Comparative efficacy of sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists in chronic kidney disease and type 2 diabetes: A systematic review and network meta-analysis.

AIM: To compare the relative efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs) and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) in improving the cardiovascular and renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). MATERIALS AND METHODS: We searched PubMed, Embase and Cochrane Library from inception through 25 November 2022. We selected randomized controlled trials that studied patients with CKD and T2D with a follow-up of at least 24 weeks and compared SGLT-2is, GLP-1RAs and nsMRAs with each other and with placebo. Primary outcomes were major adverse cardiovascular events (MACE) and composite renal outcomes (CRO). Secondary outcomes were cardiovascular death, all-cause death, stroke, myocardial infarction and heart failure hospitalization (HFH). A frequentist approach was used to pool risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Twenty-nine studies with 50 938 participants for MACE and 49 965 participants for CRO were included. SGLT-2is did not significantly reduce MACE but were associated with significantly lower risks of CRO compared with GLP-1RAs (RR, 0.77; 95% CI, 0.64-0.91; P = .003) and nsMRAs (RR, 0.78; 95% CI, 0.68-0.90; P = .001). Compared with GLP-1RAs and nsMRAs, SGLT-2is significantly reduced risks of HFH by 31% (RR, 0.69; 95% CI, 0.55-0.88; P = .002) and 22% (RR, 0.78; 95% CI, 0.63-0.95; P = .016), respectively, but did not significantly reduce other secondary outcomes. There were no significant differences between GLP-1RAs and nsMRAs in lowering all outcomes. CONCLUSIONS: SGLT-2is were associated with better cardiorenal protection than GLP-1RAs and nsMRAs in patients with CKD and T2D.

Cost-effectiveness of canagliflozin and dapagliflozin for treatment of patients with chronic kidney disease and type 2 diabetes.

AIM: To examine the cost-effectiveness of adding canagliflozin or dapagliflozin to standard of care (SoC) versus SoC alone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). MATERIALS AND METHODS: We used a Markov microsimulation model to assess the cost-effectiveness of canagliflozin plus SoC (canagliflozin + SoC), dapagliflozin plus SoC (dapagliflozin + SoC) and SoC alone. Analyses were conducted from a healthcare system perspective. Costs were measured in 2021 Canadian dollars (C$), and effectiveness was measured in quality-adjusted life-years (QALYs). RESULTS: Over a patient's lifetime, canagliflozin + SoC and dapagliflozin + SoC yielded cost savings of C$33 460 and C$26 764 and generated 1.38 and 1.44 additional QALYs compared with SoC alone, respectively. While QALY gains with dapagliflozin + SoC were higher than those with canagliflozin + SoC, this strategy was also more costly with the incremental cost-effectiveness ratio exceeding the willingness to pay threshold of C$50 000 per QALY. Dapagliflozin + SoC, however, generated cost savings and QALY gains compared with canagliflozin + SoC over shorter time horizons of 5 or 10 years. CONCLUSIONS: Dapagliflozin + SoC was not cost-effective versus canagliflozin + SoC in patients with CKD and T2D over the lifetime horizon. However, adding canagliflozin or dapagliflozin to SoC was less costly and more effective relative to SoC alone for treatment of CKD and T2D.

Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom.

BACKGROUND: Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. METHODS: We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. RESULTS: Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). CONCLUSION: Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.

Regional variation in the potentially inappropriate first-line use of fluoroquinolones in Canada as a key to antibiotic stewardship? A drug utilization review study.

BACKGROUND: Serious adverse effects of fluoroquinolone antibiotics have been described for more than decade. Recently, several drug regulatory agencies have advised restricting their use in milder infections for which other treatments are available, given the potential for disabling and possibly persistent side effects. We aimed to describe variations in fluoroquinolone use for initial treatment of urinary tract infection (UTI), acute bacterial sinusitis (ABS), and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in the outpatient setting across Canada. METHODS: Using administrative health data from six provinces, we identified ambulatory visits with a diagnosis of uncomplicated UTI, uncomplicated AECOPD or ABS. Antibiotic exposure was determined by the first antibiotic dispensed within 5 days of the visit. RESULTS: We identified 4,303,144 uncomplicated UTI events among 2,170,027 women; the proportion of events treated with fluoroquinolones, mostly ciprofloxacin, varied across provinces, ranging from 18.6% (Saskatchewan) to 51.6% (Alberta). Among 3,467,678 ABS events (2,087,934 patients), between 2.2% (Nova Scotia) and 11.2% (Ontario) were dispensed a fluoroquinolone. For 1,319,128 AECOPD events among 598,347 patients, fluoroquinolones, mostly levofloxacin and moxifloxacin, ranged from 5.8% (Nova Scotia) to 35.6% (Ontario). The proportion of uncomplicated UTI and ABS events treated with fluoroquinolones declined over time, whereas it remained relatively stable for AECOPD. CONCLUSIONS: Fluoroquinolones were commonly used as first-line therapies for uncomplicated UTI and AECOPD. However, their use varied widely across provinces. Drug insurance formulary criteria and enforcement may be a key to facilitating better antibiotic stewardship and limiting potentially inappropriate first-line use of fluoroquinolones.

