ObjectivesRecent results from ‘ORAL Surveillance’ trial have raised concerns regarding the cardiovascular safety of tofacitinib in patients with rheumatoid arthritis (RA). We further examined this ...safety concern in the real-world setting.MethodsWe created two cohorts of patients with RA initiating treatment with tofacitinib or tumour necrosis factor inhibitors (TNFI) using deidentified data from Optum Clinformatics (2012–2020), IBM MarketScan (2012–2018) and Medicare (parts A, B and D, 2012–2017) claims databases: (1) A ‘real-world evidence (RWE) cohort’ consisting of routine care patients and (2) A ‘randomised controlled trial (RCT)-duplicate cohort’ mimicking inclusion and exclusion criteria of the ORAL surveillance trial to calibrate results against the trial findings. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate HR and 95% CIs for composite outcome of myocardial infarction and stroke and accounting for 76 potential confounders. Database-specific effect estimates were pooled using fixed effects models with inverse-variance weighting.ResultsIn the RWE cohort, 102 263 patients were identified of whom 12 852 (12.6%) initiated tofacitinib. The pooled weighted HR (95% CI) comparing tofacitinib with TNFI was 1.01 (0.83 to 1.23) in RWE cohort and 1.24 (0.90 to 1.69) in RCT-duplicate cohort which aligned closely with ORAL-surveillance results (HR: 1.33, 95% CI 0.91 to 1.94).ConclusionsWe did not find evidence for an increased risk of cardiovascular outcomes with tofacitinib in patients with RA treated in the real-world setting; however, tofacitinib was associated with an increased risk of cardiovascular outcomes, although statistically non-significant, in patients with RA with cardiovascular risk factors.Trial registration number NCT04772248.
Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of treatments for rheumatoid arthritis. Unlike randomized controlled trials (RCTs), ...however, observational studies of drug effects have methodological limitations such as confounding by indication. Active-comparator designs and new-user designs can help mitigate such biases in observational studies and improve the validity of their findings by making them more closely approximate RCTs. In an active-comparator study, the drug of interest is compared with another agent commonly used for the same indication, rather than with no treatment (a 'non-user' group). This principle helps to ensure that treatment groups have similar treatment indications, attenuating both measured and unmeasured differences in patient characteristics. The new-user study includes a cohort of patients from the time of treatment initiation, enabling assessment of patients' pretreatment characteristics and capture of all events occurring during follow-up. These two principles should be considered when designing or reviewing observational studies of drug effects.
Hyperuricemia is common in patients with type 2 diabetes mellitus and is known to cause gout. Sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent glucose reabsorption and lower serum uric acid ...levels.
To compare the rate of gout between adults prescribed an SGLT2 inhibitor and those prescribed a glucagon-like peptide-1 (GLP1) receptor agonist.
Population-based new-user cohort study.
A U.S. nationwide commercial insurance database from March 2013 to December 2017.
Persons with type 2 diabetes newly prescribed an SGLT2 inhibitor were 1:1 propensity score matched to patients newly prescribed a GLP1 agonist. Persons were excluded if they had a history of gout or had received gout-specific treatment previously.
The primary outcome was a new diagnosis of gout. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of the primary outcome and 95% CIs.
The study identified 295 907 adults with type 2 diabetes mellitus who were newly prescribed an SGLT2 inhibitor or a GLP1 agonist. The gout incidence rate was lower among patients prescribed an SGLT2 inhibitor (4.9 events per 1000 person-years) than those prescribed a GLP1 agonist (7.8 events per 1000 person-years), with an HR of 0.64 (95% CI, 0.57 to 0.72) and a rate difference of -2.9 (CI, -3.6 to -2.1) per 1000 person-years.
Unmeasured confounding, missing data (namely incomplete laboratory data), and low baseline risk for gout.
Adults with type 2 diabetes prescribed an SGLT2 inhibitor had a lower rate of gout than those prescribed a GLP1 agonist. Sodium-glucose cotransporter-2 inhibitors may reduce the risk for gout among adults with type 2 diabetes mellitus, although future studies are necessary to confirm this observation.
Brigham and Women's Hospital.
The risk of serious infections associated with vedolizumab in patients with inflammatory bowel disease (IBD) is uncertain. We assessed the risk of serious infections associated with use of ...vedolizumab versus anti-TNF in patients with IBD, according to IBD subtype and previous exposure to anti-TNF.
Based on two U.S. nationwide commercial insurance databases and the French nationwide health insurance database, anti-TNF naïve and experienced patients diagnosed with Crohn's disease (CD) and ulcerative colitis (UC) aged 18 years or older who initiated vedolizumab or an anti-TNF agent after 2010 were identified. Hazard ratios for serious infections comparing vedolizumab and anti-TNF were estimated in propensity score matched cohorts.
