Colin R. Dormuth

Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients

Background: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications. Methods: We used linked health care utilization data of all BC residents to identify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and December 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents taking conventional antipsychotic medications and those taking atypical antipsychotic medications. Results: Of 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 24 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence interval [CI] 1.39–1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23–1.42). In comparison with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.86–2.45) and loxapine the lowest (mortality ratio 1.29, 95% CI 1.19–1.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.50–1.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.42–1.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding. Interpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.

Statin Adherence and Risk of Accidents A Cautionary Tale

Background— Bias in studies of preventive medications can occur when healthier patients are more likely to initiate and adhere to therapy than less healthy patients. We sought evidence of this bias by examining associations between statin exposure and various outcomes that should not be causally affected by statin exposure, such as workplace and motor vehicle accidents. Methods and Results— We conducted a prospective cohort study of statin patients using data from British Columbia, Canada, a multiethnic society with a population of 4.3 million people. Study subjects were 141 086 patients who initiated statins for primary prevention. We examined the association between adherence and multiple outcomes such as accidents and screening procedures using multivariable-adjusted Cox proportional hazards models. The study population was 49% female and had an average age of 61 years. The results from our multivariable-adjusted models showed that more adherent patients were less likely to have accidents than less adherent patients. This effect was greatest for motor vehicle accidents (hazard ratio, 0.75; 95% confidence interval, 0.72 to 0.79) and workplace accidents (hazard ratio, 0.77; 95% confidence interval, 0.74 to 0.81). More adherent patients had a greater likelihood of using screening services (hazard ratio, 1.17; 95% confidence interval, 1.15 to 1.20) and a lower likelihood of developing other diseases likely to be unrelated to a biological affect of a statin (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89). Conclusions— Our study contributes compelling evidence that patients who adhere to statins are systematically more health seeking than comparable patients who do not remain adherent. Caution is warranted when interpreting analyses that attribute surprising protective effects to preventive medications.

Good Research Practices for Comparative Effectiveness Research: Analytic Methods to Improve Causal Inference from Nonrandomized Studies of Treatment Effects Using Secondary Data Sources: The ISPOR Good Research Practices for Retrospective Database Analysis Task Force Report—Part III

OBJECTIVES Most contemporary epidemiologic studies require complex analytical methods to adjust for bias and confounding. New methods are constantly being developed, and older more established methods are yet appropriate. Careful application of statistical analysis techniques can improve causal inference of comparative treatment effects from nonrandomized studies using secondary databases. A Task Force was formed to offer a review of the more recent developments in statistical control of confounding. METHODS The Task Force was commissioned and a chair was selected by the ISPOR Board of Directors in October 2007. This Report, the third in this issue of the journal, addressed methods to improve causal inference of treatment effects for nonrandomized studies. RESULTS The Task Force Report recommends general analytic techniques and specific best practices where consensus is reached including: use of stratification analysis before multivariable modeling, multivariable regression including model performance and diagnostic testing, propensity scoring, instrumental variable, and structural modeling techniques including marginal structural models, where appropriate for secondary data. Sensitivity analyses and discussion of extent of residual confounding are discussed. CONCLUSIONS Valid findings of causal therapeutic benefits can be produced from nonrandomized studies using an array of state-of-the-art analytic techniques. Improving the quality and uniformity of these studies will improve the value to patients, physicians, and policymakers worldwide.

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.

Thiazolidinediones and Fractures in Men and Women

BACKGROUND Clinical trials and meta-analyses have found that rosiglitazone maleate, a thiazolidinedione that is prescribed for type 2 diabetes mellitus, increases the risk of fractures in women. The association between the use of thiazolidinediones and fractures in men and women is not adequately understood. METHODS We conducted a prospective cohort study. The primary outcome was peripheral fractures in men and women who were exposed to thiazolidinediones compared with sulfonylureas. We studied 84 339 patients from British Columbia, Canada, who began treatment with a thiazolidinedione or a sulfonylurea. The association between the use of thiazolidinediones and fractures was examined using multivariate-adjusted Cox models. RESULTS The mean age of the patients in the study was 59 years, and 43% were women. In this cohort, treatment with a thiazolidinedione was associated with a 28% increased risk of peripheral fractures compared with treatment with a sulfonylurea (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.10-1.48). The use of pioglitazone hydrochloride was associated with an increased risk of peripheral fracture of 77% in women (HR, 1.76; 95% CI 1.32-2.38). Compared with exposure to sulfonylureas, exposure to pioglitazone was associated with more peripheral fractures in men (HR, 1.61; 95% CI 1.18-2.20), but we did not observe a similar association with exposure to rosiglitazone (HR, 1.00; 95% CI, 0.75-1.34). CONCLUSIONS Both men and women who take thiazolidinediones could be at increased risk of fractures. Pioglitazone may be more strongly associated with fractures than rosiglitazone. Larger observational studies are needed, and fracture data from clinical trials need to be fully published so that fracture risks can be known with greater certainty.

