Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.

BACKGROUND: Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program. METHODS: We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. RESULTS: The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92-2.63). INTERPRETATION: We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers.

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.

Effect of human papillomavirus (HPV) vaccination on clinical indicators of sexual behaviour among adolescent girls: the Ontario Grade 8 HPV Vaccine Cohort Study.

BACKGROUND: Suboptimal human papillomavirus (HPV) vaccine coverage in some jurisdictions is partly attributed to fears that vaccination may increase risky sexual behaviour. We assessed the effect of HPV vaccination on clinical indicators of sexual behaviour among adolescent girls in Ontario. METHODS: Using Ontario's administrative health databases, we identified a population-based cohort of girls in grade 8 in the 2 years before (2005/06 and 2006/07) and after (2007/08 and 2008/09) implementation of Ontario's grade 8 HPV vaccination program. For each girl, we then obtained data on vaccine receipt in grades 8 and 9 and data on indicators of sexual behaviour (pregnancy and non-HPV-related sexually transmitted infections) in grades 10-12. Using a quasi-experimental method known as regression discontinuity, we estimated, for each outcome, the risk difference (RD) and relative risk (RR) attributable to vaccination and to program eligibility. RESULTS: The cohort comprised 260 493 girls, of whom 131 781 were ineligible for the program and 128 712 were eligible. We identified 15 441 (5.9%) cases of pregnancy and sexually transmitted infection and found no evidence that vaccination increased the risk of this composite outcome: RD per 1000 girls -0.61 (95% confidence interval [CI] -10.71 to 9.49) and RR 0.96 (95% CI 0.81 to 1.14). Similarly, we found no discernible effect of program eligibility: RD per 1000 girls -0.25 (95% CI -4.35 to 3.85) and RR 0.99 (95% CI 0.93 to 1.06). The findings were similar when outcomes were assessed separately. INTERPRETATION: We present strong evidence that HPV vaccination does not have any significant effect on clinical indicators of sexual behaviour among adolescent girls. These results suggest that concerns over increased promiscuity following HPV vaccination are unwarranted and should not deter from vaccinating at a young age.

Evidence of effective delivery of the human papillomavirus (HPV) vaccine through a publicly funded, school-based program: the Ontario Grade 8 HPV Vaccine Cohort Study.

BACKGROUND: Proper administration of the human papillomavirus (HPV) vaccine (three doses at 0, 2, and 6 months) will likely influence the vaccine's effectiveness and the impact of vaccination programs on health outcomes. Therefore, we assessed HPV vaccine series completion and on-time dosing in Canada's largest publicly funded, school-based HPV vaccination program. METHODS: Using administrative health and immunization databases, we identified a population-based cohort of girls eligible for Ontario's Grade 8 HPV vaccination program in the 2007/08-2009/10 program years who received at least one dose of the vaccine. We determined the number of doses received and calculated the percentage of girls that completed the three-dose series in Grade 8 and Grades 8-9. To assess on-time dosing, the number of days between doses 1-2, 2-3, and 1-3 was calculated and categorized (e.g., too short, on schedule, too long) based on the manufacturer's recommendations. Analyses were also stratified by program year. RESULTS: We identified a cohort of 55,798 girls who initiated the vaccination series. Series completion was high in the Grade 8 window (81.8%) and increased by approximately 6% in Grade 9. Series completion was similar across the three program years. 70.8%, 98.5%, and 86.1% of girls were classified as 'on schedule' for dosing intervals 1-2, 2-3, and 1-3, respectively; 70.0% of girls received all three doses in perfect accordance with dosing recommendations. Stratification revealed that on-time dosing was highest in the first two years of the program (85.6% and 80.6%), but dropped to 42.1% in the 2009/10 year when H1N1 vaccination programs were prioritized. CONCLUSIONS: Our study demonstrates that delivery of the HPV vaccine through a free, school-based program is an effective method of ensuring high completion and on-time dosing, but may not be sufficient to guarantee high coverage.

Individual- and regional-level determinants of human papillomavirus (HPV) vaccine refusal: the Ontario Grade 8 HPV vaccine cohort study.

