研究高血压亚组结果与分析

ACTION研究高血压亚组 结果与分析 稳定型心绞痛是冠心病 最常见的临床表现，不仅明显 影响患者的生活和工作能力， 而且有高度发生各种心、脑血 管病的危险。 稳定型冠心病的药物治疗现状 抗心绞痛 硝酸酯类 阻滞剂 钙拮抗剂 改善病变进程 抗血小板药 他汀类 ACEI ACTION: 设计 在冠心病基础治疗上加用 安慰剂, 每天一次 n=3,840 在冠心病基础治疗上加用 拜新同3060mg, 每天一次 n=3,825 01 2345 年 研究结束 稳定性心绞痛 年龄35 岁 n=7,665 6 ACTION: 基础治疗情况 基线用药情况(%) 患者(%) 抗心绞痛 99 降脂治疗 68 阿司匹林 86 -受体阻滞剂 80 ACTION: 终点事件 一级有效性终点 全因死亡 致残性脑卒中 心梗 一级安全性终点 1) 全因死亡，任何心血管事件或介入操 作 (一级有效性终点 冠脉造影， PCI, CABG) 2) 任何血管事件或介入操作: CV 死亡 急性MI 顽固性心绞痛 外周血管事件 致残性卒中 PCI CABG 3) 任何心血管事件 (一级有效性终点 - 非CV 死亡) 二级有效性终点 全因死亡 心梗 心衰 致残性脑卒中 顽固性心绞痛 外周血管重建术 ACTION: 分组 随机入组7,665名患者 7,661 名患者 进入亚组分析 4名患者被排除 3,977 名患者基线高血压3,684 名患者基线血压正常 1,975名患者 拜新同组 2,002名 安慰剂组 1,847 名患者 拜新同组 1,837名患者 安慰剂组 ACTION：血压升高患者终点事件 终点 0.015 0.027 0.008 危险度(95% CI) p 0.873(0.7680.993) 0.896(0.8120.998) 0.832(0.7260.954) 00.511.52 一级终点 一级终点和介入治疗 任何CV原因导致的死亡 拜新同 更优 安慰剂 更优 ACTION: 高血压亚组结果 单个终点 减少一级有效终点13% 证明拜新同安全性 减少任何心血管事件17% 减少全因死亡，任何心血管事件和介入治疗10% 减少任何血管或介入11% 血压降低 14.6/7.6mmHg 减少致残性卒中33% 减少住院心衰38% 减少冠状动脉造影术 16% 减少卒中或一过性脑缺血发作28% 减少顽固性心绞痛23% * *无统计学差异 二级终点 一级终点 Overview of nifedipine GITS effects on composite endpoints All patientsHypertensive patients Normotensive patients Interaction between groups Indicative implication Primary efficacy Not significant Significant +ve benefit Not significant Significant +ve benefit in hypertensives SafetyPrimary safety Not significant Not significant Not significant Not significant Any CV event Not significant Significant +ve benefit Not significant Significant +ve benefit in hypertensives +ve benefit in all patients Death, any CV event or procedure Significant +ve benefit Not significant Significant +ve benefit Significant +ve benefit Any vascular event/procedure Significant +ve benefit Not significant Endpoints Significant +ve benefit Significant +ve benefit +ve benefit in all patients 临床意义(一) 在已经实施降压治疗但血压依然升高的 稳定性冠心病患者, 硝苯地平控释片(拜新同 )能进一步有效地降低血压，显示拜新同与 其它类型降压药联合治疗的协同叠加作用， 显著有益于冠心病患者的血压控制和达标。 EUROASPIRE and 冠心病合并高血压占冠心病患者51%(37%-64%)。 即使采用兼有降压作用的治疗冠心病药物，即-阻滞 剂和ACEI，仍然有1/2以上患者血压未获得控制。 血压控制达标率 EUROASPIRE (1995-1996): 44% EUROASPIRE (1999-2000): 45% Boersma E, et al. J Hypertens 2003;21:1831-1840 ACTION(高血压亚组) 基线时降压药使用情况 拜新同组组安慰剂组剂组 -阻滞剂 77%79% ACEI/ARB 28%28% 利尿剂 15%14% 任何降压药 88%88% ACTION(高血压亚组)：血压控制达标率 基线时线时治疗疗4年时时 BP 140/90 100%47% SBP 140 94%45% DBP 90 42%13% SBP (mmHg) 14.6 19.1 DBP (mmHg) 7.6 10.6 Nifedipine GITS reduced add-on therapy in the hypertensive subgroup *Including nifedipine GITS 6 3 0 3 6 9 12 15 18 21 -blockers ACE inhibitors/ARBs Diuretics Any antihypertensive* Nifedipine GITS Placebo Normotensive Nifedipine GITSPlacebo Hypertensive Change in add-on therapy from baseline (%) 临床意义(二) 稳定性冠心病合并高血压具有较高的 心血管危险, 硝苯地平控释片(拜新同)治 疗能有效地阻止或减轻这类患者的病情进 展, 并显著降低心脑血管病事件。 