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Eur J Vasc Endovasc Surg 35, 701e708 (2008) doi:10.1016/j.ejvs.2008.01.007, available online at http://www.sciencedirect.com on

REVIEW

Management of Hypertension in Peripheral Arterial : Does the Choice of Drugs Matter?

D.R.J. Singer1,2* and A. Kite2

1Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, and 2University Hospital, Coventry CV2 2DX, United Kingdom

Cardiovascular disease and are major life-threatening problems in patients with atheromatous peripheral arterial disease (PAD). This review focuses on management of hypertension in the context of cardiovascular risk in patients with PAD. PAD is underdiagnosed and hypertension in PAD is often poorly managed. Current evidence supports a low threshold for pressure treatment in PAD and intensive control to reduce the high risk of and death in patients with PAD. Optimal treatment targets should be <140/85 mmHg, with the lower target of <130/80 mmHg in the presence of diabetes mellitus or chronic renal disease. Class-specific selection of anti-hypertensive treatments in PAD should be based on caution in relation to co-existing renovascular disease and indi- cations and contraindications based on other significant co-morbidity. There is a pressing need for primary end-point stud- ies targeted specifically at patients with PAD. In particular, prospective studies in PAD are needed to obtain evidence for benefits from specific blood pressure classes of treatment as well as the optimal blood pressure treatment target level. These studies should consider impact in PAD of different demographic, , and co-morbidity profiles. Ó 2008 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Keywords: Atheromatous peripheral disease; Hypertension; Cardiovascular risk.

Introduction Level of evidence

Hypertension is a key risk factor for the development A major limitation of the literature on this topic is that of atheromatous peripheral arterial disease (PAD). In the evidence largely derives from sub-groups with patients presenting with PAD, hypertension is a ma- PAD studied within major outcome trials for patients jor associated cardiovascular risk factor, present in with high overall cardiovascular risk factor burden. up to 55% patients with PAD.1 Hypertension also There are no within treatment class comparisons of ef- increases risk of cardiovascular disease (CVD) com- fects on PAD-related disease end-points. plications and mortality in patients with established PAD. Up to 5% of hypertensive patients have been Why worry about high blood pressure in peripheral reported to have clinical evidence of peripheral arterial disease? artery disease at presentation, with a marked age- related increase in hypertension associated PAD.2 Peripheral arterial disease is a manifestation of sys- The main aim of this review is to consider choice temic that is common and often un- of treatment in the management of hypertension in der-diagnosed, and yet is associated with a high risk patients with PAD. of death and disabling ischaemic events. Patients with PAD are at risk of blood pressure-attributable pro- *Corresponding author. D. R. J. Singer, Professor of Clinical Pharma- gression of the peripheral vascular problems. PAD is cology & Therapeutics, Clinical Sciences Research Institute, War- also an independent predictor of increased risk of car- wick Medical School, University of Warwick, University Hospital, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom. diovascular and cerebrovascular death, with high 3,4 E-mail address: [email protected] blood pressure a major reversible risk factor.

1078–5884/000701 + 08 $34.00/0 Ó 2008 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. 702 D. R. J. Singer and A. Kite

