Medical Therapy in Peripheral Artery Disease
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.111.033886
ISSN1524-4539
AutoresJeffrey S. Berger, William R. Hiatt,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeCirculationVol. 126, No. 4Medical Therapy in Peripheral Artery Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMedical Therapy in Peripheral Artery Disease Jeffrey S. Berger, MD, MS, FAHA and William R. Hiatt, MD, FAHA Jeffrey S. BergerJeffrey S. Berger From the Divisions of Cardiology and Vascular Surgery, New York University School of Medicine, New York, NY (J.S.B.); University of Colorado School of Medicine, Division of Cardiology, and CPC Clinical Research, Aurora, CO (W.R.H.). and William R. HiattWilliam R. Hiatt From the Divisions of Cardiology and Vascular Surgery, New York University School of Medicine, New York, NY (J.S.B.); University of Colorado School of Medicine, Division of Cardiology, and CPC Clinical Research, Aurora, CO (W.R.H.). Originally published24 Jul 2012https://doi.org/10.1161/CIRCULATIONAHA.111.033886Circulation. 2012;126:491–500IntroductionThe epidemiology of peripheral artery disease (PAD) is well described and related to age and, in particular, the risk factors of diabetes mellitus and smoking. Recent data from the National Health and Nutrition Examination Survey found a 5.9% prevalence in subjects ≥40 years of age resulting in an estimated prevalence of 7.2 million affected individuals in the United States.1 These subjects have a significant increased risk of all-cause mortality because of the underlying atherosclerotic disease process and general undertreatment of PAD risk factors.2There is a wide spectrum of clinical manifestations for PAD: (1) the completely asymptomatic patient found to have PAD from a screening ankle-brachial index (ABI), (2) atypical leg symptoms associated with an exercise limitation, (3) classic intermittent claudication, and (4) ischemic pain and ulceration in the lower extremity from chronic limb ischemia. However, despite the level and degree of limb symptoms, even asymptomatic persons with PAD have a greatly reduced functional capacity. This suggests that occlusive disease in the lower extremity is associated with reduced exercise capacity and functional status regardless of the symptomatic state.As noted above, symptomatic and asymptomatic PAD is associated with an increased risk for morbidity and mortality, and for impairment of quality of life, as well. A prospective cohort in subjects >65 years of age found a similar high ischemic risk in symptomatic and asymptomatic adults with PAD.3 Pooled data from 11 studies in 6 countries found that PAD, defined by a an ABI of 100%.18 In 2008, a rigorous systematic review by the Cochrane group19 involving 1200 participants from 22 randomized trials with stable claudication demonstrated a significant benefit in improving treadmill walking time and walking distance with a supervised exercise program. Although no benefit was seen in reducing major adverse cardiovascular events or on improving the ABI, subjects randomly assigned to exercise had improvement in claudication symptoms out to 2 years.19Although supervised exercise is very effective in PAD subjects with claudication, several questions remain: (1) is exercise effective in PAD subjects without claudication and (2) what is the role of a nonsupervised exercise program? Two recent randomized trials address these issues.21,22 The effect of supervised treadmill exercise or lower-extremity resistance training on functional performance and quality of life was evaluated in a randomized trial of 156 PAD patients, of whom <20% had symptoms of classic claudication.20 Although any exercise (treadmill or resistance training) improved functional performance, the treadmill exercise group had greater increases in the 6-minute walk distance and in the maximum treadmill walking time in comparison with the resistance group. Of note, the changes in the primary outcomes were similar between subjects with and without claudication and between asymptomatic and symptomatic participants. Despite the efficacy of a supervised exercise program in PAD, lack of reimbursement in the United States remains a major barrier to utilization of this treatment.Evaluating the role of home-based exercise, Gardner and colleagues randomly assigned 119 subjects with claudication to either home-based exercise, supervised exercise, or a usual care control group.21 Both exercise programs increased claudication onset time and peak treadmill walking time versus the control group; however, the changes in average walking cadence time were greater in the home-based exercise group. Although this study was small, and nearly 25% of