Validity of an algorithm to identify cardiovascular deaths from administrative health records: a multi-database population-based cohort study.

BACKGROUND: Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data. METHODS: Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age. RESULTS: The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths. CONCLUSIONS: A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA). OBJECTIVE: To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes. DESIGN: Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221). SETTING: Electronic health care databases from 7 Canadian provinces and the United Kingdom. PATIENTS: 208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors. MEASUREMENTS: Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin. RESULTS: Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk. LIMITATIONS: There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites. CONCLUSION: SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Sodium-glucose co-transporter-2 inhibitors and the risk of urosepsis: A multi-site, prevalent new-user cohort study.

AIM: To compare urosepsis rates in patients with type 2 diabetes treated using sodium-glucose co-transporter-2 inhibitors (SGLT2i) with dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world setting. METHODS: We conducted a matched cohort study using a prevalent new-user design with time-conditional propensity scores. New users of SGLT2i from seven Canadian provinces and the UK were matched to DPP4i users. The primary outcome was hospitalization with a diagnosis of urosepsis and the secondary outcome was Fournier's gangrene. Site-specific hazard ratios for urosepsis comparing SGLT2i with DPP4i were estimated using Cox proportional hazards models and pooled using a random effects meta-analysis. RESULTS: We included 208 244 users of SGLT2i and 208 244 users of DPP4i. Among SGLT2i users, 42% initiated canagliflozin, 31% dapagliflozin and 27% empagliflozin. During a mean follow-up of 0.9 years, patients initiating SGLT2i had a lower rate of urosepsis compared with those receiving DPP4i. The pooled adjusted hazard ratio was 0.58 (95% confidence interval [CI]: 0.42-0.80). The incidence rates of Fournier's gangrene were numerically similar in SGLT2i (0.08 per 1000 person-years; 95% CI: 0.05-0.13) and DPP4i users (0.14; 95% CI: 0.09-0.21). CONCLUSIONS: In this large, multi-site study, we did not observe an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting.

Time to benefit and the long-term persistence of new users of oral bisphosphonates.

INTRODUCTION: This study aimed to examine long-term persistence in new users of oral bisphosphonates in a population-wide cohort in Manitoba, Canada. MATERIALS AND METHODS: A longitudinal observational study was conducted using administrative health data characterizing long-term bisphosphonate persistence in those who started treatment between 1997 and 2018. Treatment discontinuation was evaluated using Kaplan-Meier methods. Cox regression was used to examine associations between discontinuation and osteoporosis diagnosis, previous fractures, and age. A sub-analysis of users with FRAX scores examined the relationship between 10-year fracture risk estimations and discontinuation. RESULTS: Of 42,249 new bisphosphonate users, median age was 71 years, with 88.6% being female. Median duration of bisphosphonate use was 0.95 years (IQR 0.25, 3.9 years). Overall, 47.9% of incident users persisted up to 1 year, 25.0% persisted up to 3 years, and 14.1% up to 5 years. Presence of an indication for bisphosphonate use was associated with decreased discontinuation risk. Persistence generally increased with age. Having a BMD test performed was a predictor of lower discontinuation. The strongest predictor was having an osteoporosis diagnosis [HR for discontinuation = 0.68 (95% CI 0.66, 0.70)]. In users with FRAX scores (n = 14,114), moderate-risk [HR = 0.86 (95% CI 0.77, 0.96)] and high-risk users [HR = 0.77 (95% CI 0.69, 0.85)] were less likely to discontinue compared to lower-risk users. CONCLUSIONS: A rapid decline in bisphosphonate persistence was shown. Almost half of users would not be expected to achieve clinically relevant benefits with a persistence of less than 1 year. Allowing informed choice in high-risk patients may be the best way to focus on those likely to benefit and persist with treatment.