Hypertension and prevalence of PAD angiographic study of 629 patients with PAD, hyper- tension was found in 63% of the patients in the group As for CVD, the major underlying risk factors for PAD with renal artery compared with 41% of con- are , hypertension, abnormal lipid trols.11 There are large differences between studies in e profile and mellitus.5 7 Untreated hyperten- prevalence of RAS in PAD. One explanation is that sion, and treated but uncontrolled hypertension, are some studies are retrospective. Geographical differ- important risk factors for PAD, after adjustment for ences in ethnicity and risk factor burden may contrib- other risk factors, with around a doubling in odds ra- ute, as may definitions of severe RAS, some reports tio for presence of ABPI [ankle brachial pressure in- using at least 50% others at least 60% stenosis as thresh- dex] evidence of PAD, similar to the impact of old definitions. As for other patients with hypertension, previous smoking, diabetes mellitus, or mild renal patients with PAD may have other secondary causes of failure.6 Systolic blood pressure after multivariate hypertension including endocrine problems, such as analysis conferred an odds ratio for PAD of 1.3(CI primary and diabetes mellitus.12 1.2e1.5) per 10 mmHg systolic pressure.7 It is impor- tant therefore to consider ABPI monitoring in older and PAD hypertensive patients especially those with cardiovas- cular disease. There is controversy as to whether renal artery imag- ing should be routinely performed in patients with Hypertension under treated in PAD PAD and hypertension. PAD is an independent pre- dictor of risk of vascular death however it is unclear Blood pressure management in PAD tends to be poor. whether aggressive treatment of patients with PAD 13 In PARTNERS,5 hypertension was less often treated in and incidental RAS leads to clinical benefits. A prag- new (84%) and prior PAD (88%) compared to treat- matic approach is to image renal in patients ment of hypertension in subjects with CVD (95%; with hypertension and more severe PAD, or in P < 0.001). This poor management extends to treat- patients with PAD and resistant hypertension and/ ment of other cardiovascular risk factors in subjects or renal impairment, in particular when there is pro- with PAD.5 gressive decline in renal function. The incidence of RAS increases with increasing severity of PAD. After adjustment for age and hypertension, RAS incidence Ethnicity, hypertension and PAD was 4 times greater in patients with 3e4 peripheral ar- teries affected.9 Not all RAS is functionally significant. 8 The GENOA study reported that in older African- However RAS is a major contributory cause of hyper- Americans, the prevalence of diabetes, hypertension tension in patients with PAD, prevalence dependent and clinical PAD was higher and ABPI lower than on severity of renal artery narrowing. Wachtell in non-Hispanic white subjects. African-American et al.,10 using aortography in 100 patients with severe ethnicity was a predictor of lower ABPI and clinical peripheral ischaemia found 81% [25/31] of patients PAD after adjusting for age and hypertension. A with RAS had hypertension. 13/14 patients (93%) higher prevalence of PAD in non-Hispanic black with a renal artery lumen reduction of >50% had hy- men and women, and Mexican-American women pertension (P 0.001) compared with 12/17(71%) for than non-Hispanic white men and women was re- renal artery lumen diameter reduced by <50%. ported in NHANES.6 Higher risk ethnic groups should assessed for presence of PAD and particular attention paid to managing cardiovascular risk factors Lifestyle and Blood Pressure in ethnic groups at higher risk of PAD. Lifestyle measures are effective in preventing devel- opment and reducing progression of hypertension.14 in Patients with In the absence of specific studies in PAD, it would Peripheral Arterial Disease be pragmatic to advise patients to adopt a multiple life style approach to management of hypertension It is important to identify possible underlying causes in the context of overall cardiovascular risk. Reducing so that specific treatment may be targeted against intake below 100 mmol/day, combined with causes of hypertension where identified. - the Dietary Approaches to Stopping Hypertension tous renal artery stenosis (RAS) is a common underly- (DASH) diet, is more effective than either approach ing cause of hypertension in PAD.9,10 In a prospective alone in reducing both onset of hypertension and