BACKGROUND: Studies on the determinants of human papillomavirus (HPV) vaccine use have generally focused on individual-level characteristics, despite the potentially important influence of regional-level characteristics. Therefore, we undertook a population-based, retrospective cohort study to identify individual- and regional-level determinants of HPV vaccine refusal (non-receipt) in Ontario's (Canada) Grade 8 HPV Immunization Program. METHODS: Ontario's administrative health and immunization databases were used to identify girls eligible for free HPV vaccination in 2007-2011 and to ascertain individual-level characteristics of cohort members (socio-demographics, vaccination history, health care utilization, medical history). The social and material characteristics of the girl's region (health unit) were derived from the 2006 Canadian Census. Generalized estimating equations (binomial distribution, logit link) were used to estimate the population-average effects of individual- and regional-level characteristics on HPV vaccine refusal. RESULTS: Our cohort consisted of 144,047 girls, 49.3% of whom refused HPV vaccination. Factors associated with refusal included a previous diagnosis of Down's syndrome (OR = 1.37, 95% CI 1.16-1.63) or autism (OR = 1.60, 95% CI 1.34-1.90), few physician visits (OR = 1.45, 95% CI 1.35-1.55), and previous refusal of mandatory (OR = 2.23, 95% CI 2.07-2.40) and optional (OR = 3.96, 95% CI 3.87-4.05) vaccines. Refusal was highest among the lowest and highest income levels. Finally, a previous diagnosis of obesity and living in an area of high deprivation were associated with lower refusal (OR = 0.87, 95% CI 0.83-0.92 and OR = 0.82 95%, CI 0.79-0.86, respectively). CONCLUSIONS: Studies on HPV vaccine determinants should consider regional-level factors. Efforts to increase HPV vaccine acceptance should include vulnerable populations (such as girls of low income) and girls with limited contact with the healthcare system.

Antipsychotic drugs and the risk of hyperglycemia in older adults without diabetes: a population-based observational study.

OBJECTIVE: To determine whether current antipsychotic use among older persons without diabetes is associated with a higher risk of hospital visits for hyperglycemia, as previous studies in this population have yielded conflicting results. DESIGN, SETTING AND PARTICIPANTS: A nested case-control study within a population-based cohort of persons aged 66 years or older without diabetes, who initiated antipsychotic therapy between April 1, 2002, and March 31, 2006. Cohort members were identified using health databases from Ontario, Canada, and were followed from treatment start until March 31, 2007. MEASUREMENTS: Cases were patients with a hospital visit (emergency department visit or hospital admission) for hyperglycemia. We matched each case with up to 10 controls. We compared the risk of hyperglycemia among current antipsychotic users to that of remote users (discontinued > 180 days). RESULTS: The cohort consisted of 44,121 subjects, mean age of 78.3 years, followed for a mean of 2.2 years. Compared to remote antipsychotic use, current treatment with any antipsychotic was associated with a significantly increased risk of hospital visits for hyperglycemia (adjusted odds ratio [aOR]: 1.52; 95% confidence interval [CI]: 1.07-2.17). The risk was elevated for both atypical (aOR: 1.44; 95% CI: 1.01-2.07) and typical (aOR: 2.86; 95% CI: 1.46-5.59) antipsychotic agents. CONCLUSIONS: Current use of either atypical or typical antipsychotic agents was associated with a significantly increased risk of hospital visits for hyperglycemia among older persons without diabetes. These findings highlight the need for close glucose monitoring during antipsychotic therapy in older populations.

Factors associated with initiation and completion of the quadrivalent human papillomavirus vaccine series in an Ontario cohort of grade 8 girls.

BACKGROUND: Although over a hundred million dollars have been invested in offering free quadrivalent human papillomavirus (HPV) vaccination to young girls in Ontario, there continues to be very little information about its usage. In order to successfully guide future HPV vaccine programming, it is important to monitor HPV vaccine use and determine factors associated with use in this population. METHODS: Linking administrative health and immunization databases, we conducted a population-based, retrospective cohort study of girls eligible for Ontario's Grade 8 HPV vaccination program in Kingston, Frontenac, Lennox, and Addington. We determined the proportion of girls who initiated (at least one dose) and completed (all three doses) the vaccination series overall and according to socio-demographics, vaccination history, health services utilization, medical history, and program year. Multivariable logistic regression was used to estimate the strength of association between individual factors and initiation and completion, adjusted for all other factors. RESULTS: We identified a cohort of 2519 girls, 56.6% of whom received at least one dose of the HPV vaccine. Among vaccinated girls, 85.3% received all three doses. Vaccination history was the strongest predictor of initiation in that girls who received the measles-mumps-rubella, meningococcal C, and hepatitis B vaccines were considerably more likely to also receive the HPV vaccine (odds ratio 4.89; 95% confidence interval 4.04-5.92). Nevertheless, HPV vaccine uptake was more than 20% lower than that of these other vaccines. In addition, while series initiation was not influenced by income, series completion was. In particular, girls of low income were the least likely to receive all three indicated doses of the HPV vaccine (odds ratio 0.45; 95% confidence interval 0.28-0.72). CONCLUSIONS: The current low level of HPV vaccine acceptance in Kingston, Frontenac, Lennox, and Addington will likely have important implications in terms of the health benefits and cost-effectiveness of its publicly funded program. We identified important factors associated with series initiation and completion that should be considered in efforts to improve HPV vaccine use in this population.

