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Should all patients with peripheral arterial disease be treated with an angiotensin-converting enzyme inhibitor?
Mohammed Al-Omran MD MSc FRCSC, Thomas F Lindsay MDCM MSc FRCSC Section Editor: Subodh Verma MD PhD M Al-Omran, TF Lindsay. Should all patients with peripheral arterial disease be treated with an angiotensin-converting enzyme inhibitor? Can J Cardiol 2005;21(2):189-193.
Peripheral arterial disease (PAD) is a marker of advanced atherosclerosis with an elevated risk of cardiovascular mortality and morbidity. The modification of risk factors to improve the outcomes of patients with coronary artery atherosclerosis is proven and has become an accepted standard of care that is widely followed. Recent evidence from randomized controlled clinical trials has demonstrated the effectiveness of angiotensin-converting enzyme inhibitors as an important risk reduction therapy for patients with PAD. This therapy has yet to become well recognized and implemented in the PAD population. This article reviews the evidence that supports the use of angiotensinconverting enzyme inhibitors in patients with PAD to reduce the burden of the associated cardiovascular morbidity and mortality in this high-risk population.

Les patients atteints dartriopathie oblitrante priphrique devraient-ils tous tre traits aux inhibiteurs de lenzyme de conversion de langiotensine?
Lartriopathie oblitrante priphrique (AOP) est un marqueur dathrosclrose avance, associ un risque lev de morbidit et de mortalit dorigine cardiovasculaire. La modification des facteurs de risque visant amliorer ltat de sant des patients atteints dathrosclrose coronarienne a fait ses preuves et sest impose comme norme de soins au sein de la collectivit mdicale. Des donnes rcentes provenant dessais cliniques comparatifs avec hasardisation ont montr lefficacit des inhibiteurs de lenzyme de conversion de langiotensine (ECA) pour rduire de faon sensible les risques de complication chez les patients atteints dAOP. Il reste maintenant bien reconnatre le traitement et lappliquer dans la population concerne. Le prsent article passe en revue les donnes qui plaident en faveur du recours aux inhibiteurs de lECA chez les patients atteints dAOP afin de rduire le fardeau associ la morbidit et la mortalit dorigine cardiovasculaire dans ce groupe de patients fortement prdisposs ce type de troubles.

Key Words: ACE inhibitors; Peripheral arterial disease; Risk reduction

OVERVIEW OF PERIPHERAL ARTERIAL DISEASE

Background Peripheral arterial disease (PAD) is an arteriosclerotic occlusive disease of the aortoiliac, femoral, popliteal and tibial arteries. Clinical manifestations of this disease typically begin with intermittent claudication (IC) (1-3), and may progress in a small percentage of patients to disabling pain at rest, gangrene and ultimately limb loss (4). The risk factors for PAD are the same as those for atherosclerosis in general and include male sex, advanced age, cigarette smoking, hypertension, diabetes and hyperlipidemia (5-10). The prevalence of IC varies from 0.4% to 14.4% (1,11-14). This wide variation in prevalence can be explained by the age, sex and geographical location of the population studied and by the diagnostic technique used to identify patients with IC. An American population-based study (15) noted the prevalence of PAD to be 4.3% among individuals aged 40 years and older as defined by an anklebrachial index (ABI) measurement of less than 0.90 in either leg. This corresponds to five million adults over the age of 40 years. Among individuals 70 years of age and older, the prevalence increased dramatically to 14.5%. The Canadian prevalence of PAD is not known. However, use rates for the interventional procedures for patients with PAD have been studied in Ontario. The age- and sex-adjusted

rates for peripheral arterial bypass surgery, peripheral percutanous angioplasty and major amputations were 68.6, 65.2 and 38.3, respectively, per 100,000 population aged 45 years and older (16). Medical and surgical management of PAD is directed toward relieving symptoms, improving the quality of life, salvaging limbs, decreasing the risk of adverse cardiovascular events and reducing mortality. Currently, the treatment of PAD includes risk factor modification, exercise, foot care, and radiological and surgical intervention when required. Coexisting vascular disease PAD, coronary artery disease (CAD) and cerebrovascular disease are all manifestations of atherosclerosis and often coexist in the same patient. Patients with PAD, with or without symptoms, generally have widespread arterial disease and, therefore, are at a significantly increased risk of stroke, myocardial infarction (MI) and cardiovascular death (17). In patients with PAD, the prevalence of CAD varies between 35% and 60%, depending on the diagnostic modality used (history, clinical examination or electrocardiography) (3,5,11,18,19). Coronary angiography of patients with PAD identified a CAD prevalence of 92% in patients presenting for surgical management (20). CAD was classified as mild to moderate in 32% of the surgical cohort;

