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1.
Exercise for intermittent claudication.
Lane, R, Harwood, A, Watson, L, Leng, GC
The Cochrane database of systematic reviews. 2017;(12):CD000990
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Abstract
BACKGROUND Exercise programmes are a relatively inexpensive, low-risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent claudication (IC)). This is the fourth update of a review first published in 1998. OBJECTIVES Our goal was to determine whether an exercise programme was effective in alleviating symptoms and increasing walking treadmill distances and walking times in people with intermittent claudication. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events, and improving quality of life. SEARCH METHODS For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 15 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) via the Cochrane Register of Studies Online, along with trials registries. SELECTION CRITERIA Randomised controlled trials of an exercise regimen versus control or versus medical therapy for people with IC due to peripheral arterial disease (PAD). We included any exercise programme or regimen used for treatment of IC, such as walking, skipping, and running. Inclusion of trials was not affected by duration, frequency, or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximum walking distance), ankle brachial index (ABI), quality of life, morbidity, or amputation; if none of these was reported, we did not include the trial in this review. DATA COLLECTION AND ANALYSIS For this update (2017), RAL and AH selected trials and extracted data independently. We assessed study quality by using the Cochrane 'Risk of bias' tool. We analysed continuous data by determining mean differences (MDs) and 95% confidence intervals (CIs), and dichotomous data by determining risk ratios (RRs) and 95% CIs. We pooled data using a fixed-effect model unless we identified significant heterogeneity, in which case we used a random-effects model. We used the GRADE approach to assess the overall quality of evidence supporting the outcomes assessed in this review. MAIN RESULTS We included two new studies in this update and identified additional publications for previously included studies, bringing the total number of studies meeting the inclusion criteria to 32, and involving a total of 1835 participants with stable leg pain. The follow-up period ranged from two weeks to two years. Types of exercise varied from strength training to polestriding and upper or lower limb exercises; supervised sessions were generally held at least twice a week. Most trials used a treadmill walking test for one of the primary outcome measures. The methodological quality of included trials was moderate, mainly owing to absence of relevant information. Most trials were small and included 20 to 49 participants. Twenty-seven trials compared exercise versus usual care or placebo, and the five remaining trials compared exercise versus medication (pentoxifylline, iloprost, antiplatelet agents, and vitamin E) or pneumatic calf compression; we generally excluded people with various medical conditions or other pre-existing limitations to their exercise capacity.Meta-analysis from nine studies with 391 participants showed overall improvement in pain-free walking distance in the exercise group compared with the no exercise group (MD 82.11 m, 95% CI 71.73 to 92.48, P < 0.00001, high-quality evidence). Data also showed benefit from exercise in improved maximum walking distance (MD 120.36 m, 95% CI 50.79 to 189.92, P < 0.0007, high-quality evidence), as revealed by pooling data from 10 studies with 500 participants. Improvements were seen for up to two years.Exercise did not improve the ABI (MD 0.04, 95% CI 0.00 to 0.08, 13 trials, 570 participants, moderate-quality evidence). Limited data were available for the outcomes of mortality and amputation; trials provided no evidence of an effect of exercise, when compared with placebo or usual care, on mortality (RR 0.92, 95% CI 0.39 to 2.17, 5 trials, 540 participants, moderate-quality evidence) or amputation (RR 0.20, 95% CI 0.01 to 4.15, 1 trial, 177 participants, low-quality evidence).Researchers measured quality of life using Short Form (SF)-36 at three and six months. At three months, the domains 'physical function', 'vitality', and 'role physical' improved with exercise; however this was a limited finding, as it was reported by only two trials. At six months, meta-analysis showed improvement in 'physical summary score' (MD 2.15, 95% CI 1.26 to 3.04, P = 0.02, 5 trials, 429 participants, moderate-quality evidence) and in 'mental summary score' (MD 3.76, 95% CI 2.70 to 4.82, P < 0.01, 4 trials, 343 participants, moderate-quality evidence) secondary to exercise. Two trials reported the remaining domains of the SF-36. Data showed improvements secondary to exercise in 'physical function' and 'general health'. The other domains - 'role physical', 'bodily pain', 'vitality', 'social', 