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Levintow SN, Orroth KK, Breskin A, et al. Use of negative control outcomes to assess the comparability of patients initiating lipid-lowering therapies. Pharmacoepidemiol Drug Saf. 2021;doi: 10.1002/pds.5396.
Levintow, S. N., Orroth, K. K., Breskin, A., Park, A. S., Flores Arredondo, J. H., Dluzniewski, P., Navar, A. M., Sørensen, H. T., & Brookhart, M. A. (2021). Use of negative control outcomes to assess the comparability of patients initiating lipid-lowering therapies. Pharmacoepidemiology and drug safety, . https://doi.org/10.1002/pds.5396
Levintow, Sara N, et al. "Use of negative control outcomes to assess the comparability of patients initiating lipid-lowering therapies." Pharmacoepidemiology and drug safety vol. (2021). doi: https://doi.org/10.1002/pds.5396
Levintow SN, Orroth KK, Breskin A, Park AS, Flores Arredondo JH, Dluzniewski P, Navar AM, Sørensen HT, Brookhart MA. Use of negative control outcomes to assess the comparability of patients initiating lipid-lowering therapies. Pharmacoepidemiol Drug Saf. 2021 Dec 11; doi: 10.1002/pds.5396. Epub 2021 Dec 11. PMID: 34894377.
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Pharmacoepidemiol Drug Saf. 2021 Dec 11; doi: 10.1002/pds.5396. Epub 2021 Dec 11.

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

Pharmacoepidemiology and drug safety

Sara N Levintow, Kate K Orroth, Alexander Breskin, Andrew S Park, Jose H Flores Arredondo, Paul Dluzniewski, Ann Marie Navar, Henrik T Sørensen, M Alan Brookhart

Affiliations

  1. NoviSci, Inc., Durham, North Carolina, USA.
  2. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
  3. Amgen, Inc., Thousand Oaks, California, USA.
  4. Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  5. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
  6. Department of Population Health Sciences, Duke University, Durham, North Carolina, USA.

PMID: 34894377 DOI: 10.1002/pds.5396

Abstract

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.

© 2021 John Wiley & Sons Ltd.

Keywords: cardiovascular disease; cohort study; comparative analyses; ezetimibe; negative control; proprotein convertase subtilisin/kexin type 9 inhibitors; residual confounding; statins

References

  1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. - PubMed
  2. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. - PubMed
  3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. - PubMed
  4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. - PubMed
  5. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. - PubMed
  6. Seeger JD, Williams PL, Walker AM. An application of propensity score matching using claims data. Pharmacoepidemiol Drug Saf. 2005;14(7):465-476. - PubMed
  7. Seeger J, Kurth T, Walker A. Use of propensity score technique to account for exposure-related covariates: an example and lesson. Med Care. 2007;45(10):S143-S148. - PubMed
  8. Cannon CP, de Lemos JA, Rosenson RS, et al. Getting to an ImprOved understanding of low-density lipoprotein-cholesterol and dyslipidemia management (GOULD): methods and baseline data of a registry of high cardiovascular risk patients in the United States: GOULD registry methods and baseline data. Am Heart J. 2020;219:70-77. - PubMed
  9. Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal antibodies by identifying patients most likely to benefit. A consensus statement from the National Lipid Association. J Clin Lipidol. 2019;13(4):525-537. - PubMed
  10. Hines DM, Rane P, Patel J, Harrison DJ, Wade RL. Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors. Vasc Health Risk Manag. 2018;14:409-418. - PubMed
  11. Lipsitch M, Tchetgen Tchetgen E, Cohen T. Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology. 2010;21(3):383-388. - PubMed
  12. Arnold BF, Ercumen A. Negative control outcomes: a tool to detect bias in randomized trials. JAMA. 2016;316:2597-2598. - PubMed
  13. Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol. 2006;35(2):337-344. - PubMed
  14. Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol. 2007;166(3):348-354. - PubMed
  15. Dormuth CR, Patrick AR, Shrank WH, et al. Statin adherence and risk of accidents a cautionary tale. Circulation. 2009;119(15):2051-2057. - PubMed
  16. McGrath LJ, Spangler L, Curtis JR, et al. Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States. Pharmacoepidemiol Drug Saf. 2020;29(8):854-863. - PubMed
  17. Smitherman AB, Anderson C, Lund JL, Bensen JT, Rosenstein DL, Nichols HB. Frailty and comorbidities among survivors of adolescent and young adult cancer: a cross-sectional examination of a hospital-based survivorship cohort. J Adolesc Young Adult Oncol. 2018;7(3):374-383. - PubMed
  18. Overcash J, Cope DG, Van Cleave JH. Frailty in older adults: assessment, support, and treatment implications in patients with cancer. Clin J Oncol Nurs. 2018;22(6):8-18. - PubMed
  19. Nakasian SS, Rassen JA, Franklin JM. Effects of expanding the look-back period to all available data in the assessment of covariates. Pharmacoepidemiol Drug Saf. 2017;26(8):890-899. - PubMed
  20. Hubbard AE, van der Laan MJ, Robins JM. Nonparametric Locally Efficient Estimation of the Treatment Specific Survival Distribution with Right Censored Data and Covariates in Observational Studies. Springer; 2000:135-177. - PubMed
  21. Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics. 2000;56(3):779-788. - PubMed
  22. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing; 2021. - PubMed
  23. Edwards JK, Hester LL, Gokhale M, Lesko CR. Methodologic issues when estimating risks in Pharmacoepidemiology. Curr Epidemiol Reports. 2016;3(4):285-296. - PubMed

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