降压治疗策略的核心张维忠06[1].4.23

1、降压治疗策略的核心降压治疗策略的核心血压控制达标和联合治疗血压控制达标和联合治疗 张维忠张维忠0.51.02.0Relative RiskBP-Lowering Treatment TrialistsComparisons of Different Active TreatmentsINVEST: primary endpoint (MI and stroke free survival)Pepine et al JAMA 2003;290:2805-2816log rank p=0.6210095908580750 6 12 18 24 30 36 42 48 54 60 66CCB bas

2、ed regimen verapamil SR 240 mg odBeta blocker based regimen atenolol 50 mgCumulative endpoint (%)Months22576 hypertensive CAD patients, 24 months, open labelINVESTINVEST血压控制达标与终点事件发生的关系血压控制达标与终点事件发生的关系15.05.72.410.84.32.39.23.81.68.13.11.1161412108642025% 25%至50% 50%至75% 75% 随诊时血压达标百分比（140/90 mmHg）患

3、者总数（n） 3838 3757 6664 8316一级终点心肌梗死（致死非致死性）脑卒中（致死非致死性）发生临床终点事件百分比P 值均小于0.001Fatal/Non-fatal cardiac eventsFatal/Non-fatal strokeAll-cause deathMyocardial infarctionHeart failure hospitalisations0.40.60.81.01.21.4Controlled patients*(n = 10755)Non-controlled patients(n = 4490)Hazard Ratio 95% CI*SBP 1

4、40 mmHg at 6 months.Pooled Treatment Groups*P 0.01.0.75 (0.670.83)0.55 (0.460.64)0.79 (0.710.88)0.86 (0.731.01)0.64 (0.550.74)Odds RatioWeber MA et al. Lancet. 2004;363:204749.VALUE:根据根据6个月时血压控制情况的结果分析个月时血压控制情况的结果分析Fatal/Non-fatal cardiac eventsFatal/Non-fatal strokeAll-cause deathMyocardial infarct

5、ionHeart failure hospitalisations*SBP 140 mmHg at 6 months.*P 0.01.Patients Treated With ValsartanPatients Treated With AmlodipineHazard Ratio 95% CI0.40.60.81.01.2Controlled patients*(n = 5253)Non-controlled patients(n = 2396)*0.40.60.81.01.2Controlled patients*(n = 5502)Non-controlled patients(n =

6、 2094)Hazard Ratio 95% CI*0.76 (0.660.88)0.60 (0.480.74)0.79 (0.690.91)0.83 (0.661.03)0.62 (0.500.77)Odds Ratio0.73 (0.630.85)0.50 (0.390.64)0.79 (0.690.92)0.91 (0.711.17)0.64 (0.520.79)Odds RatioWeber MA et al. Lancet. 2004;363:204749.VALUE:VALUE:根据根据6 6个月时血压控制情况的结果分析个月时血压控制情况的结果分析Major cardiovascu

7、lar events (per 100 patients-years) in all treated hypertensive and in hypertensive patients with diabetes in relation to target blood pressures of 90. 85, and 80 mm Hg. 302520151050 80 85 90 90 85 80P=0.50 for trendP=0.005 for trendAll hypertensive patients(n=18790)Hypertensive with diabetes(n=1501

8、)Target blood pressure groupsMajor cardiovascular events/1000 patients-yearsHOT:HOT:糖尿病与非糖尿病患者的糖尿病与非糖尿病患者的CVCV事件发生率事件发生率INVESTINVEST糖尿病患者血压控制达标与终点事件发生的关系糖尿病患者血压控制达标与终点事件发生的关系 15 11 15 9 20 8111425% 25%至50% 50%至75% 75% 随诊时血压达标百分比(140/90 mmHg)患者总数（n）3838 1246 3757 1127 6664 1791 8316 223620151050 所有患者