'role emotional', and 'mental health' - did not show improvement at six months.Evidence was generally limited in trials comparing exercise versus antiplatelet therapy, pentoxifylline, iloprost, vitamin E, and pneumatic foot and calf compression owing to small numbers of trials and participants.Review authors used GRADE to assess the evidence presented in this review and determined that quality was moderate to high. Although results showed significant heterogeneity between trials, populations and outcomes were comparable overall, with findings relevant to the claudicant population. Results were pooled for large sample sizes - over 300 participants for most outcomes - using reproducible methods. AUTHORS' CONCLUSIONS High-quality evidence shows that exercise programmes provided important benefit compared with placebo or usual care in improving both pain-free and maximum walking distance in people with leg pain from IC who were considered to be fit for exercise intervention. Exercise did not improve ABI, and we found no evidence of an effect of exercise on amputation or mortality. Exercise may improve quality of life when compared with placebo or usual care. As time has progressed, the trials undertaken have begun to include exercise versus exercise or other modalities; therefore we can include fewer of the new trials in this update.
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Statins and peripheral arterial disease.
Markel, A
International angiology : a journal of the International Union of Angiology. 2015;(5):416-27
Abstract
Peripheral arterial disease (PAD) in the context of this review refers to the presence of atherosclerotic disease in the arteries of the lower limbs. PAD is the third main site of atherosclerosis, after coronary heart disease and cerebrovascular disease. Intermittent claudication (IC) is the most known clinical manifestation of PAD, although most patients with leg ischemia are either asymptomatic of have atypical leg symptoms. Different drugs have been used in the past for the treatment of IC with limited results. As hypercholesterolemia is one of the main risk factors for atherosclerosis, cholesterol reduction has been shown to be effective in reducing cardiovascular morbidity and mortality. Statins are inhibitor of HMG CoA reductase, an enzyme essential in cholesterol synthesis. They effectively reduce total cholesterol and LDL cholesterol levels and are the most efficient drugs available today in the treatment of hypercholesterolemia. Several studies have demonstrated that statin administration in patients with PAD results in a decreased progression and even regression in the growth of the atherosclerotic plaque. As patients with atherosclerosis of the lower limbs have frequently concurrent coronary or cerebrovascular disease, treatment of PAD with statins results in a simultaneous decrease in the incidence of coronary events and stroke. Statins have associated pleiotropic effects, including anti-inflammatory properties that contribute to their beneficial effects and to the reduction in cardiovascular death. In addition, several studies during the last years showed that statins improved pain-free walking distance, ankle brachial index and treadmill exercise time. As a result, current guidelines for cholesterol reduction in PAD patients adhere to the same indications as for other cardiovascular diseases and strongly recommend the administration of statins in these patients.
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Disease understanding in patients with intermittent claudication: A qualitative study.
Lokin, JL, Hengeveld, PJ, Conijn, AP, Nieuwkerk, PT, Koelemay, MJ
Journal of vascular nursing : official publication of the Society for Peripheral Vascular Nursing. 2015;(3):112-8
Abstract
The aim of our qualitative study was to investigate the understanding of patients with intermittent claudication (IC) regarding the etiology and atherosclerotic nature of their disease. Patients were recruited from participants of the SUPER study, a randomized trial comparing angioplasty and supervised exercise therapy for alleviation of IC owing to an iliac artery obstruction. Patients were submitted to explorative, semistructured, in-depth interviews that were fully transcribed, coded, and categorized. We interviewed 19 patients. The majority of respondents (79%) recognized smoking as a major risk factor contributing to the etiology of IC. However, nearly one-half (47%) underestimated the effects of unhealthy dietary and exercise patterns. In contrast, a substantial number of respondents (42%) overestimated the contribution of genetics to the etiology of their disease. Most respondents (79%) were unaware of the fact that IC implies systemic atherosclerosis.This study shows that the patients' interpretation of the etiology and nature of IC was mostly incorrect. Therefore, we suggest that health care providers enhance counseling about etiologic factors and the systemic nature of IC to optimize outcomes of lifestyle adjustments.
