Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Antidiabetic Medication Utilisation before and during Pregnancy in Switzerland between 2012 and 2019: An Administrative Claim Database from the MAMA Cohort.

Background: The incidence of diabetes mellitus (both pregestational and gestational) is increasing worldwide, and hyperglycemia during pregnancy is associated with adverse pregnancy outcomes. Evidence on the safety and efficacy of metformin during pregnancy has accumulated resulting in an increase in its prescription in many reports. Aims: We aimed to determine the prevalence of antidiabetic drug use (insulins and blood glucose-lowering drugs) before and during pregnancy in Switzerland and the changes therein during pregnancy and over time. Methods: We conducted a descriptive study using Swiss health insurance claims (2012-2019). We established the MAMA cohort by identifying deliveries and estimating the last menstrual period. We identified claims for any antidiabetic medication (ADM), insulins, blood glucose-lowering drugs, and individual substances within each class. We defined three groups of pattern use based on timing of dispensation: (1) dispensation of at least one ADM in the prepregnancy period and in or after trimester 2 (T2) (pregestational diabetes); (2) dispensation for the first time in or after T2 (GDM); and (3) dispensation in the prepregnancy period and no dispensation in or after T2 (discontinuers). Within the pregestational diabetes group, we further defined continuers (dispensation for the same group of ADM) and switchers (different ADM group dispensed in the prepregnancy period and in or after T2). Results: MAMA included 104,098 deliveries with a mean maternal age at delivery of 31.7. Antidiabetic dispensations among pregnancies with pregestational and gestational diabetes increased over time. Insulin was the most dispensed medication for both diseases. Between 2017 and 2019, less than 10% of pregnancies treated for pregestational diabetes continued metformin rather than switching to insulin. Metformin was offered to less than 2% of pregnancies to treat gestational diabetes (2017-2019). Conclusion: Despite its position in the guidelines and the attractive alternative that metformin represents to patients who may encounter barriers with insulin therapy, there was reluctance to prescribe it.

Sensing the (digital) pulse. Future steps for improving the secondary use of data for research in Switzerland.

Introduction: Ensuring that the health data infrastructure and governance permits an efficient secondary use of data for research is a policy priority for many countries. Switzerland is no exception and many initiatives have been launched to improve its health data landscape. The country now stands at an important crossroad, debating the right way forward. We aimed to explore which specific elements of data governance can facilitate - from ethico-legal and socio-cultural perspectives - the sharing and reuse of data for research purposes in Switzerland. Methods: A modified Delphi methodology was used to collect and structure input from a panel of experts via successive rounds of mediated interaction on the topic of health data governance in Switzerland. Results: First, we suggested techniques to facilitate data sharing practices, especially when data are shared between researchers or from healthcare institutions to researchers. Second, we identified ways to improve the interaction between data protection law and the reuse of data for research, and the ways of implementing informed consent in this context. Third, we put forth ideas on policy changes, such as the steps necessary to improve coordination between different actors of the data landscape and to win the defensive and risk-adverse attitudes widespread when it comes to health data. Conclusions: After having engaged with these topics, we highlighted the importance of focusing on non-technical aspects to improve the data-readiness of a country (e.g., attitudes of stakeholders involved) and of having a pro-active debate between the different institutional actors, ethico-legal experts and society at large.

Recording of Chronic Diseases and Adverse Obstetric Outcomes during Hospitalizations for a Delivery in the National Swiss Hospital Medical Statistics Dataset between 2012 and 2018: An Observational Cross-Sectional Study.

The prevalence of chronic diseases during pregnancy and adverse maternal obstetric outcomes in Switzerland has been insufficiently studied. Data sources, which reliably capture these events, are scarce. We conducted a nationwide observational cross-sectional study (2012−2018) using data from the Swiss Hospital Medical Statistics (MS) dataset. To quantify the recording of chronic diseases and adverse maternal obstetric outcomes during delivery in hospitals or birthing centers (delivery hospitalization), we identified women who delivered a singleton live-born infant. We quantified the prevalence of 23 maternal chronic diseases (ICD-10-GM) and compared results to a nationwide Danish registry study. We further quantified the prevalence of adverse maternal obstetric outcomes (ICD-10-GM/CHOP) during the delivery hospitalization and compared the results to existing literature from Western Europe. We identified 577,220 delivery hospitalizations, of which 4.99% had a record for ≥1 diagnosis of a chronic disease (versus 15.49% in Denmark). Moreover, 13 of 23 chronic diseases seemed to be substantially under-recorded (8 of those were >10-fold more frequent in the Danish study). The prevalence of three of the chronic diseases was similar in the two studies. The prevalence of adverse maternal obstetric outcomes was comparable to other European countries. Our results suggest that chronic diseases are under-recorded during delivery hospitalizations in the MS dataset, which may be due to specific coding guidelines and aspects regarding whether a disease generates billable effort for a hospital. Adverse maternal obstetric outcomes seemed to be more completely captured.

