ACTION研究高血压亚组结果与分析

1、 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 ACEIACTION: 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=3,825012345年研究结束稳定性心绞痛年龄 35 岁n=7,6656ACTION: 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 80ACTION: 终点事件一级有效性终点 全因死亡 致

2、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 CABG3) 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 名患者基线高血压名患者基线高血压3,684 名患者基线血压正常1,975名患者名患者拜新同拜新同组组2,002名名安慰剂组安慰剂组1,847

3、 名患者拜新同组1,837名患者安慰剂组ACTIONACTION：血压升高患者终点事件终点终点0.0.0150150.0270.0270.0080.008危险度危险度(95% (95% CI)CI)p p0.873(0.7680.873(0.7680.993)0.993)0.896(0.8120.896(0.8120.998)0.998)0.832(0.7260.832(0.7260.954)0.954)0 00.50.51 11.51.52 2一级终点一级终点一级终点和介入治疗一级终点和介入治疗任何任何CVCV原因导致的死亡原因导致的死亡拜新同拜新同更优更优安慰剂安慰剂更优更优ACTION:

4、 高血压亚组结果单个终点单个终点减少一级有效终点减少一级有效终点13%证明拜新同安全性证明拜新同安全性减少任何心血管事件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减少任何血管或介入11% 血压降低血压降低 14.6/7.6mmHg减少致残性卒中减少致残性卒中33% 减少住院心衰减少住院心衰38% 减少冠状动脉造影术减少冠状动脉造影术 16%减少卒中或一过性脑缺血发作减少卒中或一过性脑缺血发作28% 减少顽固性心绞痛减少顽固性心绞痛23% *无统计学差异二级终点二级终点一级终点一级终点Overview of ni

5、fedipine GITS effects on composite endpointsAll patientsHypertensive patientsNormotensive patientsInteraction between groupsIndicative implicationPrimary efficacy Not significantSignificant+ve benefitNot significantSignificant+ve benefit in hypertensivesSafetyPrimary safetyNot significantNot signifi

6、cantNot significantNot significantAny CV eventNot significantSignificant+ve benefitNot significantSignificant+ve benefit in hypertensives+ve benefit in all patientsDeath, any CV event or procedureSignificant+ve benefitNot significantSignificant+ve benefitSignificant+ve benefitAny vascularevent/proce

7、dureSignificant+ve benefitNot significantEndpointsSignificant+ve benefitSignificant+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

8、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;21:1831-1840ACTION(高血压亚组)基线时降压药使用情况基线时降压药使用情况 拜新同组拜新同组安慰剂组安慰剂组-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 基线时基线时治疗治疗4 4年时年时BP 140/90 100%47%SBP 140 94%45%DBP 9

9、0 42%13% SBP (mmHg) 14.6 19.1 DBP (mmHg) 7.6 10.6Nifedipine GITS reduced add-on therapy in the hypertensive subgroup *Including nifedipine GITS63036912151821 -blockers ACE inhibitors/ARBs Diuretics Any antihypertensive* Nifedipine GITS PlaceboNormotensive Nifedipine GITSPlaceboHypertensive Change in

10、 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 Studyvan den Hoogen et al. N Engl J Med. 2000;342:1-8.United StatesNorther

11、n EuropeMediterranean Southern EuropeInland Southern EuropeSerbiaJapanMortality From CHD(no./10,000 Person-Years)1401301201101009080706050403020100120130140150160170Systolic BP (mm Hg)1401301201101009070605040302010657075808595100Diastolic BP (mm Hg)90动脉粥样硬化斑块动脉粥样硬化斑块ACTION: 入选对象有心绞痛症状占有心绞痛症状占93%93%

12、患者的血管病变阶段Risk factorNormotensive(n=3,684)Hypertensive(n=3,977)pCurrent smoker (%)20160.001Total cholesterol 5mmol/L (%)61660.001Body mass index 30kg/m2 (%)19260.001Any of the above (%)73770.001Diabetes mellitus (%)12170.001Treated with insulin (%)22.70.04Mean (SD) heart rate (beats/min)63.5 (10.0)65

13、.1 (10.5)0.003Hypertensive patients were at high risk of CVDACTION: 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 2.96BP-Lowering Treatment TrialistsStrokeSystolic BP Difference Between Randomized Group

14、s (mm Hg)Systolic BP Difference Between Randomized Groups (mm Hg)CHDBlood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.RR of Outcome EventRR of Outcome Event0.60.811.21.4Favours nifedipine GITSFavours placeboSignificant reductions in composite endpointsEndpointPati