subjects did not complete follow-up, it suggests that a quantified home-based approach may be useful in this high-risk population with impaired quality of life. However, a meta-analysis of home-based exercise training in PAD was negative.22 Future exercise studies with improved home-training methods, larger populations, and clinically meaningful end points are certainly warranted. In the meantime, subjects with PAD (symptomatic or not) are likely to benefit from an aggressive exercise regimen.CilostazolCilostazol is a phosphodiesterase type 3 inhibitor approved in the United States in 1999 to treat intermittent claudication. Its possible mechanism of action includes increasing intracellular concentrations of cAMP, thereby causing vasodilation and inhibiting platelet aggregation.23 Although other drugs with vasodilating and platelet-inhibiting properties have not been demonstrated to improve claudication symptoms, cilostazol is effective in ameliorating symptoms. A meta-analysis of 8 randomized trials including 2702 PAD subjects with claudication found that cilostazol improved maximum and pain-free treadmill walking distance and quality-of-life measures.24 Of note, cilostazol decreased triglyceride concentration by 16% and increased high-density lipoprotein levels by 13%, but also increased the incidence of headache, bowel concerns, and palpitations.Cilostazol may have an additional benefit of reducing restenosis and repeat revascularization following endovascular therapy.25 Similar to patients with coronary artery disease,26–28 patients with PAD have lower rates of target vessel revascularization following cilostazol therapy.29,30 However, these studies have been small and open label in design, thus hypothesis generating.Milrinone, another phosphodiesterase type 3 inhibitor, was noted to increase mortality in subjects with heart failure.31 In response, the US Food and Drug Administration mandated a long-term safety study of cilostazol. Hiatt and colleagues performed a phase 4 (postmarketing) randomized, double-blind, placebo-controlled trial of cilostazol in 1435 PAD subjects with claudication.32 Although underpowered because of a lower mortality than projected and poor study drug adherence, this is the largest study to date that has evaluated serious adverse events and mortality. No difference was observed for overall mortality or serious bleeding events between the cilostazol and placebo groups; however, the study could not exclude a modest increased risk. In comparison with milrinone, cilostazol has fewer cardiac inotropic effects but equivalent vasodilating and platelet-inhibiting properties.33 Nonetheless, an advisory from the US Food and Drug Administration stated that cilostazol should not be used in subjects with congestive heart failure.Statin TherapySubgroup analyses of PAD patients from large randomized trial data in subjects with PAD found a reduction in cardiovascular events from statin therapy. Exploratory analyses suggested an improvement of claudication symptoms in subjects with PAD.34 In a randomized trial of 354 PAD subjects with claudication, Mohler and colleagues35 demonstrated that atorvastatin (10 or 80 mg daily) improved pain-free walking distance and community-based physical activity. However, the functional benefits of statins on claudication have not been proven.Carnitine and Propionyl-l-Carnitine Therapyl-Carnitine and propionyl-l-carnitine may improve muscle metabolism and exercise performance in patients with PAD. Initial studies evaluated l-carnitine given orally as 2 g twice daily, and also given as a single 3-g dose intravenously.36 These early studies in PAD were indicative of clinical benefit and therefore led to the development of propionyl-l-carnitine, an acyl form of l-carnitine.In 2 published phase 3 trials, propionyl-l-carnitine had a significant improvement on claudication-limited treadmill exercise performance. In Europe, a total of 501 subjects were randomly assigned to propionyl-l-carnitine 2 g/d for 12 months (n=248) or placebo (n=253).37 The primary analysis was the subgroup of 171 patients who had a maximum walking distance between 50 and 250 m and baseline variability ≤25%. After 12 months of treatment, patients randomly assigned to placebo increase maximal walking distance 44% versus 61% on drug. This difference had a probability value of 0.055 by the primary analysis and 0.048 with a secondary analysis. The quality-of-life questionnaire was also positive in favor of drug (P=0.002). In the second pivotal trial, a total of 161 subjects were randomly assigned to propionyl-l-carnitine, 2 g/d (n=85), or placebo (n=76).38 After 6 months of therapy, treated patients increased peak walking time 78% with a 37% increase