Use of Prescribed Drugs to Treat Chronic Diseases during Pregnancy in Outpatient Care in Switzerland between 2014 and 2018: Descriptive Analysis of Swiss Health Care Claims Data.

Evidence on the use of drugs during pregnancy in Switzerland is lacking. We aimed to evaluate the utilisation of drugs to treat chronic diseases during pregnancy in Switzerland. We identified all pregnancies (excluding abortions) in Swiss Helsana claims data (2014-2018). In those, we identified all claims for drugs to treat a chronic disease, which typically affects women of childbearing age. Potentially teratogenic/fetotoxic drugs were evaluated during specific risk periods. Results were demographically weighted relative to the Swiss population. We identified claims for ≥1 drug of interest during 22% of 369,371 weighted pregnancies. Levothyroxine was most frequently claimed (6.6%). Antihypertensives were claimed during 5.3% (3.9% nifedipine in T3). Renin-Angiotensin-Aldosterone System (RAAS) inhibitors were dispensed to 0.3/10,000 pregnancies during trimester 2 (T2) or trimester 3 (T3). Insulin was claimed during 3.5% of pregnancies, most frequently in T3 (3.3%). Exposure to psychotropic drugs was 3.8% (mostly Selective serotonin reuptake inhibitors (SSRIs)) and to drugs for obstructive airway diseases 3.6%. Traditional immunosuppressants (excluding corticosteroids) were claimed during 0.5% (mainly azathioprine and hydroxychloroquine), biologic immunosuppressants (Tumour necrosis factor-alpha (TNF-alpha) inhibitors and interleukin inhibitors) during 0.2%, and drugs to treat multiple sclerosis during 0.09% of pregnancies. Antiretrovirals were claimed during 0.15% of pregnancies. Patterns of drug claims were in line with treatment recommendations, but relatively rare events of in utero exposure to teratogenic drugs may have had severe implications for those involved.

Use of drugs to treat symptoms and acute conditions during pregnancy in outpatient care in Switzerland between 2014 and 2018: analysis of Swiss healthcare claims data.

BACKGROUND: Evidence on the use of drugs during pregnancy in Switzerland is lacking. OBJECTIVES: To evaluate utilisation of prescribed drugs during pregnancy in outpatient care in Switzerland, focusing on treatments for pain, infections, gastro-oesophageal reflux, nausea/vomiting, and constipation. METHODS: We conducted a descriptive study using the Swiss Helsana claims database (2014­2018). We established a cohort of pregnancies by identifying deliveries and estimating the date of the last menstrual period. We identified claims for the following drugs during pregnancy; analgesics (opioids, paracetamol, and nonsteroidal anti-inflammatory drugs [NSAIDs]), oral antibiotics, antacids, proton pump inhibitors (PPIs), anti-nausea drugs (propulsives and 5HT3-antagonists), and laxatives. Within these drug groups we quantified exposure prevalence to the most prescribed drugs (to >1% of pregnancies) during pregnancy as well as to specific potentially teratogenic or fetotoxic drugs during specific risk periods. Results were extrapolated relative to the demographic distribution of the Swiss population. RESULTS: We identified an extrapolated population of 369,371 pregnancies, with a weighted mean maternal age of 32.0 years (weighted standard deviation 5.1). Analgesics were claimed in 34.5% (95% confidence interval [CI] 33.9­35.0%) of pregnancies, most frequently paracetamol (30.3%, 29.8­30.8%), followed by NSAIDs (8.6%, 8.3­8.8%), and opioids (2.6%, 2.4­2.8%). NSAIDs were claimed in 1.3% (1.2­1.4%) of pregnancies after week 24, and opioids were claimed in 1.3% (1.2­1.4%) in trimester 3. Antibiotics were dispensed in 26.3% (25.8­26.8%) of pregnancies, most frequently amoxicillin (14.6%, 95% CI 14.2­14.9%). Claims for potentially teratogenic or fetotoxic antibiotics during risk periods were each recorded in <0.6% of pregnancies. PPIs were claimed in 16.0% (15.6­16.3%) and antacids in 10.6% (10.3­11.0%) of pregnancies, but several antacid products are not reimbursed and thus not present in insurance claims. Anti-nausea drugs were claimed in 16.4% (16.0­16.7%) of pregnancies, most frequently metoclopramide in 14.4% (14.0­14.7%). Ondansetron was mainly dispensed in trimester 1, 1.0% (0.9­1.1%). In total, 6.4% (6.2­6.7%) of pregnancies had a claim for laxatives, most frequently for macrogol (2.4%, 95% CI 2.2­2.5%). CONCLUSION: The observed pattern of claimed drugs during pregnancy is in line with existing treatment guidelines. Exposure to potentially teratogenic and fetotoxic drugs was small, but given the lack of recorded diagnosis, we cannot determine if their use was clinically indicated.

