The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial ...since the US Food and Drug Administration issued a public health advisory in 2006.
To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy.
Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010.
A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use.
Recorded diagnosis of PPHN during the first 30 days after delivery.
A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74).
Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.
Aim
To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from ...linked electronic health records (EHR) data.
Methods
Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase‐4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims‐based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims–EHR‐linked subset, evaluated the balance of claims‐ and EHR‐based covariates before and after PS‐matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances.
Results
From a claims‐based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims‐based characteristics in the EHR‐linked and EHR‐unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR‐linked subset. The balance of claims‐based and EHR‐based patient characteristics appeared to be reasonable before PS‐matching and generally improved in the PS‐matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding.
Conclusion
In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new‐user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely.
Claims databases provide information on the effects of direct oral anticoagulants (DOACs) as used in routine care but may not contain important data on clinical characteristics, which may be captured ...in electronic health records (EHRs). Within a US claims database, we identified patients initiating a DOAC or warfarin between October 2010 and December 2014. Propensity score (PS) matching, 1:1, was used to balance 78 claims‐defined baseline characteristics. We evaluated whether balance was achieved in patient characteristics immeasurable in the claims data study by evaluating the balance in clinical information (using absolute standardized differences (aSDs)) from linked EHR data. From a claims data cohort study of 140,187 patients, 5,935 (4.2%) were linked to EHR data. After PS matching, almost all EHR‐defined patient characteristics were well balanced (aSD < 0.1). A new user active comparator design with 1:1 PS matching on many patient characteristics improved balance on clinical risk factors observed in EHRs but not in claims data.
Background The increasing availability of electronic healthcare data enables ongoing monitoring of the effectiveness and safety of newly marketed medications. We sought to demonstrate a 5-year ...prospective monitoring system of dabigatran for stroke prevention that may expedite discovery and allow ongoing evidence development. Methods and Results Between 2011 and 2015, we conducted 9 sequential analyses of dabigatran versus warfarin users in a sequential cohort design in 2 US claims databases. Analyses 4 through 9 were prespecified, and analyses 1 through 3 were added subsequently using the same methodology. New users of anticoagulants with nonvalvular atrial fibrillation were followed until a study outcome of hospitalization for stroke (hemorrhagic and ischemic) or hospitalization for major hemorrhage (intracranial and extracranial). Hazard ratios and 95% CIs were estimated after 1:1 propensity score matching. Sequential analyses 1 through 3 on stroke prevention using data through June 2012 were limited by few events leading to wide CIs. As data accumulated the effect estimate in analysis 4 visually stabilized at a 25% risk reduction with increasingly narrower CIs (-46% to +9% in December 2012 and -42% to -2% in September 2015). Improved data-adaptive confounding adjustment with high-dimensional propensity score reached a stable state already at analysis 3 and was slightly closer to the randomized clinical trial finding (-39%). The risk of major hemorrhage was 28% lower in dabigatran initiators (-35% to -20%) a finding that was stable throughout analyses 2 to 9. Conclusions Prospectively monitoring the effectiveness and safety of dabigatran for stroke prevention allowed for early insights with increasing precision over time.
Previous observational studies have suggested that fluoroquinolones are associated with aortic aneurysm or dissection, but these studies may be subject to confounding by indication or surveillance ...bias.
To assess the association of fluoroquinolones with risk of aortic aneurysm or aortic dissection (AA/AD) while accounting for potential confounding by fluoroquinolone indication and bias owing to differential surveillance.
In an observational cohort study using a US commercial claims database, 2 pairwise 1:1 propensity score-matched cohorts were identified: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating treatment with a fluoroquinolone or azithromycin and patients aged 50 years or older with a urinary tract infection (UTI) diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole. Hazard ratios (HRs) and 95% CIs were estimated controlling for 85 baseline confounders. In a secondary analysis, patients receiving fluoroquinolones were compared with those receiving amoxicillin, both with and without considering baseline aortic imaging, to address differences in detection of AA/AD before antibiotic use. Data on patients within the database from January 1, 2003, through September 30, 2015, were analyzed. Data analysis was conducted from July 23, 2019, to July 6, 2020.
Hospitalization for AA/AD occurring within 60 days following treatment initiation.
