摘要
研究背景肺高血压是一大类临床上常见、病因复杂的进展性疾病,表现为肺血管阻力不断升高最终引起右心衰竭和死亡。研究显示：诊断为肺动脉高压而未行治疗的患者其平均生存年限仅为2.8年。目前临床上仍未研发出治愈肺高血压的药物。在过去的十几年里,世界范围内仅有3种治疗肺高血压的靶向药物上市,包括前列环素及类似物、内皮素受体拮抗剂以及磷酸二酯酶抑制剂。然而肺血管靶向药物治疗费用昂贵、药物剂型使用不便且安全性较差。他汀类(statins)药物即羟甲基戊二酰辅酶A还原酶抑制剂(HMG-CoA还原酶抑制剂),通过抑制胆固醇合成的限速步骤降低血清胆固醇,是当前广泛应用于临床的降胆固醇药物。近年来,他汀类药物的多效性引起人们的广泛关注。越来越多的动物实验及临床研究显示他汀类药物可以减缓肺高血压肺血管结构重构、抑制肺血管平滑肌细胞增生,但其治疗肺高血压的观点尚未成熟,仍待进一步证实。
目的本研究旨在通过Meta分析,进一步明确他汀类药物对肺高血压的治疗作用,为临床合理药物治疗提供循证医学证据。
方法在PubMed数据库和中国期刊全文数据库(CNKI)检索截至2010年12月的所有关于他汀类药物治疗肺高血压的随机对照临床试验研究文献进行Meta分析,采用Jadad量表对所有纳入文献进行方法学质量评价。疗效评价指标包括6分钟步行距离(6 MWD)、心脏指数(CI)、肺动脉平均压(mPAP)、肺动脉收缩压(sPAP)、动脉血氧分压(Pa02)、内皮素-1(ET-1)、一氧化氮(NO)、体循环收缩压(systolic BP)、体循环舒张压(diastolic BP)。使用的Meta分析软件为RevMan5.0。1
结果共纳入9个随机对照临床试验,包括590例患者。Meta分析结果显示：他汀类药物治疗与空白对照相比,(1)肺动脉收缩压(sPAP):sPAP平均下降了4.71 mmHg (95%CI[-8.09,-1.33], P=0.006),两组差异有统计学意义；(2)肺动脉平均压(mPAP):mPAP下降了3.26mmHg (95%CI[-4.10,-2.42],P<0.00001),两组差异有统计学意义；(3)6分钟步行距离(6 MWD):6 MWD平均增加了31.72 m(95%CI[-23.06,86.51],P=0.26),差异没有统计学意义；(4)心脏指数(CI)：CI增加了0.21L/min m2(95%CI[0.14,0.27],P<0.00001),差异有统计学意义；(5)血浆NO：血浆NO增加了4.10μ/L(95%CI[3.51,4.68],P<0.00001),差异有统计学意义；(6)血浆ET-1：血浆ET-1降低了1.31pg/ml(95%CI[-3.18,0.56],P=0.17),差异没有统计学意义；(7)动脉血氧分压(Pa02)：Pa02上升了7.10mmHg (95%CI[0.62,13.58], P=0.03),差异有统计学意义；(8)收缩压(systolic BP):systolic BP平均降低了0.97mmHg (95%CI[-3.29,1.35],P=0.41),两组差异没有统计学意义,即他汀类药物治疗肺高血压不会影响体循环收缩压；(9)舒张压(diastolic BP):diastolic BP平均降低了0.93mmHg(95%CI[-2.22,0.36],P=0.16),两组差异没有统计学意义,即他汀类药物治疗肺高血压不会影响体循环舒张压。
结论Meta分析结果显示应用他汀类药物可以改善肺高血压患者的心功能,降低患者平均肺动脉压和收缩期肺动脉压,同时不影响患者体循环血压。纳入的临床研究中受试者较少发生与他汀类药物相关的不良反应,无严重不良反应事件发生,临床应用相对安全,患者一般能够耐受。
Background Pulmonary hypertension (PH) is a common, complex and progressive disease. Increased pulmonary vascular resistance leads to right heart failure and finally even death. An American study showed that the median survival time for patients with untreated idiopathic pulmonary arterial hypertension (IPAH) was 2.8 years. So far there is still no cure for PH. In the last decades, there were three pulmonary-specific drugs approved for PH including prostanoids, endothelin-1 (ET-1) receptor antagonists and phosphodiesterase-type 5 (PDE5) inhibitors. However, these three drugs are too expensive and neither convenient nor safe enough.