9、（n22,576） 糖尿病者（n6,400）一级终点发生率（）9 Clinical Trials of Diabetic and Nondiabetic Nephropathy收缩压下降差异与终末期肾功能衰竭收缩压下降差异与终末期肾功能衰竭( (ACEI or ARB ACEI or ARB 肾病降压临床试验荟萃分析肾病降压临床试验荟萃分析) ) SBPSBP下降差异下降差异 ACEI/ARB ACEI/ARB 其它干预其它干预 RR (95% CI)RR (95% CI) (n/N) (n/N) 对照组对照组(n/N)(n/N) -6.9 mmHg 117/1346 155/1291 0.7

10、4(0.59-0.92)(-9.1 to -4.8)-1.6 mmHg 273/6344 356/6327 0.77(0.67-0.89)(-2.8 to -0.4) 1.5 mmHg 206/11049 397/26043 0.90(0.72-1.12)(0.1-0.2)Casas JP. Lancet 2005;366:2026-2033IDNT: IDNT: 治疗后收缩压水平与肾脏终点事件治疗后收缩压水平与肾脏终点事件 SBP(mmHg) No. of patients 379 357 428 426 1590No. of events (%) 17 22.7 29.2 38.5 27

11、irbesartan vs. amlodipine + placebo 12 vs 20 21 vs 24 23 vs 32 31 vs 42 21 vs 30 RR irbesartan vs. 0.55 0.92 0.66 0.70 0.67 amlodipine + placebo (p=0.034) (p0.05) (p0.05) (p0.05) (p=0.0002)Pohl MA, et al. J Am Soc Nephrol 2005; 16:3027-3037 149 TotalPohl MC, et al. J Am Soc Nephrol 2005;16:3027-3037

12、IDNT: Impact of BP Control and AT1 Blockade on Renal Outcomes125.24.4051015CVD Survival in Treated Hypertensives at Goal and Not at Goal如何使血压控制达标如何使血压控制达标q通常需要2种或2种以上不同降压机制的药物联合治疗。q联合治疗时，噻嗪类利尿剂能明显改善血压控制达标率。q不同的降压药物和联合治疗方案对长期血压控制存在差异。q固定剂量联合制剂提高长期治疗依从性和持续性，有利于血压控制达标。 降压治疗方案降压治疗方案 序贯治疗序贯治疗( (Sequentia

13、l Monotherapy) 阶梯治疗阶梯治疗( (Stepped-care) 联合治疗联合治疗( (Combination)(a) Percentage of patients having their blood pressure (BP) normalized (140/90 mmHg) at the last visit trial.(b) Percentage of patients who normalized their BP with developing any adverse event (AE).P=0.0170%60%50%40%30%20%10%0%70%60%50%

14、40%30%20%10%0%Low-dosecombination(n=180)Sequentialmonotherapy(n=176)Stepped-case(n=177)% of patients with BP 140/90 mmHg and no AE% of patients with BP 140/90 mmHg(a)(b)P=0.005P=0.01P=0.004Mourad J, et al. J Hypertens. 2004;22:2379-2386. INVEST: INVEST: 临床意义临床意义 采用积极的治疗策略，联合多种降压药物进行治疗，能够使高血压患者的血压控制在

15、较低水平(平均130/76mmHg),70%患者的血压控制在140/90mmHg以下。要达到上述目标, 82%患者需要2种以上药物,51%患者需要3种以上药物。Diureticsb b-blockers AT1-receptor blockers a a-blockersCalcium antagonistsACE inhibitors合理的降压联合治疗方案合理的降压联合治疗方案Initial Combinations of Medications for Management of Hypertension* Compelling indications may modify this噻嗪类

16、利尿剂治疗高血压的机制噻嗪类利尿剂治疗高血压的机制噻嗪类利尿剂降压机制噻嗪类利尿剂降压机制血管平滑肌细胞钾通道部分开放血管平滑肌细胞钾通道部分开放抑制碳酸酐酶(carbonic anhydrase)pHi Kca通道激活、开放SMC超极化，电压依赖性钙通道Pickkers P, et al. Hypertension. 1999;33:1034-1048Reduction in BP With Combination Therapy BP (mm Hg)Weir MR et al. Am J Hypertens. 2001;14:665-671.BNZ + 160 mgValsartan(n

