European Journal of Vascular & Endovascular Surgery
Volume 32, Issue 5 , Pages 478-483, November 2006

Managing Risk Factors for Atherosclerosis in Critical Limb Ischaemia

  • A. Gottsäter

      Affiliations

    • Corresponding Author InformationCorresponding author. A. Gottsäter, University of Lund, Department of Vascular Diseases, Malmö University Hospital, S-205 02 Malmö, Sweden.

University of Lund, Department of Vascular Diseases, Malmö University Hospital, S-205 02 Malmö, Sweden

Accepted 3 March 2006. published online 24 April 2006.

Article Outline

Objective

To review the best medical management of critical limb ischaemia (CLI).

Methods

Published studies dealing with CLI and risk factors were searched for via PUBMED.

Findings and conclusions

Patients with critical limb ischaemia (CLI) have a one and ten year mortality of approximately 20% and 75% respectively. Risk factors for the development of peripheral atherosclerosis are the same as for coronary and cerebrovascular atherosclerosis namely diabetes mellitus, hyperlipidaemia, arterial hypertension, and smoking. As there are few studies of risk factor for peripheral arterial occlusive disease (PAOD), treatment recommendations are often based on studies in patients with coronary or cerebrovascular atherosclerosis. While waiting for specific studies, CLI patients should be treated according to current guidelines for other atherosclerotic patients.

Keywords: Critical limb ischaemia, Atherosclerosis, Medical treatment, Hyperlipidemia, Hypertension, Antiplatelet, Smoking

 

Back to Article Outline

Critical Limb Ischaemia, Cardiovascular Disease, and Mortality 

Critical limb ischaemia (CLI) is clinically defined as chronic ischaemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease.1 For scientific purposes, the definition also includes an ankle pressure of <50–70mmHg, or toe pressure of <30–50mmHg, or TCPO2<30–50mmHg.1 Patients with CLI represent about 1% of the total number of patients with peripheral arterial occlusive disease (PAOD).1 Patients with PAOD and CLI usually have extensive atherosclerotic disease in other arteries. A high frequency of coronary heart disease,2, 3 congestive heart failure,3, 4, 5 and cardiac valve disease6 has been demonstrated in patients with CLI. Between 50–70% of patients with PAOD have symptoms or electrocardiographic signs of ischaemic heart disease.4, 5, 7 In a necropsy study3 92% of patients requiring an amputation for CLI showed advanced coronary atherosclerosis. A decreased ankle-brachial index is closely related to both cardiovascular events and all-cause mortality.8, 9 Total cardiovascular mortality is 3 to 5-fold increased in PAOD patients compared with age-matched controls.10, 11, 12 The one-year mortality in CLI is around 20%,13, 14, 15 mainly as a result of cardiac events.15, 16, 17 After major vascular surgery CLI patients have a 30-day mortality of 5–6%.18 The 10-year survival rate in severe symptomatic PAOD is as low as 25%.10

Back to Article Outline

Risk Factors for Atherosclerosis in CLI 

The risk factors for development of PAOD and CLI are the same as for atherosclerosis in coronary and cerebral vessels. In contrast to coronary and cerebral atherosclerosis, however, there are few intervention studies evaluating the effects of medical treatment of risk factors for CLI. In order to provide recommendations for risk factor treatment, extrapolations from intervention studies in patients with intermittent claudication or coronary atherosclerosis are therefore necessary. This review focuses upon five major modifiable risk factors for CLI: diabetes mellitus, hyperlipidemia, arterial hypertension, platelet activity, and smoking. Background articles for this review were identified in 2005 through PubMed with the search term “critical limb ischaemia” combined with the different risk factors. In the absence of data on CLI patients, articles on PAOD in general have been used as references.