Statins are HMG-CoA (Hydroxymethylglutaryl-Coenzyme A) reductase inhibitors which were used for lowing serum cholesterol by inhibiting HMG-CoA reductase (the rate-limiting step in cholesterol synthesis) and had been used for many years in the treatment of hypercholesterolemia. Studies had identified the pleiotropic effects of statins beyond their cholesterol-lowering properties. More and more evidence of animal trials and clinical studies suggest that statins appear to attenuate the pulmonary vascular structural remodeling and inhibite vascular smooth muscle proliferation as a novel drug in treating PH.
Objectives We conducted a Meta-analysis of treatments for PH, aiming at evaluating the therapeutic effects of statins in patients with PH through all randomized controlled trials (RCTs) on the therapeutic yield of statins in PH.
Methods A total of 9 RCTs were identified to assess the effects of statins on PH by searching PubMed and CNKI (both inception to December 2010). The methodological quality of included RCTs was made using Jadad scale. Efficacy measures include 6-minute-walk distance (6 MWD), cardiac index (CI), mean pulmonary artery pressure (mPAP), systolic pulmonary artery pressure (sPAP), PaO2, plasma NO, plasma ET-1, systolic blood pressure (systolic BP) and diastolic blood pressure (diastolic BP). RevMan 5.0 was used for analying datas.
Results Nine RCTs involving a total of 590 people with PH were included in this Meta-analyses. The results of Meta-analyses showed that (1) Systolic pulmonary arterial pressure (mPAP) decreased by 5.41mmHg (95%CI[-6.73,-4.09], P<0.00001); (2) Mean pulmonary arterial pressure (mPAP):mPAP decreased by 3.26mmHg (95%CI[-4.10,-2.42], P<0.00001); (3) Six-minute walk distance (6 MWD):6 MWD increased 31.72m (95%CI[-23.06,86.51], P=0.26); (4) cardiac index (CI):CI increased 0.21L/min m2 (95%CI[0.14,0.27], P<0.00001); (5) Plasma NO:plasma NO increased 4.10μg/L(95%CI[3.51,4.68], P<0.00001); (6) Plasma ET-1:plasma ET-1 decreased by 1.31pg/ml (95%CI[-3.18,0.56], P=0.17); (7) PaO2:PaO2 decreased by 6.32mmHg (95%CI[-1.07,13.7], P=0.09); (8) Systolic blood pressure (systolic BP):systolic BP decreased by 0.97mmHg (95%CI[-3.29,1.35], P=0.41); (9) Diastolic blood pressure (diastolic BP):diastolic BP decreased by 0.93mmHg (95%CI[-2.22,0.36],P=0.16).
Conclusions Our Meta-analyses suggest that statins are effective in treating patients with PH. Statin therapy is associated with an improvement of cardiac function and hemodynamics in patients with PH. Furthermore the results show that statins do not influence systolic BP or diastolic BP of patients with PH.
引文
1. Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension[J]. Eur Respir J,1995;8(12):2129-2138.
2.胡大一,荆志成.规范肺动脉高压的筛查诊断与治疗[J].中华心血管病杂志,2007：35：979-987.
3. Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension[J]. Am J Cardiol,1995;75(3):51A-54A.
4. Gabbay E, Yeow W, Playford D. Pulmonary arterial hypertension (PAH) is an uncommon cause of pulmonary hypertension (PH) in an unselected population:the Armadale echocardiography study[J]. Am J Resp Crit Med,2007;175:A713.
5. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association[J]. JAm Coll Cardiol,2009;53(17):1573-619.
6. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in Patients with Primary Pulmonary hypertension. Results from a national prospective registry [J]. Am Intern Med,1991;115:343-349.
7.杜军保,唐朝枢主编.肺动脉高压[M].北京：北京大学医学出版社2009.
8. Cool CD, Stewart JS, Werahera P, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth[J]. Am J Pathol,1999;155(2):411-419.
9. Goldstein JL, Brown MS. Regulation of the mevalonate pathway[J]. Nature,1990; 343(6257):425-430.
10.王吉耀主编.循证医学与临床实践[M].北京：科学出版社,2006.
