Efficacy and safety of different drugs for the treatment of intermittent claudication due to peripheral arterial disease: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

LIANG Xinyu ¹ , FENG Xia ¹ , GAO Yujie ² , XU Hongtao ³ , WANG Yuzhen ³ , ZHAO Cheng ³ ,  CAO Yemin ³

1. Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China;
2. Department of Pain, Shanghai Yangsi Hospital, Shanghai 202126, P. R. China;
3. Department of Vascular Surgery, Shanghai TCM-Integrated Hospital, Shanghai, 200082, P. R. China;

Corresponding author：

CAO Yemin, Email: Professorcao2021@126.com

Keywords：

Peripheral arterial disease; Intermittent claudication; Drug therapy; Walk ability; Network meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202112111

Video：

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Objective To systematically review the efficacy and safety of different drugs for the treatment of intermittent claudication in patients with peripheral arterial disease. Methods The PubMed, Scopus, EMbase, The Cochrane Library, Web of Science, CNKI, WanFang Data and VIP databases were searched to collect randomized controlled trials (RCTs) of intermittent claudication due to peripheral arterial disease from database inception to December 31^st, 2021. Two researchers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Network meta-analysis was then performed using Stata 16.0 software. Results A total of 36 studies were included, which involved vasodilators (i.e., cilostazol), lipid-lowering agents (i.e., atorvastatin), antiplatelet drugs (i.e., sarpogrelate), and other types of medicine (i.e., L-carnitine and allopurinol). The results of meta-analysis showed that the effects of simvastatin, bencyclane, and ramipril were superior to cilostazol and other drugs in improving PFWD, among which bencyclane was the most efficient. Besides, simvastatin and ramipril were also superior to cilostazol and other drugs in improving MWD (P<0.05). However, there was no statistically significant difference between cilostazol and other drugs (P>0.05). In terms of adverse events, iloprost was inferior to other drugs, while sulodexide was better tolerated. Conclusion Bencyclane is a preferred choice to improve PFWD for the treatment of IC due to PAD, simvastatin and ramipril to improve MWD; however, their safety is poor. Overall, sulodexide and L-carnitine are ideal medicines for IC. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： LIANG Xinyu, FENG Xia, GAO Yujie, XU Hongtao, WANG Yuzhen, ZHAO Cheng, CAO Yemin. Efficacy and safety of different drugs for the treatment of intermittent claudication due to peripheral arterial disease: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2022, 22(6): 655-666. doi: 10.7507/1672-2531.202112111 Copy

