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Meta-Analysis
. 2017 Jun 8;6(6):CD011741.
doi: 10.1002/14651858.CD011741.pub2.

Growth factors for angiogenesis in peripheral arterial disease

Vitali Gorenoi  1 , Michael U Brehm, Armin Koch, Anja Hagen
Affiliations
Meta-Analysis

Growth factors for angiogenesis in peripheral arterial disease

Vitali Gorenoi et al. Cochrane Database Syst Rev. .

Abstract

Background: Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD.

Objectives: To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities.

Search methods: The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies.

Selection criteria: We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain.

Data collection and analysis: Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta-analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome.

Main results: We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF).

Authors' conclusions: The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty.

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Conflict of interest statement

VG: institution received funding from the German Federal Ministry of Education and Research (research grant 01KG1411) to conduct the review. MB: institution received funding from the German Federal Ministry of Education and Research (research grant 01KG1411) to conduct the review. AK: institution received funding from the German Federal Ministry of Education and Research (research grant 01KG1411) to conduct the review. AH: institution received funding from the German Federal Ministry of Education and Research (research grant 01KG1411) to conduct the review.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 1 Limb amputation (major or not specified; at 1 year).
1.2
1.2. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 2 Limb amputation (major or not specified; last data to 2 years).
1.3
1.3. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 3 Limb amputation (any or not specified; at 1 year).
1.4
1.4. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 4 Limb amputation (any or not specified; last data to 2 years).
1.5
1.5. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 5 Death (of any cause; at 1 year).
1.6
1.6. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 6 Death (from any cause; last data to 2 years).
1.7
1.7. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 7 Adverse events (serious; only aggregate data, up to 2 years).
1.8
1.8. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 8 Adverse events (serious; incl. data for single events, up to 2 years).
1.9
1.9. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 9 Adverse events (any; only aggregated data, up to 2 years).
1.10
1.10. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 10 Adverse events (any; incl. data for single events, up to 2 years).
1.11
1.11. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 11 Walking ability (change in peak walking time [min]; last data to 6 months).
1.12
1.12. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 12 Walking ability (change in claudication onset time [min]; last data to 6 months).
1.13
1.13. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 13 Haemodynamic measures (change in ABI; last data to 6 months).
1.14
1.14. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 14 Haemodynamic measures (change in TBI; last data to 6 months).
1.15
1.15. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 15 Ulceration (complete ulcer healing; last data to 1 year).
1.16
1.16. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 16 Ulceration (improvement in ulcer size; last data to 1 year).
1.17
1.17. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 17 Rest pain (change on 10 cm VAS; last data to1 year).
1.18
1.18. Analysis
Comparison 1 Growth factors versus placebo (or no therapy), Outcome 18 Rest pain (improvement; last data to 1 year).
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    1. Olson E, Demopoulos L, Haws TF, Hu E, Fang Z, Mahar KM, et al. Short‐term treatment with a novel HIF‐prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication‐limited peripheral artery disease. Vascular Medicine (London) 2014;19(6):473‐82. - PubMed
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Perin 2011 {published data only}
    1. Perin ECS. A randomized, controlled study of autologous therapy with bone marrow‐derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia. Catheterization and Cardiovascular Interventions 2011; Vol. 78, issue 7:1060‐7. [CRS: 8600101000001591] - PubMed
