Pharmacology in Peripheral Arterial Disease: What the Interventional Radiologist Needs to Know

Abstract

Peripheral arterial disease (PAD) is a progressive disease with significant morbidity and mortality. Risk factor control, using diet and lifestyle modification, exercise, and pharmacological methods, improves symptoms and reduces associated cardiovascular events in these patients. Antiplatelet agents and anticoagulants may be used to reduce the incidence of acute events related to thrombosis. The armamentarium available for symptom relief and disease modification is discussed. Novel treatments such as therapeutic angiogenesis are in their evolutionary phase with promising preclinical data.

Keywords

peripheral arterial disease - pharmacotherapy - antiplatelet therapy - symptom relief - gene therapy - interventional radiology

• References

• 1 Diehm C, Allenberg JR, Pittrow D , et al; German Epidemiological Trial on Ankle Brachial Index Study Group. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120 (21) 2053-2061
• 2 National Institute for Health and Care Excellence. Lower limb peripheral arterial disease: diagnosis and management (CG147) London: National Institute for Health and Care Excellence; 2012. Available at: https://www.nice.org.uk/guidance/cg147 . Accessed June 30, 2014
• 3 Tendera M, Aboyans V, Bartelink ML , et al; European Stroke Organisation; ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011; 32 (22) 2851-2906
• 4 2011 WRITING GROUP MEMBERS; 2005 WRITING COMMITTEE MEMBERS; ACCF/AHA TASK FORCE MEMBERS. 2011 ACCF/AHA Focused Update of the Guideline for the Management of patients with peripheral artery disease (Updating the 2005 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011; 124 (18) 2020-2045
• 5 Scottish Intercollegiate Guidelines Network. Diagnosis and Management of Peripheral Arterial Disease: A National Clinical Guideline Number 89. Edinburgh: Scottish Intercollegiate Guidelines Network; 2006
• 6 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG ; TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45 (Suppl S): S5-S67
• 7 Lu L, Mackay DF, Pell JP. Meta-analysis of the association between cigarette smoking and peripheral arterial disease. Heart 2014; 100 (5) 414-423
• 8 Katsiki N, Papadopoulou SK, Fachantidou AI, Mikhailidis DP. Smoking and vascular risk: are all forms of smoking harmful to all types of vascular disease?. Public Health 2013; 127 (5) 435-441
• 9 Lu L, Mackay DF, Pell JP. Association between level of exposure to secondhand smoke and peripheral arterial disease: cross-sectional study of 5,686 never smokers. Atherosclerosis 2013; 229 (2) 273-276
• 10 Lu L, Mackay DF, Pell JP. Secondhand smoke exposure and intermittent claudication: a Scotland-wide study of 4231 non-smokers. Heart 2013; 99 (18) 1342-1345
• 11 Willigendael EM, Teijink JA, Bartelink ML, Peters RJ, Büller HR, Prins MH. Smoking and the patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg 2005; 42 (1) 67-74
• 12 Myers K, Hajek P, Hinds C, McRobbie H. Stopping smoking shortly before surgery and postoperative complications: a systematic review and meta-analysis. Arch Intern Med 2011; 171 (11) 983-989
• 13 National Institute for Health and Care Excellence. Smoking cessation services (PH10). London: National Institute for Health and Care Excellence; 2013. . Available at: http://www.nice.org.uk/guidance/ph102013 . Accessed June 30, 2014
• 14 Carson KV, Brinn MP, Robertson TA , et al. Current and emerging pharmacotherapeutic options for smoking cessation. Subst Abus 2013; 7: 85-105
• 15 Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation 2014; 129 (1) 28-41
• 16 Murabito JM, D'Agostino RB, Silbershatz H, Wilson WF. Intermittent claudication. A risk profile from The Framingham Heart Study. Circulation 1997; 96 (1) 44-49
• 17 Feringa HH, Karagiannis SE, van Waning VH , et al. The effect of intensified lipid-lowering therapy on long-term prognosis in patients with peripheral arterial disease. J Vasc Surg 2007; 45 (5) 936-943
• 18 Stalenhoef AF. The benefit of statins in non-cardiac vascular surgery patients. J Vasc Surg 2009; 49 (1) 260-265
• 19 Momsen AH, Jensen MB, Norager CB, Madsen MR, Vestersgaard-Andersen T, Lindholt JS. Drug therapy for improving walking distance in intermittent claudication: a systematic review and meta-analysis of robust randomised controlled studies. Eur J Vasc Endovasc Surg 2009; 38 (4) 463-474
• 20 Westin GG, Armstrong EJ, Bang H , et al. Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival in patients with critical limb ischemia. J Am Coll Cardiol 2014; 63 (7) 682-690