Cannabis use in pregnancy and breastfeeding: The pharmacist's role.

BACKGROUND: The recent legalization of cannabis use in Canada requires pharmacists to be able to support their patients with accurate knowledge of its known risks and benefits. Certain populations, such as pregnant and breastfeeding women and their developing children, may be at higher risk than other populations. METHODS: The authors independently searched the literature for clinical reports or reviews of the literature regarding the safety of cannabis use in pregnancy and breastfeeding using search terms such as cannabis, marijuana, pregnancy and breastfeeding. RESULTS: This review combines the relevant pharmacological, pharmacokinetic and clinical evidence for the effects of cannabis in this special patient population. The literature demonstrates that some of the constituents of cannabis can reach children in utero and through breastmilk. Given that Δ9-tetrahydrocannabinol can be present in breastmilk as quickly as 1 hour after consumption and last up to 6 days, it may not be possible to use cannabis and avoid infant exposure. There is evidence that this exposure may result in cognitive, social and motor defects. Some of these effects may be long term, lasting years. The pharmacist must be able to educate and screen patients regarding marijuana use in pregnancy and breastfeeding, with the ultimate aim of harm reduction.

Treating Children with ASD: The Perspective of Caregivers.

PURPOSE: Treatment of Autism Spectrum Disorders (ASD) is challenging. Parents/caregivers' perspective on the effectiveness of therapies and services available to their children is important but neglected in the literature on ASD.  This study investigated such perspective through questionnaire-guided interviews with a group of parents in the province of Manitoba (Canada). A secondary objective of the study was to explore how health care professionals and specifically pharmacists can assist in providing better care to children with ASD.  Methods: Informed consent was obtained from all participants. Data on diagnoses and prescribed medications were collected from medical charts. Parents/caregivers completed questionnaires during interviews scheduled at their convenience. Specific questions were asked to gather caregivers/parents' perspectives on the effectiveness of medications and non-pharmacological interventions in controlling symptoms experienced by their children.  Information on access to education and health services was also assessed. Common themes were identified using thematic analysis. RESULTS: All children attended school, 88% were males, 50% experienced eating/sleeping difficulties; 69% reported Attention Deficit Hyperactivity Disorder comorbidity. Risperidone was reported to be effective in controlling aggressive behaviours. Methylphenidate and aripiprazole were often discontinued. Melatonin and occupational therapy services were said to be very useful. Access to behavioural therapy was often limited. Parents were concerned about lack of trained professionals in schools, limited understanding of their children's needs, and uncertainty for the future. CONCLUSIONS: Better education and awareness are necessary to help ASD children and their families. Pharmacists should explore opportunities to provide better services. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Cost of shingles: population based burden of disease analysis of herpes zoster and postherpetic neuralgia.

BACKGROUND: Around 30% of the population will experience herpes zoster (HZ), 10% of whom develop postherpetic neuralgia (PHN). Together, these illnesses produce a significant economic burden to the healthcare system. METHODS: Administrative healthcare data collected over the period of April 1st 1997 to March 31st 2014 were analyzed to determine the healthcare system burden of HZ using direct medical costs. Episodes of HZ were identified using international classification of disease (ICD) codes. Trends in age-adjusted (AA) HZ-rates were analyzed by piecewise-regression. Total annual and per-episode costs were determined for drug treatment, medical care, and hospitalizations within each year. RESULTS: The incidence of HZ increased by 49.5% from 1997/98 to 2013/14. Piecewise-regression of AA-rates revealed a steady AA-rate of 4.7 episodes/1000 person-years (PY) from 1997/98 to a breakpoint in 2008/09, after which rates began to increase reaching 5.7 episodes/1000 PY in 2013/14. Drug costs rose significantly (p <0.03) from $89.77/episode (95% CI: $82.96, $96.59) to $127.34/episode (95% CI: $117.24, $137.44). Medical costs increased (p <0.0001) from $57.98/episode (95% CI; $55.26, $60.70) to $78.84/episode (95% CI; $74.08, $83.61). Hospitalization rates declined from 3.10% in 1997/98 to 1.36% in 2011/12, resulting in cost dropping from $397/episode (95% CI; $284, $511) to $195/episode (95% CI; $129, $260). Total annual costs of HZ and PHN were $1,997,183 in 2011/12, 4.7% lower than the 1997/98 costs of $2,095,633. CONCLUSION: A significant increase in annual number of HZ cases was observed, driven largely by demographic factors. A 21% increase in the AA-incidence reveals changes in HZ rates beyond those expected by population shifts. The large increase in incidence of HZ, with rising per episode medical and prescription costs were offset by dramatic drops in hospitalization rates, the net effect of which has been to hold the total costs relatively constant. However, the decrease in hospitalization rates slowed over the last half of the study, settling at 1.3% in the last 4 study years. The likely future of HZ burden is one of rising costs, primarily driven by the demographic shifts of an increasing and aging population.