Safety and use of tetanus-diphtheria-acellular pertussis-5 (Tdap5) vaccine during pregnancy: findings from 11 years of reporting to a pregnancy registry.

The "Adacel (Tdap5) Pregnancy Registry" was used to identify 1182 women who received the tetanus, diphtheria, acellular pertussis [5 components] (Tdap5) vaccine during pregnancy from 2005 to 2016. To evaluate the safety and use of prenatal Tdap5, we calculated the rate of maternal, obstetrical, pregnancy and neonatal outcomes following Tdap5 pregnancy exposure and assessed vaccine uptake by year and trimester of exposure. The most commonly reported maternal adverse events included injection site reactions (2.6%; 95% Confidence Interval 1.8%, 3.7%), nervous system events (1.3%; 0.8%, 2.1%) and musculoskeletal events (1.1%; 0.6%, 1.9%). The most commonly reported complications of pregnancy were hypertension/preeclampsia (5.5%; 3.3%, 8.9%) and gestational diabetes (2.5%; 1.1%, 5.3%), while those for labor and delivery were premature labor (2.9%; 1.4%, 5.7%) and premature membrane rupture (1.5%; 0.4%, 3.8%). These rates were similar to, or lower than those reported for the general population of pregnant women. Among pregnancies with known birth outcomes (N = 275), 90.4% (86.2%, 93.4%) resulted in a live birth, 5.9% (3.6%, 9.5%) in spontaneous abortion, 3.0% (1.4%, 5.8%) in stillbirth, and 0.7% (0.0%, 2.8%) in ectopic pregnancies. Most newborns had normal APGAR scores and birth weights (98.1% and 93.0%, respectively), and only two reported a congenital anomaly (0.7%; 0.0%, 2.8%). An influx of reports in 2012 with third trimester Tdap5 exposure coincided with the 2012 updated Advisory Committee on Immunization Practices recommendations. This analysis did not identify any safety concerns across the continuum of maternal, obstetrical, pregnancy, and neonatal outcomes in women who received Tdap5 vaccination during pregnancy.

A comparison of methods for forecasting emergency department visits for respiratory illness using telehealth Ontario calls.

OBJECTIVES: Anticipating increases in hospital emergency department (ED) visits for respiratory illness could help time interventions such as opening flu clinics to reduce surges in ED visits. Five different methods for estimating ED visits for respiratory illness from Telehealth Ontario calls are compared, including two non-linear modeling methods. Daily visit estimates up to 14 days in advance were made at the health unit level for all 36 Ontario health units. METHODS: Telehealth calls from June 1, 2004 to March 14, 2006 were included. Estimates generated by regression, Exponentially Weighted Moving Average (EWMA), Numerical Methods for Subspace State Space Identification (N4SID), Fast Orthogonal Search (FOS), and Parallel Cascade Identification (PCI) were compared to the actual number of ED visits for respiratory illness identified from the National Ambulatory Care Reporting System (NACRS) database. Model predictor variables included Telehealth Ontario calls and upcoming holidays/weekends. Models were fit using the first 304 days of data and prediction accuracy was measured over the remaining 348 days. RESULTS: Forecast accuracy was significantly better (p < 0.0001) for the 12 Ontario health units with a population over 400,000 (75% of the Ontario population) than for smaller health units. Compared to regression, FOS produced better estimates (p = 0.03) while there was no significant improvement for PCI-based estimates. FOS, PCI, EWMA and N4SID performed worse than regression over the remaining smaller health units. CONCLUSION: Telehealth can be used to estimate ED visits for respiratory illness at the health unit level. Non-linear modeling methods produced better estimates than regression in larger health units.

Investigation of an interaction between statins and clopidogrel after percutaneous coronary intervention: a cohort study.