• 21 Schanzer A, Hevelone N, Owens CD, Beckman JA, Belkin M, Conte MS. Statins are independently associated with reduced mortality in patients undergoing infrainguinal bypass graft surgery for critical limb ischemia. J Vasc Surg 2008; 47 (4) 774-781
• 22 O'Neil-Callahan K, Katsimaglis G, Tepper MR , et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: the Statins for Risk Reduction in Surgery (StaRRS) study. J Am Coll Cardiol 2005; 45 (3) 336-342
• 23 Poldermans D, Bax JJ, Kertai MD , et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107 (14) 1848-1851
• 24 Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007; 45 (4) 645-654
• 25 Ardati AK, Kaufman SR, Aronow HD , et al. The quality and impact of risk factor control in patients with stable claudication presenting for peripheral vascular interventions. Circ Cardiovasc Interv 2012; 5 (6) 850-855
• 26 Sharma S, Thapa R, Jeevanantham V , et al. Comparison of lipid management in patients with coronary versus peripheral arterial disease. Am J Cardiol 2014; 113 (8) 1320-1325
• 27 Blum AS. Management of dyslipidemia with statins in the patient with peripheral arterial disease. Tech Vasc Interv Radiol 2006; 9 (2) 50-55
• 28 National Institute for Health and Care Excellence. Lipid Modification Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease (CG 67). London: National Institute for Health and Care Excellence; 2010
• 29 National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events (TA94). London: National Institute for Health and Care Excellence; 2008. Available at: http://www.nice.org.uk/guidance/ta94 . Accessed June 30, 2014
• 30 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 (9326) 7-22
• 31 National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial hypercholesterolaemia (TA132). London: National Institute for Health and Care Excellence; 2007
• 32 Joosten MM, Pai JK, Bertoia ML , et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA 2012; 308 (16) 1660-1667
• 33 Rapsomaniki E, Timmis A, George J , et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014; 383 (9932) 1899-1911
• 34 Adler AI, Stratton IM, Neil HA , et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321 (7258) 412-419
• 35 Williams B, Poulter NR, Brown MJ , et al; British Hypertension Society. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004; 18 (3) 139-185
• 36 National Institute for Health and Clinical Excellence. Hypertension: clinical management of primary hypertension in adults (CG 127). London: National Institute for Health and Care Excellence; 2011. . Available at: http://www.nice.org.uk/guidance/cg127 . Accessed June 30, 2014
• 37 Singer DR, Kite A. Management of hypertension in peripheral arterial disease: does the choice of drugs matter?. Eur J Vasc Endovasc Surg 2008; 35 (6) 701-708
• 38 Lane DA, Lip GY. Treatment of hypertension in peripheral arterial disease. Cochrane Database Syst Rev 2013; 12: CD003075
• 39 Ostergren J, Sleight P, Dagenais G , et al; HOPE study investigators. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J 2004; 25 (1) 17-24
• 40 Shahin Y, Barnes R, Barakat H, Chetter IC. Meta-analysis of angiotensin converting enzyme inhibitors effect on walking ability and ankle brachial pressure index in patients with intermittent claudication. Atherosclerosis 2013; 231 (2) 283-290
• 41 Høgh A, Lindholt JS, Nielsen H, Jensen LP, Johnsen SP. Use of angiotensin-converting enzyme inhibitors and cardiovascular outcomes following primary vascular surgery: a nationwide propensity score matched follow-up study. Vasc Endovascular Surg 2012; 46 (7) 515-523
• 42 Paravastu SC, Mendonca DA, Da Silva A. Beta blockers for peripheral arterial disease. Cochrane Database Syst Rev 2013; 9: CD005508
• 43 American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003; 26 (12) 3333-3341
• 44 Axelrod DA, Upchurch Jr GR, DeMonner S , et al. Perioperative cardiovascular risk stratification of patients with diabetes who undergo elective major vascular surgery. J Vasc Surg 2002; 35 (5) 894-901
• 45 Goodney PP, Nolan BW, Schanzer A , et al; Vascular Study Group Of Northern New England. Factors associated with death 1 year after lower extremity bypass in Northern New England. J Vasc Surg 2010; 51 (1) 71-78
• 46 Abularrage CJ, Conrad MF, Hackney LA , et al. Long-term outcomes of diabetic patients undergoing endovascular infrainguinal interventions. J Vasc Surg 2010; 52 (2) 314-322 , e1–e4
• 47 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352 (9131) 837-853
• 48 Pozzilli P, Strollo R, Bonora E. One size does not fit all glycemic targets for type 2 diabetes. J Diabetes Investig 2014; 5 (2) 134-141