11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials:is blinding necessary[J]. Control Clin Trials,1996;17(1): 1-12.
12. Moher D, Cook DJ, Jadad AR, et al. Assessing the quality of reports of randomised trials:implications for the conduct of meta-analyses[J]. Health Technol Assess,1999;3(12):i-iv,1-98.
13. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses[J]. Lancet,1998; 352(9128):609-613.
14. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses[J]. Ann Intern Med,2001;135(11):982-989.
15.王家良.循证医学[M].北京：人民卫生出版社,2008,86-90.
16.康德英,洪旗,刘关键,等.Meta分析中发表性偏倚的识别与处理[J].中国循证医学杂志,2003,3(1)：45-49.
17. Ganzevoort W, Rep A, Bonsel GJ, et al. PETRA investigators randomised controlled trial comparing two temporizing management strategies, one with and one without plasma volume expansion,or severe and early onset preeclampsia[J]. BJOG, 2005;112(10):1358-1368.
18.张郁青,张秀伟,朱颖等.阿托伐他汀对慢性阻塞性肺疾病肺疾病合并肺动脉高压患者的影响[J].心肺血管病杂志,2009；7(28)：250-287.
19.邹国亮,陈波,邱英梅等.辛伐他汀对慢性肺源性心脏病中肺动脉高压的影响[J].医院医学杂志,2009；29(8)：657-659.
20.陈建华.辛伐他汀治疗低氧性肺动脉高压疗效观察[J].医药论坛杂志,2009；3(30)：20-21.
21.逢立侠,李永芳,匡素清.阿托伐他汀钙治疗慢性肺源性心脏病肺动脉高压86例疗效观察[J].牡丹江医学院学报,2010；31(3)：82-83.
22.李兰菊,岳红卫,魏一平等.辛伐他汀联合川芎嗪治疗慢性阻塞性肺疾病肺疾病肺动脉高压的临床研究[J].现代医学,2009；4(37)：126-128.
23.徐启康.辛伐他汀联合低分子肝素治疗重症肺心病疗效观察[J].河南职工医学院学报,2009；21(2)：137-139.
24.赵献明,许春平,曾波等.阿托伐他汀联合西地那非在慢性阻塞性肺疾病肺疾病相关肺动脉高压患者的临床观察[J].医学信息,2010；(10)：2673-2675.
25. Wilkins MR, Ali O, Bradlow W, et al.Simvastatin Pulmonary Hypertension Trial (SiPHT) Study Group. Simvastatin as a treatment for pulmonary hypertension trial[J]. Am J Respir Crit Care Med,2010;181(10):1106-13.
26. Lee TM, Chen CC, Shen HN, et al.Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension[J]. Clin Sci (Lond),2009;116(6):497-505.
27. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients:cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study[J]. Lancet, 1999;354(9192):1751-1756.
28. Nauser TD, Stites SW. Diagnosis and treatment of Pulmonary hypertension[J]. Am Fam Physician,2001;63:1789-1798.
29. Stenmark KR, McMurtry IF. Vascular remodeling versus vasoconstriction in chronic hypoxic pulmonary hypertension:A time for reappraisal[J]. Cir Res, 2005;97:95-98.
30. Voelkel NF TR, Wwir EK, Rubin L, et al. Primary pulmonary hypertension. Pathophysiology of primary pulmonary hypertension[J]. NewYork; Maccel Dekker, 1997;83-129.
31. Opitz CF, Wensel R, Winker J, et al. Clinical efficacy and survival with first-line Inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension[J]. Eur Heart J,2005;26:1895-1902.
32. Barsst RJ. Medical therapy of pulmonary hypertension. An overview of treatment and goals[J]. Chest Clinics in Medicine,2001;22:509-516
33. Naeije R, Vachieny JL. Medical therapy of pulmonary hypertension: Conventional therapies[J]. Chest Clinics in Medicine,2001;22:517-528
34. Hoeper MM, Galie N, Simonneau G, et al. New treatments for pulmonary arterial hypertension[J]. Am JRespir Crit Care Med,2002;165:1209-1216.
35. Nagaya N. Drug therapy of primary pulmonary hypertension[J]. Am J Cardiovasc Drugs,2004;4:75-85.
36. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension[J]. Circulation, 2005;111(23):3105-11.
