TY - JOUR
T1 - High- vs. low-dose diclofenac and cardiovascular risks
T2 - a target trial emulation
AU - Schmidt, Morten
AU - Arendt-Nielsen, Lars
AU - Hauge, Ellen-Margrethe
AU - Sørensen, Henrik Toft
AU - Pedersen, Lars
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Aims: To examine the dose dependency of diclofenac's cardiovascular risks. Methods and results: Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12). Conclusions: Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.
AB - Aims: To examine the dose dependency of diclofenac's cardiovascular risks. Methods and results: Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12). Conclusions: Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.
KW - Adult
KW - Anti-Inflammatory Agents, Non-Steroidal/adverse effects
KW - Brain Ischemia/chemically induced
KW - Cardiovascular System
KW - Diclofenac/adverse effects
KW - Humans
KW - Stroke/chemically induced
KW - Cardiovascular disease
KW - Nonsteroidal anti-inflammatory drugs
KW - Dose
KW - Diclofenac
UR - http://www.scopus.com/inward/record.url?scp=85168437844&partnerID=8YFLogxK
U2 - 10.1093/ehjcvp/pvad018
DO - 10.1093/ehjcvp/pvad018
M3 - Journal article
C2 - 36921986
SN - 2055-6837
VL - 9
SP - 453
EP - 461
JO - European Heart Journal - Cardiovascular Pharmacotherapy
JF - European Heart Journal - Cardiovascular Pharmacotherapy
IS - 5
M1 - pvad018
ER -