in controls (P=0.002). Patients randomly assigned to propionyl-l-carnitine also had significant improvements in the physical function scores of the SF-36 (P=0.31), but not with the Waling Impairment Questionnaire (P=0.26). However, more recent studies in which propionyl-l-carnitine was given on a background of exercise training, although showing favorable trends, were not statistically significant on the primary end point.39 Thus, the overall incremental benefit of propionyl-l-carnitine in PAD remains to be determined.Other Medical TherapiesPentoxifyllinePentoxifylline is a xanthine derivative used to treat patients with intermittent claudication. Its mechanism of action is thought to be a rheological modifier that includes improving the deformability of red blood cells and white blood cells, and decreasing fibrinogen concentration, platelet adhesiveness, and whole-blood viscosity. A meta-analysis demonstrated a modestly improved walking distance, substantially less effective than either cilostazol or a supervised exercise program.40NaftidrofurylNaftidrofuryl is a serotonin 5-hydroxytryptamine 2 receptor antagonist with vasoactive properties in addition to its effect on oxidative metabolism and rheological properties on the red blood cell and platelet.41 Although not approved in the United States, it is currently used in Europe for the treatment of claudication. In a patient-level meta-analysis, naftidrofuryl improved symptomatic claudication without any serious adverse events.42Medical Treatment of the Patient Undergoing RevascularizationAntiplatelet therapy has good evidence for the prevention of graft occlusion after peripheral vascular surgical procedures. In the Antithrombotic Trialists' Collaboration meta-analysis, 3000 patients with peripheral artery procedures had a 16% graft occlusion rate on antiplatelet therapy in comparison with 25% in the control group (P<0.00001).43 Aspirin with or without other antiplatelet therapy was associated with a significantly lower risk of graft occlusion.44 Ticlopidine has also been shown to promote vein graft patency without any difference in cardiovascular events.45 Dual-antiplatelet therapy with aspirin plus clopidogrel versus aspirin alone was tested in the clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.46 There was no significant difference in the primary end point (graft occlusion, amputation, or death) between groups. In a subgroup analysis, clopidogrel plus aspirin was better than aspirin alone among patients who received prosthetic grafts. As expected, bleeding was more common in the dual-antiplatelet therapy group.47Anticoagulation has also been recommended as an adjuvant to maintain surgical graft patency.47 The use of heparin anticoagulation in the immediate postoperative period, particularly low-molecular-weight heparin, may improve the patency of infrainguinal bypass grafts (vein and prosthetic), but has also been associated with increased bleeding.48,49 The role of long-term oral anticoagulation is more controversial. In one trial of patients undergoing infrainguinal bypass surgery (including the use of vein, prosthetic material, and endarterectomy), long-term warfarin was associated with an increased bleeding risk but no benefit in patency or survival.50 In contrast, another study performed in a similar population demonstrated that oral anticoagulation improved graft patency, limb salvage, and survival.51Several trials have compared the benefits of anticoagulation versus antiplatelet therapy. Among patients treated with infrainguinal bypass procedures (predominantly using prosthetic material), randomization to low-molecular-weight heparin versus aspirin and dipyridamole was associated with better graft patency, especially in the patients treated for critical limb ischemia.52 The Dutch Bypass Oral Anticoagulants or Aspirin study evaluated 2690 patients undergoing infrainguinal bypass.53 Half the patients were treated for claudication and the other half were treated for critical limb ischemia with a fairly even distribution of vein versus prosthetic material. The aspirin dose was 80 mg/d, and, in patients randomly assigned to anticoagulation, the international normalized ratio was maintained at 3.0 to 4.5. The primary end point of patency was equal between groups after 21 months follow-up. In subgroup analysis, anticoagulation maintained vein graft patency better than aspirin but at a higher risk of bleeding complications. In contrast, aspirin maintained prosthetic graft patency better than anticoagulation. Although these results suggest that patients receiving vein grafts should be preferentially treated with warfarin and those with prosthetic material with aspirin, adequately powered