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4.
Exercise for intermittent claudication.
Lane, R, Ellis, B, Watson, L, Leng, GC
The Cochrane database of systematic reviews. 2014;(7):CD000990
Abstract
BACKGROUND Exercise programmes are a relatively inexpensive, low-risk option compared with other more invasive therapies for leg pain on walking (intermittent claudication (IC)). This is an update of a review first published in 1998. OBJECTIVES The prime objective of this review was to determine whether an exercise programme in people with intermittent claudication was effective in alleviating symptoms and increasing walking treadmill distances and walking times. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events and improving quality of life. SEARCH METHODS For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2013) and CENTRAL (2013, Issue 8). SELECTION CRITERIA Randomised controlled trials of an exercise regimen versus control or versus medical therapy in people with IC due to peripheral arterial disease. Any exercise programme or regimen used in the treatment of intermittent claudication was included, such as walking, skipping and running. Inclusion of trials was not affected by the duration, frequency or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximal walking distance), ankle brachial index (ABI), quality of life, morbidity or amputation; if none of these were reported the trial was not included in this review. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed trial quality. MAIN RESULTS Eleven additional studies were included in this update making a total of 30 trials which met the inclusion criteria, involving a total of 1816 participants with stable leg pain. The follow-up period ranged from two weeks to two years. The types of exercise varied from strength training to polestriding and upper or lower limb exercises; generally supervised sessions were at least twice a week. Most trials used a treadmill walking test for one of the outcome measures. Quality of the included trials was moderate, mainly due to an absence of relevant information. The majority of trials were small with 20 to 49 participants. Twenty trials compared exercise with usual care or placebo, the remainder of the trials compared exercise to medication (pentoxifylline, iloprost, antiplatelet agents and vitamin E) or pneumatic calf compression; people with various medical conditions or other pre-existing limitations to their exercise capacity were generally excluded.Overall, when taking the first time point reported in each of the studies, exercise significantly improved maximal walking time when compared with usual care or placebo: mean difference (MD) 4.51 minutes (95% confidence interval (CI) 3.11 to 5.92) with an overall improvement in walking ability of approximately 50% to 200%. Walking distances were also significantly improved: pain-free walking distance MD 82.29 metres (95% CI 71.86 to 92.72) and maximum walking distance MD 108.99 metres (95% CI 38.20 to 179.78). Improvements were seen for up to two years, and subgroup analyses were performed at three, six and 12 months where possible. Exercise did not improve the ABI (MD 0.05, 95% CI 0.00 to 0.09). The effect of exercise, when compared with placebo or usual care, was inconclusive on mortality, amputation and peak exercise calf blood flow due to limited data. No data were given on non-fatal cardiovascular events.Quality of life measured using the Short Form (SF)-36 was reported at three and six months. At three months, physical function, vitality and role physical all significantly improved with exercise, however this was a limited finding as this measure was only reported in two trials. At six months five trials reported outcomes of a significantly improved physical summary score and mental summary score secondary to exercise. Only two trials reported improvements in other domains, physical function and general health.Evidence was generally limited for exercise compared with antiplatelet therapy, pentoxifylline, iloprost, vitamin E and pneumatic foot and calf compression due to small numbers of trials and participants. AUTHORS' CONCLUSIONS Exercise programmes are of significant benefit compared with placebo or usual care in improving walking time and distance in people with leg pain from IC who were considered to be fit for exercise intervention.