17、= 23)HCTZ + 160 mgValsartan(n = 30)320 mgValsartan(n = 28)ARBsARBs降压疗效的荟萃分析降压疗效的荟萃分析4343项研究，项研究，1128111281例例 DBPDBP (mmHg) (mmHg) 降压有效率降压有效率(%)(%) 单药低剂量单药低剂量 8.2-8.9 508.2-8.9 50 单药高剂量单药高剂量 9.5-10.4 559.5-10.4 55 低剂量低剂量+HCTZ 9.9-13.6 70+HCTZ 9.9-13.6 70Conlin PR, et al. Am J Hypertens. 2000;13:418AR

18、BsARBs降压疗效的荟萃分析降压疗效的荟萃分析4343项研究，项研究，1128111281例例 SBP (mmHg) DBP (mmHg) Losartan 8.0 5.5 Valsartan 7.5 4.0 Irbesartan 10.0 6.5 Telmisartan 9.5 6.0 Candesartan 10.0 6.0 Conlin PR, et al. J Clin Hypertens. 2000;2:253-257BP Reductions Observed in Monotherapywith Irbesartan 150mg and Valsartan 80mg* BP /

19、 Baseline (mm Hg)irbesartan 150 mgvalsartan 80 mgSelf Measurement(Morning values)ABPM(Trough)Office Measurement (Trough)ADBPASBP(P0.01)(P0.01)(P0.01)(P0.01)-12-8-40(P=0.035)(P0.01)DBPSBPSBPDBP-16-12-8-40Mancia G et al. Blood Press Monit. 2002;7:1-8*8 week study2.5(66%)3.2(46%)3.2(44%)6.2(62%)-10.5-1

20、6.2-7.3-10.0-6.3-10.2-3.8-7.0-4.8-7.5-6.7-11.61.9(40%)4.1(55%)Comparative Study of Efficacy of Irbesartan/HCTZ with Valsartan/HCTZ Using Home Blood Pressure Monitoringin the TreAtment of Mild-to-Moderate HypertensionCOSIMA StudyCOSIMA：研究设计研究设计W0Visit 1 Enrolment of hypertensive patients untreated or

21、 uncontrolled by monotherapyRHCTZ : 12.5 mg od - 5 weeks W4Visit 2Exclusion if SBP 140 mm Hg(office)HBPM 5 daysW13Visit 4Final evaluation W5Visit 3Randomisation if SBP 135 mm Hg(HBPM)irbesartan 150/HCTZ 12.5valsartan 80/HCTZ 12.58 weeksHBPM 5 daysHBPM 5 days5 weeks8 weeksPhase 1Phase 2COSIMA：结果结果( (

22、一一) ) BP final - baseline (mm Hg)irbesartan/HCTZ 150/12.5 mg (n=198)valsartan/HCTZ 80/12.5 mg (n=216)HBPM(average of all values)DBPSBPOffice BP(trough)DBPSBPP0.001P0.012.8(26%)-16-12-8-402.2(30%)-16-12-8-40P0.05P0.013.2(28%)1.4(21%)G. Bobrie et al. Archives Mal Coeur Vaiss 2004 (12): p96 and p116-9.

23、6-7.4-13.4-10.6-8.2-6.8-14.8-11.6COSIMA：结果结果( (二二) )SBPAMPMAMPMDBP BP final - baseline (mm Hg)P0.01P0.001P0.05P0.00135%-12-10-8-6-4-20-16-1420%35%24%Absolute difference (mm Hg)-3.3-2.4-2.3-2.0-12.7-14.3-9.4-11.9-8.9-10.5-6.6-8.5irbesartan/HCTZ 150/12.5 mg (n=198)valsartan/HCTZ 80/12.5 mg (n=216)*The

24、 PP results presented are consistent with the ITT results8 week studyG. Bobrie et al. Archives Mal Coeur Vaiss 2004 (12): p96 and p116COSIMAMore Patients Normalised on Irbesartan Combination Therapy*% PatientsP0.0001OfficeHBPM0102030405060P0.05Normal HBPM values:SBP 135 mm Hg andDBP 85 mm HgNormal o

