Greg Carney

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.

Nocturnal Leg Cramps and Prescription Use That Precedes Them: A Sequence Symmetry Analysis

BACKGROUND The use of diuretics, statins, and inhaled long-acting β2-agonists (LABAs) is linked to muscle cramps but largely by anecdotal evidence. This study sought population-level data to better evaluate these associations. METHODS Linked health care databases containing prescribing information (December 1, 2000, to November 30, 2008) about 4.2 million residents of British Columbia, Canada, were evaluated using sequence symmetry analysis to determine in adults 50 years or older whether new quinine prescriptions (initiations of cramp treatment) increase in the year following diuretic, statin, or LABA starts. The statistic of interest was the sequence ratio: the number of quinine starts in the year following index drug introduction compared with the number of quinine starts in the preceding year (adjusted for age and time trends in population prescribing). RESULTS Adjusted sequence ratios (95% CIs) for the 3 drug classes were 1.47 (1.33-1.63 [P < .001]) for diuretics, 1.16 (1.04-1.29 [P = .004]) for statins, and 2.42 (2.02-2.89 [P < .001]) for LABAs. For diuretic subclasses, adjusted sequence ratios (95% CIs) were 2.12 (1.61-2.78 [P < .001]) for potassium sparing, 1.48 (1.29-1.68 [P < .001]) for thiazidelike, and 1.20 (1.00-1.44 [P = .07]) for loop. For LABA subclasses, adjusted sequence ratios (95% CIs) were 2.17 (1.56-3.02) for LABAs alone and 2.55 (2.06-3.12) for LABAs-corticosteroids (P < .001 for both). CONCLUSIONS Cramp treatment was substantially more likely in the year following introduction of LABAs, potassium-sparing diuretics, or thiazidelike diuretics, and 60.3% of quinine users (individuals experiencing cramp) received at least 1 of these medications during a 13-year period. In contrast, statin and loop diuretic associations were small. Physicians should be mindful that the use of these medications may worsen symptoms in patients experiencing nocturnal leg cramps.

Osteoporosis medication prescribing in British Columbia and Ontario: impact of public drug coverage

SummaryWe compared the patterns of osteoporosis medication prescribing between two provinces in Canada with different public drug coverage policies. Oral bisphosphonates were the primary drugs used, yet access to the second-generation oral bisphosphonates (alendronate, risedronate) was limited in one region. Implications of differential access to oral bisphosphonates warrants further study.IntroductionApproved therapies for treating osteoporosis in Canada include bisphosphonates, calcitonin, denosumab, raloxifene, and teriparatide. However, significant variation in access to these medications through public drug coverage exists across Canada. We sought to compare patterns of osteoporosis medication prescribing between British Columbia (BC) and Ontario.MethodsUsing dispensing data from BC (PharmaNet) and Ontario (Ontario Drug Benefits), we identified all new users of osteoporosis medications aged 66 or more years from 1995/1996 to 2008/2009. We summarized the number of new users by fiscal year, sex, and index drug for each province. BC data were also stratified by whether drugs were dispensed within or outside public PharmaCare.ResultsWe identified 578,254 (n = 122,653 BC) eligible new users. Overall patterns were similar between provinces: (1) most patients received an oral bisphosphonate (93% in BC and 99% in Ontario); (2) etidronate prescribing declined after 2001/2002, reaching a low of 41% in BC and 10% in Ontario in 2008/2009; and (3) the proportion of males treated increased over time, from 7% in 1996/1997 to 25% in 2008/2009. However, we note major differences within versus outside the BC PharmaCare system. In particular, <2% of drugs dispensed within PharmaCare compared to 79% of drugs dispensed outside PharmaCare were for a second-generation bisphosphonate (alendronate or risedronate).ConclusionsOral bisphosphonates are the primary drugs used to treat osteoporosis in Canada. Prescribing practices changed over time as newer medications came to market, yet access to second-generation bisphosphonates through BC PharmaCare was limited. Implications of differential access to oral bisphosphonates warrants further study.

