Muhammad Mamdani

A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

Background: Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown. Methods: We conducted a population-based nested case–control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31–90 days) or remote (91–180 days). Results: Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03–1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70–1.47). Interpretation: Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.

Effectiveness of virtual reality using Wii gaming technology in stroke rehabilitation: a pilot randomized clinical trial and proof of principle

Background and Purpose— Hemiparesis resulting in functional limitation of an upper extremity is common among stroke survivors. Although existing evidence suggests that increasing intensity of stroke rehabilitation therapy results in better motor recovery, limited evidence is available on the efficacy of virtual reality for stroke rehabilitation. Methods— In this pilot, randomized, single-blinded clinical trial with 2 parallel groups involving stroke patients within 2 months, we compared the feasibility, safety, and efficacy of virtual reality using the Nintendo Wii gaming system (VRWii) versus recreational therapy (playing cards, bingo, or “Jenga”) among those receiving standard rehabilitation to evaluate arm motor improvement. The primary feasibility outcome was the total time receiving the intervention. The primary safety outcome was the proportion of patients experiencing intervention-related adverse events during the study period. Efficacy, a secondary outcome measure, was evaluated with the Wolf Motor Function Test, Box and Block Test, and Stroke Impact Scale at 4 weeks after intervention. Results— Overall, 22 of 110 (20%) of screened patients were randomized. The mean age (range) was 61.3 (41 to 83) years. Two participants dropped out after a training session. The interventions were successfully delivered in 9 of 10 participants in the VRWii and 8 of 10 in the recreational therapy arm. The mean total session time was 388 minutes in the recreational therapy group compared with 364 minutes in the VRWii group (P=0.75). There were no serious adverse events in any group. Relative to the recreational therapy group, participants in the VRWii arm had a significant improvement in mean motor function of 7 seconds (Wolf Motor Function Test, 7.4 seconds; 95% CI, −14.5, −0.2) after adjustment for age, baseline functional status (Wolf Motor Function Test), and stroke severity. Conclusions— VRWii gaming technology represents a safe, feasible, and potentially effective alternative to facilitate rehabilitation therapy and promote motor recovery after stroke.

Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.

CONTEXT Severe acute kidney injury among hospitalized patients often necessitates initiation of short-term dialysis. Little is known about the long-term outcome of those who survive to hospital discharge. OBJECTIVE To assess the risk of chronic dialysis and all-cause mortality in individuals who experience an episode of acute kidney injury requiring dialysis. DESIGN, SETTING, AND PARTICIPANTS We conducted a population-based cohort study of all adult patients in Ontario, Canada, with acute kidney injury who required in-hospital dialysis and survived free of dialysis for at least 30 days after discharge between July 1, 1996, and December 31, 2006. These individuals were matched with patients without acute kidney injury or dialysis during their index hospitalization. Matching was by age plus or minus 5 years, sex, history of chronic kidney disease, receipt of mechanical ventilation during the index hospitalization, and a propensity score for developing acute kidney injury requiring dialysis. Patients were followed up until March 31, 2007. MAIN OUTCOME MEASURES The primary end point was the need for chronic dialysis and the secondary outcome was all-cause mortality. RESULTS We identified 3769 adults with acute kidney injury requiring in-hospital dialysis and 13 598 matched controls. The mean age was 62 years and median follow-up was 3 years. The incidence rate of chronic dialysis was 2.63 per 100 person-years among individuals with acute kidney injury requiring dialysis, and 0.91 per 100 person-years among control participants (adjusted hazard ratio, 3.23; 95% confidence interval, 2.70-3.86). All-cause mortality rates were 10.10 and 10.85 per 100 person-years, respectively (adjusted hazard ratio, 0.95; 95% confidence interval, 0.89-1.02). CONCLUSIONS Acute kidney injury necessitating in-hospital dialysis was associated with an increased risk of chronic dialysis but not all-cause mortality.