Division of Vascular Surgery, Toronto General Hospital, and the Department of Surgery, University of Toronto, Toronto, Ontario Correspondence: Dr Thomas F Lindsay, Toronto General Hospital, 200 Elizabeth Street, Eaton 5-306, Toronto, Ontario M5G 2C4. Telephone 416-340-4620, fax 416-340-5029, e-mail thomas.lindsay@uhn.on.ca Received for publication August 31, 2004. Accepted September 13, 2004 Can J Cardiol Vol 21 No 2 February 2005
2005 Pulsus Group Inc. All rights reserved

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advanced but compensated CAD for which coronary bypass was not yet necessary was found in 29% of patients; severe but correctable CAD was documented in 25% of patients; and severe, inoperable CAD was found in 6% of patients (20). Significant carotid disease has been found in 26% to 50% of patients with PAD as defined by carotid duplex scanning (21-24). These data confirm the diffuse systemic atherosclerosis present in individuals suffering from PAD. Outcomes The overall prognosis for patients with IC is considered to be favourable. The disease is stable in 70% to 80% of patients (25-28), although it is generally clinically accepted that only approximately 25% of claudicants will deteriorate (17,29). Reconstructive surgery is required in 1% to 10% of patients with IC to improve their circulatory flow (29). Amputation may be required in 1% to 2% of all patients (17). The longterm survival rates of these patients are 75%, 50% and 30% at five, 10 and 15 years, respectively (17), and most deaths result from CAD (17). However, for patients who present with critical limb ischemia, the prognosis is dramatically different. The primary amputation rate ranges from 10% to approximately 40% (30-33). The five-year survival rate ranges from 38% to 48% in patients treated operatively, and from 12% to 68% in patients requiring reoperative surgery (34). De Wess and Rob (35) found that virtually all patients (95%) who presented with ischemic gangrene and 80% of those presenting with rest pain were dead within 10 years. In patients with PAD, the most common cause of death is CAD (40% to 60%). Cerebrovascular disease accounts for 10% to 20% of deaths. Other vascular events, predominantly ruptured aortic aneurysms, account for 10% of the mortality. Only 20% to 30% of patients with PAD die of noncardiovascular causes (17). Predictors of increased mortality for patients with PAD are age (36-38), male sex (37,39), CAD (18,36,38), diabetes (18,19,26,35,40,41) and hypertension (18,26). Also, age (17,42), male sex (17,39), diabetes (5-9,43-45), hyperlipidemia (46,47) and smoking (7-9) are associated with increased risk for the development and local progression of PAD. A population-based study in Ontario (48) investigated the outcomes of limb revascularization procedures in patients with PAD from 1991 to 1998. A total of 15,824 patients underwent bypass operations. The five-year cumulative survival was 61.5% and the major amputation-free survival rate for patients who underwent bypass surgery was 83.4%. Multivariate models were used to simultaneously account for risk factors in predicting death and major amputation following revascularization procedures. Age (RR 1.054, 95% CI 1.051 to 1.057 [per each year of age]), male sex (RR 1.26, 95% CI 1.19 to 1.33), diabetes (RR 1.48, 95% CI 1.40 to 1.78) and CAD (RR 1.48, 95% CI 1.40 to 1.57) were associated with an increased risk of death following revascularization procedures. An increased risk of major amputation following revascularization procedures was associated with male sex (RR 1.22, 95% CI 1.12 to 1.34), increased age (RR 1.03, 95% CI 1.03 to 1.04 [per each year of age]), diabetes (RR 2.5, 95% CI 2.28 to 2.73) and CAD (RR 1.14, 95% CI 1.04 to 1.26). A limitation of this study was that adjustment of the outcomes for the effects of smoking (not recorded in the database) and hyperlipidemia (under-recorded in the database) could not be accurately defined. Although adverse outcomes for patients with PAD are well documented, awareness of this information among all physicians
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is believed to be low. This had led a group of experts to advocate for the creation of a national PAD public awareness program, including screening, prevention and treatment measures, to improve cardiovascular health (49).