A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy.

Introduction: The majority of women with epilepsy require treatment with antiseizure medications (ASM) throughout pregnancy. However, in utero exposure to several ASM has been associated with an increased risk of congenital malformations and/or neurodevelopmental disorders (CM/NDD) in the child, but observational evidence is methodologically heterogeneous.Areas covered: We critically evaluate current evidence on the risk of CM/NDD in children of women with epilepsy after in utero exposure to different ASM. We highlight characteristics of different data sources and discuss their benefits and drawbacks. This review includes evidence published before December 2020.Expert opinion: Given the lack of randomized controlled trials, evidence on in utero safety of ASM originates from methodologically heterogeneous post-marketing observational studies based on registries, prospective cohorts, and large electronic health databases. It has been clearly demonstrated that valproate is associated with a high risk of CM/NDD, whereas lamotrigine and levetiracetam are relatively safe. However, evidence is less explicit for other ASM. Reported risks vary depending on the size and origin of the underlying study population, the definition of exposure and outcomes, and other aspects of the study design. Increased collaboration between data sources to increase sample size is desirable.

The Risk of Muscular Events Among New Users of Hydrophilic and Lipophilic Statins: an Observational Cohort Study.

BACKGROUND: Statins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells. OBJECTIVE: To compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins. DESIGN/SETTING: Propensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD. PATIENTS: New statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg. MAIN MEASURES: The outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year. KEY RESULTS: The propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses. LIMITATIONS: We could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources. CONCLUSIONS: Our results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses.

Use of valproate in pregnancy and in women of childbearing age between 2014 and 2018 in Switzerland: a retrospective analysis of Swiss healthcare claims data.

AIMS OF THE STUDY: The prevalence of the use of valproate during pregnancy and by women of childbearing age in Switzerland is not known. We aimed to study the use of antiseizure drugs by these women in Switzerland, with a particular focus on valproate. METHODS: We conducted a retrospective descriptive study using the healthcare claims database of the Swiss health insurance Helsana (2014–18). We established two separate study populations: (1) a cohort of pregnancies leading to a delivery, and (2) all women of childbearing age (15–45 years) who were insured with Helsana for at least one year during the study period. We identified the dispensation of valproate, lamotrigine, carbamazepine, levetiracetam, topiramate, pregabalin, gabapentin, phenobarbital, and phenytoin (1) between delivery and three months prior to the estimated date of the last menstrual period, and (2) by calendar year. We quantified exposure prevalence of each antiseizure drug as the number of women with ≥1 prescription fill per 10,000 (1) pregnancies, and (2) women by calendar year. Results were weighted for the demographic distribution of the Helsana population relative to the Swiss population. RESULTS: We identified a weighted pregnancy population of 387,418 pregnancies, with a mean maternal age at delivery of 31.9 years (standard deviation 5.1). Lamotrigine was the most frequently dispensed antiseizure drug during pregnancy (20/10,000), followed by levetiracetam (11/10,000), and pregabalin (3.8/10,000). Valproate was dispensed to 1.9/10,000 women during pregnancy and to 1.3/10,000 women within 90 days prior to the last menstrual period but not during pregnancy. The weighted study population of women aged 15–45 years consisted of 2,781,151 women, of whom 74,080 (270/10,000) were exposed to ≥1 of the evaluated antiseizure drugs. Pregabalin was the most frequently dispensed antiseizure drug (64/10,000), followed by lamotrigine (46/10,000), topiramate (32/10,000), and valproate (25/10,000). The use of valproate decreased from 28/10,000 women in 2014 to 21/10,000 women in 2018. CONCLUSIONS: The prevalence of exposure to valproate during pregnancy was comparable to Denmark and lower than in other European countries. Despite decreasing exposure prevalence, the use of valproate in women of childbearing age in Switzerland seems higher than the actual clinical need.