• 49 Fullerton B, Jeitler K, Seitz M, Horvath K, Berghold A, Siebenhofer A. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev 2014; 2: CD009122
• 50 Hemmingsen B, Lund SS, Gluud C , et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; 11: CD008143
• 51 Goergen SK, Rumbold G, Compton G, Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology 2010; 254 (1) 261-269
• 52 The Royal College of Radiologists. Standards for Intravascular Contrast Agent Administration to Adult Patients, Second edition. London: The Royal College of Radiologists; 2010
• 53 Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg 2001; 88 (6) 787-800
• 54 Wong PF, Chong LY, Mikhailidis DP, Robless P, Stansby G. Antiplatelet agents for intermittent claudication. Cochrane Database Syst Rev 2011; (11) CD001272
• 55 Whayne TF. A review of the role of anticoagulation in the treatment of peripheral arterial disease. Int J Angiol 2012; 21 (4) 187-194
• 56 Committee CS ; CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038) 1329-1339
• 57 Saadeh C, Sfeir J. Discontinuation of preoperative clopidogrel is unnecessary in peripheral arterial surgery. J Vasc Surg 2013; 58 (6) 1586-1592
• 58 Greenhalgh J, Bagust A, Boland A , et al. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis. Health Technol Assess 2011; 15 (31) 1-178
• 59 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008; 336 (7637) 195-198
• 60 Laine M, Arméro S, Peyrol M , et al. Clinical impact of genetically determined platelet reactivity. J Cardiovasc Transl Res 2013; 6 (3) 398-403
• 61 Mijajlovic MD, Shulga O, Bloch S, Covickovic-Sternic N, Aleksic V, Bornstein NM. Clinical consequences of aspirin and clopidogrel resistance: an overview. Acta Neurol Scand 2013; 128 (4) 213-219
• 62 Kastrati A. New anti-platelet agents: the end of resistance?. Thromb Res 2012; 130 (Suppl. 01) S53-S55
• 63 Cattaneo M. The role of laboratory monitoring in antiplatelet therapy. Handbook Exp Pharmacol 2012; (210) 471-494
• 64 Janssen PW, ten Berg JM. Platelet function testing and tailored antiplatelet therapy. J Cardiovasc Transl Res 2013; 6 (3) 316-328
• 65 Robertson L, Ghouri MA, Kovacs F. Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment. Cochrane Database Syst Rev 2012; 8: CD002071
• 66 Alonso-Coello P, Bellmunt S, McGorrian C , et al. Antithrombotic therapy in peripheral artery disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2) (Suppl) e669S-690S
• 67 Allemang MT, Rajani RR, Nelson PR, Hingorani A, Kashyap VS. Prescribing patterns of antiplatelet agents are highly variable after lower extremity endovascular procedures. Ann Vasc Surg 2013; 27 (1) 62-67
• 68 Lee CW, Ahn JM, Park DW , et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129 (3) 304-312
• 69 Park SJ, Park DW, Kim YH , et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010; 362 (15) 1374-1382
• 70 Matas M, Domínguez González JM, Montull E. Antiplatelet therapy in endovascular surgery: the RENDOVASC study. Ann Vasc Surg 2013; 27 (2) 168-177
• 71 Barradell LB, Brogden RN. Oral naftidrofuryl. A review of its pharmacology and therapeutic use in the management of peripheral occlusive arterial disease. Drugs Aging 1996; 8 (4) 299-322
• 72 de Backer TL, Vander Stichele R, Lehert P, Van Bortel L. Naftidrofuryl for intermittent claudication. Cochrane Database Syst Rev 2012; 12: CD001368
• 73 Squires H, Simpson E, Meng Y , et al. A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. Health Technol Assess 2011; 15 (40) 1-210
• 74 Meng Y, Squires H, Stevens JW , et al. Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease. Angiology 2014; 65 (3) 190-197
• 75 Stevens JW, Simpson E, Harnan S , et al. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. Br J Surg 2012; 99 (12) 1630-1638
• 76 National institute for Health and Care Excellence. Cilostazol, Naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease (TA223). Available at: http://www.nice.org.uk/guidance/ta223 . Accessed June 30, 2014
• 77 Smith FB, Bradbury A, Fowkes G. Intravenous naftidrofuryl for critical limb ischaemia. Cochrane Database Syst Rev 2012; 7: CD002070
• 78 Pearce L, Ghosh J, Counsell A, Serracino-Inglott F. Cilostazol and peripheral arterial disease. Expert Opin Pharmacother 2008; 9 (15) 2683-2690
• 79 Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane Database Syst Rev 2008; (1) CD003748
• 80 de Franciscis S, Gallelli L, Battaglia L , et al. Cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease. Int Wound J 2013; (e-pub ahead of print). doi:10.1111/iwj.12085
• 81 Iida O, Yokoi H, Soga Y , et al; STOP-IC investigators. Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. Circulation 2013; 127 (23) 2307-2315
