Farkouh Michael E, Kirshner Howard, Harrington Robert A, Ruland Sean, Verheugt Freek W A, Schnitzer Thomas J, Burmester Gerd R, Mysler Eduardo, Hochberg Marc C, Doherty Michael, Ehrsam Elena, Gitton Xavier, Krammer Gerhard, Mellein Bernhard, Gimona Alberto, Matchaba Patrice, Hawkey Christopher J, Chesebro James H
Cardiovascular Clinical Research Center, New York University School of Medicine, 530 First Avenue, New York, NY 10016, USA.
Lancet. 2004;364(9435):675-84. doi: 10.1016/S0140-6736(04)16894-3.
The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.
18325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat.
81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0.75 [0.20-2.79], p=0.6669), overall (0.66 [0.21-2.09], p=0.4833), and in patients taking aspirin (0.47 [0.04-5.14], p=0.5328).
The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin.
环氧化酶2（COX2）选择性抑制剂增加心肌梗死风险的可能性存在争议。治疗性关节炎研究与胃肠道事件试验（TARGET）旨在评估COX2抑制剂鲁米昔布与两种非甾体抗炎药萘普生和布洛芬相比的胃肠道及心血管安全性。
在两项设计相同的子研究中，将18325例年龄50岁及以上的骨关节炎患者随机分为三组，分别每日一次服用400mg鲁米昔布（n = 9156）、每日两次服用500mg萘普生（4754例）或每日三次服用800mg布洛芬（4415例）。随机分组根据低剂量阿司匹林使用情况和年龄进行分层。主要心血管终点为非致命性及无症状性心肌梗死、中风或心血管死亡的抗血小板试验协作组终点。分析采用意向性治疗。
81例（0.44%）患者未开始治疗，7120例（39%）未完成研究。在1年随访时，主要终点的发生率较低，鲁米昔布组（59例事件[0.65%]）和非甾体抗炎药组（50例事件[0.55%]）相似；风险比为1.14[95%CI 0.78 - 1.66]，p = 0.5074）。在各子研究的总体人群中，鲁米昔布组心肌梗死（临床及无症状性）发生率为0.38%（18例事件），萘普生组为0.21%（10例），鲁米昔布组为0.11%（5例），布洛芬组为0.16%（7例）。在萘普生子研究中，在未服用低剂量阿司匹林的人群中，心肌梗死（临床及无症状性）发生率与鲁米昔布组相比无显著差异（风险比2.37[95%CI 0.74 - 7.55]，p = 0.1454），总体人群中（1.77[0.82 - 3.84]，p = 0.1471），以及服用阿司匹林的患者中（1.36[0.47 - 3.93]，p = 0.5658）。在布洛芬子研究中，在未服用低剂量阿司匹林的人群中，鲁米昔布组和布洛芬组的这些发生率无差异（0.75[0.20 - 2.79]，p = 0.6669），总体人群中（0.66[0.21 - 2.09]，p = 0.4833），以及服用阿司匹林的患者中（0.47[0.04 - 5.14]，p = 0.5328）。
无论是否使用阿司匹林，鲁米昔布与布洛芬或萘普生相比，主要终点包括心肌梗死发生率均无差异。这一发现表明，鲁米昔布对于常处于高心血管风险且服用低剂量阿司匹林的骨关节炎患者是一种合适的治疗药物。
