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Figure. Study Flow
Figure. Study Flow

Data were imputed for the 12 patients who did not complete 6-month follow-up. ACE indicates angiotensin-converting enzyme; PAD, peripheral artery disease.

Table 1. Baseline Characteristics of the Study Populationa
Table 1. Baseline Characteristics of the Study Populationa
Table 2. Primary and Secondary Outcome Measures of the Study Populationa
Table 2. Primary and Secondary Outcome Measures of the Study Populationa
1.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG.TASC II Working Group.  Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).  J Vasc Surg. 2007;45:(suppl S)  S5-S67PubMedArticle
2.
Vodnala D, Rajagopalan S, Brook RD. Medical management of the patient with intermittent claudication.  Cardiol Clin. 2011;29(3):363-379PubMedArticle
3.
McDermott MM, Greenland P, Liu K,  et al.  Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment.  JAMA. 2001;286(13):1599-1606PubMedArticle
4.
McDermott MM, Liu K, Greenland P,  et al.  Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms.  JAMA. 2004;292(4):453-461PubMedArticle
5.
Castaño G, Más R, Gámez R, Fernández L, Illnait J. Effects of policosanol and ticlopidine in patients with intermittent claudication: a double-blinded pilot comparative study.  Angiology. 2004;55(4):361-371PubMedArticle
6.
Dawson DL, Cutler BS, Hiatt WR,  et al.  A comparison of cilostazol and pentoxifylline for treating intermittent claudication.  Am J Med. 2000;109(7):523-530PubMedArticle
7.
Lièvre M, Morand S, Besse B, Fiessinger JN, Boissel JP.Beraprost et Claudication Intermittente (BERCI) Research Group.  Oral beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial.  Circulation. 2000;102(4):426-431PubMedArticle
8.
Mannarino E, Pasqualini L, Innocente S, Scricciolo V, Rignanese A, Ciuffetti G. Physical training and antiplatelet treatment in stage II peripheral arterial occlusive disease: alone or combined?  Angiology. 1991;42(7):513-521PubMedArticle
9.
Pande RL, Hiatt WR, Zhang P, Hittel N, Creager MA. A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication.  Vasc Med. 2010;15(3):181-188PubMedArticle
10.
Spengel F, Clément D, Boccalon H, Liard F, Brown T, Lehert P. Findings of the Naftidrofuryl in Quality of Life (NIQOL) European study program.  Int Angiol. 2002;21(1):20-27PubMed
11.
Stevens JW, Simpson E, Harnan S,  et al.  Systematic review of the efficacy of cilostazol, naftidrofuyrl oxalate and pentoxifillin for the treatment of intermittent claudication.  Br J Surg. 2012;99(12):1630-1638Article
12.
Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA. Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial.  Ann Intern Med. 2006;144(9):660-664PubMedArticle
13.
Overlack A, Adamczak M, Bachmann W,  et al; Perindopril Therapeutic Safety Collaborative Research Group.  ACE inhibition with perindopril in essential hypertensive patients with concomitant diseases.  Am J Med. 1994;97(2):126-134PubMedArticle
14.
Roberts DH, Tsao Y, Linge K, McLoughlin GA, Breckenridge A. Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication.  Angiology. 1992;43(9):748-756PubMedArticle
15.
Schindler C, Mueller A, Bramlage P, Boecking W, Kirch W, Schweizer J. Comparison of selective AT1-receptor blockade versus ACE inhibition for restenosis prophylaxis in patients with peripheral occlusive arterial disease after stent angioplasty: a randomized, controlled, proof-of-concept study.  Angiology. 2007;58(6):710-716PubMedArticle
16.
Shahin Y, Mazari F, Chetter I. Do angiotensin-converting enzyme inhibitors improve walking distance in patients with symptomatic lower limb arterial disease? a systematic review and meta-analysis of randomised controlled trials.  Int J Surg. 2011;9(3):209-213PubMedArticle
17.
Spence JD, Arnold JM, Munoz C, Viswanatha A, Huff M, Derose G. Angiotensin-converting enzyme inhibition with cilazapril does not improve blood flow, walking time, or plasma lipids in patients with intermittent claudication.  J Vasc Med Biol. 1993;4(1):23-28
18.
Van de Ven LL, Van Leeuwen JT, Smit AJ. The influence of chronic treatment with betablockade and angiotensin-converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication: a comparative cross-over trial.  Vasa. 1994;23(4):357-362PubMed
19.
Sumner DS, Strandness DEJ Jr. The relationship between calf blood flow and ankle blood pressure in patients with intermittent claudication.  Surgery. 1969;65(5):763-771PubMed
20.
Degischer S, Labs KH, Aschwanden M, Tschoepl M, Jaeger KA. Reproducibility of constant-load treadmill testing with various treadmill protocols and predictability of treadmill test results in patients with intermittent claudication.  J Vasc Surg. 2002;36(1):83-88PubMedArticle
21.
Momsen AH, Jensen MB, Norager CB, Madsen MR, Vestersgaard-Andersen T, Lindholt JS. Drug therapy for improving walking distance in intermittent claudication: a systematic review and meta-analysis of robust randomised controlled studies.  Eur J Vasc Endovasc Surg. 2009;38(4):463-474PubMedArticle
22.
Labs KH, Nehler MR, Roessner M, Jaeger KA, Hiatt WR. Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded-load treadmill protocol.  Vasc Med. 1999;4(4):239-246PubMedArticle
23.
Sacks D, Robinson ML, Marinelli DL, Perlmutter GS. Peripheral arterial Doppler ultrasonography: diagnostic criteria.  J Ultrasound Med. 1992;11(3):95-103PubMed
24.
Regensteiner JG, Steiner JF, Hiatt WR. Exercise training improves functional status in patients with peripheral arterial disease.  J Vasc Surg. 1996;23(1):104-115PubMedArticle
25.
Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey Manual and Interpretation Guide. Boston, MA: The Health Institute; 1993
26.
Altman DG, Schulz KF, Moher D,  et al; CONSORT GROUP (Consolidated Standards of Reporting Trials).  The revised CONSORT statement for reporting randomized trials: explanation and elaboration.  Ann Intern Med. 2001;134(8):663-694PubMedArticle