Eur J Vasc Endovasc Surg Vol 35, June 2008 Hypertension and Peripheral Arterial Disease 703 blood pressure in patients with milder hyperten- beta-blockade with . Adding bisoprolol re- sion.14 The DASH diet includes increased intake of duced cardiac death or myocardial after sur- fruits, vegetables, low- dairy , , cal- gery [0$30 (95% CI: 0$11e0$83)]. However the design cium, magnesium, dietary fibre and protein and in- was open and beta-blockade was prescribed for car- cludes whole grains, poultry, fish, and nuts. It also dio-protection, not hypertension. A separate prospec- includes less , sweets, and sugar-containing tive observational study22 reported that, in the drinks than a typical Western diet.14 Long term reduc- survivors of , patients with inter- tion in dietary intake by 30e40 mmol/day in pa- mittent not treated with beta-blockers had tients with pre-hypertension reduced both blood 3-fold mortality excess versus those receiving beta- pressure and cardiovascular events.15 blockers. There is clinical interest in potential advan- tages of beta-blockers such as or with the additional property of mediated -based treatment by nitric oxide release or anti-oxidant properties.23 Double-blind, randomised controlled studies are Mild distal tubular in younger and elder needed to find to whether this additional mechanism populations with uncomplicated hypertension reduce confers end-point benefits over other types of beta- a wide range of CVD endpoints.16 A was blocker in patients with PAD. It is unclear whether used within the INVEST Trial (see below) as add-on cardio-protection applies to beta-blockade targeted at treatment, with evidence of overall endpoint benefit hypertension in PAD, beyond that conferred by other from intensive blood pressure lowering.17 In patients blood pressure-lowering treatments. taking thiazide treatment it is important to monitor Although there are concerns about new onset of dia- blood glucose, , potassium and sodium levels betes mellitus with beta-blocker treatment,24 it is cur- to anticipate possible metabolic cardiovascular effects rently recommended that beta-blockers should not be of treatment. withdrawn in patients with compelling indications for beta-blockade, e.g. myocardial infarction or .25 Beta-blockers If blood pressure therapy is initiated with a beta-blocker and a second drug is required, BHS/NICE guidelines25 Although beta-blockers would be expected to worsen recommend adding a -channel blocker rather PAD by reducing muscle blood flow, there is no clear than a thiazide-type diuretic to reduce the patient’s evidence of long-term disadvantage of beta-blocker risk of developing diabetes. When a beta-blocker is treatment in PAD and some evidence that patients withdrawn, the dose should be reduced gradually to with concomitant have better avoid a rapid increase in sympathetic drive.25 cardiovascular outcomes when treated with a beta- blocker. A meta-analysis of randomised controlled trials in PAD treated with beta-blockers reported no sig- Blocker [CCB] Treatment nificant worsening of intermittent claudication or distance.18 However when combined, Major options are dihydropyridines, which vasodilate and reduced maximum walking distance by and increase renal sodium and water excretion and the 9%, indicating the importance of context of beta- cardioselective CCBs and phenylalkalamine blocker treatment.19 A microscopy study20 , which vasodilate, and reduce cardiac out- reported no microcirculatory or symptom differences put by reducing rate and force of cardiac con- between measurements obtained before and during traction. In the VALUE Trial the primary outcomes withdrawal of beta-blocking therapy, and again 2 were cardiac morbidity and mortality26 with a primary weeks after re-introduction of beta-blocker treatment intention to assess response to treatment with the in patients with intermittent claudication or ischaemic angiotensin receptor blocker compared to rest pain and mild-moderate hypertension. Beta- the dihydropyridine CCB in the subgroup blocking drugs appear to be cardioprotective in pa- of patients with PAD. There was no difference in com- tients with PAD however evidence is largely from posite cardiac outcome in the1052 PAD patients observational or unblinded randomised studies. Polde- treated with valsartan and 1062 patients treated with mans et al21 studied patients with abnormal amlodipine.26 The Invest Trial (International Trando- who were undergoing elective ab- lapril Study) included 2699 PAD patients.17 The ACE dominal aortic or infra-inguinal arterial reconstruction. inhibitor trandolapril and diuretic hydrochlorothia- Patients were randomised to receive standard care zide were added to verapamil sustained release alone or with the addition of bisoprolol treatment to (n ¼ 1345) or beta-blocker (atenolol-based) initial