After propensity score matching, patient characteristics were well balanced, with 279 554 patients (mean SD age, 63.66 10.93 years; 149 976 women 53.6%) in the pneumonia cohort and 948 364 patients (mean SD age, 62.06 10.33 years; 823 667 women 86.9%) in the UTI cohort. Initiators of fluoroquinolones (n = 139 772 pairs in the pneumonia cohort and n = 474 182 pairs in the UTI cohort) had an increased rate of AA/AD compared with initiators of azithromycin (HR, 2.57; 95% CI, 1.36-4.86; incidence, 0.03% for fluoroquinolones vs 0.01% for azithromycin) but no increased rate compared with initiators of combined trimethoprim and sulfamethoxazole (HR, 0.99; 95% CI, 0.62-1.57; incidence, <0.01% in both UTI groups). Secondary analysis using amoxicillin as a comparator (n = 3 976 162 pairs) produced results consistent with those from earlier studies (HR, 1.54; 95% CI, 1.33-1.79; incidence, <0.01% in both groups). Requiring baseline imaging in this cohort (n = 542 649 pairs) to address surveillance bias attenuated the increased rate (HR, 1.13; 95% CI, 0.96-1.33; incidence, 0.06% for fluoroquinolones vs 0.05% for amoxicillin).
The findings of this nationwide cohort study of adults with pneumonia or UTI suggest an increased relative rate of AA/AD associated with fluoroquinolones within the pneumonia cohort but not within the UTI cohort. In both cohorts, the absolute rate of AA/AD appeared to be low (<0.1%). The increased relative rate observed in the pneumonia cohort may be due to residual confounding or surveillance bias.
Frailty is important in diabetes management but its impact on the cardiovascular (CV) effectiveness of SGLT-2i and GLP-1 RA as used in routine care is unexplored. Using Medicare claims data, we ...identified three pairwise 1:1 propensity score (PS) matched cohorts of people with type 2 diabetes who initiated a SGLT-2i, a GLP-1 RA, or a DPP-4i between 04/2013-12/2018. The primary outcome was a composite of major adverse CV events (MACE) including acute myocardial infarction, ischemic stroke, hospitalization for heart failure, or all-cause mortality. We estimated hazard ratios (HR) and absolute rate differences (RD) per 1`000 person-years, with their 95% CI, in each PS-matched cohort by level of frailty, using a validated claims-based frailty index (3 strata: non-frail, <0.15; pre-frail, 0.15-0.24; frail, ≥0.25) , controlling for >150 baseline covariates. We used the Wald test for homogeneity to assess treatment heterogeneity across strata. The HR for MACE associated with SGLT-2i vs. DPP4i (n=91`141 PS-matched pairs) was 0.82 (95% CI 0.72 to 0.93) in frail, 0.71 (0.67 to 0.75) in pre-frail, and 0.78 (0.71 to 0.86) in non-frail people (p for homogeneity=0.033) . The HR for MACE associated with GLP-1 RA vs. DPP4i (n=90`988 pairs) was 0.84 (0.76 to 0.93) in frail, 0.77 (95% CI 0.73 to 0.81) in pre-frail, and 0.82 (0.74 to 0.91) in non-frail people (p for h.=0.150) . The HR for MACE associated with SGLT-2i versus GLP-1 RA (n=67`067 pairs) was 0.87 (0.75 to 1.01) in frail, 0.93 (95% CI 0.87 to 1.01) in pre-frail, and 0.90 (0.79 to 1.03) in non-frail people (p for h.=0.692) . Compared to DPP-4i, the absolute benefit of either SGLT-2i or GLP-1 RA was largest in frail people RD, -25.0 (-42.1 to -7.9) , p for h.<0.001, NNT=20; and RD, -24.9 (-39.0 to -10.7) , p for h.<0.001, NNT=21; respectively. While, compared to DPP4i, SGLT-2i and GLP-1 RA were associated with similar relative risk reductions in MACE among people with and without frailty, their absolute benefits were largest in frail people.
Disclosure
A.Kutz: Research Support; Novo Nordisk. C.Gopalakrishnan: None. D.H.Kim: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute.