Adherence to Statin Therapy Under Drug Cost Sharing in Patients With and Without Acute Myocardial Infarction A Population-Based Natural Experiment

Background— As medication spending grows, Medicare Part D will need to adapt its coverage policies according to emerging evidence from a variety of insurance policies. We sought to evaluate the consequences of copayment and coinsurance policies on the initiation of statin therapy after acute myocardial infarction and adherence to therapy in statin initiators using a natural experiment of all British Columbia residents aged 66 years and older. Methods and Results— Three consecutive cohorts that included all patients who began statin therapy during full drug coverage (2001), coverage with a

Commitment to change statements can predict actual change in practice

10 or

Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children

25 copay (2002), and coverage with a 25% coinsurance benefit (2003–2004) were followed up with linked healthcare utilization data (n=51 561). Follow-up of cohorts was 9 months after each policy change. Adherence to statin therapy was defined as ≥80% of days covered. Relative to full-coverage policies, adherence to new statin therapy was significantly reduced, from 55.8% to 50.5%, under a fixed copayment policy (−5.4% points; 95% CI, −6.4% to −4.4%) and the subsequent coinsurance policy (−5.4% points; 95% CI, −6.3% to −4.4%). An uninterrupted increase in the proportion of patients initiating statin therapy after an acute myocardial infarction (1.7% points per quarter) was observed over the study period, similar to a Pennsylvania control population with full coverage. Sudden changes to full out-of-pocket spending, similar to Medicare’s Part D “doughnut hole,” almost doubled the risk of stopping statins (adjusted odds ratio, 1.94, 95% CI, 1.82 to 2.08). Conclusions— Fixed patient copayment and coinsurance policies have negative effects on adherence to statin lipid-lowering drug therapy but not on their initiation after myocardial infarction.

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure

Introduction: Statements of commitment to change are advocated both to promote and to assess continuing education interventions. However, most studies of commitment to change have used self‐reported outcomes, and self‐reports may significantly overestimate actual performance. As part of an educational randomized controlled trial, this study documented changes that family physicians committed to make in their prescribing and then used third‐party data to examine actual changes. Method: Following participation in a continuing medical education program using interactive small groups, physicians were asked to identify changes that they planned to make in their practices. For prescribing changes related to four conditions, data from a provincial pharmacy registry were analyzed for 6‐month periods before and after the educational intervention. Results: A total of 207 physicians participated in the project, which involved monthly meetings of 30 peer learning groups. Ninety‐nine physicians received experimental case‐based educational modules ± personal prescribing feedback, and 91 of these indicated that they planned to make at least one change in practice. Of the 209 intended changes, 71% were directly related to the prescribing messages in the materials. Discussion: In three of four indicator conditions, physicians who expressed a commitment to change were significantly more likely to change their actual prescribing for the target medications in the following 6 months. The percentage of physicians who did change their prescribing varied significantly by condition. Further study of the process of translating commitment to change into real practice change is needed.

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

Background: The annual cut-off date of birth for entry to school in British Columbia, Canada, is Dec. 31. Thus, children born in December are typically the youngest in their grade. We sought to determine the influence of relative age within a grade on the diagnosis and pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD) in children. Methods: We conducted a cohort study involving 937 943 children in British Columbia who were 6–12 years of age at any time between Dec. 1, 1997, and Nov. 30, 2008. We calculated the absolute and relative risk of receiving a diagnosis of ADHD and of receiving a prescription for a medication used to treat ADHD (i.e., methylphenidate, dextroamphetamine, mixed amphetamine salts or atomoxetine) for children born in December compared with children born in January. Results: Boys who were born in December were 30% more likely (relative risk [RR] 1.30, 95% confidence interval [CI] 1.23–1.37) to receive a diagnosis of ADHD than boys born in January. Girls born in December were 70% more likely (RR 1.70, 95% CI 1.53–1.88) to receive a diagnosis of ADHD than girls born in January. Similarly, boys were 41% more likely (RR 1.41, 95% CI 1.33–1.50) and girls 77% more likely (RR 1.77, 95% CI 1.57–2.00) to be given a prescription for a medication to treat ADHD if they were born in December than if they were born in January. Interpretation: The results of our analyses show a relative-age effect in the diagnosis and treatment of ADHD in children aged 6–12 years in British Columbia. These findings raise concerns about the potential harms of overdiagnosis and overprescribing. These harms include adverse effects on sleep, appetite and growth, in addition to increased risk of cardiovascular events.