From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Circulation. 2015 Sep 29;132(13):1224-33. doi: 10.1161/CIRCULATIONAHA.115.018381. Epub 2015 Sep 1.
BACKGROUND: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). METHODS AND RESULTS: The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets. CONCLUSIONS: Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878.
背景：他汀类药物可降低低密度脂蛋白胆固醇（LDL-C）和高敏 C 反应蛋白（hs-CRP）；在他汀类药物的基础上加用依折麦布可进一步降低 LDL-C 和 hs-CRP。依折麦布/辛伐他汀与辛伐他汀改善降低终点：依泽替米贝疗效国际试验（IMPROVE-IT）预先设定了分析达到 LDL-C 和 hs-CRP 目标与结局之间关系的分析。
方法和结果：IMPROVE-IT 试验将 18144 例急性冠脉综合征稳定后的患者随机分为辛伐他汀或依折麦布/辛伐他汀组。在随机分组后 1 个月时测量 LDL-C 和 hs-CRP。根据 LDL-C<70mg/dL 和 hs-CRP<2mg/L 这两个预设目标的达成情况，对结局进行评估，调整了基线特征的差异。一项探索性分析检查了 LDL-C<50mg/dL 和 hs-CRP<1mg/L 的目标。排除了在基线时即达到两个目标且无 1 个月时数值或在 1 个月前出现终点的患者。在 15179 例患者中，39%的患者在 1 个月时达到 LDL-C（<70mg/dL）和 hs-CRP（<2mg/L）的双重目标，14%的患者未达到任何目标，14%的患者仅达到 hs-CRP 目标，33%的患者仅达到 LDL-C 目标。达到双重目标的患者的主要终点发生率低于未达到任何目标的患者（心血管死亡、主要冠脉事件或卒中；38.9%对 28.0%；调整后的危险比为 0.73；0.66-0.81；P<0.001）。接受依折麦布/辛伐他汀治疗的患者达到双重目标的比例高于单独接受辛伐他汀治疗的患者（50%对 29%，P<0.001）。无论治疗分配如何，双重目标的实现与改善结局之间的关联均相似（P 交互作用=0.65）。使用探索性目标也观察到了相似的发现。
结论：与单独使用辛伐他汀相比，接受依折麦布/辛伐他汀治疗的患者达到预设和探索性 LDL-C 和 hs-CRP 双重目标的比例显著更高。多变量调整后，达到 LDL-C 和 hs-CRP 双重目标与改善结局相关。
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