Eur J Vasc Endovasc Surg Vol 35, June 2008 704 D. R. J. Singer and A. Kite treatment (n ¼ 1354). Achieving a pressure <140 receptor by using angiotensin type I receptor blocker systolic or <90 diastolic reduced adverse cardiovascu- risks may cause significant renal impairment, risk of lar outcomes [Hazard Ratio (HR): 0.82 or 0.70]. Com- and renal failure.30 The Utrecht group bining trandolapril with verapamil was associated noted a rise of >20% in in all patients with fewer adverse outcomes than beta-blocker based with bilateral RAS [n ¼ 52] given ACEi treatment, af- strategy [HR 0.79]. The inverse relationship between ter a delay from <4 days in 26 patients and <2 weeks ABPI and cardiovascular events was lost in subjects in 31 patients.30 The authors suggest that controlled undergoing intensive blood pressure treatment, sug- exposure to ACEi is safe in the setting of suspected gesting that the expected greater cardiovascular risk severe RAS, as no acute renal failure occurred and associated with a lower ABPI is avoidable when blood creatinine always recovered on stopping treatment. pressure is intensively lowered.17 The ABCD study in- However in 12 patients, plasma creatinine only in- cluded patients with PAD associated with Type II dia- creased after diuretic treatment was added to improve betes. It reported a major benefit from tight vs. usual blood pressure control.31 Furthermore renal failure BP control, irrespective of whether control was may develop in bilateral RAS within 36 hr of ACEi achieved with a CCB () or an ACEi (enalap- treatment and renal function may not recover.31 ril). However the PAD sub-group was not powered to Thus it is critically important in PAD that before using allow comparison of independent effects of nisoldi- ACEi or Angiotensin Receptor Blocker treatment pine or on cardiovascular outcomes.27 (ARB: see below), significant RAS is excluded and re- nal function monitored regularly.

ACE Inhibitor (ACEi) Treatment Angiotensin Receptor Blockers (ARBs) The HOPE trial (Heart Outcomes Protection Evalua- Selective blockade of the Type 2 receptor for angioten- tion Study) is important in having a predefined PAD sin II inhibits angiotensin II mediated , hypothesis.28 Patients with PAD were followed for secretion, cardiovascular hypertrophy and 4.5 years. 4051 of 9297 patients had PAD evidence fibrosis and salt and water retention. The VALUE based on ABPI < 0.9, 1725 had clinical features of study included specified sub-group analyses of the PAD. The primary endpoint of death from vascular primary endpoint according to history of peripheral causes or nonfatal myocardial infarction or non-fatal artery disease.26 The primary outcome measure of was reduced by ACEi treatment with cardiac morbidity and mortality was not significantly 10 mg/day to 14.1% [placebo 17.7%]. Ramipril bene- different between the ARB valsartan (n ¼ 1052) and fits were about two-fold for low ABPI vs. ABPI > 0.9 CCB amlodipine-based PAD treatment groups (1062), (50/1000 events prevented: vs. 24/1000 events pre- although blood pressure reductions and myocardial vented). A prospective observational study noted infarction incidence were significantly lower in the that ACEi-based PAD treatment was associated with amlodipine-based regimen.26 reduced renal failure progression;4 since this was not a randomised study, results should be treated with caution. Effects of ACEi and angiotensin receptor Alpha-blocker treatment blockers may lead to clinical benefits independent of blood pressure lowering. These effects include attenu- There is currently no primary endpoint data in PAD ating the pleiotropic effects of angiotensin II such as populations with -based treatment. stimulation of oxidant stress, cardiovascular fibrosis, However alpha blockers may be of practical benefit vascular and hypertrophy.29 However, in patients who have benign prostatic hypertrophy 24 hour ambulatory blood pressure monitoring sug- by reducing symptoms and deferring need for sur- gested blood pressure decrease with ramipril could gery. Furthermore, long-acting alpha blockers are have explained cardiovascular benefits. HOPE raises a pragmatically recognised agent as 4th line (step 4) the question about target blood pressure in PAD, as treatment in the 2006 BHS/NICE Guidelines where treatment based on CCB, ACEi and diuretic is insuffi- many patients in HOPE had blood pressure below 25 the conventional hypertensive range.28 In significant cient to achieve blood pressure control. renal artery stenosis (RAS), blood flow within the af- fected or kidneys is critically dependent on lo- Intensive vs. usual management of raised blood pressure cal levels of angiotensin II. In RAS, blocking the synthesis of angiotensin II by inhibiting the enzyme There is concern that critical blood pressure reduc- ACE or blocking the action of angiotensin II at the tion may cause end- ischaemia by decreasing