1.	Hamburg NM, Creager MA. Pathophysiology of intermittent claudication in peripheral artery disease. Circ J, 2017, 81(3): 281-289.
2.	Campia U, Gerhard-Herman M, Piazza G, et al. Peripheral artery disease: past, present, and future. Am J Med, 2019, 132(10): 1133-1141.
3.	Kröger K, Stang A, Kondratieva J, et al. Prevalence of peripheral arterial disease - results of the Heinz Nixdorf recall study. Eur J Epidemiol, 2006, 21(4): 279-285.
4.	Bolton L. Peripheral arterial disease: scoping review of patient-centred outcomes. Int Wound J, 2019, 16(6): 1521-1532.
5.	Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 815S-843S.
6.	Halliday A, Bax JJ. The 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg, 2018, 55(3): 301-302.
7.	中华医学会外科学分会血管外科学组. 下肢动脉硬化闭塞症诊治指南. 中华普通外科学文献(电子版), 2016, 10(1): 1-18.
8.	李伦, 田金徽, 姚亮, 等. 网状Meta分析的统计学基础, 假设和证据质量评估. 循证医学, 2015, 15(3): 180-183.
9.	易跃雄, 张蔚, 刘小媛, 等. 网状Meta分析图形结果解读. 中国循证医学杂志, 2015, 15(1): 103-109.
10.	Robertson AJ, Struthers AD. A randomized controlled trial of allopurinol in patients with peripheral arterial disease. Can J Cardiol, 2016, 32(2): 190-196.
11.	Chu YS, Li DX, Zhang M, et al. Trimetazidine hydrochloride as a new treatment for patients with peripheral vascular disease-an exploratory trial. Eur Rev Med Pharmacol Sci, 2016, 20(1): 188-193.
12.	Shahin Y, Cockcroft JR, Chetter IC. Randomized clinical trial of angiotensin-converting enzyme inhibitor, ramipril, in patients with intermittent claudication. Br J Surg, 2013, 100(9): 1154-1163.
13.	Goldenberg NA, Krantz MJ, Hiatt WR. L-Carnitine plus cilostazol versus cilostazol alone for the treatment of claudication in patients with peripheral artery disease: a multicenter, randomized, double-blind, placebo-controlled trial. Vasc Med, 2012, 17(3): 145-154.
14.	Hiatt WR, Creager MA, Amato A, et al. Effect of propionyl-L-carnitine on a background of monitored exercise in patients with claudication secondary to peripheral artery disease. J Cardiopulm Rehabil Prev, 2011, 31(2): 125-132.
15.	Vitale C, Marazzi G, Pelliccia F, et al. Trimetazidine improves exercise performance in patients with peripheral arterial disease. Pharmacol Res, 2011, 63(4): 278-283.
16.	Zankl AR, Ivandic B, Andrassy M, et al. Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease. Clin Res Cardiol, 2010, 99(12): 787-794.
17.	Bregar U, Poredos P, Sabovic M, et al. The influence of atorvastatin on walking performance in peripheral arterial disease. Vasa, 2009, 38(2): 155-159.
18.	O'Donnell ME, Badger SA, Sharif MA, et al. The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. J Vasc Surg, 2009, 49(5): 1226-1234.
19.	Jaff MR, Dale RA, Creager MA, et al. Anti-chlamydial antibiotic therapy for symptom improvement in peripheral artery disease: prospective evaluation of rifalazil effect on vascular symptoms of intermittent claudication and other endpoints in Chlamydia pneumoniae seropositive patients (PROVIDENCE-1). Circulation, 2009, 119(3): 452-458.
20.	Creager MA, Pande RL, Hiatt WR. A randomized trial of iloprost in patients with intermittent claudication. Vasc Med, 2008, 13(1): 5-13.
21.	Gardner CD, Taylor-Piliae RE, Kiazand A, et al. Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. J Cardiopulm Rehabil Prev, 2008, 28(4): 258-265.
22.	Brass EP, Anthony R, Cobb FR, et al. The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease. J Am Coll Cardiol, 2006, 48(12): 2539-2545.
23.	Oka RK, Szuba A, Giacomini JC, et al. A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease. Vasc Med, 2005, 10(4): 265-274.
24.	Hiatt WR, Hirsch AT, Cooke JP, et al. Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy. Vasc Med, 2004, 9(1): 18-25.
25.	Hiatt WR, Klepack E, Nehler M, et al. The effect of inhibition of acyl coenzyme A-cholesterol acyltransferase (ACAT) on exercise performance in patients with peripheral arterial disease. Vasc Med, 2004, 9(4): 271-277.
26.	Mohler ER 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation, 2003, 108(12): 1481-1486.
27.	Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med, 2003, 114(5): 359-364.
28.	Mohler ER 3rd, Hiatt WR, Olin JW, et al. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. J Am Coll Cardiol, 2003, 41(10): 1679-1686.
29.	Coccheri S, Scondotto G, Agnelli G, et al. Sulodexide in the treatment of intermittent claudication. Results of a randomized, double-blind, multicentre, placebo-controlled study. Eur Heart J, 2002, 23(13): 1057-1065.
30.	Strandness DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg, 2002, 36(2): 83-91.
31.	Lee TM, Su SF, Hwang JJ, et al. Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. Atherosclerosis, 2001, 158(2): 471-476.
32.	Hiatt WR, Regensteiner JG, Creager MA, et al. Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Am J Med, 2001, 110(8): 616-622.
33.	Gresele P, Migliacci R, Di Sante G, et al. Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life. CRAMPS Investigator Group. Cloricromene Randomized Arteriopathy Multicenter Prospective Study. Vasc Med, 2000, 5(2): 83-89.
34.	Lièvre M, Morand S, Besse B, et al. Oral Beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial. Beraprost et Claudication Intermittente (BERCI) Research Group. Circulation, 2000, 102(4): 426-431.
35.	Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol, 1999, 34(5): 1618-1624.
36.	Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med, 1999, 159(17): 2041-2050.
37.	Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg, 1998, 27(2): 267-274.
38.	Brevetti G, Perna S, Sabba C, et al. Effect of propionyl-L-carnitine on quality of life in intermittent claudication. Am J Cardiol, 1997, 79(6): 777-780.
39.	Lievre M, Azoulay S, Lion L, et al. A dose-effect study of beraprost sodium in intermittent claudication. J Cardiovasc Pharmacol, 1996, 27(6): 788-793.
40.	Drabaek H, Mehlsen J, Himmelstrup H, et al. A botanical compound, Padma 28, increases walking distance in stable intermittent claudication. Angiology, 1993, 44(11): 863-867.
41.	Herrmann WM, Schärer E. The long-term tolerability of bencyclane ('Fludilat') in patients with peripheral occlusive disease: a 48-week prospective double-blind controlled study versus placebo. Curr Med Res Opin, 1991, 12(6): 356-365.
42.	Norgren L, Jawien A, Mátyás L, et al. Sarpogrelate, a 5-hT2A receptor antagonist in intermittent claudication. A phase II European study. Vasc Med, 2006, 11(2): 75-83.
43.	Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med, 2000, 109(7): 523-530.
44.	甄秉言, 续平, 徐嘉林, 等. 丹参葛根胶囊辅助治疗外周血管病伴间歇性跛行—一项随机双盲安慰剂对照的临床试验. 岭南心血管病杂志, 2018, 24(6): 701-704.
45.	Aronow WS, Nayak D, Woodworth S, et al. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am J Cardiol, 2003, 92(6): 711-712.
46.	Macha S, Lang B, Pinnetti S, et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther, 2014, 52(11): 973-980.
47.	周毅新. 辛伐他汀的药代动力学特征及不良反应分析. 中国合理用药探索, 2018, 15(10): 26-28.
48.	Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg, 2008, 47(2): 330-336.