Using Healthcare Databases to Replicate Trial Findings for Supplemental Indications: Adalimumab in Patients with Ulcerative Colitis.

Regulators wish to understand whether real world evidence can be used for secondary indications of biologics. Using the secondary indication of adalimumab for ulcerative colitis (UC) as an example, we aimed to replicate the ULTRA-2 randomized controlled trial finding on the effectiveness of adalimumab in patients with UC using realworld data analyses. Adalimumab, a TNF-alpha receptor inhibitor initially approved for Crohn's disease, was approved for moderate to severe UC in 2012. The ULTRA-2 trial had shown improved remission against placebo in patients with UC. Using claims data (2006-2012), we conducted a cohort study of patients with UC who initiated adalimumab and compared them with (i) nonusers and (ii) new users of infliximab using propensity score matching. The coprimary end points were corticosteroid (CS) discontinuation within 8 weeks and 1 year of treatment. We computed hazard ratios (HRs) and 95% confidence intervals (CIs). We identified 398 matched pairs of adalimumab users vs. nonusers and 326 pairs of adalimumab vs. infliximab users. Adalimumab users were 28% more likely to achieve CS-discontinuation compared with nonusers over 1 year (HR = 1.28; 95% CI 0.94-1.73). However, unlike in ULTRA-2, this effect was not observed in the first 8 weeks (HR = 0.79; 95% CI 0.65-0.97). Compared with infliximab, adalimumab initiators showed no incremental benefit over 1 year (HR = 1.08; 95% CI 0.80-1.04), but showed a 22% reduction (HR = 0.78; 95% CI 0.64-0.95) during the first 8 weeks of treatment. In summary, our results highlight opportunities and some limitations of database analysis to identify treatment effects for secondary indications.

Risk of hand osteoarthritis in new users of hormone replacement therapy: A nested case-control analysis.

OBJECTIVE: To estimate the risk of hand osteoarthritis (HOA) associated with hormone replacement therapy (HRT). METHODS: We conducted a nested case-control study using data from the UKbased Clinical Practice Research Datalink (1998-2017). In the study inception cohort comprised women at age 45. We matched women with incident HOA during follow-up (cases) to osteoarthritisfree controls on age and calendar date (index date, ID), in a ratio of 1:4. We applied conditional logistic regression to calculate odds ratios (OR) with 95 % confidence intervals (CI) of HOA associated with new HRT use compared with non-use overall, and for women with recorded menopause we calculated separate ORs according to the time between menopause and HRT initiation (current users), and the time between HRT cessation and the ID (past users), versus non-users. RESULTS: There were 3440 cases and 13,760 controls (mean age: 50.9 ± 4.1 years). We observed an adjusted OR (aOR) of HOA of 1.32 (95 % CI 1.17-1.48) in HRT users (versus nonusers), which attenuated to 0.98 (95 % CI 0.85-1.14) in women with recorded menopause. Current users (versus nonusers) who initiated HRT 3 months before or after menopause had an aOR of 0.72 (95 % CI 0.55-0.96), while aORs increased with later HRT initiation. Among past users (versus non-users), we observed an aOR of 1.25 (95 % CI 0.86-1.81) when HRT use was stopped ≤18 months before the ID, approaching the null with increasing duration between HRT cessation and the ID. CONCLUSION: Current HRT use was associated with a decreased risk of HOA if initiated around menopause, but the risk reduction disappeared after HRT cessation.

Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients.

Reports of metamizole-induced neutropenia have increased in Switzerland and Germany over the last decades, most likely reflecting increased use of metamizole. To date, there are no effective strategies to identify patients at increased risk of metamizole-induced neutropenia. In this observational, multi-center comparative study, characteristics of patients with metamizole-associated neutropenia were compared with patients treated with metamizole without developing adverse hematological reactions. Patients with metamizole-induced neutropenia treated at the University Hospitals Basel and Bern between 2005 and 2017 were included. Tolerant comparison patients with continuous metamizole treatment (≥500 mg/day for at least 28 days) were recruited from GP offices and community pharmacies. Forty-eight patients with metamizole-induced neutropenia, consisting of 23 and 25 cases with inpatient-acquired and outpatient-acquired neutropenia, respectively, were compared to 39 metamizole tolerant comparison patients. Median latency until first diagnosis of neutropenia was 6 days (1-61 days) in inpatient cases and 19 days (2-204 days) in outpatient cases. There was no association between non-myelotoxic and non-immunosuppressive co-medication (p = .6627), history of drug allergy (p = .1304), and preexisting auto-immune diseases (p = .2313) and the development of metamizole-induced neutropenia. Our results suggest that autoimmune diseases, history of drug allergy, and concomitant treatment with non-myelotoxic and non-immunosuppressive drugs are likely not individual risk factors for metamizole-associated neutropenia.

