TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Am J Cardiol. 2013 Aug 15;112(4):472-8. doi: 10.1016/j.amjcard.2013.04.011. Epub 2013 May 24.
The dosing of anticoagulants is critical when balancing efficacy and safety. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome 2-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial was designed to evaluate 2 low doses of rivaroxaban compared with placebo in patients with recent acute coronary syndromes being treated with antiplatelet therapies. Because the 2 doses significantly reduced the primary efficacy end point, a further comparison of the 2 treatment strategies was deemed important. In total, 15,526 patients were randomized to twice-daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Comparing the 2 active doses, there were no significant differences between 2.5 and 5 mg for the primary efficacy end point of cardiovascular death, myocardial infarction, or stroke (9.1% vs 8.8%, p = 0.89), myocardial infarction (6.1% vs 4.9%, p = 0.23), or stent thrombosis (2.2% vs 2.3%, p = 0.59). However, there was a divergence in cardiovascular death, which included ischemic and hemorrhagic events, with the 2.5-mg dose resulting in lower rates than the 5-mg dose (2.7% vs 4.0%, p = 0.009). Notably, with 2.5 versus 5 mg, there were fewer study drug discontinuations (p = 0.004) and fewer non-coronary artery bypass grafting TIMI major or minor bleeds (p = 0.021) and fatal bleeds (p = 0.044). Of the patients who died, 8 in the 2.5-mg group and 20 in the 5-mg group experienced non-coronary artery bypass grafting TIMI major or minor bleeding events before death. In conclusion, the 2 doses of rivaroxaban reduced cardiovascular events in patients with recent acute coronary syndromes treated with antiplatelet therapies; however, the 2.5-mg dose was associated with lower mortality and fewer bleeding complications than the 5-mg dose. Thus, the addition of rivaroxaban 2.5 mg twice daily offers a more favorable balance of efficacy and safety in patients with recent acute coronary syndromes.
在平衡疗效和安全性时，抗凝剂的剂量非常关键。急性冠状动脉综合征患者加用或不加用噻吩吡啶类药物的抗 Xa 治疗以降低心血管事件的阿哌沙班（ATLAS ACS 2-TIMI 51）试验旨在评估与安慰剂相比，最近接受抗血小板治疗的急性冠状动脉综合征患者的两种低剂量利伐沙班。由于这两种剂量显著降低了主要疗效终点，因此进一步比较两种治疗策略非常重要。共有 15526 名患者被随机分配至每日两次利伐沙班 2.5mg、利伐沙班 5mg 或安慰剂组。与两种活性剂量相比，主要疗效终点（心血管死亡、心肌梗死或卒中）方面，2.5mg 与 5mg 之间无显著差异（9.1% vs. 8.8%，p = 0.89），心肌梗死（6.1% vs. 4.9%，p = 0.23）和支架血栓形成（2.2% vs. 2.3%，p = 0.59）也无显著差异。然而，心血管死亡（包括缺血性和出血性事件）方面存在差异，2.5mg 剂量的发生率低于 5mg 剂量（2.7% vs. 4.0%，p = 0.009）。值得注意的是，与 5mg 相比，2.5mg 组的研究药物停药率更低（p = 0.004），非冠状动脉旁路移植术 TIMI 主要或次要出血（p = 0.021）和致命性出血（p = 0.044）也更少。在死亡患者中，2.5mg 组有 8 例和 5mg 组有 20 例在死亡前发生了非冠状动脉旁路移植术 TIMI 主要或次要出血事件。总之，两种剂量的利伐沙班降低了接受抗血小板治疗的近期急性冠状动脉综合征患者的心血管事件；然而，与 5mg 剂量相比，2.5mg 剂量与较低的死亡率和较少的出血并发症相关。因此，每日两次给予利伐沙班 2.5mg 可在近期急性冠状动脉综合征患者中提供更有利的疗效和安全性平衡。