15、ents with events (n)Hazard ratio(95% CI)pNifedipine GITSPlaceboPrimary efficacy Normotensive Hypertensive3644393685000.02Primary safety Normotensive Hypertensive2443172133450.08Any CV event Normotensive Hypertensive3173762864500.007Death, any CV event or procedure Normotensive Hypertensive6707687378

16、460.8Any vascular event or procedure Normotensive Hypertensive4795465116100.7NICOLE 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

17、0.02Dens 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。FavorsFirst ListedFavorsSecond Listed0.51.02.0BP-Lowering Treatment TrialistsComparisons of Different Active TreatmentsCA vs D/BB1.33 (1.21, 1.47)1/00.93 (0.86, 1.01)CA vs D/BB1/01.01

18、 (0.94, 1.08)CA vs D/BB1/0ACE Inhibitor vs CA0.82 (0.73, 0.92)1/11.12 (1.01, 1.25)ACE Inhibitor vs CA1/10.96 (0.88, 1.05)ACE Inhibitor vs CA1/1StrokeCHD1.09 (1.00, 1.18)ACE Inhibitor vs D/BB2/00.98 (0.91, 1.05)ACE Inhibitor vs D/BB2/01.07 (0.96, 1.19)ACE Inhibitor vs D/BB2/0Blood Pressure Lowering T

19、reatment Trialists Collaboration. Lancet. 2003;362:1527-1535.HFBP-Lowering Treatment TrialistsComparisons of Active Treatments and Control0.51.02.0Relative RiskRR (95% CI)BP DifferenceStroke0.72 (0.64, 0.81ACEI vs placebo-5/-20.62 (0.47, 0.82)CA vs placebo 8/-4Coronary heart disease0.80 (0.73, 0.88)

20、-5/-2ACEI vs placebo0.78 (0.62, 0.99)-8/-4CA vs placeboACEI vs placebo0.78 (0.73, 0.83)-5/-2CA vs placebo0.82 (0.71, 0.95)-8/-4Heart failureMajor CV events-5/-20.82 (0.69, 0.98)ACEI vs placebo1.21 (0.93, 1.58)CA vs placebo-8/-4CV mortalityACEI vs placebo0.80 (0.71, 0.89)-5/-2CA vs placebo0.78 (0.61,

21、 1.00)-8/-4Total mortalityACEI vs placebo0.88 (0.81, 0.96)-5/-2CA vs placebo0.89 (0.75, 1.05)-8/-4Nifedipine GITS prevents new overt heart failure38%lHeart failure significantly reduced in patients with CHDlGreater reduction in hypertensive subgrouplNifedipine GITS is the only CCB proven to prevent

22、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1512963036PlaceboNifedipine GITS NormotensiveBP change from baseline (mmHg)Systolic BPDiastolic BPNifedipine GITSPlaceboHypertensive Significant mean change in BP after 4 yearsACTION: 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 (

23、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) 151050100-109120-129180-189140-149150-159SystolicDiastolic1050Pretreatment blood pressure (mmHg)60-6970-7980-8990-99 100-109 110-119Decrease in blood pressure (treated - placebo) (mmHg)Law MR. BMJ 2003;326:1427稳定型冠心病临

24、床试验基线血压水平基线血压水平SBP(mmHg)HOPEEUROPAQUIETPEACECAMELOTACTION(血压不高亚组)139/79137/82123/74134/78129/78122/75结 论 ACTION研究确立了硝苯地平控释片(拜新同)在稳定性冠心病患者中的治疗地位，尤其合并血压升高患者，为合理选择抗心绞痛治疗药物提供了证据。Short acting sublingualor buccal nitrate prn Beta blockerAdd dihydropyridinecalcium antagonistSymptoms not controlledHeart rat

25、e loweringcalcium antagonist eg diltiazem/verapamilLevel of evidenceLong acting nitrate ortransdermal nitrateImmediate short term reliefTreatment aimed atrelief ofsymptomsIntolerant (eg fatigue)or contraindicationIntolerantor ineffectiveSymptoms not controlled after dose optimisation 1C1A1A1A 1B1CGu

26、idelines for the management of stable angina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 ACEIACTIONACTION：血压升高患者终点事件终点终点0.0.0150150.0270.0270.0080.008危险度危险度(95% (95% CI)CI)p p0.873(0.7680.873(0.7680.993)0.993)0.896(0.8120.896(0.8120.998)0.998)0.832(0.7260.832(0.7260.954)0.954)0 00.50.51 11.51.52

27、2一级终点一级终点一级终点和介入治疗一级终点和介入治疗任何任何CVCV原因导致的死亡原因导致的死亡拜新同拜新同更优更优安慰剂安慰剂更优更优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;21:1831-1840Mortality Due to CHD per Quartile of Usual Systolic and Diastolic BP: Seven Countries Studyvan den Hoogen et al. N Engl J Me