洋地黃類藥物治療心衰再評價獲益與風(fēng)險并存

1、洋地黃類藥物治療心衰再評價：獲益與風(fēng)險并存,復(fù)旦大學(xué)附屬中山醫(yī)院 周京敏,2,心衰治療觀念的改變,強心利尿,改善血流動力學(xué),改善神經(jīng)體液水平,地高辛 利尿劑,擴血管藥物,ACEI ARB BB,,,非藥物治療：CRT,3,洋地黃在心衰應(yīng)用減少,OPTIMIZE-HF 注冊登記僅30％心室收縮功能下降者住院前用地高辛僅8％有心衰表現(xiàn)者出院前加用地高辛,Am Heart J. 2004; 148: 43-51,4,

2、應(yīng)用逐年減少的原因,認(rèn)為地高辛不能降低病死率對地高辛毒性的顧慮各類會議極少關(guān)注ACEI. ARB. BB. CRT的強勢宣傳沒有制藥公司的推動,5,洋地黃應(yīng)用歷史,1542年 用digitalis名（foxglove）1785年 用于水腫、心衰>200年 的臨床應(yīng)用目前口服制劑基本為地高辛,6,全面認(rèn)識地高辛的作用,7,藥理作用,正性肌力作用正常心?。?LVED壓力↓，LVED 容積↓，LVEF↑心衰心?。?/p>

3、心率↓，交感神經(jīng)張力↓ ，迷走神經(jīng)張力↑,8,,周圍血管，冠脈：正常：抵消ouabain的收縮血管作用心衰：血流↑ ，血管阻力↓， CVP↓，血管擴張（CO ↑，反射性交感活性↓,9,,Baroreflexes恢復(fù)baroreflex的正常敏感性，在血流動力學(xué)改變之前,10,地高辛的效應(yīng),用于心衰時的血流動力學(xué)效應(yīng) ↑心排量 ↓PCWP ↑LVEF,Curr Probl Cardiol. 1

4、996;21:781–756.,11,神經(jīng)體液效應(yīng),↑迷走張力↑壓力感受器的敏感性↓血清去甲腎上腺素的濃度↓交感作用↓RAS系統(tǒng)的激活↓Cytokine 濃度↑ANP BNP釋放,神經(jīng)體液改善利尿,Circulation 2005;112:e154-235,12,電生理效應(yīng),竇房結(jié)：降低竇率心房?。骸粦?yīng)期房室結(jié)：減慢傳導(dǎo)浦氏纖維：低劑量無影響,13,其它效應(yīng),抗纖維化實驗室發(fā)現(xiàn)可預(yù)防醛固酮刺激導(dǎo)致的血管周圍纖維化

5、,14,,digoxin also acts as neurohormonal modulator, and much of the beneficial effects of digoxin may be due to its neurohormonal suppressing properties,Circulation 2005;112:e154-235,15,地高辛的臨床試驗的結(jié)果,雙盲、隨機、安慰劑對照的試驗1977－199

6、7年共16個絕大多數(shù)病例數(shù)少，不以病死率為觀察終點較一致的終點：心衰惡化減少死亡率無改變,16,收縮性心衰地高辛的應(yīng)用,PROVED試驗（＋利尿劑）RADIANCE試驗（ ＋用利尿劑和ACEI） 用利尿劑 用ACEI＋利尿劑踏板時間 ↑

7、 ↑六分鐘步行時間 － ↑治療失敗率 ↓ ↓心衰體征和癥狀的變化 － － 生活質(zhì)量

8、 － ↑慢性心衰分?jǐn)?shù) － ↓總體預(yù)后評估 － ↑LVEF

9、 ↑ ↑心率和血壓 ↓ ↓體重 ↓ ↓,,17,PROVED和RADIANCE中聯(lián)合治療的優(yōu)勢,,,4.7 *,19,2

10、5,39,( 4 of 85 ),( 8 of 42 ),( 23 of 89 ),( 18 of 46 ),,,,P = NS,% Worsening Heart Failure,* P <0.01 vs all other groups,18,Freedom from worsening HF in the digoxin withdrawn group and the digoxin group at 3 levels of

11、 SDC,J Am Coll Cardiol. 2002; 39:946–953,19,The Effect of Digoxin on Mortality and Morbidity in Patients with Heart FailureThe Digitalis Investigation Group,N Engl J Med 1997;336:525-33,,DIG的進一步分析,21,DIG試驗中地高辛和安慰劑治療的因心衰