Atrial Fibrillation in Patients with Cryptogenic Stroke

BACKGROUND Atrial fibrillation is a leading preventable cause of recurrent stroke for which early detection and treatment are critical. However, paroxysmal atrial fibrillation is often asymptomatic and likely to go undetected and untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA). METHODS We randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or TIA within the previous 6 months (cause undetermined after standard tests, including 24-hour electrocardiography [ECG]), to undergo additional noninvasive ambulatory ECG monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-hour monitor (control group). The primary outcome was newly detected atrial fibrillation lasting 30 seconds or longer within 90 days after randomization. Secondary outcomes included episodes of atrial fibrillation lasting 2.5 minutes or longer and anticoagulation status at 90 days. RESULTS Atrial fibrillation lasting 30 seconds or longer was detected in 45 of 280 patients (16.1%) in the intervention group, as compared with 9 of 277 (3.2%) in the control group (absolute difference, 12.9 percentage points; 95% confidence interval [CI], 8.0 to 17.6; P<0.001; number needed to screen, 8). Atrial fibrillation lasting 2.5 minutes or longer was present in 28 of 284 patients (9.9%) in the intervention group, as compared with 7 of 277 (2.5%) in the control group (absolute difference, 7.4 percentage points; 95% CI, 3.4 to 11.3; P<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group than in the control group (52 of 280 patients [18.6%] vs. 31 of 279 [11.1%]; absolute difference, 7.5 percentage points; 95% CI, 1.6 to 13.3; P=0.01). CONCLUSIONS Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal atrial fibrillation was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT00846924.).

Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study

BACKGROUND Non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of congestive heart failure, but little is known about the cardiovascular effects of a newer group of NSAIDS called selective cyclo-oxygenase (COX)-2 inhibitors. We aimed to compare rates of admission for congestive heart failure in elderly patients who were newly dispensed COX-2 inhibitors or non-selective NSAIDs. METHODS In this population-based retrospective cohort study we identified NSAID-naive individuals aged 66 years or older, who were started on rofecoxib (n=14,583), celecoxib (n=18,908), and non-selective NSAIDs (n=5,391), and randomly selected non-NSAID users as controls (n=100,000). FINDINGS Relative to non-NSAID users, patients on rofecoxib and non-selective NSAIDS had an increased risk of admission for congestive heart failure (adjusted rate ratio 1.8, 95% CI 1.5-2.2, and 1.4, 1.0-1.9, respectively), but not celecoxib (1.0, 0.8-1.3). Compared with celecoxib users, admission was significantly more likely in users of non-selective NSAIDs (1.4, 1.0-1.9) and rofecoxib (1.8, 1.4-2.4). Risk of admission for rofecoxib users was higher than that for non-selective NSAID users (1.5, 1.1-2.1). Of patients with no admission in the past 3 years, only rofecoxib users were at increased risk of subsequent admission relative to controls (1.8, 1.4-2.3). INTERPRETATION These findings suggest a higher risk of admission for congestive heart failure in users of rofecoxib and non-selective NSAIDs, but not celecoxib, relative to non-NSAID controls.

Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women

CONTEXT Osteoporosis is associated with significant morbidity and mortality. Oral bisphosphonates have become a mainstay of treatment, but concerns have emerged that long-term use of these drugs may suppress bone remodeling, leading to unusual fractures. OBJECTIVE To determine whether prolonged bisphosphonate therapy is associated with an increased risk of subtrochanteric or femoral shaft fracture. DESIGN, SETTING, AND PATIENTS A population-based, nested case-control study to explore the association between bisphosphonate use and fractures in a cohort of women aged 68 years or older from Ontario, Canada, who initiated therapy with an oral bisphosphonate between April 1, 2002, and March 31, 2008. Cases were those hospitalized with a subtrochanteric or femoral shaft fracture and were matched to up to 5 controls with no such fracture. Study participants were followed up until March 31, 2009. MAIN OUTCOME MEASURES The primary analysis examined the association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure. To test the specificity of the findings, the association between bisphosphonate use and fractures of the femoral neck or intertrochanteric region, which are characteristic of osteoporotic fractures, was also examined. RESULTS We identified 716 women who sustained a subtrochanteric or femoral shaft fracture following initiation of bisphosphonate therapy and 9723 women who sustained a typical osteoporotic fracture of the intertrochanteric region or femoral neck. Compared with transient bisphosphonate use, treatment for 5 years or longer was associated with an increased risk of subtrochanteric or femoral shaft fracture (adjusted odds ratio, 2.74; 95% confidence interval, 1.25-6.02). A reduced risk of typical osteoporotic fractures occurred among women with more than 5 years of bisphosphonate therapy (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.93). Among 52,595 women with at least 5 years of bisphosphonate therapy, a subtrochanteric or femoral shaft fracture occurred in 71 (0.13%) during the subsequent year and 117 (0.22%) within 2 years. CONCLUSION Among older women, treatment with a bisphosphonate for more than 5 years was associated with an increased risk of subtrochanteric or femoral shaft fractures; however, the absolute risk of these fractures is low.

