The Challenges of Healing Arterial Ulcers

Dear Readers,

Peripheral arterial disease (PAD), defined as ankle-brachial index (ABI) < 0.9, affects 29% of people over 70 years or 50 to 69 years for smokers or those with diabetes.¹ It often begins with symptoms of lower limb pain while walking (ie, claudication) and may remain underdiagnosed with limited or sporadic treatment until the patient experiences critical limb ischemia (CLI), defined as rest pain, tissue loss, or gangrene, typically with an ABI < 5.0.² One in 4 patients with CLI dies during the first year following diagnosis.² Treatment options are often limited for patients with PAD. Traditionally, those with PAD and a leg or foot ulcer receive endoscopic or open revascularization to restore arterial circulation,³ rendering the occluded vessel(s) patent for up to 70% of revascularized vessels for at least 5 years and salvaging 80% of revascularized limbs.⁴ Ongoing research will help determine what revascularization procedure(s) are appropriate for which patients and how to optimize their outcomes,⁵ as revascularization is not appropriate for all patients. For patients with a salvageable limb who were not candidates for revascularization,  recent research showed aggressive conservative wound care healed 52% of full-thickness ulcers within 1 year if the ABI was < 0.7 in the affected limb⁶ or healed 67% of nonhealing ulcers in a mean of 4.7 months in patients with no pedal pulse if the affected limb ABI was < 0.9 and periulcer transcutaneous partial pressure of oxygen was > 30 mm Hg.³ However, 43% recurred in a mean of 10.7 months.⁷ Major amputations, more likely for those with an ABI < 0.5, have a grim prognosis. Among the elderly, 94% of major amputations are associated with PAD, with a 47% mortality within 2 years after amputation.⁸ Those with PAD requiring conservative management of their ulcers need better options to improve their chronic ulcer outcomes. This Evidence Corner explores recent reviews of topical vascular growth factors⁹ and electrical spinal cord stimulation¹⁰ aimed at improving chronic ulcer healing outcomes for patients with PAD before major amputation limits their options.

Reference: Gorenoi V, Brehm MU, Koch A, Hagen A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst Rev. 2017;6:CD011741. doi: 10.1002/14651858.CD011741.pub2.

Rationale: Growth factors, delivered directly or indirectly as viral vectors or the DNA plasmids encoding these proteins, have potential to stimulate angiogenesis, suggesting that they may have promise in treating patients with peripheral arterial disease (PAD).

Objective: The authors conducted a systematic review and meta-analysis of published literature exploring the efficacy of growth factors that promote angiogenesis in treating patients with PAD.

Methods: A Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register through June 9, 2016, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) comparing effects of angiogenic growth factors to nongrowth factor interventions on people with clinically confirmed PAD. Primary outcomes were limb amputation, death, or severe complications, such as stroke, myocardial infarction, or neoplasias. Secondary outcomes were walking ability measured as peak walking time or distance, or time or distance to onset of claudication; hemodynamic measures of ankle-brachial index (ABI) or toe-brachial index (TBI); ulcer surface area reduction or complete healing; or improvement in rest pain as measured on a visual analogue scale (VAS). Two independent reviewers assessed the study inclusion characteristics and potential for bias, resolving disagreements by consensus. Results were tabulated and appropriate statistical odds ratios or relative risk of differences were tested using fixed-effects or random effects meta-analyses with statistical significance set at P = .05.

Results: Of 87 relevant reports, 20 RCTs qualified for inclusion. Six of these were not yet published, so only 14 RCTs on 1400 patients with PAD were analyzed for growth factor effects on outcomes. These included 6 RCTs on fibroblast growth factors (FGFs), 4 RCTs on hepatocyte growth factors (HGFs), and 4 RCTs on vascular endothelial growth factors (VEGFs). Each RCT compared a growth factor with a placebo or no therapy. Low-quality evidence supported a decreased rate of limb amputations (P = .049; 6 studies, N = 415). The TBI improved for up to 6 months in patients treated with growth factors (low-quality evidence: P = .0006; 1 HGF RCT on 21 subjects). Healing effects were supported by very low-quality evidence; during 1 year, more ulcers healed completely (P = .046; 3 HGF RCTs on 62 subjects) and reduced in area (P = .0037 for 2 HGF RCTs on 41 patients; P = .00067 for 1 VEGF RCT on 38 patients) in the growth factor groups. Rest pain, measured on a 10-cm VAS, improved for up to 1 year as supported by very low-quality evidence on subjects mainly treated with FGF (P = .0012 for 2 RCTs on 118 subjects). Growth factors generally increased adverse events reported after 1 or 2 years, but results were too heterogeneous for differences to be consistent. No relevant differential effects were reported that compared the 3 growth factors. 