Eur J Vasc Endovasc Surg Vol 35, June 2008 Hypertension and Peripheral Arterial Disease 705 perfusion distal to occlusive atheromatous vascular Co-morbidity may also suggest contra-indications in disease. Two studies suggest that intensive blood view of potential adverse effects. Renal artery stenosis pressure-lowering reduces high cardiovascular risk should be excluded before exposure of patients to po- in PAD, in the INVEST Trial [see above;17], by add- tential risks of renal impairment if given a sys- ing ACEi and thiazide to prior treatment based on tem blocker (including beta-blocker, ACEi, ARB or the CCB verapamil or the beta-blocker atenolol; renin inhibition). Dihydropyridine CCBs should be in ABCD,27 for , by adding the used with caution in patients with benign prostatic CCB nisoldipine or ACEi enalapril [see CCB section hypertrophy as the resulting increase in urine flow above]. may increase symptoms of nocturia and polyuria.33 Beta-blockers exacerbate airways disease in patients with asthma or chronic obstructive lung disease and Compelling indications for class-specific selection should therefore be avoided in these disorders. Other of anti-hypertensive agents contra-indications or cautions for beta-blockers in- clude: avoidance in patients with heart block or on a) Impact of cardiovascular risk factors drug treatment which predisposes to heart block; cau- There is little primary evidence on interaction be- tion in diabetes mellitus in view of risk of masking tween blood pressure lowering treatment and cardio- symptoms of hypoglycaemia; avoidance in acute heart vascular risk factors in patients with PAD. Thiazide failure and caution in established heart failure.24,25 diuretics and beta-adrenergic blockers may adversely affect lipid profile.24 However, thiazide associated increase in lipid levels is dose-related and less of an National treatment guidelines issue with modern use of low dose diuretics e.g. bend- roflumethazide 2.5 mg or equivalent. Furthermore, There are to date no specific national recommenda- the relative risk from mild lipid profile abnormalities tions for choice of blood pressure therapy in periph- appears greatly outweighed by the reduction in car- eral arterial disease patients with hypertension. diovascular end-points from anti-hypertensive treat- However, it is widely accepted that existing guide- ment with or beta-adrenergic blockers in lines should be used to help to provide the best pos- younger patients and for thiazide-based treatment sible medical care to patients with PAD. For for hypertensive patients at least up to the age of example, for the USA, this is based on a 7th revision 80.16,32 Beta-adrenergic blockers predispose to devel- of JNC guidelines and for the UK in 2006, Scottish opment of diabetes mellitus and limit awareness of di- SIGN guidelines34 and joint guidelines of the British abetic symptoms.24 Hypertension Society and National Institute of Clini- b) Impact of co-morbidity on choice of treatment cal Healthcare Excellence (NICE).24,25 Other relevant (Table 1) guidelines include those for Type 2 diabetes associ- The impact of co-morbidity on choice of treatment ated with hypertension [UK:NICE, 2002;35]. A further may be to provide a specific additional indication relevant UK guideline entitled ‘‘Early identification for treatment, for example cardio-protection from and management of adults with chronic kidney dis- ACEi or beta-blockade following acute myocardial in- ease in primary and secondary care’’ is due for com- farction, and value of alpha-adrenergic blockade to re- pletion in September 2008. The latest BHS/NICE duce symptoms of benign prostatic hypertrophy.24 hypertension guideline25 states that persistent raised

Table 1. Impact of co-morbidity on selection of blood pressure-lowering treatment

Thiazide Potassium-sparing Beta- CCB CCB ACE inhibitor or Alpha diuretic blocker dihydro- diltiazem or angiotensin receptor blocker pyridine verapamil blocker or Asthma or COPD Avoid Renal artery stenosis Caution: Avoid: renal failure risk hyper-kalaemia risk Renal failure Caution: Caution: exclude hyper-kalaemia risk renal artery stenosis Diabetes mellitus Caution Caution Benign prostatic hypertrophy Caution Preferred Ischaemic heart disease Preferred Heart failure Caution Avoid Preferred Heart block Avoid Avoid

CCB: . ACE: angiotensin converting enzyme. COPD: chronic obstructive pulmonary disease.