27.
Harel O, Zhou XH. Multiple imputation: review of theory, implementation and software.  Stat Med. 2007;26(16):3057-3077PubMedArticle
28.
Spratt M, Carpenter J, Sterne JA,  et al.  Strategies for multiple imputation in longitudinal studies.  Am J Epidemiol. 2010;172(4):478-487PubMedArticle
29.
Murphy TP, Cutlip DE, Regensteiner JG,  et al; CLEVER Study Investigators.  Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study.  Circulation. 2012;125(1):130-139PubMedArticle
30.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342(3):145-153PubMedArticle
31.
Creager MA, Pande RL, Hiatt WR. A randomized trial of iloprost in patients with intermittent claudication.  Vasc Med. 2008;13(1):5-13PubMedArticle
32.
Mohler ER III, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.  Circulation. 2003;108(12):1481-1486PubMedArticle
33.
McDermott MM, Ades PA, Dyer A, Guralnik JM, Kibbe M, Criqui MH. Corridor-based functional performance measures correlate better with physical activity during daily life than treadmill measures in persons with peripheral arterial disease.  J Vasc Surg. 2008;48(5):1231-1237PubMedArticle
34.
Beebe HG, Dawson DL, Cutler BS,  et al.  A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.  Arch Intern Med. 1999;159(17):2041-2050PubMedArticle
35.
Creager MA, Olin JW, Belch JJ,  et al.  Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication.  Circulation. 2011;124(16):1765-1773PubMedArticle
36.
Elam MB, Heckman J, Crouse JR,  et al.  Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication.  Arterioscler Thromb Vasc Biol. 1998;18(12):1942-1947PubMedArticle
37.
Grossman PM, Mendelsohn F, Henry TD,  et al.  Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease.  Am Heart J. 2007;153(5):874-880PubMedArticle
38.
Money SR, Herd JA, Isaacsohn JL,  et al.  Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.  J Vasc Surg. 1998;27(2):267-275PubMedArticle
39.
Sonecha TN, Nicolaides AN, Kyprianou P,  et al.  The effect of enalapril on leg muscle blood flow in patients with claudication.  Int Angiol. 1990;9(1):22-24PubMed
40.
Henriksen EJ, Prasannarong M. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle [published online May 4, 2012].  Mol Cell EndocrinolArticlePubMed
41.
Isami S, Kishikawa H, Araki E,  et al.  Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway.  Diabetologia. 1996;39(4):412-420PubMedArticle
42.
Kishi K, Muromoto N, Nakaya Y,  et al.  Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway.  Diabetes. 1998;47(4):550-558PubMedArticle
43.
Schaufelberger M, Andersson G, Eriksson BO, Grimby G, Held P, Swedberg K. Skeletal muscle changes in patients with chronic heart failure before and after treatment with enalapril.  Eur Heart J. 1996;17(11):1678-1685PubMedArticle
44.
Vescovo G, Dalla Libera L, Serafini F,  et al.  Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition.  Circulation. 1998;98(17):1742-1749PubMedArticle
45.
Ebrahimian TG, Tamarat R, Clergue M, Duriez M, Levy BI, Silvestre JS. Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice.  Arterioscler Thromb Vasc Biol. 2005;25(1):65-70PubMed
46.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo.  Circulation. 1999;99(23):3043-3049PubMedArticle
47.
Rakusan K, Cicutti N, Maurin A, Guez D, Schiavi P. The effect of treatment with low-dose ACE inhibitor and/or diuretic on coronary microvasculature in stroke-prone spontaneously hypertensive rats.  Microvasc Res. 2000;59(2):243-254PubMedArticle
48.
Takeshita S, Tomiyama H, Yokoyama N,  et al.  Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.  Cardiovasc Res. 2001;52(2):314-320PubMedArticle
49.
Toblli JE, DeRosa G, Rivas C,  et al.  Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats.  J Hypertens. 2003;21(3):611-620PubMedArticle
50.
Zimmermann R, Kastens J, Linz W, Wiemer G, Schölkens BA, Schaper J. Effect of long-term ACE inhibition on myocardial tissue in hypertensive stroke-prone rats.  J Mol Cell Cardiol. 1999;31(8):1447-1456PubMedArticle
51.
Reneland R, Haenni A, Andersson PE, Andrén B, Lithell H. Skeletal muscle angiotensin-converting enzyme and its relationship to blood pressure in primary hypertension and healthy elderly men.  Blood Press. 1999;8(1):16-22PubMedArticle
52.
Scheidegger KJ, Nelissen-Vrancken MH, Leenders PJ, Daemen MJ, Smits JF, Wood JM. Structural adaptation to ischemia in skeletal muscle: effects of blockers of the renin-angiotensin system.  J Hypertens. 1997;15(12, pt 1):1455-1462PubMedArticle
53.
Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial.  CMAJ. 2007;177(8):867-874PubMedArticle
54.
Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J.PEP-CHF Investigators.  The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) study.  Eur Heart J. 2006;27(19):2338-2345PubMedArticle
55.
Onder G, Penninx BW, Balkrishnan R,  et al.  Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study.  Lancet. 2002;359(9310):926-930PubMedArticle
56.
Di Bari M, van de Poll-Franse LV, Onder G,  et al; Health, Aging and Body Composition Study.  Antihypertensive medications and differences in muscle mass in older persons: the Health, Aging and Body Composition Study.  J Am Geriatr Soc. 2004;52(6):961-966PubMedArticle
57.
Cesari M, Pedone C, Incalzi RA, Pahor M. ACE inhibition and physical function: results from the Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study.  J Am Med Dir Assoc. 2010;11(1):26-32PubMedArticle
58.
Gray SL, LaCroix AZ, Aragaki AK,  et al; Women's Health Initiative Observational Study.  Angiotensin-converting enzyme inhibitor use and incident frailty in women aged 65 and older: prospective findings from the Women's Health Initiative Observational Study.  J Am Geriatr Soc. 2009;57(2):297-303PubMedArticle
Original Contribution
February 6, 2013

Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent ClaudicationA Randomized Controlled Trial

Author Affiliations

Author Affiliations: Baker IDI Heart and Diabetes Institute, Melbourne (Drs Ahimastos and Kingwell); University of Queensland School of Medicine and Royal Brisbane and Women's Hospital, Herston (Dr Walker); Queensland University of Technology, Brisbane (Dr Askew); Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville (Drs Leicht and Golledge and Ms Pappas); Alfred Hospital, Prahran (Dr Blombery); and Department of Epidemiology and Preventive Medicine, Monash University, Melbourne (Dr Reid), Australia.

JAMA. 2013;309(5):453-460. doi:10.1001/jama.2012.216237
Abstract

This article has been retracted.

See Notice of Retraction.

Importance Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life.

Objective To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication.

Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia.

Intervention Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks.

Main Outcome Measures Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively.

Results At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score.

Conclusions and Relevance Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score.

Trial Registration clinicaltrials.gov Identifier: NCT00681226

Approximately 27 million individuals in Europe and North America have peripheral artery disease (PAD).1 Intermittent claudication occurs in approximately one-third of patients with PAD and typically presents as pain within leg muscle groups that occurs during walking but is relieved by rest.2 Patients with intermittent claudication have significant impairment in ambulatory function, resulting in functional disability and significant lifestyle limitation.3,4

Treatment of these patients is aimed at reducing cardiovascular risk, increasing functional performance, and improving health-related quality of life. However, current drug treatments to improve walking distance have limited efficacy and only increase walking distance by between 12% and 60%510 (the only 2 drug treatments approved by the Food and Drug Administration for use in the United States, pentoxifylline and cilostazol, increase walking distance by 15% and 25%, respectively11).

We previously reported in a pilot trial that the angiotensin-converting enzyme (ACE) inhibitor ramipril is associated with significantly increased treadmill-assessed pain-free and maximum walking time.12 However, that trial was small, and the findings were restricted to patients with limiting infrainguinal disease without diabetes, who comprise approximately one-half of all patients with claudication.12 Other previous ACE inhibitor studies in patients with claudication have been equivocal, owing to issues including small sample size, short intervention duration, and absence of a placebo group.1218

The current investigator-initiated trial was conducted to examine the association of ramipril therapy for 24 weeks on walking distance and health-related quality of life as compared with placebo in a larger, more general PAD population including patients with diabetes and patients with aortoiliac as well as infrainguinal disease.

METHODS

The institutional review boards of the participating hospitals approved the protocol. Participants provided written informed consent, and the study was performed in accordance with the Declaration of Helsinki, Fifth Revision (2000). Data collection and interventions were performed at the Alfred Hospital (Melbourne), the Townsville Hospital (Townsville), and Royal Brisbane and Women's Hospital (Brisbane), Australia, between May 10, 2008, and August 23, 2011.

All patients were receiving usual care appropriate to their individual risk profile and symptoms, such as lipid-lowering therapy or antiplatelet therapy, and were supervised by their physicians throughout the trial. All patients also received lifestyle advice prior to commencing the trial.

Inclusion and Exclusion Criteria

The inclusion criteria were an ankle brachial index (ABI) of less than 0.90 at rest in at least 1 leg; history of intermittent claudication (unilateral or bilateral) and stable for the previous 6 months; and a stable medication regimen for at least 6 months. The exclusion criteria were resting brachial blood pressure of 160/100 mm Hg or greater; current use of either ACE inhibitors or angiotensin II receptor blockers or use of these drugs in the prior 6 months; current use of potassium-sparing diuretics or potassium supplements or use of these drugs in the prior 6 months; renal failure (serum creatinine level >2.3 mg/dL [200 μmol/L]); renal artery stenosis; previous coronary revascularization procedures, lower extremity revascularization procedures, or both; myocardial infarction in the previous 3 months; major surgery planned during the following year; critical limb ischemia and any condition other than PAD limiting walking ability, including limiting coronary artery disease, chronic obstructive pulmonary disease, and musculoskeletal conditions (assessed during physical examination and medical history performed by the study physician) (Figure).

Study Design, Randomization, and Masking

A tamper-proof randomization process generated by The Alfred Hospital Research Center, Melbourne, randomly assigned participants into blocks of 10 to receive either ramipril (Ramace, sanofi-aventis) (10 mg/d for 24 weeks) or matching placebo in a parallel-group, double-blind design.

All investigators, analysts, and patients were blinded to drug assignment as well as to baseline data when they performed follow-up measurements. No patient assigned to receive placebo crossed over to ramipril, or vice versa, during the trial. Medication adherence was measured by monthly pill counts.

Safety Reporting

Patients were advised about potential adverse effects and requested to report any adverse event. Safety was assessed by adverse-event monitoring, blood biochemistry analysis, measurement of vital signs, physical examination (at 3 weeks, 3 months, and 6 months following initiation of treatment), and monthly telephone calls.