Psychotropic Drug Use before, during, and after Pregnancy: A Population-Based Study in a Canadian Cohort (2001-2013).

OBJECTIVE: To describe the extent of increase in use and the rate of continuation versus discontinuation of psychotropic agents before, during, and after pregnancy. METHODS: Rates of psychotropic use (antidepressants, anxiolytic/sedative-hypnotics, antiepileptics, antipsychotics, lithium, stimulants) among women with a hospital-recorded pregnancy outcome were assessed using databases at the Manitoba Centre for Health Policy. Rate of use was defined as ≥1 prescription over the total number of pregnancies in the 3-12 months before pregnancy, 0-3 months before pregnancy, during pregnancy, or 3 months after pregnancy. Continued use was defined as ≥2 prescriptions with gap ≤14 days. Poisson regression was used to analyze trends. RESULTS: Over the study period, a psychotropic drug was used before, during, or after pregnancy in 41,923 of 224,762 pregnancies. From 2001 to 2013, psychotropic use increased 1.5-fold from 11.1% to 16.2% ( p < 0.0001) in the 3-12 months before pregnancy, 1.6-fold from 6.4% to 10.5% ( p < 0.0001) in the 3 months before pregnancy, 1.8-fold from 3.3% to 6.0% ( p < 0.0001) during pregnancy, and 1.5-fold from 6.2% to 9.5% ( p < 0.0001) in the 3 months postpartum. Among the 13,579 women who received at least 1 psychotropic agent in the 3 months prior to pregnancy, 38.5% stopped the agent prior to pregnancy and only 10.3% continued use throughout pregnancy. Continued use throughout pregnancy was higher (56.9%) among the 6693 women who received at least 2 prescriptions for a psychotropic agent and were at least 80% adherent in the 3 months prior to pregnancy. CONCLUSION: The use of psychotropic agents increased over 12 years. The safety of continuing versus discontinuing these agents during pregnancy remains uncertain, but we observed a decrease in psychotropic drug use during the pregnancy period.

Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson's disease.

AIM: Domperidone is preferentially used over other antiemetic agents to treat digestive symptoms in Parkinson's disease (PD). Concerns have been raised regarding an increased risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD) associated with domperidone in the general population. However, the risk in PD is unknown. METHODS: We conducted a multicentre retrospective cohort study using administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink. Using a nested case-control analysis, we estimated the rate ratios (RRs) of VT/SCD associated with domperidone use compared to no use in patients newly-diagnosed with PD. VT/SCD events were identified using administrative medical records and vital statistics with a manual review of all potential cases. Meta-analytic methods were used to estimate overall effects across sites. RESULTS: Among 214 962 patients with PD, 2907 cases of VT/SCD were identified during 886 581 person-years of follow-up (incidence rate 3.28 per 1000 persons per year). Current use of domperidone was associated with a non-statistically significant 22% increased risk of VT/SCD (RR 1.22; 95% CI 0.99-1.50) compared with no use. The risk was significantly elevated in those with a history of cardiovascular disease (RR 1.38; 95% CI 1.07-1.78), but not in those without (RR 1.21; 95% CI 0.81-1.81). Dose and duration of use did not affect the magnitude of the risk. CONCLUSION: Domperidone use may increase the risk of VT/SCD in patients with PD, particularly those with a history of cardiovascular disease. This risk may be underestimated because of imprecision in identifying VT/SCD events.

Safety of fentanyl initiation according to past opioid exposure among patients newly prescribed fentanyl patches.

