临床研究和心力衰竭的治疗策略

临临床研究和心力衰竭的治疗疗策略 南京医科大学第一附院心内科 江苏省心血管病临床医学中心 李新立 教授 临床治疗策略的演变 1900s 个人经验 权威性教学 无对照病例报告 病例对照研究临床试验 以科学为本的病因学 1970s 临床终点研究+ 临床经验 以证据为本的临床用药 1995 1989年一项震惊整个医学界的研究 Of 226 maneuvers in obstetrics Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL should is recommended is indicated is useful/effective/ beneficial is reasonable can be useful/effective/ beneficial is probably recommended or indicated may/might be considered may/might be reasonable usefulness/effectiveness is unknown /unclear/uncertain or not well established is not recommended is not indicated should not is not useful/effective/beneficial may be harmful Applying Classification of Recommendations and Level of Evidence 慢性心力衰竭治疗模式的历史沿革 n40-60年代心肾模式 n强心、利尿 n60-70年代血流动力学 n强心、利尿、扩血管 n受体激动剂 n80年代以后心室重构 n阻滞神经体液因子和细胞因子的激活 nACEI n受体阻滞剂 n醛固酮受体拮抗剂 n现在器械及辅助装置 nICD nCRT/CRTD nLVAD n其它 n将来基因治疗 ; 细胞植入/ 再生 ; 异种移植 ？ 慢性心力衰竭治疗药物历史沿革 1700180019002000 DiagnosisMercurial diuretics Loop diuretics ACEi ARBs BBs 年代 NEW nNEW conception (新概念） CSHF是不可逆的终末期过程 结构和功能的内 源性缺陷 - 可以有真正 的生物学改善。 nNEW strategy （新策略） 短期的血液动力学/药理学措施长期的、修复性 的策略。 nNEW focus （新焦点） 传统的强心、利尿、扩血管药当代的阻断神经内 分泌系- 统，阻断心肌重 塑。 nNEW drug combination （新药物联合 ） 利尿剂、ACEI、受体阻滞剂、地高辛、ALD、 ARB。 nNEW origin treat start （新起始治疗 点） LVEF40%, not on ACEI candesartan, 432 mg qd (2002) NYHA IIIV ARB Trials in Symptomatic HF ELITE I/IIOPTIMAALVALIANTValHeFTCHARM Patients NYHA II-IVAMI/CHFAMI/CHFNYHA II-IVNYHA II-IV Study design Losartan or captopril Losartan or captopril Valsartan, captopril or both Valsartan and ACEI Candesarta n and ACEI Beta- blocker 16%79%70%35%55% Mortality No difference Captopril better No difference No difference No difference HF hosp No difference Captopril better Both betterBoth betterBoth better Other Losartan better tolerated Losartan better tolerated Increased creatinine with both Increased mortality with beta- blockers Decreased mortality with -blockers; increased K and Cr with both ARB制剂、剂量 药物*起始剂量推荐剂量 坎地沙坦48mg/d32mg/d 缬沙坦2040mg/d160mg bid 氯沙坦2550mg/d50100mg/d 厄贝沙坦150mg/d300mg/d 替米沙坦40mg/d80mg/d 奥美沙坦1020mg/d2040mg/d *所列药物中坎地沙坦和缬沙坦已有一些临床试验证实，对降低CHF患者死亡率、病残率有益 IA 不能耐受ACEI的LVEF 低下的患者， 以减低死亡率和并发症 IIbB 常规治疗后心衰症状持续存在， 且LVEF低下者，可考虑加用ARB Primary Outcomes of Aldosterone Blocker in Heart Failure p5.0 or Cr2.5 nSpironolactone 25mg daily nDrug held for K6.0 or Cr4.0 Pitt et al. NEJM 1999:341:709. HR 0.70 p2.5, K5.0 nMedian follow-up 16 months Rate of death from cardiovascular causes or hospitalization or cardiovascular events Pitt et al. NEJM 2003;348:1309. IB AMI后并发心衰，LVEF40% Digoxin: Improvement in symptoms but not survival nDigitalis investigation group n6800 patients nEF45% nPast or current symptoms of HF nOn ACEI and diuretics NEJM 1997;336:525. All-cause mortality Death or hospitalization for worsening HF IIa B 洋地黄制剂对合并有症状 的低LVEF心衰患者， 可降低因心衰所致的入院率 Study characteristics of included RCTs of CRT and ICD therapy in left ventricular