J. Michael Paterson

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.

Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases

Objective To quantify an association between acute kidney injury and use of high potency statins versus low potency statins. Design Retrospective observational analysis of administrative databases, using nine population based cohort studies and meta-analysis. We performed as treated analyses in each database with a nested case-control design. Rate ratios for different durations of current and past statin exposure to high potency or low potency statins were estimated using conditional logistic regression. Ratios were adjusted for confounding by high dimensional propensity scores. Meta-analytic methods estimated overall effects across participating sites. Setting Seven Canadian provinces and two databases in the United Kingdom and the United States. Participants 2 067 639 patients aged 40 years or older and newly treated with statins between 1 January 1997 and 30 April 2008. Each person hospitalized for acute kidney injury was matched with ten controls. Intervention A dispensing event was new if no cholesterol lowering drug or niacin prescription was dispensed in the previous year. High potency statin treatment was defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin; all other statin treatments were defined as low potency. Statin potency groups were further divided into cohorts with or without chronic kidney disease. Main outcome measure Relative hospitalization rates for acute kidney injury. Results Of more than two million statin users (2 008 003 with non-chronic kidney disease; 59 636 with chronic kidney disease), patients with similar propensity scores were comparable on measured characteristics. Within 120 days of current treatment, there were 4691 hospitalizations for acute kidney injury in patients with non-chronic kidney injury, and 1896 hospitalizations in those with chronic kidney injury. In patients with non-chronic kidney disease, current users of high potency statins were 34% more likely to be hospitalized with acute kidney injury within 120 days after starting treatment (fixed effect rate ratio 1.34, 95% confidence interval 1.25 to 1.43). Users of high potency statins with chronic kidney disease did not have as large an increase in admission rate (1.10, 0.99 to 1.23). χ2 tests for heterogeneity confirmed that the observed association was robust across participating sites. Conclusions Use of high potency statins is associated with an increased rate of diagnosis for acute kidney injury in hospital admissions compared with low potency statins. The effect seems to be strongest in the first 120 days after initiation of statin treatment.

Improving cardiovascular health at population level: 39 community cluster randomised trial of Cardiovascular Health Awareness Program (CHAP)

Objective To evaluate the effectiveness of the community based Cardiovascular Health Awareness Program (CHAP) on morbidity from cardiovascular disease. Design Community cluster randomised trial. Setting 39 mid-sized communities in Ontario, Canada, stratified by location and population size. Participants Community dwelling residents aged 65 years or over, family physicians, pharmacists, volunteers, community nurses, and local lead organisations. Intervention Communities were randomised to receive CHAP (n=20) or no intervention (n=19). In CHAP communities, residents aged 65 or over were invited to attend volunteer run cardiovascular risk assessment and education sessions held in community based pharmacies over a 10 week period; automated blood pressure readings and self reported risk factor data were collected and shared with participants and their family physicians and pharmacists. Main outcome measure Composite of hospital admissions for acute myocardial infarction, stroke, and congestive heart failure among all community residents aged 65 and over in the year before compared with the year after implementation of CHAP. Results All 20 intervention communities successfully implemented CHAP. A total of 1265 three hour long sessions were held in 129/145 (89%) pharmacies during the 10 week programme. 15 889 unique participants had a total of 27 358 cardiovascular assessments with the assistance of 577 peer volunteers. After adjustment for hospital admission rates in the year before the intervention, CHAP was associated with a 9% relative reduction in the composite end point (rate ratio 0.91, 95% confidence interval 0.86 to 0.97; P=0.002) or 3.02 fewer annual hospital admissions for cardiovascular disease per 1000 people aged 65 and over. Statistically significant reductions favouring the intervention communities were seen in hospital admissions for acute myocardial infarction (rate ratio 0.87, 0.79 to 0.97; P=0.008) and congestive heart failure (0.90, 0.81 to 0.99; P=0.029) but not for stroke (0.99, 0.88 to 1.12; P=0.89). Conclusions A collaborative, multi-pronged, community based health promotion and prevention programme targeted at older adults can reduce cardiovascular morbidity at the population level. Trial registration Current controlled trials ISRCTN50550004.

Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases

Objective To evaluate the incremental increase in new onset diabetes from higher potency statins compared with lower potency statins when used for secondary prevention. Design Eight population based cohort studies and a meta-analysis. Setting Six Canadian provinces and two international databases from the UK and US. Participants 136 966 patients aged ≥40 years newly treated with statins between 1 January 1997 and 31 March 2011. Methods Within each cohort of patients newly prescribed a statin after hospitalisation for a major cardiovascular event or procedure, we performed as-treated, nested case-control analyses to compare diabetes incidence in users of higher potency statins with incidence in users of lower potency statins. Rate ratios of new diabetes events were estimated using conditional logistic regression on different lengths of exposure to higher potency versus lower potency statins; adjustment for confounding was achieved using high dimensional propensity scores. Meta-analytic methods were used to estimate overall effects across sites. Main outcome measures Hospitalisation for new onset diabetes, or a prescription for insulin or an oral antidiabetic drug. Results In the first two years of regular statin use, we observed a significant increase in the risk of new onset diabetes with higher potency statins compared with lower potency agents (rate ratio 1.15, 95% confidence interval 1.05 to 1.26). The risk increase seemed to be highest in the first four months of use (rate ratio 1.26, 1.07 to 1.47). Conclusions Higher potency statin use is associated with a moderate increase in the risk of new onset diabetes compared with lower potency statins in patients treated for secondary prevention of cardiovascular disease. Clinicians should consider this risk when prescribing higher potency statins in secondary prevention patients.

Serious infections in a population‐based cohort of 86,039 seniors with rheumatoid arthritis

To assess risk and risk factors for serious infections in seniors with rheumatoid arthritis (RA) using a case–control study nested within an RA cohort.

Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery.

CONTEXT Both benign prostatic hyperplasia (BPH) and cataract formation are common in older men. The alpha-adrenergic receptor blocker tamsulosin is frequently prescribed to treat BPH, and research suggests this drug may increase the intraoperative difficulty of cataract surgery. No studies have documented whether use of tamsulosin or other alpha-blocker drug therapies affect the risk of serious postoperative adverse events. OBJECTIVE To assess the risk of adverse events following cataract surgery in older men prescribed tamsulosin or other alpha-blocking drugs used to treat BPH. DESIGN, SETTING, AND PATIENTS Nested case-control analysis of a population-based retrospective cohort study using linked health care databases from Ontario, Canada. We included all men aged 66 years or older who had cataract surgery between 2002 and 2007 (N = 96 128). MAIN OUTCOME MEASURES A composite of procedures signifying retinal detachment, lost lens or lens fragment, or endophthalmitis occurring within 14 days after cataract surgery. The risk of these adverse events was compared between men treated with tamsulosin or other alpha-blockers and men with no exposure to these medications in the year prior to cataract surgery. We separately examined the association of drug exposure that was either recent (within the 14 days before surgery) or previous (15-365 days before surgery). RESULTS Overall, 3550 patients (3.7%) in the cohort had recent exposure to tamsulosin and 7426 patients (7.7%) had recent exposure to other alpha-blockers. Two hundred eighty-four patients (0.3%) had an adverse event. We randomly matched 280 of the cases to 1102 controls according to their age, surgeon, and year of surgery. Adverse events were significantly more common among patients with recent tamsulosin exposure (7.5% vs 2.7%; adjusted odds ratio [OR], 2.33; 95% confidence interval [CI], 1.22-4.43) but were not associated with recent exposure to other alpha-blockers (7.5% vs 8.0%; adjusted OR, 0.91; 95% CI, 0.54-1.54) or to previous exposure to either tamsulosin (< or = 1.8% vs 1%; adjusted OR, 0.94; 95% CI, 0.27-3.34) or other alpha-blockers (2.9% vs 2.1%; adjusted OR, 1.08; 95% CI, 0.47-2.48). This corresponds to an estimated number needed to harm (NNH) of 255 (95% CI, 99-1666). CONCLUSIONS Exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events. There were no significant associations with exposure to other alpha-blocker medications used to treat BPH.

The burden of premature opioid-related mortality

Background and Aims The burden of premature mortality due to opioid-related death has not been fully characterized. We calculated temporal trends in the proportion of deaths attributable to opioids and estimated years of potential life lost (YLL) due to opioid-related mortality in Ontario, Canada. Design Cross-sectional study. Setting Ontario, Canada. Participants Individuals who died of opioid-related causes between January 1991 and December 2010. Measurements We used the Registered Persons Database and data abstracted from the Office of the Chief Coroner to measure annual rates of opioid-related mortality. The proportion of all deaths related to opioids was determined by age group in each of 1992, 2001 and 2010. The YLL due to opioid-related mortality were estimated, applying the life expectancy estimates for the Ontario population. Findings We reviewed 5935 opioid-related deaths in Ontario between 1991 and 2010. The overall rate of opioid-related mortality increased by 242% between 1991 (12.2 per 1 000 000 Ontarians) and 2010 (41.6 per 1 000 000 Ontarians; P < 0.0001). Similarly, the annual YLL due to premature opioid-related death increased threefold, from 7006 years (1.3 years per 1000 population) in 1992 to 21 927 years (3.3 years per 1000 population) in 2010. The proportion of deaths attributable to opioids increased significantly over time within each age group (P < 0.05). By 2010, nearly one of every eight deaths (12.1%) among individuals aged 25–34 years was opioid-related. Conclusions Rates of opioid-related deaths are increasing rapidly in Ontario, Canada, and are concentrated among the young, leading to a substantial burden of disease.