Outcomes

Outcomes were measured before randomization and at the 6-month follow-up. The 2 prespecified primary outcomes were pain-free walking time (time to onset of claudication pain) and maximum walking time assessed by a standard treadmill exercise test. Secondary outcomes were ABI; stenosis severity assessed by duplex ultrasounds of the lower limb arteries; patient-reported symptoms and functional status assessed by the Walking Impairment Questionnaire (WIQ); and health-related quality of life assessed by the Short-Form 36 Health Survey (SF-36).

Treadmill Test. The standard constant-load treadmill exercise test was performed at a speed of 3.2 km/h and a grade of 12%.19 All patients underwent a single test at baseline and at follow-up. Consistent instructions were given in relation to hand support and upright walking posture. In Australia and Europe a constant-load treadmill test is the standard method for assessment of pain-free and maximum walking distance in patients with PAD. This method translates well to everyday walking ability, is reproducible,20 and has been used in several previous studies of drug effects on claudication distance.21 Constant-load and graded treadmill tests give comparable results in patients with claudication distances greater than 100 m, which characterized 95% of patients in our study.22

ABI Measurement. ABI was measured and calculated by the same investigator for all patient visits as the ratio of the highest systolic blood pressure in each ankle from the right and left posterior tibial or dorsalis pedis arteries, divided by the highest brachial systolic blood pressure.12

Duplex Ultrasonography. Scanning was performed by a single qualified and experienced vascular technologist, and all images were also assessed and analyzed by 2 independent experienced vascular physicians blinded to patient identity and treatment (κ = 0.94 for interobserver reliability). Peak systolic velocity in lower-limb vessel segments was measured to determine the grade of stenosis, as previously described.23 Volume flow was calculated from the lumen cross-sectional area and the integrated mean velocity.

Patient-Reported Functional Status. The WIQ24 is a PAD-specific measure of self-reported walking limitations with 3 domains; walking distance, walking speed, and stair climbing. Each domain is scored on a 0 to 100 scale, with higher scores indicating lesser symptoms and greater functional capacity. All patients completed the WIQ forms independently.

Health-Related Quality of Life. The SF-36 provides a comprehensive measure of the degree of disability experienced by the patient as a result of PAD25 and is reported as 2 aggregate summary measures, the Physical Component Summary and the Mental Component Summary. All patients completed the SF-36 forms independently.

Statistical Analyses

Baseline characteristics were compared using the χ2 test for categorical variables and 1-way analysis of variance for continuous variables. We compared 24-week changes from baseline in pain-free walking time, maximum walking time, ABI, and volumetric blood flow at the site of stenosis using an analysis of covariance model with terms for treatment and baseline values. Because of skewed distributions, differences in median values for the WIQ and SF-36 questionnaire data were compared using Kruskal-Wallis analysis of variance. Normally distributed data were expressed as means (SDs) or 95% CIs. Nonnormally distributed data were expressed as medians and interquartile ranges (IQRs) or medians with Hodges-Lehmann 95% CIs. All data were expressed as both the within-group change and the difference between the randomized groups.

To detect a 120-second change in walking time (assuming an SD of 300 seconds) and a 65-second change in pain-free walking time (assuming an SD of 161 seconds) with ramipril, 100 patients per group would provide a power of 80% at an α of .05.12 A 2-sided P value less than .05 was deemed significant. For the 200 participants who completed the 6-month follow-up, no data were missing for any clinical variable measured. Analyses were performed using SPSS version 19.0 (SPSS Inc).

Multiple imputation for missing 6-month data was performed using SPSS MI syntax (version 19.0) to obtain 5 separate imputed data points. These results were combined using the Aggregate syntax to enable intention-to-treat analysis. Imputation involved regression modeling methods in which imputed values were predicted on the basis of models including age, ABI, body mass index, sex, race, smoking status, baseline outcome values, leg symptoms, and comorbid conditions.

RESULTS

Of 921 potential participants approached for recruitment into the trial, 69 declined and 640 met an exclusion criterion, leaving 212 eligible participants (mean age, 65.5 [SD, 6.2] years) (Figure). Two hundred patients completed the 6-month follow-up. Intention-to-treat analyses including all randomized patients were performed.26 Multiple imputation was used to account for the 12 patients lost to follow-up owing to adverse events (n = 2 [0.9%]), persistent cough (n = 7 [0.3%]), or loss of interest (n = 3 [1.4%]), before completing 6-month follow-up testing (Figure).27,28

The ramipril (n = 106) and placebo (n = 106) groups were similar for all baseline parameters (Table 1). One hundred seventeen patients (55.2%) were taking antiplatelet therapy, and 117 (55.2%) were taking lipid-lowering therapy. The 200 patients completing the study adhered to the study medication (100% adherence rate), according to pill-count measures. All patients continued their individually tailored medications (usual care) throughout the trial, with no changes to these therapies in any patient. Six-month treatment with ramipril resulted in no significant change in any of the blood safety parameters (eTables 1). Twelve patients (5.6%) reported slight dizziness following initiation of treatment (9 [8.5%] in the ramipril group and 3 [2.8%] in the placebo group). Seven patients (6.6%) in the ramipril group experienced persistent cough and withdrew from the trial (Figure). Only 2 adverse events were reported in the placebo group. One patient reported chest pain once the trial medication was initiated. Another patient experienced pronounced ST-segment depression after completing the baseline treadmill exercise test, was newly diagnosed with unstable coronary artery disease, and underwent percutaneous coronary angioplasty. These 2 patients withdrew from the study (Figure).

