Critical Limb Ischemia PUBLICATION DATE: Aug 01 2008 Issue: 8
author: Laura Bolton, PhD, FAPWCA
Dear Readers: Critical limb ischemia (CLI), the most severe stage of peripheral arterial disease, affects 250,000 new patients annually in the United States with an estimated 40% requiring amputation within 12 months of a CLI episode, in addition to an annual mortality rate of more than 20%.1,2 Distal bypass surgery prompts healing of lower extremity ulcers associated with CLI if resulting arterial patency supports skin perfusion pressure of at least 35 mmHg.3 Surgical bypass of the occluded arterial segment improves3,4 and extends primary arterial patency, though there is insufficient evidence to support improved amputation rates or mortality compared to most other modalities.4 What options are available to the individual for whom bypass surgery is no longer feasible? This month’s Evidence Corner reviews two studies evaluating efficacy of modalities for treating CLI in patients without further vascular surgery options, as the search for an effective treatment of CLI continues. Critical Limb Ischemia Reference: Kavros SJ, Delis KT, Turner NS, et al. Improving limb salvage in critical ischemia with intermittent pneumatic compression: a controlled study with 18-month follow-up. J Vasc Surg. 2008;47(3):543–549. Rationale: Intermittent pneumatic compression (IPC) is a noninvasive method of increasing arterial circulation and ameliorating intermittent claudication in patients with peripheral arterial disease (PAD). Objective: Evaluate clinical efficacy of IPC in patients with chronic CLI, nonhealing foot ulcers, and minor toe or transmetatarsal amputation after further options for arterial revascularization had been exhausted. Methods: This retrospective cohort study compared two similar groups, each consisting of 24 consecutive patients, for whom further surgical bypass was not an option, and were cared for in a multidisciplinary community clinic from 1998–2004. Resting ankle-to-brachial ratios of systolic blood pressure (ABI), sitting transcutaneous oximetry (TcPO2) duplex graft surveillance, and foot radiography confirmed vascular status. Both groups received weekly debridement and biologic dressings for tissue loss and nonhealing amputation wounds of the foot due to CLI. Intermittent pneumatic compression allocation was based solely on a patient’s willingness to use it. The IPC inflation pressure was 85 mmHg to 95 mmHg and was applied for 2 seconds with a 0.2-second rise, 3 cycles per minute, for three 2-hour daily sessions. Adherence was monitored closely. Healing outcomes were “favorable” if complete healing with limb salvage occurred during 18 months. Outcomes were considered “adverse” if nonhealing caused below-knee amputation during that time. Results: Groups were comparable at baseline on all arterial and wound parameters; prior amputation and comorbid factors were assessed. Four patients (17%) in the control group and 14 IPC (58%) patients healed (P < 0.01). The likelihood of limb loss in the control group was 7 times that of IPC subjects who also increased in TcPO2 (P = 0.0038). Authors’ Conclusions: When used within a protocol of standard wound care, IPC significantly improves clinical healing and below-knee amputation outcomes of patients with inoperable CLI. This research sets the stage for rigorous prospective, multicenter, randomized, controlled trials (RCTs) of IPC to establish its role in healing while clarifying its indications for use. FGF-1 Gene Therapy Decreases Amputation Rates in Patients With CLI Reference: Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther. 2008;16(5):972–978. Rationale: Although controversial, with its long-term effects under scrutiny, angiogenic growth factor therapy has been proposed for treatment of critical limb ischemia in end-stage PAD. Acidic fibroblast growth factor (FGF-1) is a potent mitogen for vascular endothelial cells, inducing blood vessel formation in vitro and in vivo. A plasmid-based gene transfer delivery system for FGF-1, NV1FGF with “Conditional Origin of Replication” (pCOR), reduces the potential for propagation in the host environment while sustaining local FGF-1 production permitting less frequent treatment. Objective: A Phase 2b, double blind, randomized, placebo-controlled clinical trial investigated the efficacy and safety of intramuscular NV1FGF versus placebo in subjects with CLI at high risk of amputation. Methods: A European multicenter trial screened 125 patients with CLI ineligible for revascularization as confirmed by a vascular surgeon. Each patient had at least 1 nonhealing ulcer, a TcPO2 £ 20 mmHg, ankle pressure £ 70 mmHg, and toe pressure £ 50 mmHg. Patients were randomly assigned to receive 8 intramuscular injections of 2.5 mL NV1FGF in a 0.2 mg/mL solution (n = 59) or similar placebo injections (n = 56) on study days 1, 15, 30, and 45. Percent of patients with at least 1 ulcer completely healed at week 26 was the primary outcome. Secondary outcomes TcPO2, ABI, amputation, and death were evaluated at week 52. Results: Among 107 subjects evaluated for healing, 19.4% of NV1FGF-treated and 14.3% of control patients healed during 26 weeks (P = 0.514; not significant). Likelihood of amputation or of major amputation was reduced in the NV1FGF group (P = 0.011), which also experienced improvement in time to death or major amputation. No other secondary outcomes were statistically significant. Adverse events were comparable in both groups, supporting the safety of NV1FGF. Authors’ Conclusions: This was the first double blind, prospective RCT in patients ineligible for bypass surgery. Despite the fact that no improvement in wound healing was seen it showed the potential for NV1FGF to significantly reduce amputation risk, potentially lowering mortality rates in these high-risk patients.
Clinical Perspective Both publications aim to improve the lot of patients with serious vascular impairment, using either biochemical or physical modalities. Plasmid gene transfer of NV1FGF administered once every 2–3 weeks for the first 7.5 weeks of care appears to save limbs, though its effect on ischemic ulcer healing remains uncertain. Other plasmid growth factors either lack healing and amputation effects5 or heal wounds without reducing amputation.6 The capacity to save limbs in high-risk patients for whom surgery is no longer an option is equally compelling for NV1FGF and IPC. Limb salvage plus the healing benefits of properly applied IPC are unprecedented, although it was a small retrospective study and was potentially biased by selection of IPC-willing patients. Larger prospective RCTs on patients with CLI, perhaps comparing IPC with and without NV1FGF, would seem necessary. As a physical modality, IPC may be compatible with gene or biochemical therapy. These studies open potential care options for patients with CLI who are faced with possible amputation.
References: 1. Dormandy J, Heeck L, Vig S. The fate of patients with critical leg ischemia. Semin Vasc Surg. 1999;12(2):142–147. 2. Dormandy J, Mahir M, Ascady G, et al. Fate of the patient with chronic leg ischaemia: A review article. J Cardiovasc Surg. 1989;30(1):50–57. 3. Tsuji Y, Hiroto T, Kitano I, Tahara S, Sugiyama D. Importance of skin perfusion pressure in treatment of critical limb ischemia. WOUNDS. 2008;20(4):95–100. 4. Fowkes F, Leng GC. Bypass surgery for chronic lower limb ischaemia. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002000. 5. Powell RJ, Simons M, Mendelsohn FO, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008;118(1):58–65. 6. 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.