Eur J Vasc Endovasc Surg Vol 35, June 2008 706 D. R. J. Singer and A. Kite blood pressure with existing cardiovascular disease Conclusions and strategy should be treated, when after measurement at 2 sepa- rate visits systolic, diastolic or both are above 140/ Blood pressure treatment in PAD reduces cardiovascu- 90 mmHg. The aim should be to reduce blood pres- lar morbidity and mortality. Intensive blood pressure sure to an optimum target of below 140/85 mmHg. reduction provides significantly greater cardiovascu- Treatment should be based on lifestyle advice (see lar risk reduction than usual blood pressure manage- above). In non-black patients, Step 1 treatment should ment. The HOPE trial suggests that lowering blood be with an ACE inhibitor if less than 55 years old, pressure below conventional treatment thresholds in with a calcium channel blocker or thiazide-type di- patients with PAD is also effective in reducing cardio- uretic used if the patient is >55 years old, or for vascular risk.28 There is no clear level 1 evidence [low a black patient of any age.25 Where additional treat- bias prospective randomised control trial evidence;36] ment is needed, appropriate add on treatments that specific classes of treatment are to be preferred should be used (see algorithm: Fig. 1). This may in the absence of contra-indications or pressing indica- help to explain the difference in outcomes in the IN- tions because of co-morbidity [see above]. For inten- VEST study,17 as a CCB (and not a beta-blocker) com- sive blood pressure reduction, benefits appear bined with an ACE inhibitor is the rational similar for dihydropyridine or ACE-inhibitor based combination for effective blood pressure lower- regimes.27 ing.24,25 The Type 2 diabetes and hypertension guide- There is a pressing need for primary end-point lines suggest that optimal blood pressure treatment studies targeted specifically at patients with PAD, to target is below 130/80 mmHg. In the presence of mi- obtain evidence for blood pressure class and level re- croalbuminuria, treatment with an ACE inhibitor is lated benefits for PAD in general and for PAD with recommended for combined cardiovascular and renal specific risk factor, demographic and co-morbidity protection.35 profiles. This will help to support development

Choosing drugs for treatment of hypertension in patients with atheromatous peripheral arterial disease

55 years or older or African or Caribbean younger than 55 years descent patients of any age

*A (B) C or D Step 1

*A=ACE inhibitor, *A + C or *A + D Step 2 Angiotensin Receptor Blocker

(B)=Beta-blocker – indicated if history of *A + C + D Step 3 myocardial infarction

C=Calcium channel blocker Add:

^D=mild diuretic • ^Further diuretic therapy or *caution in view of high risk • Alpha blocker of renal artery stenosis Step 4 ^caution with potassium-sparing diuretics or in view of risk of renal • impairment in PAD Seek specialist advice

Fig. 1. Algorithm for blood pressure management in patients with atheromatous peripheral artery disease (PAD). Adapted from British Hypertension Society/NICE Guidelines.25 ACE inhibitors and ARBs should be used with caution if clinically significant renovascular disease is suspected. At Step 4, potassium sparing diuretics should be used with caution in view of the increased risk of renal impairment in patients with PAD.