37. Badesch DB, McLaughlin VV, Delcroix M, et al. Prostanoid therapy for Pulmonary arterial hypertension[J]. J Am Coll Cardial,2004;43:565-615.
38. Humbert M, Sitbon O, Simonneau G Treatment of Pulmonary arterial hypertension[J]. NEngJMed,2004;351:1425-1436.
39. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension[J]. N Engl J Med,2002,346:896-903.
40. Lunn RJ. Inhaled NO therapy [J]. Mayo Clin Proc,1995;70(3):247-255.
41. Michelakis ED, Tymchak W, Noga M, et al. Longterm treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial Hypertension[J]. Circulation,2003;108:2066-2069.
42. Goldstein JL, Brown MS. Regulation of the mevalonate pathway[J]. Nature, 1990;343:425-30.
43. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats[J]. Am J Respir Crit Care Med,2002;166(10):1403-1408.
44. Lepore JJ, Dec GW, Zapol WM, et al. Combined administration of intravenous dipyridamole and inhaled nitric oxide to assess reversibility of pulmonary arterial hypertension in potential cardiac transplant recipients [J]. Heart Lung Transplant, 2005;24(11):1950-1956.
45. Nishimura T, Vaszat LT, Faul JL. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells[J]. Circulation,2003; 108(13):1640-1645.
46. Kao PN. Simvastatin treatment of pulmonary hypertension:an observational case series[J]. Chest,2005; 127(4):1446-1452.
47. Rosenzweig EB. Expert treatments for pulmonary arterial hypertension[J]. Expert Opin Emerg Drugs,2006;11(4):9609-9619.
48. Vaszar LT, Nishimura T, Storey JD, et al. Longitudinal transcription alanalysis of developing neointimalvascular occlusion and pulmonary hypertension in rats[J]. Physiol Genomics,2004; 17(1):150-156.
49. Cheng G, Shan J, Xu G, et al. Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca2+-calplin and caspase-3 dependent pathway[J]. Pharmacolo Res,2003;48:571-578.
50. Wilson SH, Herrmann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation,2002; 105:415-418.
51. Lepore JJ, Dec GW, Zapol WM, et al. Combined administration of intravenous dipyridamole and inhaled nitric oxide to assess reversibility of pulmonary arterial hypertension in potential cardiac transplant recipients[J]. Heart Lung Transplant, 2005;24(11):1950-1956.
52. Jeffery TK, Morrell NW. Molecular and cellular basis of vascular remodeling in pulmonary hypertension[J]. Prog Cardiovasc Dis,2002;45(3):173-202.
53. Turner NA, OR' egan DJ, Ball SG, et al. Simvastatin inhibits MMP-9 secretio from human saphenous vein smoothmuscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels[J]. FASEB J,2005;19(7):804-806.
54. Irwig L, Tosteson AN, Gatsonis C, et al. Guidelines for meta-analyses evaluating diagnostic tests[J]. Ann Intern Med,1994 Apr 14;120(8):667-676.
55. Humbert M, Morrell, NW, Archer SL, et al.Cellular and molecular pathobiology of pulmonary arterial hypertension [J]. J Am Coll Cardiol,2004;43(12 Suppl S):13S-24S. Review.
56. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling[J]. JAM Coll Cardiol,2009;54:s10-s19.
57. Morrel N, Adnot S, Archer S, et al. Cellular and molecular basis of pulmonary arterial hypertension[J]. JAM Coll Cardiol,2009;54:s10-s19.
58. Takahisa M, Kazuya K, Masatoshi H, et al. Statin protects endothelial nitric oxide synthase activity in hyposia-induced pulmonary hyperterosion[J]. Arteriscler Thromb Vasc Biol,2005;25:2335-2342.
59. Degraeve F, Bolla M, Blaie S, et al. M odulation of COX-2 espression by statins in human aortic sm ooth muscle cells. Involvement of geranylgeranylated proteins[J]. J Biol Chem,2001;276:46894-46855.
60. Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals[J]. Nat Med,2000;6:1004-1010.
61. Galie N, Torbicki A, Barst A, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology[J]. Eur Heart J,2004;25(24):2243-2278.
62. Hoeper MM, Oudiz RJ, Peacock A, et al. End points and clinical trial designs in pulmonary arterial hypertension[J]. J Am Coll Cardiol,2004;43(12 Suppl S):48S-55S.