急性心力衰竭药物治疗的急性心力衰竭药物治疗的若干进展若干进展 内内容容ASCEND-HFDOSE急性失代偿性心衰的预后急性失代偿性心衰的预后Median length of hospital stay: 6 daysHospital readmissionsHospital readmissions 20% at 30 days20% at 30 days 50% at 6 months50% at 6 monthsMortalityMortality 11.6% at 30 days11.6% at 30 days 33.1% at 12 months 50% at 5 years50% at 5 yearsRev Cardiovasc Med. 2002;3(suppl 4) Arch Intern Med. 2002;162Intern Med. 2002;162Acute heart failure with systolic dysfunction Furosemide+/- VasodilatorSBP100 mmHgSBP 85-100 mmHgSBP 5ug/kg/minNo response:Reconsider mechanistic therapyinotropic agentsGood response:Oral therapyACEIESC2005急性心衰诊断和治疗指南急性心衰诊断和治疗指南ADHF的药物治疗终于取得了一些进的药物治疗终于取得了一些进展展在过去30年中，急性失代偿性心衰（ADHF）的药物治疗几乎没有进展 ADHF治疗新药乏善可陈在不同医院和不同医生之间利尿剂的应用剂量和应用方式均大相径庭，缺乏安全性和有效性的高质量研究终于有些进展ASCEND-HF（AHA 2010)DOSE最新结果（N Engl J Med 3月3号在线）奈西立肽(Nesiritide，人类BNP) 一种激素样物质，除扩张动脉和静脉外，还可促进利钠利尿降低患者左室充盈压和呼吸困难程度，缓解症状 FDA approved 2001The Effects of Nesiritide on NeurohormonesIn patients with evidence of severely symptomatic fluid overload in the absence of systemic hypotension, vasodilators such as intravenous nitroglycerin, nitroprusside or neseritide can be beneficial when added to diuretics and/or in those who do not respond to diuretics alone.The Hospitalized PatientSevere Symptomatic Fluid OverloadNewI IIa IIb IIIA Report of the ACCF/ AHA Task Force on Practice GuidelinesBNP可用于治疗急性心衰，患者的体征为肺充血/水肿，BP 90mmHg静注BNP时，其输注速率从到0.03 ug/kg/min均可，无论开始是否进行负荷推注（2ug/kg）。不推荐和其他静注血管扩张剂联用 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 20085个研究的荟萃分析：奈西立肽对肾功能影响个研究的荟萃分析：奈西立肽对肾功能影响Control, n/N (%) Nesiritide, n/N (%) 3114/29 (14)15/74 (20)3252/42 (5)15/85 (18)3269/102 (9)36/203 (18)VMAC45/216 (21)74/273 (27)Precedent9/83 (11)29/162 (18)Totals69/472 (15)169/797 (21)study肾功能恶化的定义：肾功能恶化的定义：SCr0.5 mg/dL. Circulation. 2005;111:1487-1491 Mortality Within 30 Days of Treatment Associated With Nesiritide or Control Therapy With Overall Risk Ratio Calculated by Mantel-Haenszel Test Using a Fixed-Effects Model.Sackner-Bernstein, J. D. et al. JAMA 2005;293:1900-1905Copyright restrictions may apply.荟萃3个小规模试验：NSGETVMACPROACTIONASCEND-HF奈西立肽治疗失代偿性心衰患者奈西立肽治疗失代偿性心衰患者临床疗效的短期研究临床疗效的短期研究Duke Heart Failure ResearchPager: 970-0736NHLBI Heart Failure Clinical Research NetworkBaylorDukeHarvardMayo ClinicMinnesotaMontrealMorehouseUtahVermontPurpose在常规治疗基础上，通过双盲安慰剂对照研究评价奈西立肽对于急性代偿性心衰患者的疗效和安全性. Double blinded study meaning subjects, MD, and research team are unaware of what treatment is being received.