However , lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure
BACKGROUND Peripheral arterial disease ( PAD ) causes considerable morbidity and mortality .
Hypertension is a risk factor for PAD .
Treatment for hypertension must be compatible with the symptoms of PAD .
Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers .
Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD .
This is the second up date of a Cochrane review first published in 2003 .
OBJECTIVES To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death , symptoms of claudication and critical leg ischaemia , and progression of atherosclerotic PAD as measured by ankle brachial index ( ABI ) changes and the need for revascularisation ( reconstructive surgery or angioplasty ) or amputation .
Brief Communication: Ramipril Markedly Improves Walking Ability in Patients with Peripheral Arterial Disease
Context Few therapies substantially reduce symptoms and improve exercise performance in patients with peripheral arterial disease ( PAD ) . Contribution In this double-blind trial , investigators r and omly assigned 40 older adults without diabetes and with symptomatic PAD to receive either ramipril or placebo , 10 mg once daily for 24 weeks . Compared with placebo , ramipril increased maximum and pain-free walking time and walking speed and distance . Caution s The trial was small and involved selected patients with limited mobility and exercise tolerance . Implication s Ramipril may improve symptoms in some patients with PAD . The Editors This article has been retracted . See Notice of Retraction . Peripheral arterial disease ( PAD ) is a common disorder , with 12 % of adults older than 50 years of age having an anklebrachial index ( ABI ) that is diagnostic of PAD ( < 0.9 ) ( 1 ) . Approximately one third of these patients experience intermittent claudication during walking , limiting normal activities . Medical treatments to improve walking distance are limited . The angiotensin-converting enzyme ( ACE ) inhibitor ramipril reduced cardiovascular morbidity and mortality compared with placebo in patients with established atherosclerotic disease , including PAD , in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) . This effect seemed to be independent of blood pressure reduction ( 3 ) and may relate to the known benefits of ACE inhibitors on both coronary and brachial endothelial function ( 4 ) . No previous controlled studies have investigated the effect of ACE inhibitors on symptoms of intermittent claudication . Given the positive effects of ramipril in the HOPE trial and its convenient once-daily dosing formulation , we hypothesized that therapy with ramipril would improve intermittent claudication symptoms . We aim ed to examine the effect of 6-month ramipril therapy on walking distance and claudication pain in a defined group of patients with claudication due to infrainguinal PAD by using a double-blind , r and omized , placebo-controlled design . Methods This article has been retracted . See Notice of Retraction . We screened 152 patients with PAD from general practice clinics in the Melbourne , Australia , metropolitan area ( Figure 1 ) . Of them , 40 patients ( mean age , 66 years [ SD , 4 ] ) were recruited and completed the trial . All patients gave written informed consent to participate in the study . The Ethics Committee of the Alfred Hospital , Melbourne , Australia , approved the study , and we performed the study in accordance with the Declaration of Helsinki 2000 . All participants had an ABI less than 0.9 at rest in at least 1 leg ; had a history of intermittent claudication ( unilateral or bilateral ) , which was stable for 6 months ; had evidence of superficial femoral artery stenosis or occlusion on duplex ultrasonography ; had blood pressure of 160/90 mm Hg or less ; had a stable medication regimen for at least 6 months ; and had not previously been treated with ACE inhibitors . We excluded patients with limiting coronary artery disease , renal failure , history of hypertension , or type 2 diabetes mellitus . Figure 1 . Flow of patients through the study . Computer-generated numbers specified the allocation sequence . A tamper-proof r and omization process generated by the hospital research center r and omly assigned participants into blocks of 10 to receive either ramipril ( Tritace , Aventis Pharma Pty . Ltd. , Macquarie Park , Australia , 10 mg once daily for 24 weeks ) or placebo ( 10 mg once daily for 24 weeks ) in a parallel-group , double-blind design . Both investigators and patients were blinded to drug assignment . Furthermore , investigators did not have access to baseline data when they performed follow-up measurements and patients were not asked which treatment they thought they were receiving . No patient assigned to placebo crossed over to ramipril during the trial or vice versa . We advised participants to maintain all aspects of their lifestyle throughout the trial and requested them to refrain from exercise , smoking , and caffeine for 24 hours before all testing . On the morning of testing , patients rested in a supine position for 15 minutes in a quiet room before the measurements . We assessed blood pressure , ABI , walking distance , duplex ultrasounds of leg arteries , and the Walking Impairment Question naire ( WIQ ) scores before and after both interventions . We advised patients about potential side effects and requested that they report any adverse event to the study coordinator . All patients performed a treadmill exercise test at a speed of 3.2 km/h and a grade of 12 % ( 5 ) , and we recorded pain-free walking time ( time to onset of claudication pain ) and maximum walking time . In our study , all patients reached a maximal level of claudication pain that limited exercise during the grade d treadmill test . The WIQ was developed and vali date d against treadmill walking and is used to evaluate limitations in community-based walking ability ( 6 ) . The WIQ assessed walking distance , speed , and stair-climbing ability , using a weighted st and ardized formula and returning a summary score between 0 % and 100 % ( 6 , 7 ) . Statistical Analyses All analysts were blinded to treatment assignment , and an independent investigator double-checked all measurement calculations and data base entries . The study was powered to detect a 180-second change in maximum walking time with ramipril , assuming a st and ard deviation of 250 seconds ( = 0.05 [ 2-sided ] ; power , 86 % ) . We compared 24-week changes from baseline in pain-free walking time , maximum walking time , and WIQ scores between treatments by using an analysis of covariance model with terms for treatment and baseline value as the analysis end points . We log-transformed the WIQ data to achieve a normal distribution before analysis . We conducted all statistical analyses by using Stata software , version 8.2 ( Stata Corp. , College Station , Texas ) . We expressed normally distributed data as means ( SDs ) or 95 % CIs and non-normally distributed data as medians ( ranges ) . A P value less 0.05 was deemed to be significant . No data were missing for any clinical variable measured in our study . Role of the Funding Sources This work was funded by the National Health and Medical Research Council of Australia . Aventis Pharma Pty . Ltd. provided ramipril ( Tritace ) and matching placebo capsules but provided no other funding for the study or to the investigators . The funding sources had no role in the design , conduct , or reporting of the study or in the decision to su bmi t the manuscript for publication . Results This article has been retracted . See Notice of Retraction . The ramipril and placebo groups were similar in age , other cardiovascular risk factors , medication use , and PAD severity , as evidence d by clinical symptoms ( walking times ) , WIQ scores , and resting ABI ( Table ) . No patient was taking cilostazol or pentoxifylline . On duplex ultrasonography , 6 of 40 patients had a superficial femoral artery occlusion ( 2 placebo patients and 4 ramipril patients ) , and the remaining patients had stenotic disease in the superficial femoral artery . Only 25 % of patients were taking antiplatelet or lipid-lowering therapy . No adverse events were reported . Table . Baseline Characteristics AnkleBrachial Index Ramipril  significantly increased ABI both at rest ( change with placebo , 0.05 mm Hg [ SD , 0.04 ] ; change with ramipril , 0.07 mm Hg [ SD , 0.08 ] ; P < 0.001 ) and after exercise ( change with placebo , 0.04 mm Hg [ SD , 0.05 ] ; change with ramipril , 0.08 mm Hg [ SD , 0.14 ] ; P < 0.001 ) . At rest , this increase was due to reduction in brachial systolic blood pressure with ramipril treatment ( 0.85 mm Hg [ SD , 1.57 ] vs. 5.05 mm Hg [ SD , 2.33 ] ; P < 0.001 ) rather than an increase in limiting leg pressure ( 0.75 mm Hg [ SD , 1.71 ] vs. 0.15 mm Hg [ SD , 1.27 ] ; P= 0.26 ) . After exercise , both a reduction in brachial pressure ( change with placebo , 0.30 mm Hg [ SD , 2.45 ] ; change with ramipril , 6.80 mm Hg [ SD , 6.07 ] ; P < 0.001 ) and an increase in limiting leg pressure ( change with placebo , 5.40 mm Hg [ SD , 7.56 ] ; change with ramipril , 7.10 mm Hg [ SD , 4.59 ] ; P < 0.001 ) contributed to the increase in ABI . Treadmill Test After adjustment for the baseline pain-free walking time , mean pain-free walking time after ramipril treatment was 227 seconds ( 95 % CI , 175 seconds to 278 seconds ; P < 0.001 ) longer than after placebo treatment ( Figure 2 ) . Similarly , maximum walking time significantly improved over the 24-week treatment period by 451 seconds ( CI , 367 seconds to 536 seconds ; P < 0.001 ) in the ramipril group after adjustment for baseline values ( Figure 2 ) . The lack of change observed over the 24-week treatment period in the placebo group ( change in mean walking time , 10 seconds [ SD , 9 ] [ CI , 14 seconds to 6 seconds ] ; P < 0.001 ) may reflect both the advanced age of participants and the fact that they all had limiting infrainguinal disease , which would probably give more reproducible treadmill data than aortoiliac disease . In addition , we asked patients to maintain all aspects of their lifestyle throughout the trial . Figure 2 . Effect of ramipril on maximum treadmill walking times . Walking Impairment Question naire Ramipril improved WIQ median distance score from 5 % ( range , 1 % to 39 % ) to 21 % ( range , 12 % to 58 % ) ( P < 0.001 ) , speed score from 3 % ( range , 3 % to 39 % ) to 18 % ( range , 8 % to 50 % ) ( P < 0.001 ) , and stair-climbing score from 17 % ( range , 4 % to 80 % ) to 67 % ( range , 38 % to 88 % ) ( P < 0.001 ) . Duplex Ultrasonography Volume flow was unaltered in the limiting leg at the stenotic site . However , ramipril significantly increased volume flow in the common femoral artery proximal to the site of stenosis in both the limiting leg ( change with placebo , 0.014 L/min [ SD , 0.022 ] ; change with ramipril , 0.017 L/min [ SD , 0.034 ] ; P= 0.008 ) and the nonlimiting leg ( change with placebo , 0.006 L/min [ SD , 0.041 ] ; change with ramipril , 0.019 L/min [ SD , 0.019 ] ; P= 0.035 ) . Discussion This article has been retracted . See Notice of Retraction . Our study shows that
However , lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure
BACKGROUND Peripheral arterial disease ( PAD ) causes considerable morbidity and mortality .
Hypertension is a risk factor for PAD .
Treatment for hypertension must be compatible with the symptoms of PAD .
Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers .
Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD .
This is the second up date of a Cochrane review first published in 2003 .
OBJECTIVES To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death , symptoms of claudication and critical leg ischaemia , and progression of atherosclerotic PAD as measured by ankle brachial index ( ABI ) changes and the need for revascularisation ( reconstructive surgery or angioplasty ) or amputation .