate information from the Ontario Health Insurance Plan database, which includes health claims for inpatient and outpatient physician services. We identified diagnostic information on all admissions to adult mental health beds from the Ontario Mental Health Reporting System. We have used these databases to research adverse drug reactions and health outcomes (including AKI) (1722). The databases were complete for all variables used in this study, except for prescriber information (which was missing for 10.8% of patients in the cohort). Codes from the International Classification of Diseases, Ninth Revision (before 2002), and Tenth Revision (after 2002), were used to assess baseline comorbid conditions in the 5 years before cohort entry (Table 2 of the Supplement). Codes used to ascertain outcomes are detailed in Table 3 of the Supplement, which lists only codes from the Tenth Revision because all events would have occurred after implementation of that coding system. A subpopulation in southwestern Ontario had information on outpatient serum creatinine levels available before cohort entry; this group was in the catchment area of 12 hospitals in which linked laboratory values were also available (23). Patients We established a cohort of older adults with evidence of a new outpatient prescription for an oral atypical antipsychotic drug (quetiapine, risperidone, or olanzapine) between June 2003 and December 2011. The date of this prescription served as the index date (cohort entry date) for the drug recipients. We matched a group of drug nonrecipients similar in health status to the recipients. We randomly assigned an index date to the entire Ontario population according to the index date of the drug recipients. For example, if more recipients had an index date between 2003 and 2005, a greater proportion of the population would have been randomly assigned an index date between 2003 and 2005. From these adults, after applying our exclusions to both groups, we matched a drug nonrecipient to each recipient on the following 11 characteristics: age (within 2 years); sex; residential status (community-dwelling or long-term care); evidence of comorbid conditions (dementia, schizophrenia or other psychotic disorder, bipolar disorder, major depression or anxiety disorder, Parkinson disease, and chronic kidney disease); constituency in the subpopulation with available information on serum creatinine levels; and the logit of the propensity score for the predicted probability of newly receiving an atypical antipsychotic drug (within a caliper of 0.2 SDs). We derived this propensity score from a logistic regression model and selected 91 variables for inclusion in the score on the basis of their potential association with the study outcomes or atypical antipsychotic drug initiation (variables listed in Table 4 of the Supplement) (24). One of the variables was the Johns Hopkins Adjusted Clinical Group Aggregated Diagnosis Groups (a validated measure of the complexity of comorbid conditions based on groups of diagnoses) (25, 26). Before matching, we excluded the following patients from both groups: those with prescriptions for any antipsychotic drug in the 180 days before their index date to ensure that the drug was newly prescribed (or had the potential to be newly prescribed in the case of the nonrecipients); those who were discharged from a hospital in the 2 days before their index date to ensure that drug use was newly initiated in the nonhospitalized setting (as in Ontario, patients continuing atypical antipsychotic drug treatment initiated in a hospital would have their oral outpatient prescription dispensed the day of or the day after hospital discharge); and those with evidence of end-stage renal disease before their index date (because the development of AKI is no longer relevant). Among the drug recipients, those who received a prescription for more than 1 type of antipsychotic drug (for example, a prescription for quetiapine and olanzapine) on their index date were excluded to compare mutually exclusive groups in subgroup analyses. Among the nonrecipients, those who did not have at least 1 outpatient medication dispensed in the 90 days before their index date were excluded to ensure that such persons were able to receive a prescription. Each drug recipient and nonrecipient could be selected only once for cohort entry. Outcomes We followed patients for 90 days after the index date to assess the prespecified outcomes. We chose 90 days to focus on acute adverse events, avoid potential crossovers between the 2 groups that might occur with longer follow-up, and mimic the duration of follow-up described in clinical trials of atypical antipsychotic drugs in older patients (1, 2, 27). The primary outcome was hospitalization with AKI. The secondary adverse outcomes were known causes of AKI (hospitalization with hypotension, acute urinary retention, the neuroleptic malignant syndrome or rhabdomyolysis, pneumonia, acute myocardial infarction, and ventricular arrhythmia) and all-cause mortality. The diagnosis codes used to identify the outcomes and information on their accuracy are presented in Table 3 of the Supplement (2830). For hospitalization records, up to 25 diagnosis codes can be assigned per hospitalization (for example, codes for AKI or rhabdomyolysis). Therefore, patients with codes for multiple study outcomes were accounted for in the assessment of each outcome. We previously examined the validity of the database code for hospitalization with AKI used in the current study. In this previous validation study (30), the database code for AKI identified a median increase in serum creatinine level of 98 mol/L (1.11 mg/dL) (interquartile range [IQR], 43 to 200 mol/L [0.49 to 2.26 mg/dL]) at the time of hospital presentation from the most recent value before hospitalization. The absence of such a code represented no statistically significant change in serum creatinine level (6 mol/L [0.07 mg/dL]; IQR, 4 to 20 mol/L [0.05 to 0.23 mg/dL]) (30). Although specificity was greater than 95%, the sensitivity of the hospital diagnosis was