Increased Risk of Complications Following Total Joint Arthroplasty in Patients With Rheumatoid Arthritis

Most of the evidence regarding complications following total hip arthroplasty (THA) and total knee arthroplasty (TKA) are based on patients with osteoarthritis (OA); less is known about outcomes in rheumatoid arthritis (RA). Using a validated algorithm for identifying patients with RA, we undertook this study to compare the rates of complications among THA and TKA recipients between those with RA and those without RA.

Risk of total knee arthroplasty after operatively treated tibial plateau fracture: a matched-population-based cohort study.

BACKGROUND The aims of operative treatment of displaced tibial plateau fractures are to stabilize the injured knee to restore optimal function and to minimize the risk of posttraumatic arthritis and the eventual need for total knee arthroplasty. The purpose of our study was to define the rate of subsequent total knee arthroplasty after tibial plateau fractures in a large cohort and to compare that rate with the rate in the general population. METHODS All patients sixteen years of age or older who had undergone surgical treatment of a tibial plateau fracture from 1996 to 2009 in the province of Ontario, Canada, were identified from administrative health databases with use of surgeon fee codes. Each member of the tibial plateau fracture cohort was matched to four individuals from the general population according to age, sex, income, and urban/rural residence. The rates of total knee arthroplasty at two, five, and ten years were compared by using time-to-event analysis. A separate Cox proportional hazards model was used to explore the influence of patient, provider, and surgical factors on the time to total knee arthroplasty. RESULTS We identified 8426 patients (48.5% female; median age, 48.9 years) who had undergone fixation of a tibial plateau fracture and matched them to 33,698 controls. The two, five, and ten-year rates of total knee arthroplasty in the plateau fracture and control cohorts were 0.32% versus 0.29%, 5.3% versus 0.82%, and 7.3% versus 1.8%, respectively (p < 0.0001). After adjustment for comorbidity, plateau fracture surgery was found to significantly increase the likelihood of total knee arthroplasty (hazard ratio [HR], 5.29 [95% confidence interval, 4.58, 6.11]; p < 0.0001). Higher rates of total knee arthroplasty were also associated with increasing age (HR, 1.03 [1.03, 1.04] per year over the age of forty-eight; p < 0.0001), bicondylar fracture (HR, 1.53 [1.26, 1.84]; p < 0.0001), and greater comorbidity (HR, 2.17 [1.70, 2.77]; p < 0.001). CONCLUSIONS Ten years after tibial plateau fracture surgery, 7.3% of the patients had had a total knee arthroplasty. This corresponds to a 5.3 times increase in likelihood compared with a matched group from the general population. Older patients and those with more severe fractures are also more likely to need total knee arthroplasty after repair of a tibial plateau fracture.

Relation between surgeon volume and risk of complications after total hip arthroplasty: propensity score matched cohort study

Objectives To identify a cut point in annual surgeon volume associated with increased risk of complications after primary elective total hip arthroplasty and to quantify any risk identified. Design Propensity score matched cohort study. Setting Ontario, Canada Participants 37 881 people who received their first primary total hip arthroplasty during 2002-09 and were followed for at least two years after their surgery. Main outcome measure The rates of various surgical complications within 90 days (venous thromboembolism, death) and within two years (infection, dislocation, periprosthetic fracture, revision) of surgery. Results Multivariate splines were developed to visualize the relation between surgeon volume and the risk for various complications. A threshold of 35 cases a year was identified, under which there was an increased risk of dislocation and revision. 6716 patients whose total hip arthroplasty was carried out by surgeons who had done ≤35 such procedure in the previous year were successfully matched to patients whose surgeon had carried out more than 35 procedures. Patients in the former group had higher rates of dislocation (1.9% v 1.3%, P=0.006; NNH 172) and revision (1.5% v 1.0%, P=0.03; NNH 204). Conclusions In a cohort of first time recipients of total hip arthroplasty, patients whose operation was carried by surgeons who had performed 35 or fewer such procedures in the year before the index procedure were at increased risk for dislocation and early revision. Surgeons should consider performing 35 cases or more a year to minimize the risk for complications. Furthermore, the methods used to visualize the relationship between surgeon volume and the occurrence of complications can be easily applied in any jurisdiction, to help inform and optimize local healthcare delivery.