Obeid Slayman, Libby Peter, Husni Elaine, Wang Qiuqing, Wisniewski Lisa M, Davey Deborah A, Wolski Katherine E, Xia Feng, Bao Weihang, Walker Chris, Ruschitzka Frank, Nissen Steven E, Lüscher Thomas F
University Heart Center, Department of Cardiology, University Hospital, CH-8091 Zurich, Switzerland.
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Eur Heart J Cardiovasc Pharmacother. 2022 Sep 3;8(6):611-621. doi: 10.1093/ehjcvp/pvac015.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established cardiovascular (CV) disease or risk factors for disease as illustrated by the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen) trial participants (NCT00346216).We further investigated whether the selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile compared with ibuprofen or naproxen in the PRECISION population.
Twenty-four thousand eighty-one patients who required NSAIDs for osteoarthritis or rheumatoid arthritis (RA) and had increased CV risk randomly received celecoxib, ibuprofen, or naproxen. The current pre-specified secondary analysis assessed the incidence, severity, and NSAID-related risk of the pre-specified composite cardiorenal outcome (adjudicated renal event, hospitalization for congestive heart failure, or hospitalization for hypertension) in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. Following a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up of 34.1 ± 13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen, and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen [hazard ratio (HR) 0.67, confidence interval (CI) 0.53-0.85, P = 0.001) and a trend to lower risk compared with naproxen (HR 0.79, CI 0.61-1.00, P = 0.058). In the ITT analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14%, and 0.89% for celecoxib, ibuprofen, and naproxen, respectively (P = 0.052), while in the on-treatment analysis the rates were 0.52%, 0.91%, and 0.78% (P < 0.001).
In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favourable cardiovascular safety compared with ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure.Clinical Trial Registration: NCT00346216.
非甾体抗炎药（NSAIDs）是处方和非处方中最常用的药物之一。NSAIDs在关节炎患者中的长期心血管安全性引发了争议。对于不良心肾效应的相对发生率和严重程度仍存在担忧，尤其是在有已确诊心血管（CV）疾病或疾病风险因素的关节炎患者中，如PRECISION（塞来昔布综合安全性与布洛芬或萘普生前瞻性随机评估）试验参与者（NCT00346216）所示。我们进一步研究了在PRECISION人群中，与布洛芬或萘普生相比，选择性COX-2抑制剂塞来昔布是否具有更优的心肾安全性。
24081名因骨关节炎或类风湿关节炎（RA）需要使用NSAIDs且心血管风险增加的患者被随机分配接受塞来昔布、布洛芬或萘普生治疗。当前预先设定的二次分析评估了意向性治疗（ITT）人群中预先设定的复合心肾结局（判定的肾脏事件、因充血性心力衰竭住院或因高血压住院）的发生率、严重程度以及与NSAIDs相关的风险。一项治疗中分析评估了服用研究药物患者的安全性。在平均治疗持续时间为20.3±16.0个月且平均随访时间为34.1±13.4个月后，ITT人群中有423名患者（1.76%）发生了主要心肾复合结局。在这423名患者中，塞来昔布组有118名（28%），布洛芬组有166名（39%），萘普生组有139名（33%）。在针对独立临床变量进行调整的多变量Cox回归模型中，与布洛芬相比，塞来昔布显示出显著更低的风险[风险比（HR）0.67，置信区间（CI）0.53 - 0.85，P = 0.001]，与萘普生相比有降低风险的趋势（HR 0.79，CI 0.61 - 1.00，P = 0.058）。在ITT分析中，220名患者发生了具有临床意义的肾脏事件，塞来昔布、布洛芬和萘普生的事件发生率分别为0.71%、1.14%和0.89%（P = 0.052），而在治疗中分析中，发生率分别为0.52%、0.91%和0.78%（P＜0.001）。
在当前时代，长期使用NSAIDs与关节炎患者发生的心肾事件较少相关。在所研究的剂量下，与布洛芬或萘普生相比，塞来昔布的肾脏事件较少，因此心血管安全性更优。这些结果对于管理患有慢性关节炎疼痛且有肾功能受损和/或心力衰竭高风险个体的从业者具有重要的临床意义。临床试验注册号：NCT00346216。