Inadequate Reporting of Research Ethics Review and Informed Consent in Cluster Randomised Trials: Review of Random Sample of Published Trials

Objectives To investigate the extent to which authors of cluster randomised trials adhered to two basic requirements of the World Medical Association’s Declaration of Helsinki and the International Committee of Medical Journal Editors’ uniform requirements for manuscripts (namely, reporting of research ethics review and informed consent), to determine whether the adequacy of reporting has improved over time, and to identify characteristics of cluster randomised trials associated with reporting of ethics practices. Design Review of a random sample of published cluster randomised trials from an electronic search in Medline. Setting Cluster randomised trials in health research published in English language journals from 2000 to 2008. Study sample 300 cluster randomised trials published in 150 journals. Results 77 (26%, 95% confidence interval 21% to 31%) trials failed to report ethics review. The proportion reporting ethics review increased significantly over time (P<0.001). Trials with data collection interventions at the individual level were more likely to report ethics review than were trials that used routine data sources only (79% (n=151) v 55% (23); P=0.008). Trials that accounted for clustering in the design and analysis were more likely to report ethics review. The median impact factor of the journal of publication was higher for trials that reported ethics review (3.4 v 2.3; P<0.001). 93 (31%, 26% to 36%) trials failed to report consent. Reporting of consent increased significantly over time (P<0.001). Trials with interventions targeting participants at the individual level were more likely to report consent than were trials with interventions targeting the cluster level (87% (90) v 48% (41); P<0.001). Trials with data collection interventions at the individual level were more likely to report consent than were those that used routine data sources only (78% (146) v 29% (11); P<0.001). Conclusions Reporting of research ethics protections in cluster randomised trials is inadequate. In addition to research ethics approval, authors should report whether informed consent was sought, from whom consent was sought, and what consent was for.

Predictors of progression to chronic dialysis in survivors of severe acute kidney injury: a competing risk study

BackgroundSurvivors of acute kidney injury are at an increased risk of developing irreversible deterioration in kidney function and in some cases, the need for chronic dialysis. We aimed to determine predictors of chronic dialysis and death among survivors of dialysis-requiring acute kidney injury.MethodsWe used linked administrative databases in Ontario, Canada, to identify patients who were discharged from hospital after an episode of acute kidney injury requiring dialysis and remained free of further dialysis for at least 90 days after discharge between 1996 and 2009. Follow-up extended until March 31, 2011. The primary outcome was progression to chronic dialysis. Predictors for this outcome were evaluated using cause-specific Cox proportional hazards models, and a competing risk approach was used to calculate absolute risk.ResultsWe identified 4 383 patients with acute kidney injury requiring temporary in-hospital dialysis who survived to discharge. After a mean follow-up of 2.4 years, 356 (8%) patients initiated chronic dialysis and 1475 (34%) died. The cumulative risk of chronic dialysis was 13.5% by the Kaplan-Meier method, and 10.3% using a competing risk approach. After accounting for the competing risk of death, previous nephrology consultation (subdistribution hazard ratio (sHR) 2.03; 95% confidence interval (CI) 1.61-2.58), a history of chronic kidney disease (sHR3.86; 95% CI 2.99-4.98), a higher Charlson comorbidity index score (sHR 1.10; 95% CI 1.05-1.15/per unit) and pre-existing hypertension (sHR 1.82; 95% CI 1.28-2.58) were significantly associated with an increased risk of progression to chronic dialysis.ConclusionsAmong survivors of dialysis-requiring acute kidney injury who initially become dialysis independent, the subsequent need for chronic dialysis is predicted by pre-existing kidney disease, hypertension and global comorbidity. This information can identify patients at high risk of progressive kidney disease who may benefit from closer surveillance after cessation of the acute phase of illness.