BACKGROUND: Clopidogrel is an antiplatelet drug that is prescribed after percutaneous coronary intervention (PCI) to prevent stent thrombosis. Previous studies have suggested that some statins may inhibit the antiplatelet effects of clopidogrel via competitive metabolism of its activating enzyme cytochrome P450 3A4 (CYP3A4). OBJECTIVES: To investigate a possible interaction between statins and clopidogrel after a PCI procedure in a population-based cohort study. METHODS: A population-based cohort study was carried out between January 2001 and December 2004 using the health insurance databases from Quebec, Canada. The primary endpoint was a composite of death from any cause, myocardial infarction (MI), unstable angina, repeat revascularization and cerebrovascular events. PCI patients >or= 66 years of age were followed from their initial post-discharge clopidogrel prescription until the earliest of study endpoint occurrence, end of clopidogrel exposure or end of study (90 days post discharge). Time-dependent Cox regression analysis was performed. RESULTS: We identified 10491 patients who were prescribed clopidogrel post-PCI and 43.5% were also prescribed statins at the baseline discharge. During 1793 patient years of follow-up, 623 composite endpoints were observed. Compared to the reference group (non-CYP3A4-metabolized statins), the co-prescription of CYP3A4-metabolized statins (hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.47), or no statin use (HR 1.22, 95%CI 0.93-1.59) were not statistically associated with an increase in adverse outcomes. CONCLUSIONS: In this PCI cohort, the association of clopidogrel with CYP3A4-metabolized statins did not demonstrate an increased early risk of adverse cardiovascular events, although a small risk could not be completely excluded.

Effectiveness of Oral Bisphosphonates in Reducing Fracture Risk Among Oral Glucocorticoid Users: Three Matched Cohort Analyses.

The benefit of oral bisphosphonates in reducing fracture risk in glucocorticoid-induced osteoporosis is controversial. We aimed to estimate the effectiveness of oral bisphosphonates in reducing fracture risk in a cohort of new chronic oral glucocorticoid users. We created three matched cohorts using health care administrative data from Ontario, Canada. We included residents aged 66 years and older initiating chronic oral glucocorticoids (≥450 mg prednisone equivalent and ≥2 glucocorticoid prescriptions within a 6-month window) between January 1998 and September 2014. Exposed patients were those who initiated an oral bisphosphonate (alendronate, etidronate, or risedronate) within the first 6 months of starting chronic oral glucocorticoid therapy. Exposed cohorts (3945 alendronate, 5825 risedronate, and 8464 etidronate) were each matched 1:1 to unexposed patients on glucocorticoid exposure, fracture risk factors, and propensity score. We examined incident hip (primary outcome), vertebral, forearm, and humerus fractures using Cox proportional hazard models. Alendronate (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.25-0.80) and risedronate (HR = 0.58, 95% CI 0.36-0.90) were associated with reduced hip fracture risk. Alendronate (HR = 0.52, 95% CI 0.39-0.68), etidronate (HR = 0.59, 95% CI 0.48-0.73) and risedronate (HR = 0.47 95% CI 0.36-0.60) were associated with reduced vertebral fracture risk. No risk reduction in forearm or humerus fractures was apparent for any bisphosphonate. Among older chronic glucocorticoid initiators, all oral bisphosphonates reduced vertebral fracture risk, yet only alendronate and risedronate reduced hip fracture risk. Results were similar between men and women. We provided compelling evidence that early initiation of oral bisphosphonates during chronic oral glucocorticoid therapy is beneficial to prevent osteoporotic fractures. © 2017 American Society for Bone and Mineral Research.

Thiazolidinediones and cardiovascular outcomes in older patients with diabetes.