这种治 疗益处来自拜新同有效降低血压和抗心 绞痛的双重作用。 Mortality Due to CHD per Quartile of Usual Systolic and Diastolic BP: Seven Countries Study van den Hoogen et al. N Engl J Med. 2000;342:1-8. United StatesNorthern EuropeMediterranean Southern Europe Inland Southern EuropeSerbiaJapan Mortality From CHD (no./10,000 Person-Years) 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 110110120130140150160170 Systolic BP (mm Hg) 140 130 120 110 100 90 8080 70 60 50 40 30 20 10 0 0 657075808595100 Diastolic BP (mm Hg) 90 动脉粥样硬化斑块 ACTION: 入选对象 有心绞痛症状占93% 患者的血管病 变阶段 Risk factor Normotensive (n=3,684) Hypertensive (n=3,977) p Current smoker (%)20160.001 Total cholesterol 5mmol/L (%)61660.001 Body mass index 30kg/m2 (%)19260.001 Any of the above (%)73770.001 Diabetes mellitus (%)12170.001 Treated with insulin (%)22.70.04 Mean (SD) heart rate (beats/min)63.5 (10.0)65.1 (10.5)0.003 Hypertensive patients were at high risk of CVD ACTION: 冠心病合并血压升高的心血管危险 (安慰剂组 /100人年) 高血压 血压正常 高血压/血压正常 心血管死亡 1.16 0.69 1.68 心肌梗死 1.56 1.21 1.29 心力衰竭 0.78 0.50 1.56 脑卒中 1.81 0.97 1.87 致残性脑卒中 0.77 0.26 2.96 BP-Lowering Treatment Trialists Stroke Systolic BP Difference Between Randomized Groups (mm Hg) 0.250.25 0.500.50 0.750.75 1.001.00 1.251.25 1.501.50 - -1010 - -8 8 -6-6-4-4-2-2 0 0 2 2 4 4 Systolic BP Difference Between Randomized Groups (mm Hg) 0.250.25 0.500.50 0.750.75 1.001.00 1.251.25 1.501.50 -10-10-8-8-6-6-4-4-2-2 0 0 2 2 4 4 CHD . . Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535. RR of Outcome Event RR of Outcome Event A A B B C C D D E EF F GG A A B BC C D D E E F F GG 0.60.811.21.4 Favours nifedipine GITSFavours placebo Significant reductions in composite endpoints EndpointPatients with events (n)Hazard ratio (95% CI) p Nifedipine GITS Placebo Primary efficacy Normotensive Hypertensive 364 439 368 500 0.02 Primary safety Normotensive Hypertensive 244 317 213 345 0.08 Any CV event Normotensive Hypertensive 317 376 286 450 0.007 Death, any CV event or procedure Normotensive Hypertensive 670 768 737 8460.8 Any vascular