Cardiovascular Outcomes of Calcium-Free vs Calcium-Based Phosphate Binders in Patients 65 Years or Older With End-stage Renal Disease Requiring Hemodialysis.

Importance: Guidelines restricting use of calcium-based phosphate binders in all patients with end-stage renal disease owing to their potential contribution to increased cardiovascular risk shifted prescribing from calcium acetate toward the costlier sevelamer carbonate products. Objective: To compare cardiovascular events and mortality between patients with end-stage renal disease (ESRD) undergoing hemodialysis receiving sevelamer vs calcium acetate in real-world practice. Design, Setting, and Participants: An observational cohort study was conducted using the United States Renal Data System linked to Medicare claims data (May 1, 2012, to December 31, 2013). Data analysis was performed from October 2017 to September 2018. Participants included patients 65 years or older with ESRD within 180 days after starting hemodialysis (sevelamer, 2647; calcium acetate, 2074). Exposures: New use of sevelamer (calcium-free phosphate binder) vs calcium acetate (calcium-based phosphate binder). Main Outcomes and Measures: Hazard ratios (HRs) with 95% CIs were estimated for fatal or nonfatal cardiovascular events (myocardial infarction or ischemic stroke: primary outcome) and all-cause mortality (secondary outcome) using Cox proportional hazards regression with fine stratification on the propensity score to control for potential confounders, including phosphorus and calcium levels. Results: After propensity score weighting, 2639 patients initiating sevelamer treatment (1184 men [44.9%]; mean [SD] age, 75.6 [6.9] years) and 2065 patients initiating calcium acetate treatment (930 men [45.0%]; mean [SD] age, 75.5 [7.1] years) were included in the analysis. Crude incidence rates (IRs) for cardiovascular events of 458 per 1000 person-years for sevelamer and 464 per 1000 person-years for calcium acetate were observed. After propensity score fine-stratification weighting, HRs of 0.96 (95% CI, 0.84-1.10) for cardiovascular events were observed. Results were consistent within subgroups of age (<75 y: primary outcome, HR, 1.02; 95% CI, 0.85-1.24; vs ≥75 years: primary outcome, HR, 0.83; 95% CI, 0.69-1.01) and sex (primary outcome in men: HR, 1.02; 95% CI, 0.83-1.26). Conclusions and Relevance: The results of the study do not suggest increased cardiovascular safety of sevelamer in the routine clinical practice of patients with ESRD compared with calcium acetate; this study's findings suggest that well-designed, long-term, randomized clinical trials are needed.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Commonly Prescribed Drugs in Outpatient Care Other than Anti-Epileptic Drugs and Antibiotics: A Population-Based Case-Control Study.

INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with the use of various drugs, but evidence is scarce. We studied the association between new use of outpatient drugs other than anti-epileptic drugs and antibiotics and Stevens-Johnson syndrome and toxic epidermal necrolysis. METHODS: We conducted a matched (1:4) case-control analysis in 480 previously validated Stevens-Johnson syndrome/toxic epidermal necrolysis cases (1995-2013). We calculated odds ratios with 95% confidence intervals for Stevens-Johnson syndrome/toxic epidermal necrolysis in new users of drugs compared to non-users. For cases of Stevens-Johnson syndrome/toxic epidermal necrolysis diagnosed ≤ 84 days after the first use of a drug, we assessed causality between drug exposure and Stevens-Johnson syndrome/toxic epidermal necrolysis using ALDEN (algorithm of drug causality in epidermal necrolysis). We calculated absolute risks by dividing the number of Stevens-Johnson syndrome/toxic epidermal necrolysis cases ≤ 84 days after new drug exposure by the total number of new users of the drug. RESULTS: There was an association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of allopurinol (odds ratio 24.51, 95% confidence interval 2.94-204.04) and cyclooxygenase-2 inhibitors (odds ratio 24.19, 95% confidence interval 2.91-200.92). Proton pump inhibitors, fluoxetine, mirtazapine, and 5-aminosalicylates (sulfasalazine, mesalamine) were also associated with an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis, though with lower odds ratios. ALDEN score application suggests a likely causality for these associations. Absolute risks of Stevens-Johnson syndrome/toxic epidermal necrolysis were 6.0/100,000 new users for allopurinol, and 1.9-4.3/100,000 new users for cyclooxygenase-2 inhibitors and 5-aminosalicylates, and 0.2-1.6/100,000 new users for proton pump inhibitors, fluoxetine, and mirtazapine. We found no association between Stevens-Johnson syndrome/toxic epidermal necrolysis and oxicams, benzodiazepines, citalopram, sertraline, paroxetine, venlafaxine, and phosphodiesterase-5 inhibitors despite > 100,000 new users. CONCLUSIONS: In this observational study, we observed likely causal associations between Stevens-Johnson syndrome/toxic epidermal necrolysis and use of allopurinol, cyclooxygenase-2 inhibitors, and 5-aminosalicylates, and potential associations for proton pump inhibitors, fluoxetine, and mirtazapine.