1. Hamburg NM, Creager MA. Pathophysiology of intermittent claudication in peripheral artery disease. Circ J, 2017, 81(3): 281-289.
2. Campia U, Gerhard-Herman M, Piazza G, et al. Peripheral artery disease: past, present, and future. Am J Med, 2019, 132(10): 1133-1141.
3. Kröger K, Stang A, Kondratieva J, et al. Prevalence of peripheral arterial disease - results of the Heinz Nixdorf recall study. Eur J Epidemiol, 2006, 21(4): 279-285.
4. Bolton L. Peripheral arterial disease: scoping review of patient-centred outcomes. Int Wound J, 2019, 16(6): 1521-1532.
5. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 815S-843S.
6. Halliday A, Bax JJ. The 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg, 2018, 55(3): 301-302.
7. 中华医学会外科学分会血管外科学组. 下肢动脉硬化闭塞症诊治指南. 中华普通外科学文献(电子版), 2016, 10(1): 1-18.
8. 李伦, 田金徽, 姚亮, 等. 网状Meta分析的统计学基础, 假设和证据质量评估. 循证医学, 2015, 15(3): 180-183.
9. 易跃雄, 张蔚, 刘小媛, 等. 网状Meta分析图形结果解读. 中国循证医学杂志, 2015, 15(1): 103-109.
10. Robertson AJ, Struthers AD. A randomized controlled trial of allopurinol in patients with peripheral arterial disease. Can J Cardiol, 2016, 32(2): 190-196.
11. Chu YS, Li DX, Zhang M, et al. Trimetazidine hydrochloride as a new treatment for patients with peripheral vascular disease-an exploratory trial. Eur Rev Med Pharmacol Sci, 2016, 20(1): 188-193.
12. Shahin Y, Cockcroft JR, Chetter IC. Randomized clinical trial of angiotensin-converting enzyme inhibitor, ramipril, in patients with intermittent claudication. Br J Surg, 2013, 100(9): 1154-1163.
13. Goldenberg NA, Krantz MJ, Hiatt WR. L-Carnitine plus cilostazol versus cilostazol alone for the treatment of claudication in patients with peripheral artery disease: a multicenter, randomized, double-blind, placebo-controlled trial. Vasc Med, 2012, 17(3): 145-154.
14. Hiatt WR, Creager MA, Amato A, et al. Effect of propionyl-L-carnitine on a background of monitored exercise in patients with claudication secondary to peripheral artery disease. J Cardiopulm Rehabil Prev, 2011, 31(2): 125-132.
15. Vitale C, Marazzi G, Pelliccia F, et al. Trimetazidine improves exercise performance in patients with peripheral arterial disease. Pharmacol Res, 2011, 63(4): 278-283.
16. Zankl AR, Ivandic B, Andrassy M, et al. Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease. Clin Res Cardiol, 2010, 99(12): 787-794.
17. Bregar U, Poredos P, Sabovic M, et al. The influence of atorvastatin on walking performance in peripheral arterial disease. Vasa, 2009, 38(2): 155-159.
18. O'Donnell ME, Badger SA, Sharif MA, et al. The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. J Vasc Surg, 2009, 49(5): 1226-1234.
19. Jaff MR, Dale RA, Creager MA, et al. Anti-chlamydial antibiotic therapy for symptom improvement in peripheral artery disease: prospective evaluation of rifalazil effect on vascular symptoms of intermittent claudication and other endpoints in Chlamydia pneumoniae seropositive patients (PROVIDENCE-1). Circulation, 2009, 119(3): 452-458.
20. Creager MA, Pande RL, Hiatt WR. A randomized trial of iloprost in patients with intermittent claudication. Vasc Med, 2008, 13(1): 5-13.
21. Gardner CD, Taylor-Piliae RE, Kiazand A, et al. Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. J Cardiopulm Rehabil Prev, 2008, 28(4): 258-265.
22. Brass EP, Anthony R, Cobb FR, et al. The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease. J Am Coll Cardiol, 2006, 48(12): 2539-2545.
23. Oka RK, Szuba A, Giacomini JC, et al. A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease. Vasc Med, 2005, 10(4): 265-274.