Eur J Vasc Endovasc Surg Vol 35, June 2008 Hypertension and Peripheral Arterial Disease 707 of evidence-based international guidelines on medical management in PAD,35,37 with implementa- Hypercalcaemia may be missed because se- tion supported by PAD networks and effective rum calcium is no longer routinely measured Registries.5,38 in ‘routine’ blood samples. Clues include un- explained nocturia, abdominal pains, joint symptoms and confusion. Raised creatinine may be due to renal Text Box 1. General cardiovascular risk factor disorders other than renovascular disease. burden

This is poorly managed in peripheral arterial disease. It is important to reduce blood pressure in the Acknowledgements context of overall cardiovascular risk to make sure other risk factors are identified and Professor Singer has been an advisory board member for treated including hyperlipidaemia, smoking, Pfizer and Takeda and has received non-promotional educa- poor diabetic control and the need for effec- tional grants from , Pfizer and Takeda. None of the tive anti-platelet treatment. authors has a stock ownership, equity, or contract of em- For the latter it is important to consider risk of ployment, position on a company board, or holds or is GI bleed or intra-cerebral haemorrhage. applying for a relevant patent. The manuscript was gener- Aspirin and other anti-platelet treatment ated specifically as an invited review by the journal. None should be used with caution in a patient of the authors was paid for writing this article by any source whose blood pressure is not well-controlled. external to the medical school and University Hospital of which they are staff members.

Text Box 2. Renal artery stenosis References

1LIP GY, MAKIN AJ. Treatment of hypertension in peripheral Renal artery stenosis is common in patients arterial disease. Cochrane Database Syst Rev 2003;(4):CD003075. with PAD. 2 The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch clues include: Intern Med 1997;157:2413e2446. increased severity of peripheral arterial 3FERINGA HH, VAN WANING VH, BAX JJ, ELHENDY A, BOERSMA E, disease SCHOUTEN O et al. Cardioprotective is associated with improved survival in patients with peripheral arterial disease. J concomitant cardiovascular disease, for ex- Am Coll Cardiol 2006;47:1182e1187. ample in the carotid or coronary circulation 4FERINGA HH, KARAGIANNIS SE, CHONCHOL M, VIDAKOVIC R, refractory hypertension NOORDZIJ PG, ELHENDY A et al. Lower progression rate of end- stage renal disease in patients with peripheral arterial disease impaired renal function. In patients with using or angiotensin converting enzyme inhibitors. J RAS there is a major risk of acute renal im- Am Soc Nephrol 2007;18:1872e1879. pairment or complete loss of renal function 5HIRSCH AT, CRIQUI MH, TREAT-JACOBSON D, REGENSTEINER JG, CREAGER MA, OLIN JW et al. Peripheral arterial disease detection, if a patient is treated with an angiotensin awareness, and treatment in . JAMA 2001;286:1317e converting enzyme inhibitor or an angioten- 1324. sin receptor antagonist. 6OSTCHEGA Y, PAULOSE-RAM R, DILLON CF, GU Q, HUGHES JP. Preva- lence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and Nutrition Examination Survey 1999e2004. J Am Geriatr Soc 2007;55:583e 589. Text Box 3. Other causes of hypertension 7MEIJER WT, GROBBEE DE, HUNINK MG, HOFMAN A, HOES AW. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med 2000;160:2934e2938. Consider other causes of hypertension in pa- 8KULLO IJ, BAILEY KR, KARDIAD SLR, MOSLEY Jr TH, BOERWINKLE E, tients with PAD e.g. endocrine hypertension TURNER ST. Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy and intrinsic renal disease. (GENOA) study. Vasc Med 2003;8:237e242. High serum sodium and low serum potas- 9MISSOURIS CG, BUCKENHAM T, CAPPUCCIO FP, MACGREGOR GA. sium indicate the need to exclude primary hy- Renal artery stenosis: a common and important problem in pa- tients with peripheral . Am J Med 1994;96:10e14. peraldosteronism (Conn’s syndrome). 10 WACHTELL K, IBSEN H, OLSEN MH, LAYBOURN C, CHRISTOFFERSEN JK, NØRGAARD H et al. Prevalence of renal artery stenosis in patients

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Eur J Vasc Endovasc Surg Vol 35, June 2008