Authors’ Conclusions: Using growth factors on patients with PAD may improve hemodynamic measures and decrease the rate of any limb amputations (likely due to preventing minor amputations), with very uncertain likelihood of improvements on ulcer healing and rest pain and an uncertain increase on adverse events. However, no significant growth factor effects were found on major amputations, death, or walking ability. Further research is needed to confirm these effects and test the effects of other growth factors on these outcomes.

Reference: Ubbink DT, Vermeulen H. Spinal cord stimulation for non-reconstructible chronic critical leg ischaemia. Cochrane Database Syst Rev. 2013;(2):CD004001. doi: 10.1002/14651858.CD004001.pub3.

Rationale: Those with nonreconstructible CLI (NR-CLI) face amputation of the leg. Spinal cord stimulation (SCS) has been proposed as an adjunct to standard conservative care to improve their outcomes.

Objective: A systematic review of the literature explored evidence of improved limb salvage, pain relief, or clinical outcomes of SCS for patients with NR-CLI.

Methods: The Cochrane Vascular Specialized Register was searched through January 2013 and the Cochrane Central Register of Controlled Trials was searched through December 2012 by the Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator for controlled clinical studies (CCTs) or RCTs comparing the effects of conservative treatment of patients with NR-CLI to the same treatment with adjunctive SCS. Atherosclerotic patients were enrolled as having NR-CLI if the attending physician saw no surgical options for their CLI (eg, when no suitable vein or artery was found for distal bypass or when the patient’s condition precluded surgery). Those with intermittent claudication or less critical conditions not requiring surgery were excluded. The primary outcome was limb salvage. Secondary outcomes were wound healing, pain relief, quality of life, and SCS complications or costs. Both authors independently assessed study quality and extracted data using structured Cochrane procedures. Meta-analyses determined the odds ratio or relative risk of measured outcomes using fixed effects models to analyze homogeneous data or random effects models to analyze heterogeneous data, with statistical significance set at P <.05.

Results: Six studies on 443 patients with NR-CLI qualified for analysis. Although blinding was not possible, study quality was generally good. Though individual studies were each too small to do so, meta-analysis of all 6 combined supported the conclusion that adding SCS to standardized conservative care for up to 1 year significantly reduced the risk of a major amputation (P = .0016). More patients clinically improved from CLI to claudication (Fontaine Stage II) in the SCS group compared with controls (2 studies on 124 patients; P < .00001). The SCS increased the likelihood of healing in hypertensive (P < .00001 on 1 study, n = 44) or nonhypertensive patients with NR-CLI (P =.002 on 1 study, n = 28). In response to SCS, transcutaneous partial pressure of oxygen (TcPO₂) improved but ABI did not. Both SCS and control patients experienced less pain on study, an effect that was accentuated in SCS groups, who also took fewer analgesics than the controls. During 12 months, there were more complications, mainly implantation problems or reintervention to change the SCS level in patients receiving SCS (P = .002), but not more infectious complications. 

Authors’ Conclusions: Evidence favors SCS over standard conservative treatment alone to improve limb salvage and clinical outcomes in NR-CLI patients. These benefits must be weighed against the complications and costs of SCS.

Considering the serious consequences of PAD as a precursor of major amputation and mortality, there is surprisingly little effort to identify and address it earlier in the course of its natural history.⁶ Valid, reliable ABI or TcPO₂ measures^1,2 might be used to alert and empower patients to prevent PAD’s progression using interventions such as smoking cessation; improved hypertension, blood lipids, or nutrition; or professionally monitored progressive exercise. The evidence of growth factor effects on improved hemodynamics, pain, and healing and reduced minor amputations in patients with PAD⁹ suggests the merit of more rigorous research exploring growth factor dose effects or identifying which patients with PAD may be responsive to which forms of therapy. To limit major amputations, prostanoids have shown promise in patients with PAD.¹¹ For those whose PAD has progressed to NR-CLI, SCS offers a ray of hope for preventing major amputations,¹⁰ though costs and adverse event issues require careful consideration for each patient. The observation that SCS increased TcPO₂ but not ABI suggests the clinical effects of SCS on NR-CLI patients may be mediated by improved microcirculation.¹⁰ These findings highlight the value of early, patient-appropriate, aggressive multidisciplinary management of lower limb ischemia^3,6 and point to potentially useful adjuncts to management that may limit major amputations. They also raise the question of whether such adjunctive interventions may help improve postoperative revascularization outcomes. 

This article was not subject to the WOUNDS peer-review process.