event or procedure Normotensive Hypertensive 479 546 511 610 0.7 NICOLE Study (Nisoldipine in Coronary Artery Disease in Leuven) Clinical event (%) Nisoldipine(408) Placebo(411) p Death 2.9 3.4 NS CVA 1.0 1.7 NS AMI 3.9 3.2 NS CABG 5.1 10.0 0.01 Repeat PTCA 30.6 37.7 0.03 Total 44.6 52.7 0.02 Dens JA, et al. Heart 2003;89:887-892 临床意义(三) 在稳定性冠心病合并高血压患者, 硝 苯地平控释片(拜新同)能显著降低需住 院治疗的心力衰竭发生率, 首次在前瞻性 临床试验中显示这种治疗益处。 Favors First Listed Favors Second Listed 0.51.02.0 BP-Lowering Treatment Trialists Comparisons of Different Active Treatments CA vs D/BB 1.33 (1.21, 1.47) 1/0 0.93 (0.86, 1.01) CA vs D/BB1/0 1.01 (0.94, 1.08) CA vs D/BB1/0 ACE Inhibitor vs CA 0.82 (0.73, 0.92) 1/1 1.12 (1.01, 1.25) ACE Inhibitor vs CA1/1 0.96 (0.88, 1.05) ACE Inhibitor vs CA1/1 Stroke CHD 1.09 (1.00, 1.18) ACE Inhibitor vs D/BB2/0 0.98 (0.91, 1.05) ACE Inhibitor vs D/BB2/0 1.07 (0.96, 1.19) ACE Inhibitor vs D/BB2/0 Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535. HF BP-Lowering Treatment Trialists Comparisons of Active Treatments and Control 0.51.02.0 Relative Risk RR (95% CI)BP Difference Stroke 0.72 (0.64, 0.81) ) ACEI vs placebo-5/-2 0.62 (0.47, 0.82) CA vs placebo - -8/-4 Coronary heart disease 0.80 (0.73, 0.88) -5/-2 ACEI vs placebo 0.78 (0.62, 0.99) -8/-4 CA vs placebo ACEI vs placebo 0.78 (0.73, 0.83) -5/-2 CA vs placebo 0.82 (0.71, 0.95) -8/-4 Heart failure Major CV events -5/-2 0.82 (0.69, 0.98) ACEI vs placebo 1.21 (0.93, 1.58) CA vs placebo-8/-4 CV mortality ACEI vs placebo 0.80 (0.71, 0.89) -5/-2 CA vs placebo 0.78 (0.61, 1.00) -8/-4 Total mortality ACEI vs placebo 0.88 (0.81, 0.96) -5/-2 CA vs placebo 0.89 (0.75, 1.05) -8/-4 Nifedipine GITS prevents new overt heart failure 38% lHeart failure significantly reduced in patients with CHD lGreater reduction in hypertensive subgroup lNifedipine GITS is the only CCB proven to prevent heart failure 为何在ACTION研究中血压不升 高的稳定性冠心病患者主要终点未 获得显著降低？ 问题与答案？ 大部分血压正常患者无降压效应 15 12 9 6 3 0 3 6 PlaceboNifedipine GITS Normotensive BP change from baseline (mmHg) Systolic BP Diastolic BP Nifedipine GITSPlacebo Hypertensive Significant mean change in BP after 4 years ACTION: 拜新同治疗过程中血压改变 治疗前 治疗过程中 正常血压 122.3 / 74.6 (9.2/7.2) 1.9 / 0.5 (14.7/9.3) 合并高血压 151.3 / 84.8 (14.0/8.6) 14.5 / 7.0 (18.2/10.0) 15 10 5 0 100-109120-129180-189140-149150-159 Systolic Diastolic 10 5 0 Pretreatment blood pressure (mmHg) 60-6970-798