TY - JOUR
T1 - Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries
T2 - interrupted time series regression analysis
AU - Morales, Daniel R.
AU - Morant, Steven V.
AU - MacDonald, Thomas M.
AU - Hallas, Jesper
AU - Ernst, Martin Thomsen
AU - Pottegard, Anton
AU - Herings, Ron M. C.
AU - Smits, Elisabeth
AU - Overbeek, Jetty A.
AU - Mackenzie, Isla S.
AU - Doney, Alexander S. F.
AU - Mitchell, Lyn
AU - Bennie, Marion
AU - Robertson, Chris
AU - Wei, Li
AU - Nicholson, Lizzie
AU - Morris, Carole
AU - Flynn, Rob W. V.
N1 - Funding Information:
The study was funded by the European Medicines Agency (Procurement procedure EMA/2014/50/RE). The EMA approved the final study protocol and had no influence on the results or decision to publish. D.M. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (Grant 214588/Z/18/Z). E.S., J.O. and R.H. are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. T.M.M.'s university holds research grants from Novartis, Ipsen, Teijin and Menarini. He is or has been the Principal Investigator on trials paid for by Novartis, Ipsen, Teijin, RTI, GlaxoSmithKline, SHIRE and Menarini. In the last 3 years he has been paid consulting fees by Novartis and Merck. None of these studies relate to diclofenac.
Publisher Copyright:
© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society
PY - 2021/3/2
Y1 - 2021/3/2
N2 - Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations.Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland.Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action.Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.
AB - Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations.Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland.Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action.Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.
KW - NSAIDs
KW - cardiovascular disease
KW - diclofenac
KW - drug safety
KW - epidemiology
KW - pharmacovigilance
UR - http://www.scopus.com/inward/record.url?scp=85088835556&partnerID=8YFLogxK
U2 - 10.1111/bcp.14478
DO - 10.1111/bcp.14478
M3 - Article
C2 - 32668021
SN - 0306-5251
VL - 87
SP - 1129
EP - 1140
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 3
ER -
