Prostanoids for intermittent claudication.
ABSTRACT Peripheral arterial disease (PAD) is a common cause of morbidity in the general population. While numerous studies have established the efficacy of prostanoids in PAD stages III and IV, the question of the role of prostanoids as an alternative or additive treatment in patients suffering from intermittent claudication (PAD II) has not yet been clearly answered. This is an update of a Cochrane Review first published in 2004.
To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II.
For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Clinical trials databases were searched for details of ongoing or unpublished studies. In addition, reference lists of relevant articles were checked.
Randomised clinical trials of prostanoids versus placebo or alternative ('control') treatment in people with intermittent claudication were considered for inclusion.
Two authors independently assessed trial quality and extracted data. Primary outcomes included pain-free walking distance (PFWD) and maximum walking distance (MWD), presented as mean change in walking distance during the course of the trial (% improvement) and as final walking distance (that is walking distance, in metres, after treatment) for the prostanoid and control groups.
Eighteen trials with a total of 2773 patients were included (16 in the original review and a further two in this update). As the majority of trials did not report standard deviations for the primary PFWD and MWD outcomes, it was often not possible to test for the statistical significance of any improvements in walking distance between groups. The quality of individual trials was variable and usually unclear due to insufficient reporting information. Comparison between trials was hampered by the use of different treadmill testing protocols, including different walking speeds and gradients. Such limitations in the data and the trial heterogeneity meant it was not possible to meaningfully pool results by meta-analysis.Four trials compared prostaglandin E1 (PGE1) with placebo; individual trials showed significant increases in walking distances with administration of PGE1 and in several trials the walking capacity remained increased after termination of treatment. Compared with pentoxifylline, PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather than changes in walking distance from baseline. When PGE1 was compared with other treatments including laevadosin, naftidrofuryl and L-arginine, improvements in walking distances over time were observed for both PGE1 and the alternative treatment, but it was not possible from the data available to analyse statistically whether or not one treatment was more effective than the other.Six studies compared various preparations of prostacyclins (PGI2) with placebo. In one study using three different dosages of iloprost, PFWD and MWD appeared to increase in a dose-dependent manner; iloprost was associated with headache, pain, nausea and diarrhoea, leading to a higher rate of treatment withdrawal. Of three studies using beraprost sodium, one showed an improvement in PFWD and MWD compared with placebo while two showed no significant benefit. Beraprost sodium was associated with an increased incidence of drug-related adverse events. Of two studies on taprostene, the results of one in particular must be interpreted with caution due to an imbalance in walking capacity at baseline.Comprehensive, high quality data on outcomes such as quality of life, ankle brachial index, venous occlusion plethysmography and haemorrheological parameters were lacking.
Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from the administration of prostanoids. Further well-conducted randomised, double blinded trials with a sufficient number of participants to provide statistical power are required to answer this question.
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ABSTRACT: Peripheral vascular disease commonly affects the arteries supplying the leg and is mostly caused by atherosclerosis. Restriction of blood flow, due to arterial stenosis or occlusion, often leads patients to complain of muscle pain on walking (intermittent claudication). Any further reduction in blood flow causes ischaemic pain at rest, which affects the foot. Ulceration and gangrene may then supervene and can result in loss of the limb if not treated. The Fontaine score is useful when classifying the severity of ischaemia. Fontaine classification of chronic leg ischaemia Stage I Asymptomatic Stage II Intermittent claudication Stage III Ischaemic rest pain Stage IV Ulceration or gangrene, or both Angiogram showing bilateral occlusions of superficial femoral arteries in thighs. Collaterals arising from the profunda femoris artery can functionally bypass this occlusion Although many patients with claudication remain stable, about 150–200 per million of the population progress to critical limb ischaemia (Fontaine III or IV) each year. Many patients with critical limb ischaemia can undergo revascularisation, which has a reasonable chance of saving the limb. A recent audit by the Vascular Surgical Society found a success rate of over 70% for these patients. However, many patients still require major amputation. Rehabilitation of elderly patients after amputation can prove difficult, with high community costs. Critical limb ischaemia has been estimated to cost over £200m a year in the United Kingdom. Intermittent claudication History and examination A history of muscular, cramp-like pain on walking that is rapidly relieved by resting, together with absent pulses, strongly supports the diagnosis of intermittent claudication. Disease of the superficial femoral artery in the thigh results in absent popliteal and foot pulses and often causes calf claudication. Disease of the aorta or iliac artery results in a weak or absent femoral pulse, often associated with a femoral bruit. Disease at this level may cause calf, thigh, or buttock claudication. Method of palpating …BMJ Clinical Research 04/2000; 320(7238):854-7. · 14.09 Impact Factor
- New England Journal of Medicine 09/1991; 325(8):577-8. · 54.42 Impact Factor
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ABSTRACT: Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients. We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients. Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production. L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4). Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.Journal of the American College of Cardiology 11/1998; 32(5):1336-44. · 15.34 Impact Factor