MD Conference Express AHA 2011 - (Page 29)

Figure 2. CLI: A Selective Revascularization Strategy. Cumulative Cost of Hospitalizations for Vascular Reasons per Patient $14,000 $12,000 $10,430 $11,693 USA, discussed genetic and cell-based studies that aim to improve limb perfusion in patients with PAD. In a 2008 study that comprised 104 patients with CLI, Powell and colleagues demonstrated that intramuscular injection of high doses (4.0 mg at Days 0, 14, and 28) of hepatocyte growth factor (HGF) plasmid was safe and led to significant increases in transcutaneous oxygen tension (TcPo2; 24.0±4.2 mm Hg) compared with placebo (9.4± 4.2 mm Hg), low dose (0.4 mg at Days 0, 14, and 28; 11.7± 3.7 mm Hg), and middle dose (4.0 mg at Days 0 and 28; 7.3±4.8 mm Hg) HGF plasmid (ANCOVA p=0.0015) [Powell RJ et al. Circulation 2008]. Recently, the same group showed that this therapy can also improve toe brachial index (0.05±0.05 vs -0.17±0.04 for placebo; p=0.047) and rest pain, as assessed using a 10-cm visual analog scale (VAS; -1.9±1.3 vs +0.06±0.2 for placebo; p=0.04) [Powell R et al. J Vasc Surg 2010]. Early bone marrow studies showed that autologous implantation of bone marrow mononuclear cells in patients with PAD-induced ischemia produced improvements in ankle brachial index, transcutaneous oxygen pressure, rest pain, and pain-free walking time [Tateishi-Yuyama E et al. Lancet 2002]. More recently, Powell and colleagues evaluated patients with CLI and showed that injection of tissue repair cells led to improvements in time to treatment failure, defined as amputation-free survival, increase in wound size, and new gangrene (Figure 3) [Powell et al. J Vasc Surg 2011]. Figure 3. Time to First Occurrence of Treatment Failure (ITT Population- All Patients). 1.0 0.9 0.8 $10,000 $8,000 $6,000 $4,000 $2,000 $0 1Y 2Y 1Y 2Y 1Y 2Y 1Y 2Y $4,199 $4,463 $7,445 $7,000 $6,262 $5,895 Asymptomatic Claudication Revascularization Amputation CLI = Critical limb ischemia; 1 year costs based on patients with available 1 year data (n=2137); Cumulative 2 year costs based on patients with available 2 year data (n=1677). Reproduced with permission from MS Conte, MD Survival Probability A relatively new and evolving approach is endovascular therapy for limb salvage. It offers the potential advantages of being less invasive with faster recoveries; however, data that have evaluated outcomes with this therapy are mixed. Disadvantages include reduced efficacy compared with existing therapy in terms of hemodynamics and durability, risk of limb deterioration, possible effect on surgical options, and increased treatment cost due to the need for repeat treatments. A meta-analysis of studies in infrapopliteal angioplasty compared with bypass surgery for chronic CLI showed limited technical success and durability with angioplasty but comparable limb salvage rates [Romiti M et al. J Vasc Surg 2008]. However, another study [Vogel TR et al. J Vasc Surg 2011] reported higher rates of in-hospital complications, rehospitalization, and amputations with angioplasty. A third study reported slightly lower mortality rates and increased costs with angioplasty treatment [Sachs T et al. J Vasc Surg 2011]. Longitudinal studies are recommended to determine the appropriateness of angioplasty in both claudication and limb-threatened patients. Surgical bypass of peripheral arterial occlusive disease with autologous vein grafts provides an effective means of restoring blood flow to the lower extremity and has been a standard therapy for patients with disabling claudication or CLI. However, failure rates may run as high as 50% within 5 years. Further, prior failed endovascular interventions in patients with CLI predict poor outcomes after lower extremity bypass. Dr. Conti predicts that centers for amputation prevention will focus on high-risk patients and provide coordinated inpatient and outpatient management. They will offer a multidisciplinary team approach, with vascular surgery and podiatry being key players. Treatment options for symptomatic PAD are limited, and while medical therapies may help to modify the underlying disease, there are no approved medical (nonrevascularization) therapies to increase blood flow to the ischemic limb. Brian Annex, MD, University of Virginia, Charlottesville, Virginia, 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 Log rank p=0.0053 TRC Control 100 200 Days After Injection Event 79% (11) 41% (13) Censored 21% (3) 59% (19) 300 400 No. of Subjects Control 14 Tissue Repair 32 Cells Median Survival (95% CI) 60 (16.0 to 224.0) NA (164.0 to NA) Reprinted from the Journal of Vascular Surgery, Vol. 54, Issue 4, Pages 1032-1041, Powell RJ et al, Interim analysis results from the RESTORE-CLI, a randomized, double-blind, multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia, Copyright 2011, with permission from Elsevier. A recent CLI study used autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells [Perin EC et al. Cath Card Int 2011] and another recently completed clinical trial evaluated the use of autologous CD34+ cells for CLI [NCT00616980]. While these early studies show promise for the development of noninterventional therapies to improve limb perfusion, further studies are required to determine whether they are useful in current clinical care. 29 Peer-Reviewed Highlights from the American Heart Association Scientific Sessions 2011 http://www.mdconferencexpress.com

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