24. Hiatt WR, Hirsch AT, Cooke JP, et al. Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy. Vasc Med, 2004, 9(1): 18-25.
25. Hiatt WR, Klepack E, Nehler M, et al. The effect of inhibition of acyl coenzyme A-cholesterol acyltransferase (ACAT) on exercise performance in patients with peripheral arterial disease. Vasc Med, 2004, 9(4): 271-277.
26. Mohler ER 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation, 2003, 108(12): 1481-1486.
27. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med, 2003, 114(5): 359-364.
28. Mohler ER 3rd, Hiatt WR, Olin JW, et al. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. J Am Coll Cardiol, 2003, 41(10): 1679-1686.
29. Coccheri S, Scondotto G, Agnelli G, et al. Sulodexide in the treatment of intermittent claudication. Results of a randomized, double-blind, multicentre, placebo-controlled study. Eur Heart J, 2002, 23(13): 1057-1065.
30. Strandness DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg, 2002, 36(2): 83-91.
31. Lee TM, Su SF, Hwang JJ, et al. Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. Atherosclerosis, 2001, 158(2): 471-476.
32. Hiatt WR, Regensteiner JG, Creager MA, et al. Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Am J Med, 2001, 110(8): 616-622.
33. Gresele P, Migliacci R, Di Sante G, et al. Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life. CRAMPS Investigator Group. Cloricromene Randomized Arteriopathy Multicenter Prospective Study. Vasc Med, 2000, 5(2): 83-89.
34. Lièvre M, Morand S, Besse B, et al. Oral Beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial. Beraprost et Claudication Intermittente (BERCI) Research Group. Circulation, 2000, 102(4): 426-431.
35. Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol, 1999, 34(5): 1618-1624.
36. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med, 1999, 159(17): 2041-2050.
37. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg, 1998, 27(2): 267-274.
38. Brevetti G, Perna S, Sabba C, et al. Effect of propionyl-L-carnitine on quality of life in intermittent claudication. Am J Cardiol, 1997, 79(6): 777-780.
39. Lievre M, Azoulay S, Lion L, et al. A dose-effect study of beraprost sodium in intermittent claudication. J Cardiovasc Pharmacol, 1996, 27(6): 788-793.
40. Drabaek H, Mehlsen J, Himmelstrup H, et al. A botanical compound, Padma 28, increases walking distance in stable intermittent claudication. Angiology, 1993, 44(11): 863-867.
41. Herrmann WM, Schärer E. The long-term tolerability of bencyclane ('Fludilat') in patients with peripheral occlusive disease: a 48-week prospective double-blind controlled study versus placebo. Curr Med Res Opin, 1991, 12(6): 356-365.
42. Norgren L, Jawien A, Mátyás L, et al. Sarpogrelate, a 5-hT2A receptor antagonist in intermittent claudication. A phase II European study. Vasc Med, 2006, 11(2): 75-83.
43. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med, 2000, 109(7): 523-530.
44. 甄秉言, 续平, 徐嘉林, 等. 丹参葛根胶囊辅助治疗外周血管病伴间歇性跛行—一项随机双盲安慰剂对照的临床试验. 岭南心血管病杂志, 2018, 24(6): 701-704.
45. Aronow WS, Nayak D, Woodworth S, et al. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am J Cardiol, 2003, 92(6): 711-712.
46. Macha S, Lang B, Pinnetti S, et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther, 2014, 52(11): 973-980.
47. 周毅新. 辛伐他汀的药代动力学特征及不良反应分析. 中国合理用药探索, 2018, 15(10): 26-28.
48. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg, 2008, 47(2): 330-336.

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Efficacy and safety of different drugs for the treatment of intermittent claudication due to peripheral arterial disease: a network meta-analysis

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