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A randomised controlled trial of supervised exercise regimens and their impact on walking performance, skeletal muscle mass and calpain activity in patients with intermittent claudication.
Delaney, CL, Miller, MD, Chataway, TK, Spark, JI
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2014;(3):304-10
Abstract
OBJECTIVES Supervised exercise training (SET) is recommended for patients with intermittent claudication (IC). The optimal exercise programme has not been identified, and the potential adverse effects of exercise on these patients warrant consideration. Calpain proteases have been linked with tissue atrophy following ischaemia-reperfusion injury. High calpain activity may therefore cause muscle wasting in claudicants undergoing SET, and skeletal muscle mass (SMM) is integral to healthy ageing. This study assesses the impact of (1) treadmill-based SET alone; and (2) treadmill-based SET combined with resistance training on pain-free walking distance (PFWD), SMM, and calpain activity. METHODS Thirty-five patients with IC were randomised to 12 weeks of treadmill only SET (group A), or combined treadmill and lower-limb resistance SET (group B). PFWD via a 6-minute walking test, SMM via dual energy X-ray absorptiometry, and calpain activity via biopsies of gastrocnemius muscles were analysed. RESULTS Intention-to-treat analyses revealed PFWD improved within group A (160 m to 204 m, p = .03), but not group B (181 m to 188 m, p = .82). There was no between group difference (p = .42). Calpain activity increased within group A (1.62 × 10(5) fluorescent units [FU] to 2.21 × 10(5) FU, p = .05), but not group B. There was no between group difference (p = .09). SMM decreased within group A (-250 g, p = .11) and increased in group B (210 g, p = .38) (p = .10 between groups). Similar trends were evident for per protocol analyses, but, additionally, change in SMM was significantly different between groups (p = .04). CONCLUSIONS Neither exercise regimen was superior in terms of walking performance. Further work is required to investigate the impact of the calpain system on SMM in claudicants undertaking SET.
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Ginkgo biloba for intermittent claudication.
Nicolaï, SP, Kruidenier, LM, Bendermacher, BL, Prins, MH, Stokmans, RA, Broos, PP, Teijink, JA
The Cochrane database of systematic reviews. 2013;(6):CD006888
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Abstract
BACKGROUND People with intermittent claudication (IC) suffer from pain in the muscles of the leg occurring during exercise which is relieved by a short period of rest. Symptomatic relief can be achieved by (supervised) exercise therapy and pharmacological treatments. Ginkgo biloba is a vasoactive agent and is used to treat IC. OBJECTIVES To assess the effect of Ginkgo biloba on walking distance in people with intermittent claudication. SEARCH METHODS For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (March 2013) and CENTRAL (2013, Issue 2). SELECTION CRITERIA Randomised controlled trials of Ginkgo biloba extract, irrespective of dosage, versus placebo in people with IC. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials for selection, assessed study quality and extracted data. We extracted number of patients, mean walking distances or times and standard deviations. To standardise walking distance or time, caloric expenditures were used to express the difference between the different treadmill protocols, which were calculated from the speed and incline of the treadmill. MAIN RESULTS Fourteen trials with a total of 739 participants were included. Eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed the absolute claudication distance (ACD). Following treatment with Ginkgo biloba at the end of the study the ACD increased with an overall effect size of 3.57 kilocalories (confidence interval (CI) -0.10 to 7.23, P = 0.06), compared with placebo. This translates to an increase of just 64.5 ( CI -1.8 to 130.7) metres on a flat treadmill with an average speed of 3.2 km/h. Publication bias leading to missing data or "negative" trials is likely to have inflated the effect size. AUTHORS' CONCLUSIONS Overall, there is no evidence that Ginkgo biloba has a clinically significant benefit for patients with peripheral arterial disease.
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Prostanoids for intermittent claudication.
