Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States

McGrath, Leah J.; Spangler, Leslie; Curtis, Jeffrey R.; Ehrenstein, Véra; Sørensen, Henrik Toft; Saul, Bradley; Levintow, Sara N.; Reams, Diane; Bradbury, Brian D.; Brookhart, M. Alan

doi:10.1002/pds.5037

Cited by 16 publications

(33 citation statements)

References 29 publications

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“…We then used the null distribution to compute the calibrated P value and confidence intervals. This approach has been used in many previous studies in different clinical areas, including covid-19 repurposed treatments, 34 35 36 and was acknowledged in the latest version of the ENCePP guide on methodological standards in pharmacoepidemiology. 37 We only presented estimates specific to databases where empirical calibrations were conducted.…”

Section: Methodsmentioning

confidence: 99%

Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US

Burn

Duarte‐Salles

et al. 2022

BMJ

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Objective To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines. Design International network cohort study. Setting Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US. Participants Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson & Johnson)), from December 2020 to mid-2021. Main outcome measures Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses. Results Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2. Conclusions In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.

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Section: Methodsmentioning

confidence: 99%

Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US

Burn

Duarte‐Salles

et al. 2022

BMJ

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“…In this study, the first 3 months after treatment initiation were chosen to represent the baseline fracture risk: prior clinical studies have shown little difference in the incidence of fracture outcomes between denosumab and placebo for at least 6 months after treatment initiation [ 21 ]. Furthermore, recent studies have used fractures occurring in the first 3 months as ‘negative control outcomes’ to detect residual confounding on the assumption that there is no measurable treatment effect on fracture within the first 3 months and that this, therefore, represents a measure of baseline fracture risk [ 28 ]. In this real-world study, using this within-cohort approach, these data show that continued treatment with osteoporosis medications is associated with reductions of fracture rates in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Real-world effectiveness of osteoporosis treatments in Germany

O’Kelly

Bartsch

Kossack³

et al. 2022

Arch Osteoporos

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Summary This observational study assessed the impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting. Purpose The efficacy of osteoporosis medications has been demonstrated in clinical trials, but a lack of evidence exists of their real-world effectiveness. This real-world study assessed the treatment patterns and impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. Methods This cohort study used data from the WIG2 benchmark database, a German anonymised healthcare claims database. All women ≥ 50 years of age with ≥ 1 prescription for osteoporosis medication between 1 January 2013 and 31 December 2017 were included. The primary outcome was treatment effectiveness, evaluated as the change in fracture incidence after initiating treatment. Fracture types included all fractures, clinical vertebral, hip and wrist/forearm. Fracture incidence was assessed during the early-treatment period (0–3 months) and the on-treatment period (4–12, 13–24, 25–36 and 37–48 months). Results Baseline covariates and treatment patterns were determined for 41,861 patients. The median duration of therapy was longer with denosumab (587 days) than with intravenous ibandronate (451 days), intravenous zoledronate (389 days) or oral bisphosphonates (258 days). The baseline incidence rate of all fractures was higher in patients receiving denosumab than in those receiving other treatments (87.6, 78.2, 56.6 and 66.0 per 1000 person-years for denosumab, oral bisphosphonates, intravenous ibandronate and intravenous zoledronate, respectively). Rates of all fractures declined with continued denosumab (by 38%, 50%, 56% and 67% at 12, 24, 36 and 48 months, respectively) and oral bisphosphonates (by 39%, 44%, 49% and 42%, respectively) treatment. Conclusion Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.

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“…An expert panel reviewed possible mechanisms of confounding in the study population and selected 10 negative control outcomes: four associated with frailty (decubitus ulcer, accident, fracture, and cancer, excluding nonmelanoma skin cancer) and six associated with health‐seeking behaviors (wellness visit, visual test, influenza vaccine, herpes zoster or pneumococcal vaccine, colon cancer screening, and nonmelanoma skin cancer or Mohs surgery). The majority of negative control outcomes were modeled after those developed in our prior work 16 . An exception was the cancer outcome, which was hypothesized to be associated with frailty given previous findings of high levels of frailty indicators in both older and younger adults diagnosed with cancer 17,18 .…”

Section: Methodsmentioning

confidence: 99%

“…For example, if the outcome of interest for a comparative effectiveness study of LLT regimens was MI, the ideal negative control outcomes would share a confounding structure with treatment selection (i.e., PCSK9i vs. ezetimibe or high‐intensity statin) and MI. Outcomes used in prior negative control studies include decubitus ulcer and accidents (i.e., confounding by disease severity or frailty), and wellness visits, vaccinations, and cancer screenings (i.e., confounding by health‐seeking behaviors) 13–16 …”

Section: Introductionmentioning

confidence: 99%

Use of negative control outcomes to assess the comparability of patients initiating lipid‐lowering therapies

Levintow

Orroth

Breskin

et al. 2021

Pharmacoepidemiology and Drug

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Purpose Clinical trials have demonstrated efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing risk of cardiovascular disease events, but effectiveness in routine clinical care has not been well‐studied. We used negative control outcomes to assess potential confounding in an observational study of PCSK9i versus ezetimibe or high‐intensity statin. Methods Using commercial claims, we identified U.S. adults initiating PCSK9i, ezetimibe, or high‐intensity statin in 2015–2018, with other lipid‐lowering therapy (LLT) use in the year prior (LLT cohort) or atherosclerotic cardiovascular disease (ASCVD) in the past 90 days (ASCVD cohort). We compared initiators of PCSK9i to ezetimibe and high‐intensity statin by estimating one‐year risks of negative control outcomes influenced by frailty or health‐seeking behaviors. Inverse probability of treatment and censoring weighted estimators of risk differences (RDs) were used to evaluate residual confounding after controlling for covariates. Results PCSK9i initiators had lower one‐year risks of negative control outcomes associated with frailty, such as decubitus ulcer in the ASCVD cohort (PCSK9i vs. high‐intensity statin RD = −3.5%, 95% confidence interval (CI): −4.6%, −2.5%; PCSK9i vs. ezetimibe RD = −1.3%, 95% CI: −2.1%, −0.6%), with similar but attenuated associations in the LLT cohort. Lower risks of accidents and fractures were also observed for PCSK9i, varying by cohort. Risks were similar for outcomes associated with health‐seeking behaviors, although trended higher for PCSK9i in the ASCVD cohort. Conclusions Observed associations suggest lower frailty and potentially greater health‐seeking behaviors among PCSK9i initiators, particularly those with a recent ASCVD diagnosis, with the potential to bias real‐world analyses of treatment effectiveness.

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Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States

Cited by 16 publications

References 29 publications

Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US

Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US

Real-world effectiveness of osteoporosis treatments in Germany

Use of negative control outcomes to assess the comparability of patients initiating lipid‐lowering therapies

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