CONTEXT: Thiazolidinediones (TZDs), used to treat type 2 diabetes, are associated with an excess risk of congestive heart failure and possibly acute myocardial infarction. However, the association between TZD use and cardiovascular events has not been adequately evaluated on a population level. OBJECTIVE: To explore the association between TZD therapy and congestive heart failure, acute myocardial infarction, and mortality compared with treatment with other oral hypoglycemic agents. DESIGN, SETTING, AND PATIENTS: Nested case-control analysis of a retrospective cohort study using health care databases in Ontario. We included diabetes patients aged 66 years or older treated with at least 1 oral hypoglycemic agent between 2002 and 2005 (N = 159 026) and followed them up until March 31, 2006. MAIN OUTCOME MEASURES: The primary outcome consisted of an emergency department visit or hospitalization for congestive heart failure; secondary outcomes were an emergency department visit or hospitalization for acute myocardial infarction and all-cause mortality. The risks of these events were compared between persons treated with TZDs (rosiglitazone and pioglitazone) and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors. RESULTS: During a median follow-up of 3.8 years, 12 491 patients (7.9%) had a hospital visit for congestive heart failure, 12,578 (7.9%) had a visit for acute myocardial infarction, and 30 265 (19%) died. Current treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases; adjusted rate ratio [RR], 1.60; 95% confidence interval [CI], 1.21-2.10; P < .001), acute myocardial infarction (65 cases; RR, 1.40; 95% CI, 1.05-1.86; P = .02), and death (102 cases; RR, 1.29; 95% CI, 1.02-1.62; P = .03) compared with other oral hypoglycemic agent combination therapies (3478 congestive heart failure cases, 3695 acute myocardial infarction cases, and 5529 deaths). The increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with TZD use appeared limited to rosiglitazone. CONCLUSION: In this population-based study of older patients with diabetes, TZD treatment, primarily with rosiglitazone, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments.

Strategies for evaluating the assumptions of the regression discontinuity design: a case study using a human papillomavirus vaccination programme.

Background: The regression discontinuity design (RDD) is a quasi-experimental approach used to avoid confounding bias in the assessment of new policies and interventions. It is applied specifically in situations where individuals are assigned to a policy/intervention based on whether they are above or below a pre-specified cut-off on a continuously measured variable, such as birth date, income or weight. The strength of the design is that, provided individuals do not manipulate the value of this variable, assignment to the policy/intervention is considered as good as random for individuals close to the cut-off. Despite its popularity in fields like economics, the RDD remains relatively unknown in epidemiology where its application could be tremendously useful. Methods: In this paper, we provide a practical introduction to the RDD for health researchers, describe four empirically testable assumptions of the design and offer strategies that can be used to assess whether these assumptions are met in a given study. For illustrative purposes, we implement these strategies to assess whether the RDD is appropriate for a study of the impact of human papillomavirus vaccination on cervical dysplasia. Results: We found that, whereas the assumptions of the RDD were generally satisfied in our study context, birth timing had the potential to confound our effect estimate in an unexpected way and therefore needed to be taken into account in the analysis. Conclusions: Our findings underscore the importance of assessing the validity of the assumptions of this design, testing them when possible and making adjustments as necessary to support valid causal inference.

Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors.

BACKGROUND: The timing of cardiovascular risks associated with the use of cyclooxygenase-2 (COX-2) inhibitors is unclear. Using data collected in a previous population-based cohort study of elderly people starting nonsteroidal anti-inflammatory drug (NSAID) therapy, we evaluated the temporal nature of the risk of a first myocardial infarction (MI) associated with the use of rofecoxib and celecoxib. METHODS: We identified people 66 years of age or older without previous MI who were currently taking rofecoxib and celecoxib using Quebec's computerized health databases (January 1999 to June 2002). Data on use and MI outcome were analyzed using a time-matched, nested case-control approach with rate ratios, comparing current users and non-users of rofecoxib and celecoxib in the year preceding the index date, estimated using conditional logistic regression. RESULTS: The risk of MI was highest following first-time use of rofecoxib (adjusted rate ratio [RR] 1.67, 95% confidence interval [CI] 1.21-2.30), with events occurring within a median of 9 (6-13) days after therapy was started. The risk increase for first-time use of celecoxib was not statistically significant (RR 1.29, 95% CI 0.90-1.83). Repeated exposure to rofecoxib was associated with a small but statistically nonsignificant delayed risk (RR 1.17, 95% CI 0.98-1.40), but no risk was seen with celecoxib (RR 0.97, 95% CI 0.82-1.14). Treatment duration was not associated with increasing risk for either agent. The risk remained elevated for the first 7 days after rofecoxib was discontinued (RR 1.23, 95% CI 1.05-1.44) but appeared to return to baseline between day 8 and 30 (RR 0.82, 95% CI 0.61-1.09). INTERPRETATION: A small proportion of patients using rofecoxib for the first time had their first MI shortly after starting the drug. This risk did not increase with the length of treatment and returned to baseline shortly after treatment was discontinued. More research is needed to identify those most susceptible to cardiotoxicity mediated by COX-2 inhibitor therapy.

The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults.