Rosiglitazone and Myocardial Infarction in Patients Previously Prescribed Metformin

Objective Rosiglitazone was found associated with approximately a 43% increase in risk of acute myocardial infarction (AMI) in a two meta-analyses of clinical trials. Our objective is to estimate the magnitude of the association in real-world patients previously treated with metformin. Research Design and Methods We conducted a nested case control study in British Columbia using health care databases on 4.3 million people. Our cohort consisted of 158,578 patients with Type 2 diabetes who used metformin as first-line drug treatment. We matched 2,244 cases of myocardial infarction (AMI) with up to 4 controls. Conditional logistic regression models were used to estimate matched odds ratios for AMI associated with treatment with rosiglitazone, pioglitazone and sulfonylureas. Results In our cohort of prior metformin users, adding rosiglitazone for up to 6 months was not associated with an increased risk of AMI compared to adding a sulfonylurea (odds ratio [OR] 1.38; 95% confidence interval [CI], 0.91–2.10), or compared to adding pioglitazone (OR for rosi versus pio 1.41; 95% CI, 0.74–2.66). There were also no significant differences between rosiglitazone, pioglitazone and sulfonylureas for longer durations of treatment. Though not significantly different from sulfonylureas, there was a transient increase in AMI risk associated with the first 6 months of treatment with a glitazone compared to not using the treatment (OR 1.53; 95% CI, 1.13–2.07) Conclusions In our British Columbia cohort of patients who received metformin as first-line pharmacotherapy for Type 2 diabetes mellitus, further treatment with rosiglitazone did not increase the risk of AMI compared to patients who were treated with pioglitazone or a sulfonylurea. Though not statistically significantly different compared from each other, an increased risk of AMI observed after starting rosiglitazone or sulfonylureas is a matter of concern that requires more research.

Seasonal effects on the occurrence of nocturnal leg cramps: a prospective cohort study

Background: It has been anecdotally reported that nocturnal leg cramps in pregnant women are worse in summer. We analyzed population-level data to determine whether the symptom burden of nocturnal leg cramps is seasonal in the general population. Methods: We examined time-series data for 2 independent measures of the symptom burden of leg cramps: (a) new quinine prescriptions (reflecting new or escalating treatment of leg cramps) from December 2001 to October 2007 among adults aged 50 years and older, which were obtained from linked health care databases that contain the prescribing information for the 4.2 million residents of British Columbia, Canada; and (b) the Internet search volume from February 2004 to March 2012 for the term “leg cramps” (reflecting public interest), which we obtained from Google Trends data and geographically limited to the United States and Australia. We assessed seasonality by determining how well a least-squares sinusoidal model predicted variability in the outcomes. Results: New quinine prescriptions and Internet searches related to leg cramps were both seasonal, with highs in mid-summer and lows in mid-winter, and a peak-to-peak variability that was about two-thirds of the mean. Seasonality accounted for 88% of the observed monthly variability in new quinine prescriptions (p < 0.001) and 70% of the observed variability in Internet searches related to leg cramps (p < 0.001). Interpretation: New quinine prescriptions and Internet searches related to leg cramps were seasonal and roughly doubled between the winter lows and summer highs. Why a disorder of peripheral motor neurons displays such strong seasonality warrants exploration.

Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy

Background: Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario. Methods: Using administrative data, we identified 4 historical cohorts of female users of isotretinoin (aged 12–48 yr) for the period 1996 to 2011. We defined pregnancy using International Statistical Classification of Diseases and billing codes. One definition included only cases with documented pregnancy outcomes (high-specificity definition); the other definition also included individuals recorded as receiving prenatal care (high-sensitivity definition). We studied new courses of isotretinoin and detected pregnancies in 2 time windows: during isotretinoin treatment only and up to 42 weeks after treatment. Live births were followed for 1 year to identify congenital malformations. Results: A total of 59 271 female patients received 102 308 courses of isotretinoin. Between 24.3% and 32.9% of participants received prescriptions for oral contraceptives while they were taking isotretinoin, compared with 28.3% to 35.9% in the 12 months before isotretinoin was started. According to the high-specificity definition of pregnancy, there were 186 pregnancies during isotretinoin treatment (3.1/1000 isotretinoin users), compared with 367 (6.2/1000 users) according to the high-sensitivity definition. By 42 weeks after treatment, there were 1473 pregnancies (24.9/1000 users), according to the high-specificity definition. Of these, 1331 (90.4%) terminated spontaneously or were terminated by medical intervention. Among the 118 live births were 11 (9.3%) cases of congenital malformation. Pregnancy rates during isotretinoin treatment remained constant between 1996 and 2011. Interpretation: Adherence to the isotretinoin pregnancy prevention program in Canada was poor during the 15-year period of this study.

A randomized trial assessing the impact of a personal printed feedback portrait on statin prescribing in primary care.

Introduction: Knowledge translation (KT) initiatives have the potential to improve prescribing quality and produce savings that exceed the cost of the KT program itself, including the cost of evaluation using pragmatic study methods. Our objective was to measure the impact and estimated savings resulting from the distribution of individualized physician portraits of statin prescribing along with therapeutic recommendations in British Columbia, Canada. Methods: A paired community design was used to study 2 725 family physicians in British Columbia. Communities were paired according to number of physicians and geographic location, with one community of each pair randomly assigned to an early (n = 1 349) or delayed (n = 1 376) intervention group. The intervention was a personalized prescribing portrait on statins that included therapeutic recommendations. The primary outcome was the impact on new prescribing (defined as statin naive) for primary prevention (defined as no diagnosis of cardiovascular disease) as recorded in the administrative claims databases of the BC Ministry of Health. Results: Compared to the delayed control group, the relative probability of a new statin prescription for primary prevention decreased by 6% in the 12 months after the Education for Quality Improvement in Patient Care (EQIP) portrait compared to the preceding 12 months (relative risk [RR] 0.94; 95% confidence interval [CI] 0.91‐0.98). There was also a non‐statistically significant decrease in new prescribing for secondary prevention in patients diagnosed with cardiovascular disease (RR 0.96; 95% CI 0.91‐1.01). We estimated that 572 fewer patients started statins for primary prevention in the first year after the portrait was mailed compared to patients in the delayed practices. We estimated the statin cost for those patients as

Trends in Health Care Utilization in British Columbia Following Public Coverage for Tiotropium

465,000 in the first two years, while the KT program to provide statin portraits cost less than

Is thiazolidinediones use a factor in delaying the need for insulin therapy in type 2 patients with diabetes? A population-based cohort study

100,000. Discussion: The individualized prescribing portrait had a significant beneficial effect on new statin prescribing for primary prevention but not secondary prevention. Provincial drug plan costs appear to have been reduced to a level that exceeded the cost of the program.

Cholinesterase Inhibitor Utilization: The Impact of Provincial Drug Policy on Discontinuation ☆

OBJECTIVES To examine the use and cost of health-care services in British Columbia, Canada, before and after public drug coverage for tiotropium bromide. METHODS A time series analysis was performed using data from British Columbias centralized administrative health-care databases. Linear regression on data from a stable 3-year prepolicy period was used to predict future use of inhaled anticholinergic (IAC) medications, visits to physicians, emergency hospitalizations, and costs. For each use measure, we estimated the policy effect as the difference between observed use in the postpolicy period and predicted use obtained from the prepolicy period. RESULTS In total, over the 2.5-year period after public coverage, tiotropium use increased by 24.4% more than predicted (95% confidence interval [CI] 23.9%-24.8%). Visits to physicians were unchanged, but there were between 596 and 948 more emergency admissions for chronic obstructive pulmonary disease, and between 582 and 1940 more hospital admissions of any kind than were predicted from prepolicy data. Total cost of inhaled IAC medications increased slightly more than predicted, by between an additional CDN