Treadmill Test

Relative to placebo, ramipril was associated with a 75-second (95% CI, 60 to 89 seconds) increase in mean pain-free walking time (P < .001) (Table 2). Similarly, ramipril was associated with a 255-second (215 to 295 seconds) increase in maximum walking time (P < .001) (Table 2). These changes were independent of the small change in blood pressure that occurred with ramipril treatment.

Blood Pressure

Relative to placebo, ramipril was associated with decreases in blood pressure (systolic: −3.1 mm Hg [95% CI, −3.8 to −2.5 mm Hg]; P < .001 and diastolic: −4.3 mm Hg [95% CI, −5.2 to −3.4 mm Hg]; P < .001). The association of ramipril with improved treadmill walking times was similar in patients with blood pressures above and below 140/90 mm Hg ( eTable 2).

Ankle Brachial Index

Relative to placebo, there was a small increase in ABI following ramipril treatment, both at rest (0.10 [95% CI, 0.08 to 0.13]; P < .001) and after exercise (0.11 [95% CI, 0.08 to 0.14]; P < .001) (Table 2). At rest, this finding was attributable to a greater decline in brachial systolic pressure in the ramipril group. The association between ramipril and treadmill times was similar in patients with a change in ABI above and below the median (eTable 3).

Duplex Ultrasonography

In 111 patients with femoropopliteal disease (50 receiving placebo [45%] and 61 receiving ramipril [55%]), we also determined volume flow in the common femoral artery 5 cm proximal to the site of stenosis in the leg with the lower ABI (limiting leg). Volume flow was unaltered at the stenotic site in both the placebo and the ramipril groups (Table 2). However, relative to placebo, there was a significant increase in volume flow after ramipril therapy in the common femoral artery proximal to the site of stenosis (63 mL/min [95% CI, 55 to 71 mL/min]; P < .001) (Table 2).

WIQ Questionnaire

Relative to placebo, ramipril was associated with improvements in WIQ scores. The median distance score improved by 13.8 (Hodges-Lehmann 95% CI, 12.2 to 15.5), the speed score by 13.3 (Hodges-Lehmann 95% CI, 11.9 to 15.2), and the stair climbing score by 25.2 (Hodges-Lehmann 95% CI, 25.1 to 29.4) (P < .001 for all) (Table 2).

SF-36 Survey

The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6 to 11.4; P = .02) in the ramipril group relative to placebo. Ramipril was not associated with change in the overall SF-36 Mental Component Summary score (Table 2).

COMMENT

Although clinical trial data substantiate the efficacy of ramipril with regard to reduction in major cardiovascular end points in patients with PAD,30 ACE inhibition is not specifically recommended for the relief of intermittent claudication. To our knowledge, this is the first adequately powered randomized trial demonstrating that treatment with ramipril is associated with improved treadmill walking performance in patients with PAD.

Ramipril was associated with a 75-second (95% CI, 60 to 89 seconds) increase in treadmill-assessed pain-free walking time and a 255-second (95% CI, 215 to 295 seconds) increase in maximum walking time, which corresponds to a clinically significant increase in uphill walking distance of 184 m (95% CI, 155-213 m). The 77% and 123% increases in pain-free and maximum walking times, respectively, with ramipril are greater than those reported for other conventional drug therapies including pentoxifylline,6 cilostazol,9 dipyridamole,5,8 ticlopidine,5,8 beraprost,7 iloprost,31 naftidrofuryl,10 and statins,32 which are associated with increases in treadmill walking distance of no more than 60%. Of these drugs, only pentoxifilline and cilostazol are approved by the US Food and Drug Administration for treatment of walking impairment resulting from claudication, with cilostazol providing the greatest improvement (25%).11

The increase in WIQ scores suggests that ramipril improves patient-perceived ability to perform normal daily activities.33 Ramipril therapy was also associated with moderate improvement in the physical health component of the SF-36 score. Importantly, these associations were additional to those achieved with standard clinical management by a general practitioner or vascular specialist. Further benefits may be achieved by adherence to lifestyle recommendations including smoking cessation and regular exercise, as well as more aggressive medical management of cardiovascular risk factors.

Some previous claudication studies have shown a change in relation to the primary outcome measure (maximum walking time, pain-free walking time, or both) ranging from −7% to 48% in patients receiving placebo.6,31,32,3438 In certain studies, these changes (ranging from 32%-48%) appear to have reached statistical significance, although the level of statistical significance was not explicitly reported.6,32,37 In other studies reporting changes ranging from −7% to 24% with placebo,31,3436,38 statistical nonsignificance in the placebo group change could be inferred from the error terms. The inclusion of a large number of study sites, inclusion of patients with comorbid conditions such as angina pectoris, and changes in background therapy are all factors that may have contributed to greater variability in walking times in these studies. Factors contributing to the consistency and small magnitude of the increase in walking times in the placebo group of the current study include the low number of study sites (3), the recruitment of patients with stable intermittent claudication, the stability of concurrent medical therapies and lifestyle, and careful exercise testing procedures.

We previously reported greater increases in pain-free and maximum walking times with 10 mg of ramipril as compared with placebo (227 seconds and 451 seconds for pain-free and maximum walking time, respectively, with ramipril). The greater magnitude of the effects of ramipril in the previous study likely relates in part to the exclusion of patients with diabetes and aortoiliac disease. In the current study, the magnitude of the association of ramipril therapy with change in maximum walking time was greater in patients with femoropopliteal disease (286 seconds [95% CI, 280 to 293 seconds]) compared with those with aortoiliac disease (127 seconds [95% CI, 118 to 137 seconds]; P < .001) (eTable 4). There was no difference in the magnitude of the ramipril response in those with multi-level vs single-level disease (eTable 5). The broader inclusion criteria and larger study population make the current findings applicable to a more representative PAD population with claudication.