ROLE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS IN PATIENTS WITH PAD

Risk factor modification plays an important role in improving the outcomes of patients with atherosclerosis, and conclusive evidence for patients with PAD has recently been established (50). Angiotensin-converting enzyme (ACE) inhibitor therapy has emerged as an important risk reduction therapy for patients with PAD (50). The role of ACE inhibitors in reducing mortality and cardiovascular events in high-risk patients with atherosclerosis has been identified in several randomized clinical trials (50-52). The results of these trials were consistent in demonstrating a reduction in mortality and cardiovascular events in patients with documented atherosclerosis. The Heart Outcomes Prevention Evaluation (HOPE) study (50) comprised 9297 patients, 55 years of age and older, who had evidence of vascular disease (history of CAD, PAD or cerebrovascular disease) or diabetes plus at least one cardiovascular risk factor (hypertension, hyperlipidemia, cigarette smoking or microalbuminuria). The patients were randomly assigned to receive an ACE inhibitor (ramipril 10 mg/day) or placebo for a mean of five years. The adjustment for other risk reduction therapies, such as antiplatelet and lipid-lowering agents, were undertaken at the time of randomization. Patients were excluded from the study if they had a history of congestive heart failure, left ventricular ejection fraction of less than 40% or uncontrolled hypertension, or if they were already receiving ACE inhibitors or vitamin E. The study was stopped prematurely because of the clear benefit of ramipril in reducing the primary outcome in the treated group. A 22% reduction in the primary outcome (composite of nonfatal MI, nonfatal stroke and death from cardiovascular causes) was identified in the ramipril-treated group. This was achieved with only a 2 mmHg to 3 mmHg reduction in blood pressure, suggesting that only a portion of the beneficial effect was secondary to lowering of blood pressure. Ramipril treatment also significantly reduced the risk of the secondary end points. MI, stroke, death from cardiovascular causes and revascularization (cardiac or peripheral) were reduced by 20%, 32%, 26% and 15%, respectively, in the ramipril-treated group. The beneficial effect of ramipril was also noted across all of the subgroups examined and became significant by two years in the study. In addition, significantly fewer patients in the ramipril group than in the placebo group had new-onset diabetes (reduced by 34%). Patients with PAD comprised 43.6% (4051 of 9297) of the study population in the trial. In those with PAD in the placebo group, 22% achieved the primary composite outcome compared with 14.3% of those treated with placebo who did not have PAD. This indicates the negative impact of PAD on the primary composite outcome. Those with PAD who were treated with ramipril benefited from therapy, with an RR of approximately 0.74. Therefore, 18 patients with PAD needed to be treated with ramipril for a period of 4.5 years to prevent one primary outcome event. It is important to note that 28.9% of the treatment group and 27.8% of the placebo group permanently discontinued the medication during the trial. A substudy of the HOPE trial (51) highlighted the impact of ramipril on the prevention of major cardiovascular events in
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TABLE 1 RR reduction effect of ramipril versus placebo in patients with peripheral arterial disease (PAD) from the Heart Outcomes Prevention Evaluation (HOPE) study
Primary outcome Clinical PAD (n=1725) (%) Subclinical PAD with ABI <0.6 (n=1391) (%) Subclinical PAD with ABI of 0.90.6 (n=727) (%) 25 23* 28 MI 25 27* 19* Cardiovascular mortality 25 24* 38 Stroke 28* 1* 66 All-cause mortality 25 19* 42 Revascularization 11* 9* 18* Diabetic Hospitalization complications for CHF 13* 17* 20* 19* 31* 34*

*Not statistically significant. Primary outcome refers to the composite of myocardial infarction (MI), cardiovascular mortality and stroke. ABI Ankle-brachial index; CHF Congestive heart failure. Data from reference 51