12、惡化死亡率和再住院率,Digitalis Investigation Group. N Engl J Med. 1997;336:525–533.,22,DIG試驗中地高辛在高危亞組的2年隨訪,Digitalis Investigation Group. N Engl J Med. 1997;336:525–533.,23,DIG試驗中基線校正后的2年死亡率和住院率,Ahmed et al. Eur Heart J. 2006;27:1

13、78 –186.,血清地高辛濃度0.5 - 0.9 ng/mL和1 ng/m患者,24,Kaplan–Meier plots for cumulative risk of all-cause death by SDC,European Heart Journal (2006) 27, 178–186,25,Kaplan–Meier plots for cumulative risk of hospitalization due to w

14、orsening HF by SDC,European Heart Journal (2006) 27, 178–186,26,Kaplan-Meier Plots for All-Cause Mortality and HF Hospitalization in HF Patiends ≥65 Years,J Gerontol A Biol Sci Med Sci 2007;62:323-9.,27,Risk of death inc

15、reased from any cause among women, but not men,N Engl J Med 2002;347:1403-11,地高辛治療效果決定于使用方法,,29,地高辛的血清濃度與劑量,0.0625-0.25mg≈0.5-1.0ng/ml0.125mg≈0.8ng/ml用藥后>8小時 或下次用藥前測定<1.3ng/ml,30,劑量個體化,影響血濃度因素 劑量、年齡、性別、體重、腎功能

16、、合并 用藥 (amiodarone, diltiazem, verapamil, certain antibiotics, quinidine).應(yīng)用目的心衰不須負(fù)荷量房顫可給0.5-0.75mg,31,如何應(yīng)用,A single daily maintenance dose of 0.25 mg is commonly employed in adults with normal renal function. In

17、 the elderly (>75y), women, renal insufficiency, are receiving large doses of diuretics, or have pulmonary edema, digoxin should be prescribed as 0.125 or 0.0625 mg o.d. per day.,32,,There is no evidence that regular

18、digoxin concentration measurements confer better outcomes.The therapeutic serum concentration should be between 0.6 and 1.2 ng/mL, lower than previously recommended.,33,哪些患者應(yīng)該使用,標(biāo)準(zhǔn)治療后仍有癥狀應(yīng)加用不能耐受或支付ACEI or ARB, β-阻滯劑和螺內(nèi)

19、酯者，應(yīng)加用已經(jīng)服用的不要停用,34,禁忌癥,II, III AVB (無起搏器)；可以，病竇謹(jǐn)慎Pre-excitation syndromesPrevious evidence of digoxin intolerance,35,Digoxin in preserved systolic function附屬地高辛的研究988例病人（LVEF 55％）Digoxin+利尿劑＋ACEI: 心衰死亡率或住院率↓12％（N

20、S）,Digoxin in HF with preserved systolic function,36,Effects of Digoxin on Morbidity and Mortality inDiastolic Heart FailureThe Ancillary Digitalis Investigation Group Trial,37,,減輕舒張性心衰的癥狀：a similar protocol to systoli

21、c dysfunction,38,慢性心衰治療目的,改善預(yù)后±,改善癥狀＋,,,39,指南中地高辛的定位,地高辛推薦級別2005 ACC/AHA：為IIa類2001 ACC/AHA：為I類,2005， ACC/AHA Practice Guidelines2009 ACC/AHA guidelinecirculation 2009;119;1977-2016,40,2005 ESC：房顫及任何程度的有癥狀

22、的心衰，無論有無左室功能不全，洋地黃類藥物都是其適應(yīng)癥，可以減慢室率，改善心功能和癥狀（推薦為IB類）房顫患者地高辛和β-阻滯劑合用優(yōu)于單用其中一種（推薦為IIa 類，B）在左室收縮功能不全并已接受ACEi， β -阻滯劑和利尿劑治療的患者，地高辛對死亡率無效，但能減少住院率，特別是心衰惡化住院（推薦為IIa 類，A）,European Heart Journal (2005) 26, 1115–1140,指南中地高辛的定位,41,

23、2009 ESC心衰癥狀 + 房顫：控制心室率房顫 + LVEF< 40%：+ β-阻滯劑控制心室率Class of recommendation I, level of evidence C心衰癥狀 + 竇率 + LVEF < 40%：提高生活質(zhì)量，降低心衰住院率，對死亡率無效Class of recommendation IIa, level of evidence B,42,Digoxin has be