BACKGROUND: Although a convenient opioid delivery system, transdermal fentanyl patches have caused several deaths and resulted in safety warnings reminding prescribers that fentanyl patches should be prescribed only for patients who have adequate prior exposure to opioids. We conducted a longitudinal analysis of the safety of fentanyl initiation by examining past opioid exposure among patients newly prescribed fentanyl patches. METHODS: We identified all patients in the province of Manitoba who were newly prescribed fentanyl patches between Apr. 1, 2001, and Mar. 31, 2013. We converted all prior opioid use to oral morphine equivalents and determined the average daily dose in the 7-30 days before initial fentanyl patch use. Fentanyl initiation was considered unsafe if the patient's pre-fentanyl opioid exposure was below the recommended level. RESULTS: We identified 11 063 patients who began using fentanyl patches during the study period. Overall, fentanyl initiation was deemed unsafe in 74.1% of cases because the patient's prior opioid exposure was inadequate. Women and patients 65 years of age and older were more likely than men and younger patients, respectively, to have inadequate prior opioid exposure (p < 0.001 for each comparison). The proportion of patients who had unsafe prescriptions for fentanyl patches decreased significantly over the study period, from 87.0% in 2001 to 50.0% in 2012 (p < 0.001). INTERPRETATION: The safety of fentanyl initiation improved over the study period, but still half of fentanyl patch prescriptions were written for patients with inadequate prior opioid exposure. Review of prior opioid exposure may be a simple but important way to improve the safe use of fentanyl patches.

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.

The safety of meperidine prescribing in older adults: A longitudinal population-based study.

BACKGROUND: Meperidine (pethidine) is an opioid analgesic that offers little advantage relative to other opioids and several disadvantages including limited potency, short duration of action, and the production of a neurotoxic metabolite (normeperidine) with a long half-life. Older adults are more sensitive to meperidine's side effects and may have diminished renal function which leads to the accumulation of normeperidine. The Institute for Safe Medication Practices has suggested avoiding meperidine in older adults, limiting its dose (≤600 mg/day) and duration of use (≤48 h). The objective of this study was to determine the level of meperidine use in older adults and assess the dosage and duration of meperidine with reference to these safety recommendations. METHODS: A longitudinal study using administrative healthcare data was conducted to examine meperidine utilization and levels of high dose and extended duration prescribing among persons ≥65 years of age between April 1, 2001, and March 31, 2014 in Manitoba, Canada. The number of meperidine prescriptions, users, duration of treatment, defined daily doses (DDD) dispensed and number of prescribers were determined over the study period. RESULTS: In the Manitoba older adult population there was a marked decline in meperidine users and prescriptions from 2001 to 2014. There was an average use of 26.4 (95 % CI 24.0-28.8) DDDs of meperidine per user per year. While only 3.7 % of the prescriptions exceeded the 600 mg maximum daily dose, 96.7 % of prescriptions exceeded the recommended 2 days of therapy. For the remaining users of meperidine, the amount of meperidine used per person rose from 18.98 to 56.14 DDDs/user/year over the study period. The number of prescribers of meperidine declined throughout the study, but low DDD prescribers declined more quickly than high DDD prescribers. CONCLUSIONS: While meperidine use has declined, the remaining use appears to be decreasing in safety, with more meperidine prescribed per user. This seems to be driven by the continued prescribing by a small number of high DDD prescribers. Targeted educational initiatives directed at this small group of prescribers may be helpful. Alternatively removing meperidine from medication insurance schemes may provide additional incentive to avoid meperidine in older adults.

The prevalence and predictors of opioid use in inflammatory bowel disease: a population-based analysis.

OBJECTIVES: Opioids are commonly used in the treatment of pain and associated symptoms of inflammatory bowel disease (IBD). The continuous use of opioids has been associated with adverse outcomes, including death. The prevalence and the risk factors for opioid use in IBD are poorly characterized. METHODS: We used the population-based Manitoba IBD Epidemiology Database to identify all individuals in Manitoba with IBD who were prescribed opioids both before and following diagnosis. We determined the point prevalence of any opioid use, as well as the risk of becoming a heavy opioid user (defined as continuous use for 30 days at a dose exceeding 50 mg morphine/day or equivalent). Logistic regression and Cox proportional hazards models were generated to assess whether IBD was an independent risk factor for opioid use, the risk factors for opioid use in individuals with IBD, and to determine whether opioid use was associated with excess mortality in IBD. RESULTS: Within 10 years of diagnosis, 5% of individuals with IBD had become heavy opioid users. Moderate use of opioids before diagnosis was strongly predictive of future heavy use. Individuals with IBD were significantly more likely to become heavy opioid users than their matched controls (odds ratio (OR) 2.91, 95% confidence interval (CI) 2.19-3.85). Heavy opioid use was strongly associated with mortality (OR 2.82, 95% CI 1.58-5.02). CONCLUSIONS: IBD is an independent risk factor for becoming a heavy opioid user, and heavy opioid use is associated with excess mortality in IBD patients. Clinicians should recognize risk factors for future heavy opioid use among their patients with IBD.