studies are needed to determine the optimal antithrombotic and antiplatelet strategy following vascular surgery.In the context of promoting patency after a revascularization procedure, antiplatelet and antithrombotic therapy have a clear role, but the data are somewhat dated. In terms of selection between type of therapy, aspirin may be favored for prosthetic grafts and anticoagulation for vein grafts or for higher-risk patients for occlusion.44 Future trials are needed.Novel TherapiesTherapeutic angiogenesis is a promising investigational strategy for the treatment of patients with claudication and chronic leg ischemia (CLI). It is an application of biotechnology to stimulate new vessel formation via local administration of proangiogenic growth factors delivered as recombinant protein or by gene therapy, or by implantation of endothelial or other progenitor cells that will synthesize multiple angiogenic cytokines.Gene TherapyGene therapy involves transfer of genetic material into cells to modify their genetic expression to produce a clinically useful effect on angiogenesis, capillary generation, and collateral formation. Clinical trials have sought to establish the role for therapeutic angiogenesis by use of gene transfer with proangiogenic factors mediated by plasmids or viral vectors in patients with PAD, although results have been inconsistent (Table 2). These proangiogenic factors include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hypoxia-inducible factor (HIF)-1α, and hepatocyte growth factor (HGF).Table 2. Phase II and Phase III Randomized, Controlled Trials of Gene Therapy and Cell Therapy in Subjects With Peripheral Artery DiseaseStudyPhasePopulationNo.TreatmentFollow-UpPrimary End PointFindingsGene therapy RAVE54IIClaudication105VEGF12112 wkPeak walking timeNo benefit. Dose-dependent peripheral edema Kusumanto et al55IIDiabetics with CLI54VEGF165100 dMajor amputationNo benefit in primary EP, but improvement in hemodynamics and skin ulcer healing DELTA56IIClaudication105Del-190 dPeak walking timeNo benefit and no major safety issues TRAFFIC57IIClaudication190FGF-2 protein90 dPeak walking timeSignificant benefit in primary EP. No major safety concern TALISMAN58IICLI125NV1FGF25 wkUlcer healingNo benefit in the primary EP. Secondary of amputation and death was reduced. No major safety issues TAMARIS59IIICLI525NV1FGF1 yDeath or major amputationNo benefit and no major safety issues (malignancy, retinopathy, or proteinuria)Cell therapy START60IIClaudication40GM-CSF14 dWalking distanceNo benefit Arai et al61IICLI39G-CSF1 moSafety and feasibilityNo significant adverse events. Improvement in ABI and transcutaneous oxygen pressureCLI indicates critical leg ischemia; VEGF, vascular endothelial growth factor; Del-1, Developmentally Regulated Endothelial Locus; FGF, fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; NV1FGF, nonviral 1 fibroblast growth factor; ABI, ankle-brachial index; and EP, end point.In a meta-analysis evaluating the efficacy and safety of different gene therapies, recombinant protein and cellular-based treatment approaches in patients with PAD, therapeutic angiogenesis was associated with a modest, albeit significant clinical improvement in peak walking time, ulcer healing, rest pain relief, and limb salvage versus placebo in subjects with PAD (odds ratio 1.44, 95% CI 1.03–2.00).62 The improvement was most impressive in subjects with CLI. There was also a 30% increase in the odds of the adverse events of edema, hypotension, and proteinuria. No significant difference was detected for the endpoints of mortality, malignancy, or retinopathy.Vascular Endothelial Growth FactorVascular endothelial growth factor is expressed under hypoxic conditions and is a potent regulator of endothelial cell migration, proliferation, repair, and survival.63 In previous studies involving animal studies, VEGF gene transfer induced rapid production of nitric oxide and prostacyclin from endothelium causing a vasculoprotective effect.64,65 In a hindlimb ischemia animal model, VEGF was demonstrated to induce angiogenesis and arteriogenesis.66,67 Initial uncontrolled clinical trials have suggested promising therapeutic effects with naked VEGF plasmid gene transfer.68,69 In a comparison of intra-arterial infusion of adenoviral VEGF165, plasmid liposome VEGF165, or Ringers lactate placebo, Makinen et al70 noted that both VEGF165 treatments appeared safe and were associated with significant increases in vascularity.In a phase I trial, Baumgartner and colleagues70 found that intramuscular injection achieves overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with CLI.In the Regional Angiogenesis with VEGF (RAVE) trial, a single intramuscular adenoviral