Diabetes mellitus 

Diabetes mellitus is an important risk factor for PAOD and CLI, also affecting the prognosis of the disease. In the United Kingdom Prospective Diabetes Study (UKPDS) of patients with type 2 diabetes, a 1% increase in HbA1c was associated with a 28% increase of the risk for development of PAOD during 6 years of follow-up.19 Progression of CLI to gangrene occurs in 40% of diabetic compared with 9% of nondiabetic patients.20 In diabetic patients limb-salvage rate in CLI has been reported to be lower21 and major amputation rate to be higher22 than in nondiabetic PAOD patients. Diabetes is an independent risk factor for postoperative amputation and complications23, 24 and has been found to predict hospital and long term mortality in some25 but not all studies.15, 24

Intensive glycaemic control decreases microvascular diabetic complications,26, 27 but had no effects on PAOD in the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes26 or upon amputation or death from PAOD in the UKPDS in type 2 diabetes.27 Furthermore, in type 2 diabetic patients with established macrovascular disease, pioglitazone treatment has recently been shown to reduce the composite of all-cause mortality, non-fatal myocardial infarction, and stroke, whereas no significant effect was seen on leg revascularisation or amputation.28 Treatment goals for glycaemic control in diabetes are well established. Current European recommendations29 (Table 1) propose target HbA1c ≤6.1% and target fasting venous plasma glucose ≤6.0mmol/l for patients with type 2 diabetes mellitus. Whether such intensive treatment favourably influences the prognosis for CLI patients is not known.

Table 1. Optimal target values according to current European recommendations29 for medical treatment in patients with established cardiovascular disease
Risk factorsTreatment goal
Total cholesterol<4.5mmol/l
LDL-cholesterol<2.5mmol/l
Blood pressure<140/90mmHg

In diabetic patients
Blood pressure<130/80mmHg
HbA1c≤6.1%
Fasting venous plasma glucose≤6.0mmol/l

Hyperlipidemia 

Plasma levels of total and low-density lipoprotein (LDL) cholesterol are important risk factors for coronary heart disease.30 Although hyperlipidemia has received considerably less attention as a risk factor in PAOD than in coronary heart disease, there are several indications of unfavourable effects of hyperlipidaemia in PAOD. Hypertriglyceridaemia independently increases the risk for progression of intermittent claudication to CLI31 and increased lipoprotein(a) levels are associated with higher mortality in CLI.32 Lipid levels should be evaluated with caution in CLI, however, since they are often falsely low in this condition.33

Effects of lipid reduction have been studied in PAOD. The Program On the Surgical Control of Hyperlipidemias (POSCH) study,34 in which a 38% reduction in LDL cholesterol was obtained by partial ileal bypass, reported a reduction in PAOD and intermittent claudication after 10 years follow-up. Statins have beneficial effects on plaque stabilisation, platelet adhesion, thrombosis, inflammation and endothelial function.35 In the Scandinavian Simvastatin Survival Study (4S)36 patients with ischaemic heart disease treated with simvastatin showed a 38% risk reduction for new or worsening intermittent claudication. Although pravastatin does not affect femoral atherosclerosis in primary prevention, it significantly reduces the intima-media thickness of the common femoral artery in subjects with coronary artery disease.37 In the Heart Protection Study38 treatment with simvastatin was associated with a significant mortality reduction in the 2701 with PAOD. Statins may be particularly beneficial in patients with increased inflammatory markers and favourable influence walking ability, graft patency and complications rates after revacularisation.39, 40, 41, 42, 43

Current European recommendations29 (Table 1) propose targets for lipid lowering treatment in subjects with established arterial disease, including PAOD, of total cholesterol <4.5mmol/l and LDL cholesterol <2.5mmol/l.

Arterial hypertension 

Arterial hypertension is a prevalent risk factor in PAOD and CLI. The frequency of arterial hypertension in American outpatients with PAOD is reported to be >80%.44 In European primary care patients with both symptomatic and non-symptomatic PAOD,45, 46 and among American patients undergoing interventions for PAOD42 prevalences of arterial hypertension of 65–78% have been presented.

The Hypertension Optimal Treatment (HOT) trial47 showed that patients who reached diastolic blood pressure (BP) 82.3mmHg achieved maximum cardiovascular protection. Current European recommendations29 (Table 1) for antihypertensive treatment in high risk subjects, including those with PAOD, propose target BP <140/90mmHg in subjects without diabetes, and <130/80mmHg in subjects with diabetes. Unfortunately, achievements of targets for BP control are low even in specialist centres.