Association between non-medical cannabis legalization and alcohol sales: Quasi-experimental evidence from Canada.

BACKGROUND: There is increasing interest in understanding the impact of non-medical cannabis legalization on use of other substances, especially alcohol. Evidence on whether cannabis is a substitute or complement for alcohol is both mixed and limited. This study provides the first quasi-experimental evidence on the impact of Canada's legalization of non-medical cannabis on beer and spirits sales. METHODS: We used the interrupted time series design and monthly data on beer sales between January 2012 and February 2020 and spirits sales between January 2016 and February 2020 across Canada to investigate changes in beer and spirits sales following Canada's cannabis legalization in October 2018. We examined changes in total sales, nationally and in individual provinces, as well as changes in sales of bottled, canned and kegged beer. RESULTS: Canada-wide beer sales fell by 96 hectoliters per 100,000 population (p=0.011) immediately after non-medical cannabis legalization and by 4 hectoliters per 100,000 population (p>0.05) each month thereafter for an average monthly reduction of 136 hectoliters per 100,000 population (p<0.001) post-legalization. However, the legalization was associated with no change in spirits sales. Beer sales reduced in all provinces except the Atlantic provinces. By beer type, the legalization was associated with declines in sales of canned and kegged beer but there was no reduction in sales of bottled beer. CONCLUSIONS: Non-medical cannabis legalization was associated with a decline in beer sales in Canada, suggesting substitution of non-medical cannabis for beer. However, there was no change in spirits sales following the legalization.

British Columbia's Safer Opioid Supply Policy and Opioid Outcomes.

Importance: In March 2020, British Columbia, Canada, became the first jurisdiction globally to launch a large-scale provincewide safer supply policy. The policy allowed individuals with opioid use disorder at high risk of overdose or poisoning to receive pharmaceutical-grade opioids prescribed by a physician or nurse practitioner, but to date, opioid-related outcomes after policy implementation have not been explored. Objective: To investigate the association of British Columbia's Safer Opioid Supply policy with opioid prescribing and opioid-related health outcomes. Design, Setting, and Participants: This cohort study used quarterly province-level data from quarter 1 of 2016 (January 1, 2016) to quarter 1 of 2022 (March 31, 2022), from British Columbia, where the Safer Opioid Supply policy was implemented, and Manitoba and Saskatchewan, where the policy was not implemented (comparison provinces). Exposure: Safer Opioid Supply policy implemented in British Columbia in March 2020. Main Outcomes and Measures: The main outcomes were rates of prescriptions, claimants, and prescribers of opioids targeted by the Safer Opioid Supply policy (hydromorphone, morphine, oxycodone, and fentanyl); opioid-related poisoning hospitalizations; and deaths from apparent opioid toxicity. Difference-in-differences analysis was used to compare changes in outcomes before and after policy implementation in British Columbia with those in the comparison provinces. Results: The Safer Opioid Supply policy was associated with statistically significant increases in rates of opioid prescriptions (2619.6 per 100 000 population; 95% CI, 1322.1-3917.0 per 100 000 population; P < .001) and claimants (176.4 per 100 000 population; 95% CI, 33.5-319.4 per 100 000 population; P = .02). There was no significant change in prescribers (15.7 per 100 000 population; 95% CI, -0.2 to 31.6 per 100 000 population; P = .053). However, the opioid-related poisoning hospitalization rate increased by 3.2 per 100 000 population (95% CI, 0.9-5.6 per 100 000 population; P = .01) after policy implementation. There were no statistically significant changes in deaths from apparent opioid toxicity (1.6 per 100 000 population; 95% CI, -1.3 to 4.5 per 100 000 population; P = .26). Conclusions and Relevance: Two years after its launch, the Safer Opioid Supply policy in British Columbia was associated with higher rates of safer supply opioid prescribing but also with a significant increase in opioid-related poisoning hospitalizations. These findings will help inform ongoing debates about this policy not only in British Columbia but also in other jurisdictions that are contemplating it.