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Senet 2011 {published data only}
    1. Senet P, Vicaut E, Beneton N, Debure C, Lok C, Chosidow O. Topical treatment of hypertensive leg ulcers with platelet‐derived growth factor‐BB: a randomized controlled trial. Archives of Dermatology 2011;147(8):926‐30. - PubMed
Skora 2015 {published data only}
    1. Skora J, Pupka A, Janczak D, Barc P, Dawiskiba T, Korta K, et al. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia. Archives of Medical Science 2015;11(2):325‐31. - PMC - PubMed
Subramaniyam 2009 {published data only}
    1. Subramaniyam V, Waller EK, Murrow JR, Manatunga A, Lonial S, Kasirajan K, et al. Bone marrow mobilization with granulocyte macrophage colony‐stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease. American Heart Journal 2009; Vol. 158, issue 1:53. [CRS: 8600101000003485] - PubMed
Tateishi‐Yuyama 2002 {published data only}
    1. Tateishi‐Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone‐marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; Vol. 360, issue 9331:427. [CRS: 8600100000005197] - PubMed
Van Royen 2005 {published data only}
    1. Royen N, Piek JJ, Legemate DA, Schaper W, Oskam J, Atasever B, et al. Design of the START‐trial: STimulation of ARTeriogenesis using subcutaneous application of GM‐CSF as a new treatment for peripheral vascular disease. A randomized, double‐blind, placebo‐controlled trial. Vascular Medicine 2003;8(3):191‐6. [CRS: 8600100000005615] - PubMed
    1. Royen N, Schirmer SH, Atasever B, Behrens CYH, Ubbink D, Buschmann EE, et al. A pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte‐macrophage colony‐stimulating factor as a new treatment for peripheral vascular disease. Circulation 2005; Vol. 112, issue 7:1040‐6. [CRS: 8600100000006572] - PubMed
Wang 2014 {published data only}
    1. Wang X, Jiang L, Wang X, Yin F, Li G, Feng X, et al. Combination of autologous transplantation of G‐CSF‐mobilized peripheral blood mononuclear cells and panax notoginseng saponins in the treatment of unreconstructable critical limb ischemia. Annals of Vascular Surgery 2014;28(6):1501‐12. - PubMed
Wen 2010 {published data only}
    1. Wen J. Autologous peripheral blood mononuclear cells transplantation in treatment of 30 cases of critical limb ischemia: 3‐year safety follow‐up. Journal of Clinical Rehabilitative Tissue Engineering Research 2010; Vol. 14, issue 45:8526‐30. [CENTRAL: 831687; CRS: 8600101000001544]
Yonemitsu 2013 {published data only}
    1. Yonemitsu Y, Matsumoto T, Itoh H, Okazaki J, Uchiyama M, Yoshida K, et al. DVC1‐0101 to treat peripheral arterial disease: a phase I/IIa open‐label dose‐escalation clinical trial. Molecular Therapy 2013;21(3):707‐14. - PMC - PubMed
Zafarghandi 2010 {published data only}
    1. Zafarghandi MRR, Fazel AP, Baharvand H. Safety and efficacy of granulocytecolony‐stimulating factor administration following autologous intramuscular implantation of bone marrow mononuclear cells: a randomized controlled trial in patients with advanced lower limb ischemia. Cytotherapy 2010;12(6):783‐91. [CENTRAL: 781692; CRS: 8600101000001383] - PubMed

References to ongoing studies

AGILITY {published data only}
    1. AnGes MG Inc. AnGes announces amendment to the global development of HGF Plasmid for critical limb ischemia. 2016. www.anges‐mg.com/en/news (accessed 27 June 2016).
    1. AnGes MG Inc. AnGes to start global phase III clinical trials of HGF gene therapy for critical limb ischemia in Europe. 2014. www.anges‐mg.com/en/news (accessed 4 September 2015).
    1. NCT02144610. Efficacy and safety of AMG0001 in subjects with critical limb ischemia (AGILITY). clinicaltrials.gov/ct2/show/NCT02144610?term=NCT02144610&rank=1 (first received 20 May 2014).
NCT00424866 {published data only}
    1. NCT00424866. FGF‐1 for intramuscular injection for the treatment of peripheral arterial disease. clinicaltrials.gov/ct2/show/NCT00424866?term=NCT00424866&rank=1 (first received 18 January 2007).
NCT02276937 {published data only}
    1. NCT02276937. Randomized Phase IIb Trial of DVC1‐0101. clinicaltrials.gov/ct2/show/NCT02276937?term=NCT02276937&rank=1 (first received 22 October 2014).

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References to other published versions of this review

Gorenoi 2015
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