ACE or angiotensin II inhibitors may have further protective effects against cardiovascular events in PAOD patients. In the Heart Outcome Prevention Evaluation (HOPE) study48 44% of patients randomised to ramipril 10mg or placebo for 4–6 years had PAOD, and ramipril was effective in reducing vascular death, myocardial infarction, and stroke in this subgroup, regardless of their ankle-brachial index.9 Furthermore, the use of ACE-inhibitors is also associated with lower mortality after infrainguinal bypass surgery.42 ß-blocking agents on the other hand have previously been proposed to have unfavourable effects upon symptoms in patients with PAOD,49 and are underprescribed after myocardial infarction among patients with PAOD, resulting in increased mortality in this group.50 A meta-analysis51 has shown that ß-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate PAOD, and that no important differences in effects exist between different types of ß-blockers in this context. Potentially unfavourable effects of ß-blockers in more severely ischaemic patients, such as those with CLI cannot be excluded, however, since there are insufficiently studies.51, 52 Therefore, clinical observation of the peripheral circulation is recommended when ß-blockers are used in this group of patients.52 In our centre, the blood pressure target for CLI patients is sometimes set above recommended levels29 in order to increase perfusion to the ischaemic limb until ulcer healing has occurred. This approach has not been scientifically tested.

Antiplatelet treatment 

Although no individual randomised trial has demonstrated the efficacy of aspirin for reduction of cardiovascular events in PAOD, meta-analyses have shown that antiplatelet agents reduce the risk of vascular death, MI, and stroke by approximately 25% among PAOD patients.53, 54 Furthermore, aspirin therapy significantly improves vascular graft patency after peripheral bypass surgery or angioplasty.55 European recommendations propose treatment with aspirin or other platelet modifying drugs in virtually all patients with cardiovascular disease.29 In the CAPRIE study56 clopidogrel conferred an 8.7% further relative risk reduction for stroke, myocardial infarction, or vascular death compared with aspirin among patients with myocardial infarction, ischaemic stroke or PAOD. Aspirin is still considered as first-line antiplatelet treatment for patients with PAOD,57 even though a subgroup analysis suggested that relative risk reduction with clopidogrel was greater among PAOD patients than among patients with myocardial infarction or stroke in CAPRIE.56 Clopidogrel is recommended as an alternative,58 when aspirin is contraindicated or not tolerated. Clopidogrel might also be considered as an alternative in patients with rapidly progressing disease or multiple events during aspirin therapy, but as data are lacking no firm recommendations can be made. To combine clopidogrel and aspirin is beneficial in patients with acute coronary syndromes without ST segment elevation,59 but not in those with recent ischaemic stroke or transient ischaemic attack.60 Most CLI patients have concomitant coronary artery disease,2, 3, 4, 5, 7 but only a minority have a concomitant acute coronary syndrome and combination treatment can therefore not be generally recommended in CLI.

Smoking 

Smoking is a major risk factor for both the occurrence and progression of PAOD and CLI.1, 20, 61 The severity of PAOD increases with the number of cigarettes smoked,1 and continued smoking in PAOD patients increases the risk for progression to CLI, amputation, and the need for invasive intervention.62, 63 Furthermore, continued smoking after leg revascularisation negatively affects both patency rates61 and survival.64 Cessation of smoking, on the other hand, leads to improved ankle pressure and exercise tolerance,65 improved graft patency after surgery, and decreased risk for fatal vascular complications66 in PAOD. The beneficial effects of smoking cessation are evident within a few years.67, 68 Apart from the advise to quit smoking that should be given to all CLI and PAOD patients, all available forms of nicotine replacement therapy (such as chewing gum, transdermal patch, nasal spray, inhaler and sublingual tablets) have in a meta-analysis been shown to increase the odds of successfully quitting smoking approximately 1.5 to 2 fold regardless of the additional support provided to the patient.69 Furthermore, a sustained release formulation of the antidepressant bupropion can help relieve nicotine abstinence symptoms.69, 70

Back to Article Outline

Treatment of Risk Factors for Atherosclerosis in CLI Patients in Clinical Practise 