Mechanisms

ACE inhibitor therapy may mediate improved functional capacity through multiple mechanisms, including increased peripheral blood flow39 and adaptations in skeletal muscle structure and function, which likely enhance production of adenosine triphosphate.4044 Improved blood flow may be mediated via vasodilatation through reduction in angiotensin II, sympathetic inhibition, and improvement in endothelial function through preservation of bradykinin.

In the current study, there was an increase in volume flow at a patent site proximal to the site of stenosis but no change at the stenotic site. The absence of a flow change at the downstream stenotic site suggests that ramipril caused dilation of collateral vessels between the 2 sites or perhaps even formation of new collateral vessels (angiogenesis).45 Certain ACE inhibitors (including quinaprilat and perindopril) increase capillary density in animal models4649 via bradykinin accumulation, whereas ramipril therapy has been associated with increased expression of vascular endothelial growth factor in cardiac tissue.50 However, other ACE inhibitors have no significant effects on angiogenesis in humans and animals.46,51,52

ACE inhibition may promote adaptive changes in skeletal muscle, which improve the efficiency of oxygen and metabolic substrate uptake and utilization. In patients with chronic heart failure, both ACE inhibition and angiotensin type I receptor blockade have been associated with increased exercise capacity and a shift of the myosin–heavy chain protein isoforms in the gastrocnemius from the type II form toward the type I, slow aerobic, fatigue-resistant isoform.44 A shorter-duration intervention had no such effect.43

ACE inhibition also may have direct effects on glucose metabolism in skeletal muscle. ACE inhibition is known to enhance insulin signaling and glucose uptake into skeletal muscle,40 which could also improve walking ability. This effect is likely mediated via reduced metabolism of bradykinin and downstream effects on nitric oxide, which increases delivery of both insulin and glucose to muscle. In addition, bradykinin directly stimulates insulin-dependent and insulin-independent glucose uptake into muscle.41,42

However, whether ACE inhibitors really have a beneficial effect on skeletal muscle function and ultimately physical function remains controversial. Two intervention studies have shown that ACE inhibitors improve functional capacity in patients with impaired mobility53 or heart failure.54 Muscle mass and strength were preserved in users of ACE inhibitors in large longitudinal cohorts including the Women's Health and Aging Study (WHAS)55 and the Health ABC population cohort.56 However, additional clinical trials and observational studies57,58 have shown no associations of ACE inhibitor treatment with functional decline. Thus, there is not a consistent association between ACE inhibitor use and functional performance in patients without PAD, and further specifically designed studies are required.

Limitations

First, the beneficial associations of ramipril in the current trial may be maintained beyond 6 months, but the current study cannot address this issue. The Heart Outcomes Prevention Evaluation (HOPE)30 showed that ramipril has beneficial effects on morbidity and mortality, supporting longer-term treatment with ramipril in patients with PAD.

Second, the inclusion and exclusion criteria were designed to select a population of patients with stable PAD in whom we could ethically administer either a placebo or an ACE inhibitor intervention and obtain follow-up data at 6 months. The population was therefore restricted to the lower end of the blood pressure spectrum and excluded patients with other major comorbid conditions and any condition other than PAD limiting walking ability. Whether the findings are generalizable to individuals with higher blood pressure or to other ethnically diverse populations is unknown.

Third, although animal studies suggest that ACE inhibitors may have favorable effects on skeletal muscle, this was not examined.

In conclusion, among patients with intermittent claudication, 24 weeks of treatment with ramipril compared with placebo was associated with significant improvement in pain-free and maximum walking times, with improvement in patient-perceived walking performance as measured by WIQ scores and the physical health aspect of quality of life.

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Article Information

Corresponding Author: Anna A. Ahimastos, PhD, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria, 8008 Australia (a.ahimastos@alfred.org.au).

Author Contributions: Dr Ahimastos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ahimastos, Blombery, Kingwell.

Acquisition of data: Ahimastos, Walker, Askew, Leicht, Pappas, Golledge.

Analysis and interpretation of data: Ahimastos, Walker, Askew, Blombery, Reid, Golledge, Kingwell.

Drafting of the manuscript: Ahimastos, Reid, Kingwell.

Critical revision of the manuscript for important intellectual content: Ahimastos, Walker, Askew, Leicht, Pappas, Blombery, Reid, Golledge, Kingwell.

Statistical analysis: Ahimastos, Reid, Kingwell.

Obtained funding: Ahimastos, Kingwell.

Administrative, technical, or material support: Walker, Askew, Leicht, Pappas.

Study supervision: Ahimastos, Walker, Askew, Blombery, Golledge, Kingwell.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Blombery reported serving as a board member for, and receiving payment for lectures from, sanofi-aventis. Dr Golledge reported receiving grants or grants pending from the government of Queensland, the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, the BUPA Foundation, and Novartis; and receiving travel expenses to speak at national and international meetings. No other authors reported disclosures.

Funding/Support: This study was supported by the National Heart Foundation of Australia, the National Health and Medical Research Council of Australia, and the Operational Infrastructure Support Program of the Victorian State Government, Australia (Dr Ahimastos and Dr Kingwell).

Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Ramipril used in the study was purchased by the investigators.

Online-Only Material: The Author Audio Interview is available here.