BACKGROUND: Cyclooxygenase-2 (COX-2) selective inhibitors have been marketed since 1999 as safer alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs). Debate about their cardiac safety has culminated in the recent withdrawal of rofecoxib. Additional studies are needed to better understand this risk and to determine whether this safety concern represents a class effect. OBJECTIVE: To assess the influence of various NSAIDs on the risk for a first myocardial infarction (MI). DESIGN: Population-based, retrospective cohort study analyzed using a time-matched, nested case-control approach. SETTING: Quebec, Canada. PARTICIPANTS: 113,927 elderly persons without previous MI and newly treated with an NSAID between 1 January 1999 and 30 June 2002. MEASUREMENTS: NSAID exposure and occurrence of MI assessed by using Quebec's administrative health databases. RESULTS: Compared with no use of NSAIDs in the year preceding the event, current use of rofecoxib was associated with an increased risk for an acute MI (rate ratio [RR], 1.24 [95% CI, 1.05 to 1.46]) that was more pronounced at higher doses (RR, 1.73 [CI, 1.09 to 2.76]). The concomitant use of aspirin appears to decrease the risk associated with low-dose rofecoxib (RR, 1.00 [CI, 0.77 to 1.28]) but not with high-dose rofecoxib (RR, 2.36 [CI, 1.27 to 4.39]). No increased risks were observed with celecoxib (RR, 0.99 [CI, 0.85 to 1.16]) or the other NSAIDs. LIMITATIONS: The study could not completely account for all potential confounders, including over-the-counter use of aspirin and ibuprofen. CONCLUSIONS: These results provide evidence of an increased risk for acute MI in current users of rofecoxib among elderly persons with no history of MI. This risk appears greater at higher doses. Aspirin use mitigates the risk associated with low-dose but not high-dose rofecoxib. There was no evidence of an increased risk with the other NSAIDs.

Urban-rural differences in the uptake of new oral bisphosphonate formulations.

UNLABELLED: We identified significantly slower uptake, and consistently lower proportions of new oral bisphosphonate formulations dispensed in rural regions compared to urban regions of Ontario. Further research examining regional differences in outcomes may provide insight as to whether urban-rural differences in prescribing translate into health disparities between regions. PURPOSE: The aim of this study was to examine urban-rural differences in the uptake of new oral bisphosphonate formulations available on the Ontario drug formulary: alendronate + vitamin D3 (January 2007), monthly risedronate (June 2009), and risedronate delayed-release (February 2012). METHODS: We plotted the monthly proportion of new formulation claims of all claims with the same drug molecule, from their formulary listing date until March 2014. Results were stratified by major urban, nonmajor urban, and rural regions as defined by the Rurality Index of Ontario. We compared the rate of uptake over the first year of formulary availability using linear regression, and compared proportions dispensed between regions using chi-squared tests. RESULTS: We identified a regional gradient in uptake for alendronate + vitamin D3 and monthly risedronate; major urban regions had the fastest uptake, followed by nonmajor urban regions, and rural regions had the slowest uptake. Rural regions also had the slowest uptake of risedronate delayed-release; however, uptake in major urban and nonmajor urban regions were similar. Rural regions dispensed the lowest proportions for all new formulations 1 year after formulary availability: alendronate + vitamin D3 (32% major urban, 23% nonmajor urban, 12% rural), monthly risedronate (26% major urban, 21% nonmajor urban, 16% rural), and risedronate delayed-release (21% major urban, 22 % nonmajor urban, 13% rural). This pattern persisted throughout our study. CONCLUSION: We identified significantly slower uptake and lower proportions of new formulations dispensed in rural regions compared to urban regions. Further research examining regional differences in outcomes may demonstrate whether urban-rural differences in prescribing translate into health disparities between regions.

Interrupted time series analysis in drug utilization research is increasing: systematic review and recommendations.

OBJECTIVES: To describe the use and reporting of interrupted time series methods in drug utilization research. STUDY DESIGN AND SETTING: We completed a systematic search of MEDLINE, Web of Science, and reference lists to identify English language articles through to December 2013 that used interrupted time series methods in drug utilization research. We tabulated the number of studies by publication year and summarized methodological detail. RESULTS: We identified 220 eligible empirical applications since 1984. Only 17 (8%) were published before 2000, and 90 (41%) were published since 2010. Segmented regression was the most commonly applied interrupted time series method (67%). Most studies assessed drug policy changes (51%, n = 112); 22% (n = 48) examined the impact of new evidence, 18% (n = 39) examined safety advisories, and 16% (n = 35) examined quality improvement interventions. Autocorrelation was considered in 66% of studies, 31% reported adjusting for seasonality, and 15% accounted for nonstationarity. CONCLUSION: Use of interrupted time series methods in drug utilization research has increased, particularly in recent years. Despite methodological recommendations, there is large variation in reporting of analytic methods. Developing methodological and reporting standards for interrupted time series analysis is important to improve its application in drug utilization research, and we provide recommendations for consideration.