Robertson, L, Andras, A
The Cochrane database of systematic reviews. 2013;(4):CD000986
Abstract
BACKGROUND 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. OBJECTIVES To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II. SEARCH METHODS 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. SELECTION CRITERIA Randomised clinical trials of prostanoids versus placebo or alternative ('control') treatment in people with intermittent claudication were considered for inclusion. DATA COLLECTION AND ANALYSIS 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. MAIN RESULTS 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. AUTHORS' CONCLUSIONS 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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Omega-3 fatty acids for intermittent claudication.
Campbell, A, Price, J, Hiatt, WR
The Cochrane database of systematic reviews. 2013;(7):CD003833
Abstract
BACKGROUND Omega-3 fatty acids have been used in the treatment and prevention of coronary artery disease although current evidence suggests they may be of limited benefit. Peripheral arterial disease and coronary artery disease share a similar pathogenesis so omega-3 fatty acids may have a similar effect on both conditions. This is an update of a review first published in 2004 and updated in 2007. OBJECTIVES To determine the clinical and haematological effects of omega-3 supplementation in people with intermittent claudication. SEARCH METHODS For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9). SELECTION CRITERIA Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. DATA COLLECTION AND ANALYSIS One review author identified potential trials. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information if necessary. MAIN RESULTS Nine studies were included representing 425 participants. All studies compared omega-3 fatty acid supplementation with placebo lasting from four weeks to two years. Three studies with long treatment periods administered additional substances, making any observed effects impossible to attribute to omega-3 fatty acids and were excluded from the statistical analyses. One study did not express any mean values and, therefore, could not be included in statistical analyses.No significant differences between intervention and control groups were observed in pain-free walking distance (mean difference (MD) 11.62 m, 95% confidence interval (CI) -67.74 to 90.98), maximal walking distance (MD 16.99 m, 95% CI -72.14 to 106.11), ankle brachial pressure index (MD -0.02, 95% CI -0.09 to 0.05), total cholesterol levels (MD 0.27 mmol/L, 95% CI -0.48 to 1.01), high-density lipoprotein cholesterol levels (MD 0.00 mmol/L, 95% CI -0.16 to 0.15), low-density lipoprotein cholesterol levels (MD 0.44 mmol/L, 95% CI -0.31 to 1.19), triglyceride levels (MD -0.39 mmol/L, 95% CI -1.10 to 0.33), systolic blood pressure (MD 5.00 mmHg, 95% CI -11.59 to 21.59) or plasma viscosity (MD 0.03 mPa/s, 95% CI -0.02 to 0.08).There was some limited evidence that blood but not plasma viscosity levels decreased with treatment and gastrointestinal side effects such as nausea, diarrhoea and flatulence were observed in two studies. AUTHORS' CONCLUSIONS Omega-3 fatty acids appear to have little haematological benefit in people with intermittent claudication and there is no evidence of consistently improved clinical outcomes (quality of life, walking distance, ankle brachial pressure index or angiographic findings). Supplementation may also cause adverse effects such as nausea, diarrhoea and flatulence. Further research is needed to evaluate fully short- and long-term effects of omega-3 fatty acids on the most clinically relevant outcomes in people with intermittent claudication before they can be recommended for routine use.
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9.
[Vascular rehabilitation in patients with peripheral arterial disease].
de Holanda, A, Aubourg, M, Dubus-Bausière, V, Eveno, D, Abraham, P
Presse medicale (Paris, France : 1983). 2013;(6 Pt 1):1032-8
Abstract
Lower limb peripheral arterial disease (PAD) is a frequent debilitating disease associated with a high morbidity and mortality rate. The benefit of rehabilitation in PAD patients has been largely demonstrated, both for patients that undergo amputation, and for patients with claudication. In these latter patients, rehabilitation programs rely on a variety of additional techniques or tools, among which: stretching, specific muscle proprioception, walking and a variety of other physical activities, exercise or situations adapted to community life, lower limb and respiratory physiotherapy, patient's education, support for smoking cessation and healthy nutrition, social support, etc. Whether rehabilitation is performed in specialised integrated structures or performed on a home-based basis, various clinicians are involved. Despite evidence-based proof of efficacy, rehabilitation of PAD patients with claudication is still under-used.