patients with PAD. ABI measurements were only available in 96.7% of patients (n=8986) who enrolled in the HOPE study. In this subanalysis, patients were classified as having either clinical or subclinical PAD. Clinical PAD was defined as either IC with an ABI of less than 0.9, or previous vascular intervention or limb amputation for PAD. Subclinical PAD was defined as an ABI of less than 0.9 and no symptoms. ABI levels were further categorized into three groups: an ABI greater than 0.9 was considered normal, an ABI of 0.9 to 0.6 was considered moderately pathological, and an ABI below 0.6 was classified as severely pathological. Clinical PAD was observed in 19.2% of patients (n=1725) and 23.6% of patients (n=2118) had subclinical PAD. Both clinical PAD and subclinical PAD with a low ABI at baseline were strong predictors of cardiovascular morbidity and mortality during the follow-up period. The mortality at 4.5 years from all causes in patients without PAD and with a normal ABI was 8.8% compared with 18.1% in those with clinical PAD. Those with moderate or severe ABI reductions and no symptoms of PAD had mortality rates of 12.8% and 14.7%, respectively. The association between a lower ABI and increased mortality persisted even after adjustment for age, sex and other risk factors (eg, hypertension, diabetes, previous MI or previous stroke) in a multivariate analysis using the Cox regression model. Ramipril therapy reduced the primary outcome (composite of nonfatal MI, nonfatal stroke and death from cardiovascular causes) by 25% (absolute risk reduction 5.7%; RR 0.75, 95% CI 0.61 to 0.92) among those with clinical PAD. Significant risk reductions were also observed for secondary end points for patients on ramipril therapy. MI, stroke, death from cardiovascular causes and revascularization (cardiac or peripheral) were reduced by 25%, 28%, 25% and 11%, respectively, among patients with clinical PAD who were on ramipril. Significant risk reductions were also observed for patients with subclinical PAD on ramipril. The primary outcome was reduced in the ramipril group by 27% for patients with subclinical PAD (RR 0.73, 95% CI 0.60 to 0.90). The RR reductions for cardiovascular events in patients with clinical and subclinical PAD are summarized in Table 1. The event rates were higher in those with an ABI of less than 0.9; thus, the absolute benefits of ramipril were approximately twice as large in this group (50 of 1000 events prevented) as in those with an ABI greater than 0.9 (24 of 1000 events prevented). Thus, when evaluating a patient with CAD for risk of future events, those with an ABI of less than 0.9 are more likely to suffer from cardiovascular death, MI or stroke, and will derive a greater benefit from ramipril therapy than will a patient without PAD. In the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) (52), 12,218 patients, 18 years of age and older, who had evidence of
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CAD were randomly assigned to perindopril 8 mg/day or placebo for a mean of 4.2 years. The adjustment for other risk reduction therapies, such as antiplatelet and lipid-lowering agents, was undertaken at the time of randomization. A higher percentage of patients in this recent trial were taking platelet inhibitors, beta-blockers and lipid-lowering agents than in the HOPE trial. Patients were excluded from the study if they had a history of congestive heart failure, hypotension, uncontrolled hypertension, renal insufficiency, serum potassium higher than 5.5 mmol/L or planned myocardial revascularization. The primary outcome (composite of nonfatal MI, cardiovascular death and cardiac arrest with successful resuscitation) was reduced by 20% in the perindopril group. Nonfatal MI was significantly reduced by 22% in the perindopril group. The beneficial effect of perindopril was also observed consistently in all subgroup analyses, although it was not significant for some subgroups. In this study, the PAD group represented 7.2% (883 of 12,218) of the study population and, unfortunately, no subanalysis of this group was performed. Benefits of ACE inhibitors have also been identified in patients treated surgically for PAD. A retrospective cohort study by Henke et al (53) examined the effect of ACE inhibitors on the outcomes following infrainguinal bypass for PAD. In 293 consecutive patients (mean age of 64 years) who underwent 338 infrainguinal bypass procedures were assessed to determine the effects of risk reduction therapy on the outcomes, including graft patency, limb salvage and mortality. Indications for infrainguinal arterial bypass were claudication in 30% (n=88), critical limb ischemia in 66.2% (n=194) and popliteal aneurysm in 4.8% (n=14). ACE inhibitors were taken by 54% of the patients. Kaplan-Meier life-table analysis demonstrated an overall mean survival of 53 months in the entire population. The analysis of medication effects showed that ACE inhibitor use was associated with improved survival. The difference was significant using the log-rank test (P=0.05). Univariate analysis of ACE inhibitor use correlated with improved graft patency and decreased amputation rates. However, this effect was not shown in a multivariate analysis. In this study, statins, beta-blockers and anticoagulants other than acetylsalicylic acid were not significantly associated with improved survival. This retrospective study in a highly selected surgical PAD population demonstrated the survival benefit of ACE inhibition. A number of mechanisms have been suggested to be responsible for the powerful risk reduction offered by ACE inhibitors. At the level of the endothelium, ACE inhibitors prevent the production of angiotensin-II, attenuating the proinflammatory, proatherosclerotic and prothrombotic effects of angiotensin-II. On the other hand, by blocking ACE, these agents prevent bradykinin degradation. Bradykinin is a key
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vascular protectant, by virtue of upregulating nitric oxide release, facilitating ischemic preconditioning and promoting fibrinolysis. In addition to the aforementioned mechanisms, ACE inhibitors reduce oxidative stress, reducing the fraction of oxidized low density lipoprotein cholesterol, which is key to the progression of atherosclerosis. At the level of vascular smooth muscle, ACE inhibitors reduce smooth muscle proliferation, migration and neointimal formation, and reduce matrix metalloproteinase levels, facilitating the stabilization of vulnerable plaques. ACE inhibitors also have powerful effects on the cardiac myocyte, preventing adverse remodelling and reducing left ventricular hypertrophy. Importantly, these effects appear to occur, in part, through a blood pressure-independent effect. The reader is referred to excellent reviews (54-57) in this area REFERENCES
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for further in-depth analysis of the mechanistic basis of the ACE-atherosclerosis connection.

CONCLUSIONS
PAD is a marker of advanced atherosclerosis with an elevated risk of cardiovascular mortality and morbidity. Therefore, evidence-based risk reduction therapy should be implemented to prevent adverse cardiovascular events and to prolong survival. The current evidence demonstrates that the use of ACE inhibitors in patients with PAD, along with the other proven risk reduction therapies, such as smoking cessation, antiplatelet and lipid-lowering agents, must be offered to reduce the burden of the associated cardiovascular morbidity and mortality in this high-risk population.

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