Evidence Corner: A Prostacyclin Vasodilator Provides No Benefit for Arterial Ulcers

Dear Readers:   Peripheral arterial disease (PAD) or its consequence, critical limb ischemia (CLI), may affect 10% - 20% of men older than 60 years of age, or up to 50% of individuals with diabetic foot ulcers (DFU), and is an independent risk factor for amputation. Related arterial ulcers challenge patients and wound care professionals; limit patients’ walking and adherence to prescribed exercise regimens; and affect quality of life and clinical outcomes. The treatment of choice for healing arterial ulcers involves identifying the occluded artery and surgical revascularization to restore perfusion to each ulcerated extremity.¹   A meta-analysis of 49 studies, 3 of which were controlled, reported more than 60% of arterial ulcers healed during the first year postoperatively after using either open surgery or endovascular surgery. No prospective randomized controlled trial (RCT) evidence supported using either option compared to the other.¹ One RCT reported percutaneous transluminal balloon angioplasty healed 80% of 33 arterial ulcers during 12 months postoperatively, compared to 38.5% of 21 similar ulcers treated with primary stenting alone; however, many individuals with CLI cannot tolerate surgery. The two RCTs summarized below explore effects of nonsurgical medical1 or stem cell interventions on outcomes for individuals with PAD who are not surgical candidates. Laura Bolton, PhD, FAPWCA Adjunct Associate Professor Department of Surgery, UMDNJ WOUNDS Editorial Advisory Board Member and Department Editor

A Prostacyclin Vasodilator Provides No Benefit for Arterial Ulcers

  Reference: Belch JJ, Ray S, Rajput-Ray M, et al. The Scottish-Finnish-Swedish PARTNER study of taprostene versus placebo treatment in patients with critical limb ischemia. Int Angiol. 2011;30(2):150-155.   Rationale: Prior studies of antiplatelet prostaglandin vasodilator effects in alleviating ischemic complications such as rest pain, ulceration, amputation, and gangrene in CLI patients have had insufficient follow-up duration to evaluate effects on amputation.   Objective: Conduct a double-blind placebo-controlled RCT to determine whether taprostene sodium, a vasodilatory prostaglandin analogue (PG12), is a safe and effective treatment to mitigate CLI complications.   Methods: Centers in Scottland, Finland, and Sweden conducted a RCT comparing 4-week pain relief and ulcer healing and 6-month amputation incidence. Subjects were randomized in a 2:1 ratio to receive 4 weeks of 2-hour infusions twice daily with either taprostene sodium (n = 74) or placebo (n = 37). A positive 4-week response was a decrease of more than 30% in ulcer size in subjects with an ischemic ulcer, or complete rest pain relief without added anesthesia requirement for those without a DFU. A decrease in amputation incidence within 6 months after the last infusion treatment was the long-term positive response. Statistical type 1 error was set at a = 0.05.   Results: No statistically significant differences between groups were observed in any outcome measured. During 6 months after the last infusion, 43% of subjects in the taprostene group and 38% of subjects in the control group were amputation-free.   Author’s Conclusions: Despite adequate enrollment, taprostene sodium did not significantly affect the outcomes measured. This may have resulted from increased levels of risk factors for PAD in the active group, including diabetes mellitus, cigarette smoking, hypertension, and a higher proportion of less-responsive female subjects.