25、ffice values:SBP 140 mm Hg andDBP 90 mm Hg19.6%10.3%52.9%33.3%51.5%41.2%irbesartan/HCTZ 150/12.5 mg (n=198)valsartan/HCTZ 80/12.5 mg (n=216)*The PP results are consistent with the ITT results8 week studyCOSIMA：结论结论COSMACOSMA研究显示研究显示Irbesartan150/HCTZ12.5Irbesartan150/HCTZ12.5比比Valsartan80/HCTZ12.5Va

26、lsartan80/HCTZ12.5能更有效地降低和控能更有效地降低和控制血压制血压, ,证实不同证实不同ARBARB单药治疗疗效的差异明显单药治疗疗效的差异明显影响复合制剂的疗效。影响复合制剂的疗效。Association Between Adherence and Goal Attainment in Antihypertensive TherapySturkenboom M, et al. 15th ESH meeting, Milan, Italy, June 17-21, 200589888988例新诊断高血压例新诊断高血压，平均随访治疗平均随访治疗2 2年年，Rotterdam,

27、The NetherlandsPersistence with antihypertensive treatment1.00.80.60.40.200100200300400500600700800Days after start of antihypertensive treatmentProportion of patients persistentwith treatmentPatient Adherence and Persistence with Antihypertensive Therapy:One- versus Two-pill CombinationSturkenboom

28、M, et al. 15th ESH meeting, Milan, Italy, June 17-21, 2005ACEI/HCTZ (n=458) vs. ACEI+HCTZ (n=297) 治疗观察治疗观察2年，年，比较长期治疗的依从性和持续性比较长期治疗的依从性和持续性Percentage of patients adherent to A) fixed-dose combination therapy or B) Coadministered 0-pill therapy100908070605040302010003691215182124Months after start of

29、 therapyPercentage of patientsB: Adherence to coadministration of 2 pillsNon-adherentPartially adherentFully adherent100908070605040302010003691215182124Months after start of therapyPercentage of patientsA: Adherence to fixed-dose combination therapyPercentage of patients fully adherent to fixed-dos

30、eCombination therapy and coadministered 2-pill therapy10090807060504030201000369121518212427Months after start of therapy21%17%Percentage of patients fully adherentFixed-dose combinationCoadministration of 2 pills安博诺安博诺 The INCLUSIVE TrialThe Irbesartan/HCTZ Blood Pressure Reduction in Diverse Patie

31、nt PopulationNeutel JM, et al. J Clin Hypertens 2005;7:578-586Minimum4 weeks1,005 Uncontrolledon SingleAntihypertensiveAgentINCLUSIVE: Study Design8 weeksIrbesartan/HCTZ300/25 mgWeek 18Screening8 weeksIrbesartan/HCTZ150/12.5 mgWeek 10HCTZ 12.5 mg2 weeksWeek 245 weeksPlaceboBaselineWeek 0INCLUSIVE: D

32、emographics46%(n=386)30%(n=254)25%(n=212)23%(n=191)14%(n=119)Patients (%)52%(n=436)INCLUSIVE: SBP132.9 13.888, 18421.5 14.322.5, 20.50.001139.6 12.4108, 17915.1 12.516.0, 14.10.001154.4 10.2130, 179Patients, n (ITT popn) 15.1(16.0, 14.1)P0.00121.5(22.5, 20.5)P0.001ITT populationINCLUSIVE: DBP81.1 9.745, 11510.4 8.711.0, 9.80.00184.6 8.860, 1137.2 8.07.8, 6.60.00191.5 8.863, 1097.2(7.8, 6.6)P0.00110.4(11.0, 9.8)P140 mmHg, 130 mmHg in type 2 diabetes; entry criterion at each stage of the study was DBP 70-109 mmHg; mean DBP at baseline = 91.3 mmHg. Some patients were at goal DBP