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Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial. Journal of the American Medical Association 2013; 309: 453-460.
Kurklinsky, AK, Levy, M
Vascular medicine (London, England). 2013;(4):234-6
Abstract
STUDY OBJECTIVE The objective of the trial was to examine whether ramipril, an angiotensin-converting enzyme (ACE), improves walking distance and health-related quality of life in patients with peripheral artery disease (PAD) associated with claudication. STUDY POPULATION The study enrolled 212 patients with risk factors and symptoms of PAD treated by conventional therapies at three centers in Australia. All patients had an ankle-brachial index (ABI) of less than 0.90 at rest and intermittent claudication in at least one leg, which were stable for at least 6 preceding months along with the medication regimen. The patients were excluded if blood pressure was not controlled (brachial blood pressure of 160/100 mmHg or greater); if there was current or recent use of either ACE inhibitors or angiotensin II receptor blockers, potassium-sparing diuretics, or potassium supplements; renal failure (serum creatinine level 2.3 mg/dL or greater [200 µmol/L]); renal artery stenosis; previous coronary or peripheral artery revascularizations, recent myocardial infarction and other health conditions other than PAD that could adversely influence walking ability at the time of screening and for 1 year thereafter. DESIGN AND METHODS This was a randomized, placebo-controlled, triple blinded study of ramipril at the high daily dose (10 mg) for 6 months. Primary outcomes were pain-free and maximum walking times assessed by a standard treadmill exercise test. Secondary outcomes were ABI changes; symptoms and functional status assessed by the Walking Impairment Questionnaire (WIQ)(1); health-related quality of life assessed by the Short-Form 36 Health Survey (SF-36)(2); and stenosis severity assessed by duplex ultrasound of the lower limb arteries. At baseline and at follow-up, pain-free and maximum walking distances were assessed by the standard constant load treadmill exercise test performed at a speed of 3.2 km/h and a grade of 12%.(3) ABI was calculated in both legs. Duplex ultrasonography was used to determine stenosis in lower-limb vessel segments. Functional changes per WIQ, and perceived disability assessed on the Physical Component Summary and the Mental Component Summary of the SF-36 were self-reported. Sample size was calculated as 100 patients per each group needed to provide a power of 80% at an α of 0.05 to detect a 120-second change in walking time and a 65-second change in pain-free walking time. A two-sided p-value of less than 0.05 was considered significant. Baseline variables were compared using the χ(2) test and one-way analysis of variance. The analysis of covariance model with baseline and post-treatment values after 6 months used Kruskal-Wallis analysis of variance. Imputations for missing 6-month data were performed. Data were analyzed on the intention-to-treat basis. RESULTS Of 921 potential participants screened, 212 eligible participants were randomized into equal-sized ramipril and placebo groups where baseline parameters were not different. Compliance was monitored by pill count and adverse effects were monitored through interval clinical assessments, laboratory tests, and telephone calls. There was a 100% adherence rate to the study medications among 200 patients who completed the study. Ramipril was associated with a 75-second increase in mean pain-free and a 255-second increase in maximum walking time. There was a modest (less than 5 mmHg) blood pressure reduction and a small (0.1) ABI increase at rest and after exercise compared to placebo. The maximum walking time increase after ramipril therapy compared to placebo was greater in the subgroup of patients with femoropopliteal disease (286 seconds) than in those with aortoiliac disease (127 seconds). Patients treated with ramipril showed improvement of the median distance, speed and stair climbing scores on the WIQ, as well as of the Physical, but not the Mental, Component Summary score on the SF-36. The most frequent side effect was dizziness, more common in the ramipril (8.5%) than in the placebo (2.8%) group. Persistent cough occurred in 6.6% of patients on ramipril, causing their withdrawal from the study.