Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark.
Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
Eur Heart J Cardiovasc Pharmacother. 2023 Jul 29;9(5):453-461. doi: 10.1093/ehjcvp/pvad018.
To examine the dose dependency of diclofenac's cardiovascular risks.
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).
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.
研究双氯芬酸的心血管风险与剂量的关系。
利用丹麦健康登记和目标试验模拟设计，我们在 1996 年至 2020 年期间进行了一系列 300 项全国性队列研究，每项研究都模拟了临床试验的严格设计标准。符合纳入标准的成年人没有最近的非甾体抗炎药处方、禁忌症（胃肠道疾病、血小板减少症或心力衰竭）或低依从性疾病（痴呆或精神疾病）。双氯芬酸的起始使用者与寻求医疗保健的非起始使用者进行了比较，并使用近似高剂量（≥150mg/天）与低剂量（<150mg/天）进行了头对头比较。使用 Cox 回归计算起始后 30 天内主要不良心血管事件（MACE）的发生率比（IRR）。我们调整了年龄、性别、日历期、合并症、合并用药和社会经济地位。与非起始使用者（n=3789617）相比，双氯芬酸起始使用者（n=1894834）的 MACE 发生率约增加 50%（IRR 1.53，95%置信区间[CI]：1.43-1.63），反映出心肌梗死的 IRR 为 1.54（95%CI：1.40-1.69），缺血性中风为 1.29（1.14-1.45），心脏性死亡为 1.92（1.71-2.16）。这种风险增加见于大多数慢性疼痛的情况下，特别是头痛（IRR 5.10，95%CI：1.46-17.85）。高剂量（IRR 1.55，95%CI：1.40-1.71）和低剂量（IRR 1.52，1.41-1.63）双氯芬酸起始使用者的风险增加相似，这在头对头分析中得到了证实（IRR 1.01，95%CI：0.90-1.12）。
高剂量和低剂量双氯芬酸的起始使用者的心血管风险增加相当。这一发现否定了低剂量双氯芬酸无风险的假设。