REFERENCES
1.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG.TASC II Working Group.  Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).  J Vasc Surg. 2007;45:(suppl S)  S5-S67PubMedArticle
2.
Vodnala D, Rajagopalan S, Brook RD. Medical management of the patient with intermittent claudication.  Cardiol Clin. 2011;29(3):363-379PubMedArticle
3.
McDermott MM, Greenland P, Liu K,  et al.  Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment.  JAMA. 2001;286(13):1599-1606PubMedArticle
4.
McDermott MM, Liu K, Greenland P,  et al.  Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms.  JAMA. 2004;292(4):453-461PubMedArticle
5.
Castaño G, Más R, Gámez R, Fernández L, Illnait J. Effects of policosanol and ticlopidine in patients with intermittent claudication: a double-blinded pilot comparative study.  Angiology. 2004;55(4):361-371PubMedArticle
6.
Dawson DL, Cutler BS, Hiatt WR,  et al.  A comparison of cilostazol and pentoxifylline for treating intermittent claudication.  Am J Med. 2000;109(7):523-530PubMedArticle
7.
Lièvre M, Morand S, Besse B, Fiessinger JN, Boissel JP.Beraprost et Claudication Intermittente (BERCI) Research Group.  Oral beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial.  Circulation. 2000;102(4):426-431PubMedArticle
8.
Mannarino E, Pasqualini L, Innocente S, Scricciolo V, Rignanese A, Ciuffetti G. Physical training and antiplatelet treatment in stage II peripheral arterial occlusive disease: alone or combined?  Angiology. 1991;42(7):513-521PubMedArticle
9.
Pande RL, Hiatt WR, Zhang P, Hittel N, Creager MA. A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication.  Vasc Med. 2010;15(3):181-188PubMedArticle
10.
Spengel F, Clément D, Boccalon H, Liard F, Brown T, Lehert P. Findings of the Naftidrofuryl in Quality of Life (NIQOL) European study program.  Int Angiol. 2002;21(1):20-27PubMed
11.
Stevens JW, Simpson E, Harnan S,  et al.  Systematic review of the efficacy of cilostazol, naftidrofuyrl oxalate and pentoxifillin for the treatment of intermittent claudication.  Br J Surg. 2012;99(12):1630-1638Article
12.
Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA. Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial.  Ann Intern Med. 2006;144(9):660-664PubMedArticle
13.
Overlack A, Adamczak M, Bachmann W,  et al; Perindopril Therapeutic Safety Collaborative Research Group.  ACE inhibition with perindopril in essential hypertensive patients with concomitant diseases.  Am J Med. 1994;97(2):126-134PubMedArticle
14.
Roberts DH, Tsao Y, Linge K, McLoughlin GA, Breckenridge A. Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication.  Angiology. 1992;43(9):748-756PubMedArticle
15.
Schindler C, Mueller A, Bramlage P, Boecking W, Kirch W, Schweizer J. Comparison of selective AT1-receptor blockade versus ACE inhibition for restenosis prophylaxis in patients with peripheral occlusive arterial disease after stent angioplasty: a randomized, controlled, proof-of-concept study.  Angiology. 2007;58(6):710-716PubMedArticle
16.
Shahin Y, Mazari F, Chetter I. Do angiotensin-converting enzyme inhibitors improve walking distance in patients with symptomatic lower limb arterial disease? a systematic review and meta-analysis of randomised controlled trials.  Int J Surg. 2011;9(3):209-213PubMedArticle
17.
Spence JD, Arnold JM, Munoz C, Viswanatha A, Huff M, Derose G. Angiotensin-converting enzyme inhibition with cilazapril does not improve blood flow, walking time, or plasma lipids in patients with intermittent claudication.  J Vasc Med Biol. 1993;4(1):23-28
18.
Van de Ven LL, Van Leeuwen JT, Smit AJ. The influence of chronic treatment with betablockade and angiotensin-converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication: a comparative cross-over trial.  Vasa. 1994;23(4):357-362PubMed
19.
Sumner DS, Strandness DEJ Jr. The relationship between calf blood flow and ankle blood pressure in patients with intermittent claudication.  Surgery. 1969;65(5):763-771PubMed
20.
Degischer S, Labs KH, Aschwanden M, Tschoepl M, Jaeger KA. Reproducibility of constant-load treadmill testing with various treadmill protocols and predictability of treadmill test results in patients with intermittent claudication.  J Vasc Surg. 2002;36(1):83-88PubMedArticle
21.
Momsen AH, Jensen MB, Norager CB, Madsen MR, Vestersgaard-Andersen T, Lindholt JS. Drug therapy for improving walking distance in intermittent claudication: a systematic review and meta-analysis of robust randomised controlled studies.  Eur J Vasc Endovasc Surg. 2009;38(4):463-474PubMedArticle
22.
Labs KH, Nehler MR, Roessner M, Jaeger KA, Hiatt WR. Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded-load treadmill protocol.  Vasc Med. 1999;4(4):239-246PubMedArticle
23.
Sacks D, Robinson ML, Marinelli DL, Perlmutter GS. Peripheral arterial Doppler ultrasonography: diagnostic criteria.  J Ultrasound Med. 1992;11(3):95-103PubMed
24.
Regensteiner JG, Steiner JF, Hiatt WR. Exercise training improves functional status in patients with peripheral arterial disease.  J Vasc Surg. 1996;23(1):104-115PubMedArticle
25.
Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey Manual and Interpretation Guide. Boston, MA: The Health Institute; 1993
26.
Altman DG, Schulz KF, Moher D,  et al; CONSORT GROUP (Consolidated Standards of Reporting Trials).  The revised CONSORT statement for reporting randomized trials: explanation and elaboration.  Ann Intern Med. 2001;134(8):663-694PubMedArticle
27.
Harel O, Zhou XH. Multiple imputation: review of theory, implementation and software.  Stat Med. 2007;26(16):3057-3077PubMedArticle
28.