Reader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding

Although confounding is an important problem of cohort studies, its effects can be minimised to enable valid comparison In cohort studies, who does or does not receive an intervention is determined by practice patterns, personal choice, or policy decisions. This raises the possibility that the intervention and comparison groups may differ in characteristics that affect the study outcome, a problem called selection bias. If these characteristics have independent effects on the observed outcome in each group, they will create differences in outcomes between the groups apart from those related to the interventions being assessed. This effect is known as confounding.1 In the first paper in the series we dealt with the design and use of cohort studies and how to identify selection bias.2 This paper focuses on the definition and assessment of confounders. For a characteristic to be a confounder in a particular study, it must meet two criteria.1 The first is that it must be related to the outcome in terms of prognosis or susceptibility. For example, in the study of the association between antipsychotic use and hip fracture that we considered in the first paper,2 age is known to be related to risk of hip fracture and therefore has the potential to be a confounder. The second criterion that defines a confounder is that the distribution of the characteristic is different in the groups being compared. It can differ in terms of either the mean or the degree of variation or variability in that characteristic. For example, for age to be a confounder in a cohort study, either the average age or the variation in the age in the groups being compared would have to be different. Assessing variation as well as average values is important because groups can have the same average value …

Opioid Dose and Drug-Related Mortality in Patients With Nonmalignant Pain

BACKGROUND Opioids are widely prescribed for chronic nonmalignant pain, often at doses exceeding those recommended in clinical practice guidelines. However, the risk-benefit ratio of high-dose opioid therapy is not well characterized. The objective of this study was to characterize the relationship between opioid dose and opioid-related mortality. METHODS We conducted a population-based nested case-control study of Ontario, Canada, residents aged 15 to 64 years who were eligible for publicly funded prescription drug coverage and had received an opioid from August 1, 1997, through December 31, 2006, for nonmalignant pain. The outcome of interest was opioid-related death, as determined by the investigating coroner. The risk of opioid-related death was compared among patients treated with various daily doses of opioids. RESULTS Among 607,156 people aged 15 to 64 years prescribed an opioid over the study period, we identified 498 eligible patients whose deaths were related to opioids and 1714 matched controls. After extensive multivariable adjustment, we found that an average daily dose of 200 mg or more of morphine (or equivalent), was associated with a nearly 3-fold increase in the risk of opioid-related mortality (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.79-4.63) relative to low daily doses (<20 mg of morphine, or equivalent). We found significant but attenuated increases in opioid-related mortality with intermediate doses of opioids (50-99 mg/d of morphine: OR, 1.92; 95% CI, 1.30-2.85; 100-199 mg/d of morphine: OR, 2.04; 95% CI, 1.28-3.24). CONCLUSION Among patients receiving opioids for nonmalignant pain, the daily dose is strongly associated with opioid-related mortality, particularly at doses exceeding thresholds recommended in recent clinical guidelines.

Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone

Introduction: Opioid-related mortality appears to be increasing in Canada. We examined the true extent of the problem and the impact of the introduction of long-acting oxycodone. Methods: We examined trends in the prescribing of opioid analgesics in the province of Ontario from 1991 to 2007. We reviewed all deaths related to opioid use between 1991 and 2004. We linked 3271 of these deaths to administrative data to examine the patients’ use of health care services before death. Using time-series analysis, we determined whether the addition of long-acting oxycodone to the provincial drug formulary in January 2000 was associated with an increase in opioid-related mortality. Results: From 1991 to 2007, annual prescriptions for opioids increased from 458 to 591 per 1000 individuals. Opioid-related deaths doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. Prescriptions of oxycodone increased by 850% between 1991 and 2007. The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02). The manner of death was deemed unintentional by the coroner in 54.2% and undetermined in 21.9% of cases. Use of health care services in the month before death was common: for example, of the 3066 patients for whom data on physician visits were available, 66.4% had visited a physician in the month before death; of the 1095 patients for whom individual-level prescribing data were available, 56.1% had filled a prescription for an opioid in the month before death. Interpretation: Opioid-related deaths in Ontario have increased markedly since 1991. A significant portion of the increase was associated with the addition of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional. The frequency of visits to a physician and prescriptions for opioids in the month before death suggests a missed opportunity for prevention.

Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis

BACKGROUND Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown. METHODS We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141,487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46,662 (33%) were prescribed a statin within 90 days of discharge, 94,825 (67%) were not. Propensity-based matching, which accounted for each individuals likelihood of receiving a statin, yielded a cohort of 69,168 patients, of whom half (34,584) received a statin and half (34,584) did not. FINDINGS Incidence of sepsis was lower in patients receiving statins than in controls (71.2 vs 88.0 events per 10,000 person-years; hazard ratio [HR] 0.81; 95% CI 0.72-0.91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0.81; 95% CI 0.72-0.90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0.83; 95% CI 0.70-0.97) and fatal sepsis (0.75; 0.61-0.93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0.95; 0.75-1.22). IMPLICATIONS Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted.