SATURN研究 解读 杭州市第一人民医院 黄进宇

   2011 年11 月15 日，美国AHA 2011科学年会上，SATURN（采用血管内超声研究冠脉粥样硬化：瑞舒伐他汀和阿托伐他汀的疗效比较）研究结果在最新揭晓的临床研究专场公布，并同期在《新英格兰医学杂志》在线发表。

背 景 他汀治疗通过降低LDL-C，可预防心血管（CV）事件以及延缓冠状动脉粥样硬化进展。但尚无研究评估强化他汀治疗或最大剂量的不同他汀类药物逆转动脉粥样硬化斑块的疗效。

血管内超声（IVUS）冠状动脉成像技术 旋转式探头 正常冠状动脉解剖 CV-1111-CR-0281 Although angiography is an extremely valuable imaging tool, and has been the predominant method for detecting atherosclerotic lesions for over 50 years, there are a number of disadvantages to its use, including: the significant variability in interpretation of the images obtained, the two-dimensional depiction of arteries, concealment of atheroma by arterial wall remodelling, and the fact that these ‘silent’ remodelled lesions are the most common substrate for ACS (Nissen & Yock 2001). Assessment of atheroma by QCA is based on measurement of luminal stenosis. Thus, it has limited sensitivity for detecting atheroma that do not protrude into the lumen and may underestimate atherosclerotic burden (Nissen & Yock 2001). IVUS directly images the arterial wall, allowing tomographic assessment of lumen area, plaque size and composition (Nissen & Yock 2001). In patients with suspected CAD but with no angiographically documented atherosclerosis, IVUS frequently detects the presence of atheroma (Topol & Nissen 1995; Erbel et al 1996; Mintz et al 1995). In a study of 44 patients with suspected CAD but normal angiograms, IVUS detected atheroma in almost half the patients (Erbel et al 1996). References Erbel R et al. Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris. Eur Heart J 1996; 17: 880–889. Mintz GS et al. Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol 1995; 25: 1479–1485. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001; 103: 604–616. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995; 92: 2333–2342. Abbreviations QCA=quantitative coronary angiography; IVUS=intravascular ultrasound; CAD=coronary artery disease 图像来自克里夫兰临床血管内超声中心实验室 IVUS=血管内超声（intravascular ultrasound） CV-1111-CR-0281 4

IVUS 检测出血管造影的“静息”粥样斑块 血管造影图片 接近远端部位： 极少有疾病的证据 接近近端部位： 大的新月形粥样硬化斑块 Reprinted from Circulation 2001; 103: 604–616 with permission from Wolters Kluwer. Studies have demonstrated discrepancies between coronary angiography and IVUS for the detection of atherosclerotic lesions (Erbel et al 1996; Briguori et al 2002; Nissen & Yock 2001). In this image, atheroma that is plainly evident on IVUS remained undetected by angiography as a result of coronary remodelling (Nissen & Yock 2001). That is, despite the large atheroma shown on IVUS at the more proximal site, the arterial lumen diameter remained almost the same as at the more distal site (where there was little evidence of disease) because of arterial wall remodelling, which resulted in a false-negative angiogram. References Briguori C et al. Discrepancy between angiography and intravascular ultrasound when analysing small coronary arteries. Eur Heart J 2002; 23: 247‒254. Erbel R et al. Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris. Eur Heart J 1996; 17: 880‒889. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001; 103: 604–616. Abbreviation IVUS=intravascular ultrasound IVUS=血管内超声（intravascular ultrasound） Nissen S, Yock P. Circulation 2001; 103: 604–616 Reprinted with permission from Wolters Kluwer. CV-1111-CR-0281 5

他汀治疗后LDL-C的改变 VOYAGER患者个体数据荟萃分析结果 剂量 (对数尺度) 5 mg 10 mg 20 mg 40 mg 80 mg -36 (n= 7837) -41# (n=3908) -39 (n=670) -46 (n=1324) For both rosuvastatin and atorvastatin, increasing statin dose resulted in an incremental reduction in LDL-C. There were differences in efficacy between the two statins, but the incremental benefit of doubling the dose was similar for each, with a 4–6% improvement in lowering of LDL-C. Reference Nicholls SJ et al. Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol 2010; 105; 69–76. Abbreviation LDL-C=low-density lipoprotein cholesterol -50## (n=2072) -44* (n=11690) -50† (n=3554) -55‡ (n=2983) * p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and 20 mg; †p<0.001 rosuvastatin 20 mg vs atorvastatin 20 mg and 40 mg; ‡p<0.001 rosuvastatin 40 mg vs atorvastatin 40 mg and 80 mg; #p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg; ##p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76. CV-1111-CR-0281 6

他汀治疗后HDL-C的变化 VOYAGER患者个体数据荟萃分析结果 7.9 (n=2983) 7.0 (n=3554) 6.1 (n=11,690) 5.5 (n=670) 4.5 (n=7837) 3.5 (n=3908) Rosuvastatin and atorvastatin both raised HDL-C concentrations across the range of doses used. However, the magnitude of HDL-C increase varied with statin doses and, at any given dose, between the statins. For rosuvastatin, the increase in HDL-C was dose-dependent over the dose range studied in each case; in the case of atorvastatin, however, the increase in HDL-C was inversely related to dose. Reference Barter PJ et al. Effect of statins on HDL: a complex process unrelated to changes in LDL: Analysis of the VOYAGER Database. J Lipid Res 2010; 51; 1546–1553. Abbreviations HDL-C=high-density lipoprotein cholesterol; LSM=least squares mean 2.4 (n=1324) 2.3 (n=2072) 5 mg 10 mg 20 mg 40 mg 80 mg 剂量 (对数尺度) HDL-C=高密度脂蛋白胆固醇(high-density lipoprotein cholesterol); LSM=最小二乘均数(least-squares mean) Barter PJ et al. J Lipid Res 2010; 51: 1546-1553 CV-1111-CR-0281 7

几项IVUS研究†中LDL-C水平和PAV变化的关系 ASTEROID3 瑞舒伐他汀 60 80 90 100 110 0.6 1.2 1.8 PAV*变化的中位数 (%) 平均LDL-C(mg/dL) -1.2 -0.6 70 120 A-Plus2 安慰剂 CAMELOT4 REVERSAL5 普伐他汀 阿托伐他汀 进展 逆转 ACTIVATE1 Whilst it is acknowledged that there are limitations in comparing data and results from different studies, this slide summarises the data from several IVUS studies and provides insight into the relationship between the LDL-C level achieved and PAV. The line of best-fit suggests there is a correlation between mean LDL-C achieved in the various studies and the progression rate for the most robust IVUS endpoint, PAV. This graph suggests that no apparent LDL-C threshold exists beyond which benefits of LDL-C reduction apply and that to achieve regression, lower is better. ASTEROID3 and REVERSAL5 investigated active statin treatment; A-PLUS2, ACTIVATE1 AND CAMELOT4 investigated non-statin therapies but included placebo arms in which a considerable proportion of patients received background statin therapy (62%, 80% and 84% respectively).   References 1. Nissen S et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2006; 354: 1253–1263. 2. Tardif J et al. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004; 110: 3372–3377. 3. Nissen S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006; 295 : 1556–1565. 4. Nissen S et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: a randomized controlled trial. JAMA 2004; 292: 2217–2225. 5. Nissen S et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis a randomized controlled trial. JAMA 2004; 291: 1071–1080. Abbreviations IVUS=intravascular ultrasound; LDL-C=low-density lipoprotein cholesterol; PAV=percent atheroma volume †ASTEROID 和REVERSAL 是关于他汀治疗的研究；A-PLUS、ACTIVATE 和CAMELOT 是非他汀研究但是在安慰剂组有患者服用他汀比例分别为：62%, 80% 和84). * ASTEROID和REVERSAL中PAV变化的中位数; A-PLUS、 ACTIVATE 和CAMELOT 中PAV变化的最小二乘均数 1. Nissen S et al. N Engl J Med 2006; 354: 1253–1263. 2. Tardif J et al. Circulation 2004; 110: 3372–3377. 3. Nissen S et al. JAMA 2006; 295: 1556–1565. 4. Nissen S et al. JAMA 2004; 292: 2217–2225. 5. Nissen S et al. JAMA 2004; 291: 1071–1080. CV-1111-CR-0281 8

SATURN 理论基础 IVUS，一项敏感的检测冠状动脉疾病进展的方法，是评估强化降脂治疗对于动脉粥样硬化进展/逆转的适当的方法, ASTEROID研究的结果提示强化的血脂管理可逆转冠状动脉粥样硬化1, 一项关于4个IVUS研究的事后分析发现当LDL-C被有效降低而且HDL-C被升高达7.5%时，可逆转冠状动脉粥样硬化2, 瑞舒伐他汀40mg和阿托伐他汀80mg均可有效降低LDL-C，瑞舒伐他汀剂量范围内可持续升高HDL-C，而阿托伐他汀升高HDL-C的效应随着剂量的增加而逐渐减小3 , SATURN 将更好的理解强化他汀治疗在降低LDL-C外升高HDL-C进而在冠状动脉粥样硬化进展上的作用, IVUS allows tomographic assessment of lumen area, plaque size and composition (Nissen & Yock 2001). IVUS has emerged as the most sensitive measure of the progression of coronary disease and the most appropriate method to assess the effects of intensive lipid lowering on progression/regression of atherosclerosis. Previous studies have suggested there may be an absolute level of LDL-C below which regression of atherosclerosis occurs. Results from the ASTEROID study showed that regression of atherosclerosis can be achieved with intensive statin therapy using rosuvastatin 40 mg (Nissen et al 2006). Additionally, the increase in HDL-C observed in the ASTEROID study suggests that therapies which both lower LDL-C and raise HDL-C have the potential to significantly impact atherosclerosis. A post-hoc analysis of four IVUS studies found that regression of coronary atherosclerosis occurs when LDL-C is substantially reduced and HDL-C is increased by more than 7.5% (Nicholls et al 2007). Rosuvastatin 40 mg and atorvastatin 80 mg both produce substantial reductions in LDL-C. However, the increases in HDL-C produced by rosuvastatin are maintained across the dose range, whereas the HDL-C effects of atorvastatin diminish with increasing dose (Jones et al 2003). The SATURN study will help provide a better understanding of the importance of HDL-C raising in addition to LDL-C lowering on the progression of coronary atherosclerosis. References Jones P et al. STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses (STELLAR trial). Am J Cardiol 2003; 92: 152–160. Nicholls SJ et al. Statins, high-density lipoprotein cholesterol, and regression of coronary athersoclerosis. JAMA 2007; 297: 499–508. Nissen SE et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006; 295: 1556–1565. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001; 103: 604–616. Abbreviations IVUS=intravascular ultrasound; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol 1. Nissen SE et al. JAMA 2006; 295: 1556–1565; 2. Nicholls SJ et al. JAMA 2007; 297: 499–508; 3. Jones P et al. Am J Cardiol 2003; 92: 152–160. CV-1111-CR-0281 9

  SATURN 研究是一项随机、双盲、平行分组的多中心研究，共纳入215家中心 1389 例经冠脉造影确诊的冠脉疾病患者，采用血管内超声检查（IVUS）比较了FDA 批准的最大剂量瑞舒伐他汀（40 mg/d）和阿托伐他汀（80 mg/d）对有冠脉造影适应证的高胆固醇血症患者的动脉粥样硬化进展的影响。主要终点是单支冠状动脉>40 mm节段内以IVUS评估的斑块体积百分比（PAV）的变化。其他观察指标包括斑块总体积（TAV）变化、血脂和生化检测，以及24个月治疗期间的安全性和耐受性。

治疗104 周的结果显示，强化他汀治疗，无论是瑞舒伐他汀40 mg 还是阿托伐他汀80mg 均可使近2/3患者的斑块逆转。阿托伐他汀80 mg 组和瑞舒伐他汀40 mg 组在主要研究终点斑块体积变化百分比（PAV）方面无统计学差异（-0.99% vs.-1.22%，P=0.17），次要终点标准化的斑块总体积（TAV）上略有差异（-4.42 mm3 vs. -6.39mm3，P=0.01）。

结果 主要终点：PAV的变化 P=0.17 CV-1111-CR-0281 (n=520) (n=519) P=0.17 CV-1111-CR-0281 Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 13

结果 TAV的变化 (n=520) (n=519) P=0.01 Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 14

2011年ESC/EAS血脂异常管理指南要求将极高危患者LDL-C降至70 mg/dl以下。在SATURN试验中，阿托伐他汀80 mg达到70.2 mg/dl，而瑞舒伐他汀40 mg使LDL-C降低达到62.6 mg/dl，同时显示出更强的逆转斑块作用。SATURN试验结果从影像学角度，也进一步支持了将LDL-C水平降至70 mg/dl以下。

2011年ESC/EAS 血脂异常治疗指南推荐： 冠心病患者的血脂应控制在70 mg/dL以下 危险分层 推荐的LDL-C目标值 推荐等级 证据级别 极高危：确诊的心血管疾病、2型糖尿病、1型糖尿病伴靶器官损害、中重度CKD或SCORE水平≥10% LDL-C目标值<1.8mmol/L（<~70mg/dL）和/或不能达标时，LDL-C降幅≥50% I A 高危：单个危险因素明显提高，SCORE水平≥5~10% LDL-C目标值<2.5mmol/L（<~100mg/dL） IIa 中危：SCORE水平>1~≤5% LDL-C目标值<3.0mmol/L（<~115mg/dL） C 1.8是上限，并非下限 CV-1111-CR-0281 European Heart Journal .2011;32:1769–1818 17

结果 达到LDL-C目标 70mg/dL的患者 P<0.001 CV-1111-CR-0281 Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 18

总 结 瑞舒伐他汀（40mg）相比阿托伐他汀（80mg）治疗后达到的LDL-C水平更低，分别为62.6+1.0 mg/dL 和 70.2+1.0 mg/dL (P<0.01) 瑞舒伐他汀（40mg）相比阿托伐他汀（80mg）治疗后达到的HDL-C水平更高， 分别为50.4+0.5 mg/dL 和 48.6+0.5 mg/dL (P=0.01) 两种治疗方案均产生显著的冠状动脉粥样硬化斑块自基线的逆转P<0.001) 在瑞舒伐他汀（40mg）和阿托伐他汀（80mg）两组间，主要终点PAV的改变没有发现显著差异，分别为-1.22% (95%CI: -1.52,-1.90) 相比-0.99% (95%CI: -1.19,-0.63) (P=0.17) 未出现差异的可能是由于HDL-C的组间差异小于预计 Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 19

结果 停药情况 参数, n(%) RSV 40mg (n=691) ATV 80mg (n=689) 停药的患者数 145 (21.0) 142 (20.6) 停药原因 患者要求停药 54 (7.8) 53 (7.7) 不良事件 45 (6.5) 48 (7.0) 失访 20 (2.9) 9 (1.3) 依从性差 13 (1.9) 16 (2.3) 其他 所有接受随机治疗的患者，n = 患者数. RSV=瑞舒伐他汀, ATV=阿托伐他汀. Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 20

结果 实验室异常值 参数, 例数/总例数(%)* RSV 40mg ATV 80mg 天冬氨酸氨基转移酶>3xULN 3/668 (0.4) 11/668 (1.6) 丙氨酸氨基转移酶 >3xULN 5/668 (0.7) 14/668 (2.0) 肌酸激酶 >5xULN 2/668 (0.3) 连续两次随访>5xULN 0/668 (0) 0/654 (0) >10xULN 1/668 (0.1) 4/668 (0.6) 发生蛋白尿‡ 25/652 (3.8) 11/654 (1.7) 肌酐>ULN 22/668(3.3) 20/668 (3.0) 所有接受随机治疗患者的结果。ULN=最大正常上限, RSV=瑞舒伐他汀, ATV=阿托伐他汀. ‡蛋白尿定义为基线值蛋白尿为阴性或者是微量，在随访期间出现2+以上蛋白尿 * 44名患者的实验室数据缺失 Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 21

结果 LDL-C水平与PAV的变化 的关系 进展 逆转 CV-1111-CR-0281 REVERSAL1 普伐他汀40mg ILLUSTRATE5 阿托伐他汀+安慰剂 ASTEROID4 瑞舒伐他汀 40mg SATURN7 阿托伐他汀 80mg SATURN7 瑞舒伐他汀 40mg CAMELOT2 安慰剂 STRADIVARIUS6 安慰剂 A-PLUS3 安慰剂 Whilst it is acknowledged that there are limitations in comparing data and results from different studies, this slide summarises the data from several IVUS studies that have employed serial intravascular ultrasound to measure changes in atheroma burden. This provides insight into the relationship between the LDL-C level achieved and median change in PAV. The line of best-fit suggests there is a correlation between mean LDL-C achieved in the various studies and the progression rate for the most robust IVUS endpoint, PAV. 应用IVUS测量动脉粥样斑块负荷研究的总结。A-PLUS, CAMELOT, ILLUSTRATE and STRADIVARIUS是非他汀研究但是在安慰剂组有患者服用他汀比例分别为：62%, 80% 、84%、100%和82%). † ILLUSTRATE研究中，阿托伐他汀在导入期以10mg起始，剂量滴定至80mg以使LDL-C达到100mg/dlL下15mg/dL。平均剂量23mg。其后患者在整个研究过程中保持该剂量。CAMELOT中LDL-C水平为基线值，而A-PLUS研究是通过自基线的变化计算得出，ASTEROID 和REVERSAL 是关于他汀治疗的研究； * ASTEROID、REVERSAL和SATURN中PAV变化的中位数; A-PLUS、 CAMELOT、ILLUSTRATE和STRADIVARIUS中PAV变化的最小二乘均数 1) Nissen S et al. JAMA 2004; 291: 1071–80; 2) Nissen S et al. JAMA 2004; 292: 2217–2225; 3) Tardif J et al. Circulation 2004; 110: 3372–77; 4) Nissen S et al. JAMA 2006; 295: 1556–1565; 5) Nissen S et al. N Engl J Med 2007; 356: 1304–16; 6) Nissen S et al. JAMA 2008; 299: 1547-1560; 7) Nicholls SJ et al. New Eng J. Med. 2011: DOI: 10.1056/NEJMoa1110874 CV-1111-CR-0281 22

SATURN试验主要的科学意义 Saturn试验提示我们，把LDL-C降得更低一些，斑块逆转会更明显。SATURN是第一次观察到如此大比例患者实现斑块逆转的临床试验，对医生和患者都是令人振奋的消息。 意义之二是告诉我们，即使已经使用阿托伐他汀的极限剂量80 mg，治疗还有改善的余地，如果使用瑞舒伐他汀40 mg使LDL-C进一步下降，可以看到斑块逆转趋势以及LDL-C水平和斑块负荷下降的线性关系进一步延续。 第三，瑞舒伐他汀40 mg使LDL-C降至目前最低的水平，仍有1/3的患者斑块仍然进展，还有很多未知数需要继续探索。 第四，对于他汀的安全性有进一步的理解，瑞舒伐他汀40 mg 和阿托伐他汀80 mg不良反应的发生率均较低，转氨酶和肌酸激酶升高均较罕见。

IVUS 可用于准确并重复获取冠脉内动脉粥样硬化斑块的连续检测结果。在临床试验中采用IVUS 可以检查冠脉疾病过程中抗动脉粥样硬化治疗的效果，可帮助医生理解疾病的生物学以及治疗方法的生物效应，有一定的价值。         但IVUS 检测结果仍然是一个替代终点，华盛顿大学的Thomas R. Fleming 等指出，替代终点有时并不能预测某种治疗干预的真正临床疗效。研究中观察的数个斑块不能代表全身动脉粥样硬化的整体情况，心血管事件的发生并不完全取决于斑块的大小，导致急性冠脉综合征发生的斑块往往也不是体积最大的斑块。

应该强调的是LDL-C达标而非剂量达标，尤其对亚洲包括中国人群，需要继续探索最适宜的他汀剂量。 斑块逆转对人类是一个很大的激励，SATURN试验使我们认识到AS疾病可逆，从而增强我们控制AS病变的信心，鼓励患者长期持续用药。

   低密度脂蛋白胆固醇（LDL-C）的降低是他汀稳定逆转斑块最主要机制。大量研究已经证实，他汀降低LDL-C 与斑块的进展程度呈负相关。SATURN 研究中，两组LDL-C 水平差异不明显造成主要研究终点PAV 在两组间无差异。研究者在讨论部分也客观地分析到，主要终点未能达到显著的差异，可能是由于两组间LDL-C 的差异不够大。

研究发现：瑞舒伐他汀组HDL-C水平高于阿托伐他汀组，虽然有统计学意义，但绝对差值只有2mg/dl,这提示，在他汀强化治疗降低LDL-C以后，如果能升高HDL-C水平，可能对于斑块的逆转有一定的益处。

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