Comparative effectiveness and safety of antiplatelet drugs in patients with diabetes mellitus and acute coronary syndrome.

PURPOSE: Comparative outcomes of treatment with antiplatelet drugs in patients with acute coronary syndrome (ACS) and co-morbid diabetes mellitus (DM) are not well studied. METHODS: We performed a cohort study using US commercial claims data (2009-2015) and conducted the following pairwise comparisons in ACS patients with DM: prasugrel vs clopidogrel, ticagrelor vs clopidogrel, and prasugrel vs ticagrelor. Outcomes of interest included (1) a composite effectiveness endpoint including myocardial infarction, ischemic stroke, or inpatient mortality; (2) a composite safety endpoint including major bleeding events requiring hospitalization; and (3) pneumonia hospitalizations as a negative control endpoint. We used calendar time-specific propensity score matching to account for confounding and applied Cox proportional hazard models to calculate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Comparative risk of the effectiveness endpoint was lower among prasugrel initiators compared to clopidogrel initiators (HR 0.82, 95% CI 0.68-0.99, N = 7011 matched pairs), but no different between ticagrelor and clopidogrel (HR 1.02, 95% CI 0.76-1.37, N = 3013 pairs) or prasugrel and ticagrelor (HR 0.83, 95% CI 0.58-1.18, N = 2207 pairs). Bleeding risk was higher among prasugrel initiators when compared to clopidogrel initiators within the first month of treatment (HR 1.85, 95% CI 1.03-3.35); no other comparison indicated any difference. No differences in the negative control outcomes were noted after PS matching for all comparisons, indicating adequate confounding control. CONCLUSIONS: Prasugrel was associated with superior cardiovascular outcomes and a higher risk of short-term bleeding compared to clopidogrel in patients with ACS and DM. Comparative outcomes were similar between ticagrelor and clopidogrel or prasugrel and ticagrelor.

Risk of Incident Osteoarthritis of the Hand in Statin Initiators: A Sequential Cohort Study.

OBJECTIVE: To investigate the association between statin therapy initiation and incident hand osteoarthritis (OA). METHODS: We performed a propensity score-matched cohort study using data from the UK-based Clinical Practice Research Datalink. Statin initiators had ≥1 statin prescription between 1996 and 2015 and were matched 1:1 on their propensity score to noninitiators within 10 sequential 2-year cohort entry blocks. After a 180-day run-in period, patients were followed in an as-treated approach until a recorded diagnosis of hand OA or until censoring (change in exposure status, development of an exclusion criterion, or maximum follow-up of 5.5 years). We applied Cox proportional hazard regression to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs) overall and in subgroups of sex, age, statin dose, statin agent, preexisting dyslipidemia, and treatment duration. To compare results, we ran all analyses with negative and positive control outcomes and assessed generalized OA as a secondary outcome. We further performed the overall analysis with an active comparator (topical glaucoma therapy initiators). RESULTS: Among 233,608 statin initiators and the same number of noninitiators, we observed an overall HR for hand OA of 0.98 (95% CI 0.88-1.09). The observed null result remained unchanged in all subgroups. Results were highly similar for generalized OA and negative control outcomes. In addition, the active comparator analysis showed a null result with an HR for hand OA of 0.85 (95% CI 0.56-1.29). Previously known associations with positive control outcomes were observed. CONCLUSION: There was no association between statin initiation and incident hand OA in this study.