入选标准入选标准静息时呼吸困难肺淤血 入院24小时内存在心衰的症状和体征 InterventionsRandomized to1 of 2 GroupsN=7141Nesiritide plus standard of care首先首先给予其静脉注射予其静脉注射负荷荷剂量的奈西立量的奈西立肽，然后持然后持续静脉滴注静脉滴注24 h，共，共给药7天天Placebo plusstandard of care USE OF OPEN LABEL NESIRITIDE IS NOT ALLOWED AT ANY TIME!USE OF OPEN LABEL NESIRITIDE IS NOT ALLOWED AT ANY TIME!Why is this study being done?Does Nesiritide decrease re-hospitalization or death in 30 days? Does Nesiritide decrease symptoms of dyspnea at 6 and 24 hrs after drug initiated? 复合主要终点NursingRoles在治疗6小时和24 小时填写问卷表* 和VAS量表问卷表和VAS量表内容包括:自我评价呼吸困难程度健康状态/一般情况, 自我护理 能力, 疼痛, 抑郁, 体力7级评定*Found in patients chart box.30天复合终点天复合终点30天复合终点的亚组分析天复合终点的亚组分析肾脏安全性肾脏安全性对对ASCEND-HF评价评价ASCEND-HF研究澄清了既往质疑，证实奈西立肽安全 ASCEND-HF研究在给药方案上可能存在问题：由于奈西利肽的有效半衰期比硝酸甘油和硝普钠长，因此其副作用的持续时间可能较长, 低血压的发生率相对高采用保守（即无负荷量）和推荐剂量治疗可减少并发症 内内容容ASCEND-HFDOSEDiuretics and Heart FailureDiuretics are mainstay of therapy for acute heart failure (given to 90% of pts in ADHERE)Relieve symptoms of dyspnea and edema in most patientsAssociated with variety of problems:Electrolyte abnormalitiesActivation of RAAS and SNSDiuretic resistanceIncreased mortality?DiureticsandPCWPCirculation. 1986;74:1303 1306.速尿静推40-100mg 强心If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose. (Level of Evidence: C). The Hospitalized PatientTreatment With Intravenous Loop DiureticsNewA Report of the ACCF/ AHA Task Force on Practice GuidelinesThe Hospitalized PatientIntensifying the Diuretic RegimenNewWhen diuresis is inadequate to relieve congestion, as evidence by clinical evaluation, the diuretic regimen should be intensified using either:a. higher doses of loop diuretics;b. addition of a second diuretic (such as metolazone, spironolactone or intravenous chlorthiazide) orc. Continuous infusion of a loop diuretic.A Report of the ACCF/ AHA Task Force on Practice Guidelines急性心衰患者利尿剂使用的指征及剂量急性心衰患者利尿剂使用的指征及剂量液体潴留 利尿剂 日剂量（mg） 注释 中度速尿速尿布美它尼布美它尼 托拉塞米托拉塞米20-4020-40 0.5-10.5-110-20 10-20 根据临床症状口服或静注，根据临床反应根据临床症状口服或静注，根据临床反应调整滴定速度，监测血钾、血钠、血肌酐调整滴定速度，监测血钾、血钠、血肌酐及血压。及血压。严重速尿速尿速尿滴注速尿滴注布美它尼布美它尼托拉塞米托拉塞米40-10040-1005-40mg/h5-40mg/h 1-4 1-4 20-100 20-100 静注增加剂量静注增加剂量优于高冲击剂量优于高冲击剂量口服或静注口服或静注口服口服绊利尿剂抵抗 加双氢克尿噻加双氢克尿噻或美托拉宗或美托拉宗或或螺内酯螺内酯50-10050-100 2.5-102.5-1025-5025-50联合用药优于高剂量髓绊利尿剂联合用药优于高剂量髓绊利尿剂，肌酐清，肌酐清除率除率30ml/min30ml/min时双氢克尿噻效果更佳；时双氢克尿噻效果更佳； 无肾衰或血钾正常或偏低时螺内酯是最佳无肾衰或血钾正常或偏低时螺内酯是最佳选择选择 。