The early benefits of human papillomavirus vaccination on cervical dysplasia and anogenital warts.

BACKGROUND: Despite widespread promotion of quadrivalent human papillomavirus (qHPV) vaccination for young girls, there is limited information on the vaccine's real-world effectiveness and none on the effectiveness of qHPV vaccination programs. We assessed the impact of the qHPV vaccine and Ontario's grade 8 qHPV vaccination program on cervical dysplasia and anogenital warts (AGW). METHODS: By using administrative health databases of Ontario, Canada, we identified a population-based retrospective cohort of girls in grade 8 before (2005/2006-2006/2007) and after (2007/2008-2008/2009) program implementation. Vaccine exposure was ascertained in grades 8 to 9 and outcomes in grades 10 to 12. A quasi-experimental approach known as regression discontinuity was used to estimate absolute risk differences (RDs), relative risks (RRs), and 95% confidence intervals (CIs) attributable to vaccination and program eligibility (intention-to-treat analysis). RESULTS: The cohort comprised 131,781 ineligible and 128,712 eligible girls (n = 260,493). We identified 2436 cases of dysplasia and 400 cases of AGW. Vaccination significantly reduced the incidence of dysplasia by 5.70 per 1000 girls (95% CI -9.91 to -1.50), corresponding to a relative reduction of 44% (RR 0.56; 95% CI 0.36 to 0.87). Program eligibility also had a significant protective effect on dysplasia: RD -2.32/1000 (95% CI -4.02 to -0.61); RR 0.79 (95% CI 0.66 to 0.94). Results suggested decreases in AGW attributable to vaccination (RD -0.83/1000, 95% CI -2.54 to 0.88; RR 0.57, 95% CI 0.20 to 1.58) and program eligibility (RD -0.34/1000, 95% CI -1.03 to 0.36; RR 0.81, 95% CI 0.52 to 1.25). CONCLUSIONS: This study provides strong evidence of the early benefits of qHPV vaccination among girls aged 14 to 17 years, offering additional justification for not delaying vaccination.

Performance of the disease risk score in a cohort study with policy-induced selection bias.

AIM: To examine the performance of the disease risk score (DRS) in a cohort study with evidence of policy-induced selection bias. METHODS: We examined two cohorts of new users of bisphosphonates. Estimates for 1-year hip fracture rates between agents using DRS, exposure propensity scores and traditional multivariable analysis were compared. RESULTS: The results for the cohort with no evidence of policy-induced selection bias showed little variation across analyses (-4.1-2.0%). Analysis of the cohort with evidence of policy-induced selection bias showed greater variation (-13.5-8.1%), with the greatest difference seen with DRS analyses. CONCLUSION: Our findings suggest that caution may be warranted when using DRS methods in cohort studies with policy-induced selection bias, further research is needed.

Comparison of the Effect of Thiazide Diuretics and Other Antihypertensive Drugs on Central Blood Pressure: Cross-Sectional Analysis Among Nondiabetic Patients.

Thiazide diuretics (TDs) are a cost-effective first-line therapy for uncomplicated hypertension; however, they are less prescribed than other options. The authors aimed to assess the noninferiority of TDs relative to different classes of antihypertensive medications in relation to central blood pressure. Cross-sectional data from the Quebec CARTaGENE project was used. Nondiabetic hypertensive participants on monotherapy for hypertension were studied. Separate adjusted models were constructed to establish noninferiority of TDs to non-TD antihypertensive medications for central blood pressure measurements. Models included a set of potential confounders. Of the 1194 hypertensive participants, 7.4% were taking TDs. We found that TDs were comparable with non-TD antihypertensive medications for central systolic blood pressure (adjusted regression coefficient, 0.45; 95% confidence interval, -1.61 to 2.50). No differences in other central measurements were noted. The results provide additional support that TDs are at least as effective as other first-line medications for treating uncomplicated hypertension.