February 06, 2013, Vol 309, No. 5

1. February 06, 2013, Vol 309, No. 5

2. PAD • Europe and North America: 27 MILLIONhave • peripheral artery disease (PAD) * • intermittent claudication occurs in 1/3of patients • typically presents as pain within leg occurs during • walking but is relieved by rest § Germany >65 age, men 19,8%, women 16,8%. (getABI Studie 2004) 45 - 75 age, men 6,4%, women 5,1%. (Heinz-Nixdorf-Recall-Studie, 2006) • intermittent claudication • significant impairment in ambulatory function resulting in functional disability and significant lifestyle limitation • Treatment • - reducing cardiovascular risk • - increasing functional performance • - improving health-related quality of life • Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007; 45(suppl S):S5-S67. • § Medical management of the patient with intermittent claudication. Cardiol Clin. 2011;29(3):363-379.

3. current drug treatments to extend the walking distance: • PDE -Inhibitors: • Cilostazol (Pletal) + • Pentoxifyllin * • 5HT2-Receptor -Inhibitor: • Naftidrofuryl (Dusodril) $ • increase walking distance by 12% to 60% • 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- 1638. • + community-based walking ability, and health-related quality of life in patients, with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials. J • Am Geriatr Soc 2002;50(12):1939-46. • $ Boccalon H, Lehert P, Mosnier M. [Effect of naftidrofuryl on physiological walking distance in patients with intermittent claudication]. Ann Cardiol Angeiol (Paris) 2001;50(3):175-82.

4. objective To determine the efficacy of ramipril for - improving walking ability - patient perceived walking performance - quality of life outcome • measured before randomization and at the 6-month followup. • primary outcomes: • pain-free walking time (time to onset of claudication pain) • Maximum walking time assessed by a standard treadmill exercise test. • secondary outcomes: • ABI • stenosis severity assessed by duplex ultrasounds of the lower limb arteries; • patient-reported symptoms • functional status (Walking Impairment Questionnaire (WIQ)) • Healthrelated Quality of life (SF- 36 Health Survey (SF-36))

5. Patient-Reported Functional Status walking impairment questionnaire (WIQ24)

6. Health-Related Quality of Life SF-36 Health Survey

7. design • randomized controlled trial • double-blind design • Alfred Hospital Research Center, Melbourne, 3 hospitals in Australia • May 2008 - August 2011 ramipril (Ramace, sanofi-aventis) 10 mg/d for 24 weeks vs placebo

8. ankle brachial index (ABI) of less than 0.90 at • history of intermittent claudication (unilateral or bilateral) and stable for the previous 6 months; • a stable medication regimen for at least 6 months. • brachial blood pressure ≥160/100mmHg • 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 mol/L]) • renal artery stenosis • previous coronary revascularization procedures • lower extremity revascularization procedures • 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) Inclusion Exclusion

9. results 212 p eligible participants 200 p completed the 6-month fu _____ - 12 p adverse events (n=2 [0.9%]), persistent cough (n=7 [0.3%]), loss of interest (n = 3 [1.4%]),

10. bc ramipril (n=106) and placebo (n=106) groups were similar for all baseline parameters

11. outcomes Abbrev.: PFWT, pain-free walking time; MWT, maximum walking time;

12. discussion ramipril after 24 weeks: 77% (PFWT) 123% (MWT) increase WIQ scores ( +141%)  improves patient perceived ability to perform normal daily activities. Increase SF-36 score ( +20%)  moderate improvement in the physical health component • Increase volume flow at the patent site proximal to the stenosis ( +8.3 %) • 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) Abbrev.: PFWT, pain-free walking time; MWT, maximum walking time;

13. discussion pentoxifylline after 24 weeks: 54% (MWT) cilostazol 9 randomized, controlled trials, after 24 weeks: 50.7% policosanol after 20 weeks: 59% (MWT) ticlopidine after 20 weeks: 60% (MWT) beraprost after 24 weeks: 53% (PFWT) iloprost after 24 weeks: 4% (MWT) naftidrofuryl 8 randomized, controlled trials: after 3-12 month: ~ 50% statins after 12 months: 34% (MWT) placebo 20 – 48 weeks: -7% to 48% (PFWT, MWT) ramipril after 24 weeks: 77% (PFWT) 123% (MWT) Abbrev.: PFWT, pain-free walking time; MWT, maximum walking time;

14. ACE inhibitors • may mediate improved functional capacity increased peripheral blood flow • via vasodilatation through • - reduction in angiotensin II • - sympathetic inhibition • - improvement in endothelial function (preservation of bradykinin) • - quinaprilat, perindopril: increase capillary density via bradykinin • accumulation (animal models) • ramipril: increased expression of • vascular endothelial growth factor (in cardiac tissue) • may promote adaptive changes in skeletal muscle, which improve the • efficiency of oxygen and metabolic substrate uptake and utilization, enhance • production of adenosine triphosphate • - is known to enhance insulin signaling and glucose uptake into skeletal muscle, • However, other ACE inhibitors have no significant effects on angiogenesis in humans and animals.

15. 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;9:209–213. „The evidence regarding ACE inhibition efficacy on treadmill walking distance in patients with intermittent claudication is contradicting and lacked properly powered RCTs. However, based on this study, ACEIs did not improve treadmill walking distance and ABPI in patients with symptomatic lower limb arterial disease. Further research from properly powered RCTs is needed“ Women’s Healthand Aging Study (WHAS) Health ABC population cohort „To our knowledge, this is the first adequately poweredrandomized trial demonstrating that treatment with ramipril is associated with improved treadmill walking performance in patients with PAD.“

16. limitations: • what is beyond 6 months ? • cohort: • designed to select a population of patients with stable PAD • restricted to the lower end of the blood pressure spectrum • excluded patients with other major comorbid conditions conclusion: • 24 weeks ramipril 10 mg/d comp.with placebo was associated with: • significant improvement in pain-free and maximum walking times • with improvement in patient-perceived walking performance • with improvement in the physical health aspect of quality of life

17. February 06, 2013, Vol 309, No. 5