Falls and Fractures With Atypical Antipsychotic Medication Use: A Population-Based Cohort Study

Discussion | In this study of health care utilization data, use of amiodarone but not of other antiarrhythmic drugs was associated with a 50% increased odds of acute pancreatitis among patients with NVAF. The odds were almost doubled in the 12 months after amiodarone therapy initiation and did not depend on cumulative use of amiodarone. Considering an incidence of acute pancreatitis of 3 to 4 cases per 10 000 adults per year,4 the observed association would result in approximately 1 to 2 additional cases of acute pancreatitis per 10 000 amiodarone users per year. A few isolated case reports of acute pancreatitis possibly linked to amiodarone use have been described in the literature.1-3 The mechanisms responsible for this association are unknown, although direct cytotoxicity or immune-mediated pathways, as described for amiodarone-related pulmonary toxic effects, could be potential explanations.5 Strengths of our study include the prospective assessment of medication use, the large sample size, and the availability of information on comorbidities and use of other medications potentially associated with increased risk of acute pancreatitis. Limitations are related to the use of health care utilization data: limited information on the validity of claims for acute pancreatitis, absence of clinical variables that characterize severity of the episode (eg, blood markers of acute pancreatitis), and the select group of patients included in this database. Our results indicate that acute pancreatitis could be an adverse effect of amiodarone use, an effect that may not be shared by other antiarrhythmic drugs. Even though the absolute risk of acute pancreatitis in the general population is low, health care professionals should be aware of this potential association in the treatment of patients with NVAF or acute pancreatitis. Further research should replicate our findings and determine potential mechanisms.

Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4

Background: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion–transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. Methods: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n = 51 523) or azithromycin (n = 52 518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. Results: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. Interpretation: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes.

Macrolide antibiotics and the risk of ventricular arrhythmia in older adults

Background: Many respiratory tract infections are treated with macrolide antibiotics. Regulatory agencies warn that these antibiotics increase the risk of ventricular arrhythmia. We examined the 30-day risk of ventricular arrhythmia and all-cause mortality associated with macrolide antibiotics relative to nonmacrolide antibiotics. Methods: We conducted a population-based retrospective cohort study involving older adults (age > 65 yr) with a new prescription for an oral macrolide antibiotic (azithromycin, clarithromycin or erythromycin) in Ontario from 2002 to 2013. Our primary outcome was a hospital encounter with ventricular arrhythmia within 30 days after a new prescription. Our secondary outcome was 30-day all-cause mortality. We matched patients 1:1 using propensity scores to patients prescribed nonmacrolide antibiotics (amoxicillin, cefuroxime or levofloxacin). We used conditional logistic regression to measure the association between macrolide exposure and outcomes, and repeated the analysis in 4 subgroups defined by the presence or absence of chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval. Results: Compared with nonmacrolide antibiotics, macrolide antibiotics were not associated with a higher risk of ventricular arrhythmia (0.03% v. 0.03%; relative risk [RR] 1.06, 95% confidence interval [CI] 0.83–1.36) and were associated with a lower risk of all-cause mortality (0.62% v. 0.76%; RR 0.82, 95% CI 0.78–0.86). These associations were similar in all subgroups. Interpretation: Among older adults, macrolide antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonmacrolide antibiotics. These findings suggest that current warnings from the US Food and Drug Administration may be overstated.

Association of Suicidality and Depression With 5α-Reductase Inhibitors

Importance There have been concerns raised by patients and regulatory agencies regarding serious psychiatric adverse effects associated with 5&agr;-reductase inhibitors. Objective To determine if there is an increased risk of suicide, self-harm, or depression among older men starting a 5&agr;-reductase inhibitor for prostatic enlargement. Design, Setting, and Participants A population-based, retrospective, matched cohort study using linked administrative data for 93 197 men ages 66 years or older (median [IQR] age, 75 [70-80] years) in Ontario, Canada, who initiated a new prescription for a 5&agr;-reductase inhibitor during the study period (2003 through 2013). Participants were matched (using a propensity score that included 44 of our 96 covariates that included medical comorbidities, medication usage, and health care system utilization) to an equal number of men not prescribed a 5&agr;-reductase inhibitor. Exposures Duration of finasteride or dutasteride usage. Main Outcomes and Measures Suicide. Secondary outcomes were self-harm and depression. Results Men who used 5&agr;-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53-1.45). Risk of self-harm was significantly increased during the initial 18 months after 5&agr;-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34-2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5&agr;-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73-2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08-1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100 000 patient-years and 237 per 100 000 patient-years, respectively. The type of 5&agr;-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression. Conclusions and Relevance In a large cohort of men ages 66 years or older, we did not demonstrate an increased risk of suicide associated with 5&agr;-reductase inhibitor use. However, the risk of self-harm and depression were increased compared with unexposed men. This is in keeping with postmarketing experience and patient concerns, and discontinuation of the medication in these circ umstances may be appropriate.