delivery of VEGF121 in patients with unilateral exercise-limiting claudication failed to achieve its primary end point of change in treadmill peak walking time.54 There was no difference in any of the secondary end points, and VEGF121 was associated with a dose-dependent increase in peripheral edema. Reasons for the lack of efficacy could be the population selected (patients with bilateral PAD were excluded), the duration of expression of the VEGF121 transgene by use of the adenoviral approach may be insufficient to induce a phenotypic response, and the single injection may be insufficient.71 It is possible that locally expressed VEGF121 has a short tissue half-life and, consequently, induces only the first step in angiogenesis, whereas the longer tissue retention of VEGF165 may permit execution of the full paradigm of angiogenesis.In a small randomized trial, Kusumanto et al55 evaluated the effect of 2 intramuscular injections of plasmid-encoded VEGF165 versus placebo in 54 diabetic patients with PAD and CLI. The authors claim the study was powered to detect a 25% absolute difference in major amputations. There were numerically fewer major amputations (3 [11%] versus 6 [22%]), but this difference failed to reach statistical significance. There was more skin ulcer healing and increased hemodynamic improvement in the VEGF165 group.Fibroblast Growth FactorFibroblast growth factor modulates and enhances new blood vessel formation and activates migration, proliferation, and differentiation of endothelial cells, resulting in angiogenesis. FGF acts on endothelial cells, smooth muscle cells, and fibroblasts via an interaction with specific receptors on the cell surface. There are 22 known FGF ligands that are involved in angiogenesis.71 FGF-1 and FGF-2 have been studied in human PAD gene therapy trials. FGF-1 and FGF-2 are different from other FGF proteins in lacking a signal sequence for extracellular transport.72 In a phase I trial, intramuscular administration of nonviral 1 fibroblast growth factor (NV1FGF) to limbs of patients with CLI was well tolerated.73 In an open-label design, patients experienced improvements in wound healing, pain, transcutaneous partial pressure of oxygen, and ABI. The Therapeutic Angiogenesis with Intramuscular NV1FGF Improves Amputation-Free Survival in Patients with Critical Limb Ischemia (TALISMAN 201) trial was a phase II trial in patients with CLI.58 There was no difference in the primary end point of ulcer healing between the NV1FGF group and placebo group. However, use of NV1FGF significantly reduced the secondary end point of risk of all amputations by ≈50% with a nonsignificant trend toward a lower mortality. These results served as the basis for a large phase 3 trial of NV1FGF on amputation-free survival.In a landmark trial, the Therapeutic Angiogenesis for the Management of Arteriopathy in a Randomized International Study (TAMARIS) study was designed to demonstrate the clinical benefit of NV1FGF in delay of the time to major amputation or death in patients with CLI.59 In this phase III trial, 525 patients were enrolled from 171 sites in 30 countries and were randomly assigned to NV1FGF or placebo in a 1:1 ratio. After follow-up of 1 year, there was no significant difference in the primary efficacy end point (36% in the NV1FGF group and 33% in the placebo group, hazard ratio 1.11, P=0.48). There was no trend for a benefit for any of the secondary end points or in any subgroup of patients. It is likely that the different results observed in the phase II trial may have occurred by chance, especially because the trial was small (n=125) and the primary outcome was null. The disappointing results of the TAMARIS study highlight the importance of performing large phase III trials in this new area of gene therapeutics.In the setting of claudication, Lederman and colleagues57 performed the Therapeutic Angiogenesis with FGF-2 for Intermittent Claudication (TRAFFIC) phase II trial testing the efficacy and safety of intra-arterial FGF-2 protein in 190 patients with moderate-to-severe intermittent claudication. Intra-arterial FGF-2 protein resulted in a significant increase in peak walking time at 90 days. No follow-up study has been performed.Hypoxia Inducible Factor-1αThe transcription factor HIF-1α is important in vascular hemostasis; HIF-1α regulates the expression of specific genes involved in the response to hypoxia and wound healing.74 Because HIF-1α involves both physiological and pathological angiogenesis, strategies that target this factor have been tested in the setting of PAD. In a phase I dose escalation study, HIF-1α delivered intramuscularly with an adenoviral vector w
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