碱中毒 乙酰唑氨乙酰唑氨 0.5mg 0.5mg 静注静注袢利尿剂及袢利尿剂及噻嗪类利尿噻嗪类利尿剂抵抗剂抵抗 增加多巴胺或多增加多巴胺或多巴酚丁胺巴酚丁胺合并肾衰或低血钠考虑使用超滤或血透合并肾衰或低血钠考虑使用超滤或血透DiureticOptimizationStrategiesEvaluationinAcuteHeartFailure(DOSE)G. Michael Felker, MD, MHS, FACCChristopher M. OConnor, MD, FACCon behalf of theNHLBI Heart Failure Clinical Research Network利尿剂优化策略治疗急性心衰评价 ACC2010 N Engl J Med 2011;364:797-805 AimsTo evaluate the safety and efficacy of various initial strategies of furosemide therapy in patients with ADHFRoute of administration:Q12 hours bolusContinuous infusion DosingLow intensification (过去日剂量)High intensification (过去日剂量的倍)ACC2010 N Engl J Med 2011;364:797-805 允许允许48hr后根据患者临床反应调整治疗方案后根据患者临床反应调整治疗方案Acute Heart Failure (1 symptom AND 1 sign)24 hours after admission 308例例 2x2 factorial randomizationLow Dose (1 x oral)Q12 IV bolus48 hours1) Change to oral diuretics2) continue current strategy3) 50% increase in doseCo-primary endpointsHigh Dose (2.5 x oral)Q12 IV bolusLow Dose (1 x oral)Continuous infusionHigh Dose (2.5 x oral)Continuous infusion72 hoursStudy DesignClinical endpoints60 days主要终点主要终点主要疗效终点： 基线至72 h内患者对症状的总体自评次要疗效终点呼吸困难、体重变化、体液净损失、受充血影响的患者比例、肾功能恶化、心力衰竭恶化 Patient Global Assessment VAS AUC:Q12 vs. ContinuousPt Global Assessment by VASQ12 VAS AUC, mean (SD) = 4236 (1440)Continuous VAS AUC, mean (SD) = 4373 (1404)Q12ContinuousHoursACC2010 N Engl J Med 2011;364:797-805 Patient Global Assessment VAS AUC:Low vs. High IntensificationHoursPt Global Assessment by VASLowHighLow VAS AUC, mean (SD) = 4171 (1436)High VAS AUC, mean (SD) = 4430 (1401)ACC2010 N Engl J Med 2011;364:797-805 Secondary Endpoints:Low vs. High IntensificationLowHighP valueDyspnea VAS AUC at 72 hours447846680.041% free from congestion at 72 hrs11%18%0.091Change in weight at 72 hrs-6.1 lbs-8.7 lbs0.011Net volume loss at 72 hrs3575 mL4899 mL0.001Change in NTproBNP at 72 hrs (pg/mL)-1194-18820.06% Treatment failure37%40%0.56Length of stay, days (median)650.55ACC2010 N Engl J Med 2011;364:797-805 死亡、心衰再住院或再进急诊室的复合终点死亡、心衰再住院或再进急诊室的复合终点两种给药方式、两种剂量的比较两种给药方式、两种剂量的比较N Engl J Med 2011;364:797-805Change in Creatinine at 72 hours Q12Q12ContinuousContinuousp = 0.45p = 0.45 0Change in Creatinine (mg/dL) Low HighLow HighACC2010 N Engl J Med 2011;364:797-805 对对DOSE研究的评价研究的评价该研究结果可能会改变目前的临床实践该研究结果可能会改变目前的临床实践许多临床医生可能会倾向于选择能够更快缓解许多临床医生可能会倾向于选择能够更快缓解呼吸困难的大剂量治疗方案呼吸困难的大剂量治疗方案另外，由于推注的效果与连续输注的效果相当，另外，由于推注的效果与连续输注的效果相当，因此临床医生可能会选择更方便的推注治疗方因此临床医生可能会选择更方便的推注治疗方案案研究的局限性研究的局限性DOSE入选的患者均为慢性心衰急性发作入选的患者均为慢性心衰急性发作DOSE 样本量较小，不足以检测各组之间发生临样本量较小，不足以检测各组之间发生临床事件的差异床事件的差异DOSE 方案允许分组治疗方案允许分组治疗48hr后根据患者临床反后根据患者临床反应调整治疗方案，这就限制了对各组疗效终点差应调整治疗方案，这就限制了对各组疗效终点差异的观察异的观察Thank you very much!患者基本特征患者基本特征患者基本特征患者基本特征