Funding
National Institute on Aging (K08AG055670)
Abstract
Dementia is an important consideration in the therapeutic management of older adults with type 2 diabetes (T2D). Given the recent availability of numerous second-line therapeutic agents, ...there is limited evidence on uptake of these newer medications by dementia status. Using Medicare fee-for-service data from 2013-18, we identified a cohort of patients with T2D who initiated a glucose-lowering drug (N=3,355,725; mean SD age, 74.8 (6.9) years) and stratified our analysis based on the presence of a diagnosis for dementia in the year prior to treatment initiation. Amongst patients with dementia (N=511,835; mean SD age, 79.9 (7.7) years), metformin use remained stable from 25.8% to 24.8%, whereas sulfonylureas (20% to 17.5%) and insulin (31.8% to 26.2%) use declined. Amongst patients without dementia (N=2,843,890; mean SD age, 73.8 (6.3) years), metformin (31.7% to 24.7%), sulfonylurea (22.1% to 19.4%) and insulin use (18.7% to 14.6%) decreased. DPP-4i and glitazones use remained largely stable whereas the use of newer agents such as SGLT-2i and GLP-1 RA increased steadily in both patients with and without dementia though the uptake was much higher in patients without dementia. By the end of 2018, 19.6% of patients initiated either a SGLT-2i or a GLP-1 RA amongst those without dementia whereas only 11.1% did so amongst those with dementia. In conclusion, older medications such as metformin, sulfonylureas and insulin accounted for about two-thirds of initiated glucose-lowering medications and were more frequently used by patients with dementia, though their use declined steadily over time with the availability of newer agents.
Abstract
Using Medicare data 2015-2017, we conducted 5 sequential 1-to-1 propensity score-matched analyses of ARNI initiators and angiotensin receptor blockers (ARB) initiators, mimicking the accrual ...of new data every 6 months. Primary effectiveness endpoint was a composite of heart failure hospitalization or all-cause mortality and primary safety endpoint was a composite of hospitalization or emergency department visits for hypotension, acute kidney injury, hyperkalemia, and angioedema. Among non-frail patients (n=5,014), the rates (per 100 person-years) for ARNI vs ARB were 12.7 and 9.2 (rate difference: 3.4, 95% CI: 0.8 to 6.1), respectively, for the effectiveness endpoint and 5.2 and 3.6 (rate difference: 1.5, 95% CI: -0.1 to 3.2), respectively, for the safety endpoint. Among frail patients (n=2,694), the corresponding rates were 19.8 and 21.6 (rate difference: -1.8, 95% CI: -7.0 to 3.4) for the effectiveness endpoint and 10.9 and 8.0 (rate difference: 2.9, 95% CI: -0.6 to 6.4) for the safety endpoint.
The comparative safety of frequently used second-line agents to treat type 2 diabetes (T2D) with respect to the risk of venous thromboembolism (VTE) in routine care is unknown. It has been ...hypothesized that the diuretic effect of SGLT2 inhibitors (SGLT2i) may have an unintended impact on VTE risk by increasing blood viscosity. Using Optum Clinformatics, a large U.S. commercial health insurance claims database, we assessed the risk of an incident hospitalization for VTE within two pair-wise 1:1 propensity score (PS)-matched cohorts of patients with T2D who initiated a SGLT2i or a comparator, i.e., a GLP-1 receptor agonist GLP-1 RA (n=59,712 pairs), or a DPP-4 inhibitor DPP-4i (n=50,178 pairs) between April 2013-March 2019. We estimated hazard ratios (HR) and 95% CI controlling for over 100 baseline characteristics including common risk factors for VTE, baseline comorbidites, medication use and healthcare utilization. SGLT2i had a similar risk of VTE compared to GLP-1 RA HR (95% CI) = 0.99 (0.68, 1.44) and DPP-4i HR (95% CI) = 1.01 (0.66, 1.52) (Table 1), with incidence rates ranging between 1.1 and 1.3 events per 1,000 person-years. Results were consistent within subgroups of age, frailty and cardiovascular disease. In a large population-based study of adult patients with T2D, SGLT2i had similar risk of VTE compared to GLP-1 RA and DPP-4i, with reassuringly low absolute rates overall.
Disclosure
C. Gopalakrishnan: None. R.J. Desai: Research Support; Self; Bayer AG, Novartis AG. S.C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.
Funding
National Institute on Aging (K08AG055670)
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