Spratt M, Carpenter J, Sterne JA,  et al.  Strategies for multiple imputation in longitudinal studies.  Am J Epidemiol. 2010;172(4):478-487PubMedArticle
29.
Murphy TP, Cutlip DE, Regensteiner JG,  et al; CLEVER Study Investigators.  Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study.  Circulation. 2012;125(1):130-139PubMedArticle
30.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342(3):145-153PubMedArticle
31.
Creager MA, Pande RL, Hiatt WR. A randomized trial of iloprost in patients with intermittent claudication.  Vasc Med. 2008;13(1):5-13PubMedArticle
32.
Mohler ER III, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.  Circulation. 2003;108(12):1481-1486PubMedArticle
33.
McDermott MM, Ades PA, Dyer A, Guralnik JM, Kibbe M, Criqui MH. Corridor-based functional performance measures correlate better with physical activity during daily life than treadmill measures in persons with peripheral arterial disease.  J Vasc Surg. 2008;48(5):1231-1237PubMedArticle
34.
Beebe HG, Dawson DL, Cutler BS,  et al.  A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.  Arch Intern Med. 1999;159(17):2041-2050PubMedArticle
35.
Creager MA, Olin JW, Belch JJ,  et al.  Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication.  Circulation. 2011;124(16):1765-1773PubMedArticle
36.
Elam MB, Heckman J, Crouse JR,  et al.  Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication.  Arterioscler Thromb Vasc Biol. 1998;18(12):1942-1947PubMedArticle
37.
Grossman PM, Mendelsohn F, Henry TD,  et al.  Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease.  Am Heart J. 2007;153(5):874-880PubMedArticle
38.
Money SR, Herd JA, Isaacsohn JL,  et al.  Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.  J Vasc Surg. 1998;27(2):267-275PubMedArticle
39.
Sonecha TN, Nicolaides AN, Kyprianou P,  et al.  The effect of enalapril on leg muscle blood flow in patients with claudication.  Int Angiol. 1990;9(1):22-24PubMed
40.
Henriksen EJ, Prasannarong M. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle [published online May 4, 2012].  Mol Cell EndocrinolArticlePubMed
41.
Isami S, Kishikawa H, Araki E,  et al.  Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway.  Diabetologia. 1996;39(4):412-420PubMedArticle
42.
Kishi K, Muromoto N, Nakaya Y,  et al.  Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway.  Diabetes. 1998;47(4):550-558PubMedArticle
43.
Schaufelberger M, Andersson G, Eriksson BO, Grimby G, Held P, Swedberg K. Skeletal muscle changes in patients with chronic heart failure before and after treatment with enalapril.  Eur Heart J. 1996;17(11):1678-1685PubMedArticle
44.
Vescovo G, Dalla Libera L, Serafini F,  et al.  Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition.  Circulation. 1998;98(17):1742-1749PubMedArticle
45.
Ebrahimian TG, Tamarat R, Clergue M, Duriez M, Levy BI, Silvestre JS. Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice.  Arterioscler Thromb Vasc Biol. 2005;25(1):65-70PubMed
46.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo.  Circulation. 1999;99(23):3043-3049PubMedArticle
47.
Rakusan K, Cicutti N, Maurin A, Guez D, Schiavi P. The effect of treatment with low-dose ACE inhibitor and/or diuretic on coronary microvasculature in stroke-prone spontaneously hypertensive rats.  Microvasc Res. 2000;59(2):243-254PubMedArticle
48.
Takeshita S, Tomiyama H, Yokoyama N,  et al.  Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.  Cardiovasc Res. 2001;52(2):314-320PubMedArticle
49.
Toblli JE, DeRosa G, Rivas C,  et al.  Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats.  J Hypertens. 2003;21(3):611-620PubMedArticle
50.
Zimmermann R, Kastens J, Linz W, Wiemer G, Schölkens BA, Schaper J. Effect of long-term ACE inhibition on myocardial tissue in hypertensive stroke-prone rats.  J Mol Cell Cardiol. 1999;31(8):1447-1456PubMedArticle
51.
Reneland R, Haenni A, Andersson PE, Andrén B, Lithell H. Skeletal muscle angiotensin-converting enzyme and its relationship to blood pressure in primary hypertension and healthy elderly men.  Blood Press. 1999;8(1):16-22PubMedArticle
52.
Scheidegger KJ, Nelissen-Vrancken MH, Leenders PJ, Daemen MJ, Smits JF, Wood JM. Structural adaptation to ischemia in skeletal muscle: effects of blockers of the renin-angiotensin system.  J Hypertens. 1997;15(12, pt 1):1455-1462PubMedArticle
53.
Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial.  CMAJ. 2007;177(8):867-874PubMedArticle
54.
Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J.PEP-CHF Investigators.  The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) study.  Eur Heart J. 2006;27(19):2338-2345PubMedArticle
55.
Onder G, Penninx BW, Balkrishnan R,  et al.  Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study.  Lancet. 2002;359(9310):926-930PubMedArticle
56.
Di Bari M, van de Poll-Franse LV, Onder G,  et al; Health, Aging and Body Composition Study.  Antihypertensive medications and differences in muscle mass in older persons: the Health, Aging and Body Composition Study.  J Am Geriatr Soc. 2004;52(6):961-966PubMedArticle
57.
Cesari M, Pedone C, Incalzi RA, Pahor M. ACE inhibition and physical function: results from the Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study.  J Am Med Dir Assoc. 2010;11(1):26-32PubMedArticle
58.
Gray SL, LaCroix AZ, Aragaki AK,  et al; Women's Health Initiative Observational Study.  Angiotensin-converting enzyme inhibitor use and incident frailty in women aged 65 and older: prospective findings from the Women's Health Initiative Observational Study.  J Am Geriatr Soc. 2009;57(2):297-303PubMedArticle
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