Among 8768 vedolizumab and 26,656 anti-TNF initiators included after 1:4 variable ratio propensity score matching, 893 serious infections occurred during 37,725 person-years of follow-up. The risk of serious infections was not different between vedolizumab and anti-TNF in the overall IBD cohort (HR, 0.95; 95% CI, 0·79-1.13), while the risk was decreased for vedolizumab users in patients with UC (HR, 0.68; 95% CI, 0.50-0.93), but not CD (HR, 1.10; 95% CI, 0.87-1.38). In patients with UC, vedolizumab was consistently associated with lower risk of serious infections after exclusion of gastrointestinal infections (HR, 0.59; 95% CI, 0.39-0.90).
While the risk of serious infections associated with vedolizumab was not different compared to anti-TNF in the overall group of patients with IBD, the risk varied according to IBD subtype, by decreasing in patients with UC, but not CD. These findings may help to clarify the optimal position of vedolizumab in the therapeutic management of IBD.
Whereas most previous studies on (super-)gang effects examined cases where two weaker constraints jointly beat another stronger constraint (Albright 2012; Shih 2017; Breiss & Albright 2022), this ...paper addresses gang effects that arise from multiple violations of a single constraint, which Jäger & Rosenbach (2006) referred to as counting cumulativity. The super-additive version of counting cumulativity is the focus of this paper; cases where multiple violations of a weaker constraint not only overpower a single violation of a stronger constraint, but also surpass the mere multiplication of the severity of its single violation. I report two natural language examples where a morphophonological alternation in a compound is suppressed by the existence of marked segments in a super-additive manner: laryngeally marked consonants in Korean compound tensification and nasals in Japanese Rendaku. Using these two test cases, this paper argues that these types of super-additivity cannot be entirely captured by the traditional MaxEnt grammar; instead, a modified MaxEnt model is proposed, in which the degree of penalty is scaled up by the number of violations, through a power function. This paper also provides a computational implementation of the proposed MaxEnt model which learns necessary parameters given quantitative language data. A series of learning simulations on Korean and Japanese show that the MaxEnt learner is able to detect super-additive constraints and find the appropriate exponent values for those, correctly capturing the probability distributions in the input data.
Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of ...bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass.
A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed.
Absolute risks over 25-36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs 95% CI: 0.98 0.84-1.14; I2 = 0.0%), atrial fibrillation (41 trials; 1.08 0.92-1.25; I2 = 0.0%), MI (10 trials; 0.96 0.69-1.34; I2 = 0.0%), stroke (10 trials; 0.99 0.82-1.19; I2 = 5.8%), and CV death (14 trials; 0.88 0.72-1.07; I2 = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 0.96-1.61; I2 = 0.0%), not for oral bisphosphonates (26 trials; 1.02 0.83-1.24; I2 = 0.0%). The CV effects did not vary by subgroups or study quality.
Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.
Objective
To evaluate the risk of venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients receiving tofacitinib versus those receiving tumor necrosis factor (TNF) inhibitors.
Methods
RA ...patients who were initiating treatment with tofacitinib or a TNF inhibitor and had not previously received any biologic agent or tofacitinib were identified from the Truven MarketScan database (2012–2016) or Medicare claims (parts A, B, and D) database (2012–2015). Patients were followed up until treatment discontinuation, treatment switch, insurance disenrollment, or administrative censoring. The outcome of VTE was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were determined using a Cox proportional hazards model after accounting for confounding through propensity score–based fine‐stratification weighting. HRs were pooled across databases using the inverse variance meta‐analytic method.
Results
A total of 34,074 RA patients (mean age 50 years; 5.6% tofacitinib initiators) and 17,086 RA patients (mean age 71 years; 5.8% tofacitinib initiators) were identified from the Truven and Medicare databases, respectively. The crude incidence rates of VTE per 100 person‐years were 0.60 (95% CI 0.26–1.19) and 0.34 (95% CI 0.27–0.41) in Truven and 1.12 (95% CI 0.45–2.31) and 0.92 (95% CI 0.76–1.11) in Medicare for patients receiving tofacitinib and patients receiving TNF inhibitors, respectively. Propensity score–adjusted HRs showed no significant differences in the risk of VTE between tofacitinib‐treated and TNF inhibitor–treated patients in either database, with a pooled HR of 1.33 (95% CI 0.78–2.24).
Conclusion
Occurrence of VTE in a total of 50,865 RA patients initiating treatment with tofacitinib or a TNF inhibitor was infrequent (<1 per 100 person‐years). We observed a numerically higher, but statistically nonsignificant, risk of VTE in RA patients receiving tofacitinib versus those receiving TNF inhibitors.
Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral ...density and a potential increased risk for fracture.
To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist.
Population-based new-user cohort study.
Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015.
Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist.
The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR).
79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 CI, 0.83 to 1.02).
Unmeasured confounding, measurement error, and low fracture rate.
In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists.
Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.
ABSTRACT
Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral ...fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta‐analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random‐effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta‐analysis: five case‐control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval CI, 1.22–2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39–359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18–2.22), although there is a wide confidence interval and severe heterogeneity (I2 = 96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29–2.04). This meta‐analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long‐term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.
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