  Reference: Walter DH, Krankenberg H, Balzer JO, et al; and PROVASA Investigators. Intra-arterial 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.   Rationale: There is currently no effective pharmacologic intervention for CLI due to PAD. Intra-arterial injection of autologous bone marrow-derived mononuclear cells (BM-MNC) may be a promising therapeutic option for PAD management, but double-blind, randomized trials are needed to test efficacy of this intervention.   Objective: Conduct a phase II prospective double-blind randomized-start controlled trial to explore safety and efficacy of BM-MNC in patients with CLI.   Methods: In a multi-center trial, patients with CLI were randomly assigned to receive either a heterogeneous mix of mesenchymal, hematopoietic, and other BM-MNC with viability confirmed using trypan blue (n = 19 ) or placebo (n= 21 ) intra-arterial injections. All subjects received at least 5000 units of heparin after arterial puncture, and before approximately 150 x 106 cells were manually injected via intra-arterial catheter into the superficial or deep femoral artery, as appropriate to address the patient’s arterial blockage. Twenty patients with fast run-off also received balloon occlusion of the superficial femoral artery during the 5-minute injection. Cell injections were delivered once on enrollment (double-blind randomized-start), followed by a 3-month observation period after which all 33 remaining subjects received active BM-MNC injections (open-label period). Subjects with ulcers and delayed healing continuing for 3 more months received 1 more injection of BM-MNC.   Results: Groups randomized to BM-MNC and placebos were initially comparable on all reported risk factors and ulcer parameters. No cell-related adverse effects were observed in subjects receiving intra-arterial BM-MNC, which was associated with increased arterial ulcer healing and reduced rest pain 3 months after the first treatment. The only independent predictors of improved ulcer healing and reduced rest pain were repeated BM-MNC administration and higher BM-MNC numbers. No significant effects on ankle-to-brachial index (ABI), limb salvage, or amputation-free survival rates were observed, though ulcer healing induced by BM-MNC was strongly correlated with limb salvage (P Author’s Conclusions: Intraarterial injection of BM-MNC does not alter ABI, but accelerates ulcer healing and pain reduction in patients with stable ulcers or rest pain within 3 months after administration. Critically ill patients with Rutherford scores of 6, suggestive of impending amputation, derive no significant benefit from BM-MNC administration. These results remain to be confirmed in larger RCTs.   Clinical Perspective: Interventions to manage patients with PAD and arterial ulcers who are not candidates for surgery are slowly being explored in RCTs. While not yet compelling, the study by Walter et al⁴ suggests that autologous bone marrow pluripotential stem cells may show promise and merit further research, though it is puzzling that the ABI was not significantly affected. If the peripheral systolic blood pressure did not increase to the BM-MNC injections, then what might the mechanism of action of these cells be in reducing rest pain and ulcer area? The larger, rigorously conducted study by Belch et al1 tells us there is no significant benefit to medically dilating the blood vessels serving zones of CLI, so simply increasing the volume of blood in these regions does not solve the underlying problem.   Still, it is as important to find out that an intervention does not work, as it is to find one that does. This research informs clinical decisions, avoiding wasted time on ineffective interventions for CLI or PAD patients, for whom every day may mean the difference between stable or improving quality of life and deteriorating morbidity or amputation. It is encouraging to see increasing research addressing the needs of individuals with compromised arterial circulation unable to benefit from surgery. Perhaps it is time to explore efficacy of techniques to prevent PAD as well. Though the coaching content may differ, this author wonders if coaching PAD patients effectively in how to increase their symptom-free or ulcer-free days may work as well as it does for individuals with venous insufficiency. Each step toward effective management of PAD is worthwhile. Now all we need is more science to reveal the right steps to take.

References

1. Belch JJ, Ray S, Rajput-Ray M, et al. The Scottish-Finnish-Swedish PARTNER study of taprostene versus placebo treatment in patients with critical limb ischemia. Int Angiol. 2011;30(2):150-155. 2. Hinchliffe RJ, Andros G, Apelqvist J, et al. A systematic review of the effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral arterial disease. Diabetes Metab Res Rev. 2012;28(suppl 1):179-217. 3. Brodmann M, Froehlich H, Dorr A, et al. Percutaneous transluminal angioplasty versus primary stenting in infrapopliteal arteries in critical limb ischemia. Vasa. 2011;40(6):482-490. 4. Walter DH, Krankenberg H, Balzer JO, et al; and 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. 5. Heinen M, Borm G, van der Vleuten C, Evers A, Oostendorp R, van Achterberg T. The Lively Legs self-management programme increased physical activity and reduced wound days in leg ulcer patients: Results from a randomized controlled trial. Int J Nurs Stud. 2012;49(2):151-161.