• 82 Iida O, Nanto S, Uematsu M, Morozumi T, Kitakaze M, Nagata S. Cilostazol reduces restenosis after endovascular therapy in patients with femoropopliteal lesions. J Vasc Surg 2008; 48 (1) 144-149
• 83 Lee SW, Park SW, Kim YH , et al. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol 2008; 51 (12) 1181-1187
• 84 Soga Y, Yokoi H, Kawasaki T , et al. Efficacy of cilostazol after endovascular therapy for femoropopliteal artery disease in patients with intermittent claudication. J Am Coll Cardiol 2009; 53 (1) 48-53
• 85 Soga Y, Iida O, Kawasaki D, Hirano K, Yamaoka T, Suzuki K. Impact of cilostazol on angiographic restenosis after balloon angioplasty for infrapopliteal artery disease in patients with critical limb ischemia. Eur J Vasc Endovasc Surg 2012; 44 (6) 577-581
• 86 Salhiyyah K, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev 2012; 1: CD005262
• 87 Di Minno MN, Milone M, Russolillo A , et al. Ropivacaine infusion in diabetics subject with peripheral arterial disease. A prospective study. Exp Clin Endocrinol Diabetes 2013; 121 (2) 91-93
• 88 Aurilio C, Pace MC, Passavanti MB , et al. Treatment of ischemic pain in patients suffering from peripheral vasculopathy with transdermal buprenorphine plus epidural morphine with ropivacaine vs. epidural morphine with ropivacaine. Pain Pract 2009; 9 (2) 105-114
• 89 Ubbink DT, Vermeulen H. Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev 2013; 2: CD004001
• 90 McCormick Z, Chang-Chien G, Marshall B, Huang M, Harden RN. Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain Med 2014; 15 (2) 292-305
• 91 Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev 2011; (12) CD006380
• 92 Ypsilantis E, Tang TY. Pre-emptive analgesia for chronic limb pain after amputation for peripheral vascular disease: a systematic review. Ann Vasc Surg 2010; 24 (8) 1139-1146
• 93 Ruffolo AJ, Romano M, Ciapponi A. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev 2010; (1) CD006544
• 94 Matsuo H, Shigematsu H. Patient-based outcomes using the Walking Impairment Questionnaire for patients with peripheral arterial occlusive disease treated with Lipo-PGE1. Circ J 2010; 74 (2) 365-370
• 95 Robertson L, Andras A. Prostanoids for intermittent claudication. Cochrane Database Syst Rev 2013; 4: CD000986
• 96 Hirsch AT, Haskal ZJ, Hertzer NR , et al; American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113 (11) e463-e654
• 97 Grochot-Przeczek A, Dulak J, Jozkowicz A. Therapeutic angiogenesis for revascularization in peripheral artery disease. Gene 2013; 525 (2) 220-228
• 98 Lederman RJ, Mendelsohn FO, Anderson RD , et al; TRAFFIC Investigators. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002; 359 (9323) 2053-2058
• 99 Shimamura M, Nakagami H, Taniyama Y, Morishita R. Gene therapy for peripheral arterial disease. Expert Opin Biol Ther 2014; 14 (8) 1175-1184
• 100 Isner JM, Pieczek A, Schainfeld R , et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996; 348 (9024) 370-374
• 101 Baumgartner I, Pieczek A, Manor O , et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97 (12) 1114-1123
• 102 Kusumanto YH, van Weel V, Mulder NH , et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum Gene Ther 2006; 17 (6) 683-691
• 103 Grossman PM, Mendelsohn F, Henry TD , et al. Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease. Am Heart J 2007; 153 (5) 874-880
• 104 Morishita R, Makino H, Aoki M , et al. Phase I/IIa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia. Arterioscler Thromb Vasc Biol 2011; 31 (3) 713-720
• 105 Mughal NA, Russell DA, Ponnambalam S, Homer-Vanniasinkam S. Gene therapy in the treatment of peripheral arterial disease. Br J Surg 2012; 99 (1) 6-15
• 106 Hammer A, Steiner S. Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials. Vasa 2013; 42 (5) 331-339
• 107 Asahara T, Murohara T, Sullivan A , et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275 (5302) 964-967
• 108 Tateishi-Yuyama E, Matsubara H, Murohara T , et al; Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360 (9331) 427-435
• 109 Iafrati MD, Hallett JW, Geils G , et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg 2011; 54 (6) 1650-1658
• 110 Botham CM, Bennett WL, Cooke JP. Clinical trials of adult stem cell therapy for peripheral artery disease. Methodist Debakey Cardiovasc J 2013; 9 (4) 201-205
• 111 Walter DH, Krankenberg H, Balzer JO , et al; PROVASA Investigators. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv 2011; 4 (1) 26-37
• 112 Moazzami K, Majdzadeh R, Nedjat S. Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev 2011; (12) CD008347