impairment and symptomatic HF Lam, S. K H et al. BMJ 2007;335:925 Lam, S. K H et al. BMJ 2007;335:925 Results of Bayesian network meta-analysis of 12 RCTs of device therapies in 8307 patients with left ventricular dysfunction Probability of best treatment for patients with Probability of best treatment for patients with left ventricular dysfunctionleft ventricular dysfunction Lam, S. K H et al. BMJ 2007;335:925 CRT IA 窦性节律，QRS波群120ms，LVEF35% 左心室舒张末期内径(LVEDD) 55mm 最佳药物治疗后心功能仍为NHYA 级或级 Diastolic HF - not been well studied in clinical trials CC B BB DIU*nitrate s* ACEi ARB Congestive symptoms BP Ischemia HR LVH Adapted from Chatterjee K. Am J Geriatr Cardiol 2002;11:178-89. CCB = calcium-channel blocker; HR = heart rate *Use with caution How Is It Treated?- By theoretical and empirical evidence General Pharmacological Treatment Strategies in HF Angiotensin Converting Enzyme Inhibitor Spironolactone Digoxin No added salt 2 gm Na HF clinics follow-up Customized lifestyle program AsymptomaticMild/ModSevereRefractory Angiotensin II Receptor Blocker -Blocker 心力衰竭患者治疗流程图 确定慢性收缩性心力衰竭的诊断 （左室心腔扩大，LVEF40%） 去除或缓解基本病因和诱因 （瓣膜性心脏病对手术治疗做出评定） （冠心病心绞痛或有存活心肌对血运重建做出评定） 判断液体潴留情况 有液体潴留的症状和体征 无液体潴留的症状和体征 利尿剂 ACE抑制剂 （滴定至病情控制后长期维持，即肺部 （NYHA 、级） 啰音消失、水肿消退、体重恒定） 地高辛 受体阻滞剂（NYHA 、 级） （主要为NYHA 、级） 醛固酮拮抗剂 （NYHA 级） Utilization of Evidence-Based Therapies in Heart Failure *Excludes patients with documented contraindications. 2300/7883 patients hospitalized with HF; prior known dx of systolic dysfunction HF; outpatient medical regimen. ADHERE Registry Report Q1 2002 (4/01-3/02) of 180 US hospitals. Presented by GC Fonarow at the Heart Failure Society of America Satellite Symposium, September 23, 2002. LVEF Documented and 0.40* 44.3 10 40.9 68 31.9 0 10 20 30 40 50 60 70 80 90 100 Outpatient HF Medication ACE InhibitorARB - BlockerDiureticDigoxin Patients Treated (%) Utilization of Evidence-Based Therapies in Heart Failure at University Hospitals University Hospital Consortium HF Registry: 33 centers, 1239 patients, Year 2000. Outpatient regimen before HF hospitalization in patients with Stage C HF. Unpublished data provided courtesy of Dr GC Fonarow, UCLA Medical Center. 69 29 19 0 10 20 30 40 50 60 70 80 90 100 ACE Inhibitors- BlockersSpironolactone Patients Treated (%) - Blockers Utilization of Evidence-Based HF Therapies IMPROVEMENT International Survey International survey: 15 countries, 1363 physicians, 11,062 patients: Year 2000. Outpatient regimen in patients with Stage C HF, documented systolic dysfunction. Cleland JG. Lancet. 2002;360:1631-1639. 60 34 20 12 0 10 20 30 40 50 60 70 80 90 100 ACE InhibitorsACEI + BBSprionolactone Patients Treated (%) McMurray JJV. Lancet 2003;362 (9386):777-81 MERIT-HF Study Group. Lancet 1999;353(9169):2001-7 SOLVD Investigators. N Engl J Med 1991;325(5):293-302 Historical Advances in Heart Failure Treatment Cardiovascular Mortality 2003 CHARM-A