While waiting for specific studies in CLI, these patients should be treated according to current guidelines for atherosclerotic patients.29 Recent studies have demonstrated that risk factors for arteriosclerosis are often suboptimally treated in PAOD patients,71, 72 including those with CLI.42, 71, 73, 74 In spite of a recommended target Hba1c ≤6.1% in diabetes, a HbA1c <7% was seen in only 52% of American outpatients with PAOD and diabetes mellitus.72

After in-hospital care for invasive treatment of PAOD, 50–60% of patients receive lipid-lowering therapy.42, 71 Among consecutive Swedish patients with CLI, 24% were treated with lipid lowering drugs, out of which 66% had reached target lipid levels.74

After invasive treatment of PAOD, 42–54% of patients are treated with ACE-inhibitors42, 71 and 58–69% with ß-blocking agents.42, 71 In consecutive Swedish CLI patients, the prevalence of BP lowering treatment was <50%.74 Furthermore, mean BP levels in patients with PAOD45, 46 and CLI74 indicate that many patients have not attained recommended levels in spite of medical treatment.

Concerning antiplatelet and anticoagulant treatment, awareness of and adherence to current guidelines29, 57, 58 seems to be better. Studies of consecutive patients with CLI have shown that antiplatelet or anticoagulant treatment are prescribed to 80–90% of patients.42, 69, 74

Back to Article Outline

Conclusion 

Risk factors for arteriosclerosis and cardiovascular disease are common among patients with CLI. As there are few studies of medical treatment in CLI patients, extrapolation from studies in patients with other manifestations of atherosclerosis are presently necessary to provide treatment recommendations. Nevertheless, medical risk-factor treatment in these high-risk patients is suboptimal in relation to current recommendations. In order to decrease their high mortality and morbidity from vascular disease, patients with CLI need to be evaluated, treated, and scientifically studied by physicians with knowledge of and interest for treatment of risk factors for atherosclerosis.

Back to Article Outline

Acknowledgements 

This work was supported by grants from the Ernhold Lundström Foundation, Research Funds at University Hospital MAS, and the Hulda Ahlmroth Foundation.

Back to Article Outline

References 

  1. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg. 2000;31:S1–S296
  2. Fowkes FG. Epidemiology of atherosclerotic arterial disease in the lower limbs. Eur J Vasc Surg. 1988;2:283–291
  3. Mautner GC, Mautner SL, Roberts WC. Amounts of coronary arterial narrowing by atherosclerotic plaque at necropsy in patients with lower extremity amputation. Am J Cardiol. 1992;70:1147–1151
  4. Aronow WS, Ahn C. Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women > or = 62 years of age. Am J Cardiol. 1994;74:64–65
  5. Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47:1255–1256
  6. Aronow WS, Ahn C, Kronzon I. Association of valvular aortic stenosis with symptomatic peripheral arterial disease in older persons. Am J Cardiol. 2001;88:1046–1047
  7. Hertzer NR. Fatal myocardial infarction following lower extremity revascularization. Two hundred seventy-three patients followed six to eleven postoperative years. Ann Surg. 1981;193:492–498
  8. Jonsson B, Skau T. Ankle-brachial index and mortality in a cohort of questionnaire recorded leg pain on walking. Eur J Vasc Endovasc Surg. 2002;24:405–410
  9. Ostergren J, Sleight P, Dagenais G, Danisa K, Bosch J, Qilong Y, et al. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J. 2004;25:17–24
  10. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386
  11. Vogt MT, Cauley JA, Newman AB, Kuller LH, Hulley SB. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA. 1993;270:465–469
  12. Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1996;25:1172–1181
  13. Wolfe J. Defining the outcome of critical ischaemia: a one year prospective study. Br J Surg. 1986;73:321
  14. The I.C.A.I. Group (Gruppo di Studio dell'Ischemia Cronica Critica degli Arti Inferiori) . The study group of criticial chronic ischemia of the lower exremities. Long-term mortality and its predictors in patients with critical leg ischaemia. Eur J Vasc Endovasc Surg. 1997;14:91–95
  15. Barani J, Nilsson JÅ, Mattiasson I, Lindblad B, Gottsäter A. Inflammatory mediators are associated with 1-year mortality in critical limb ischemia. J Vasc Surg. 2005;42:75–80
  16. Lassila R, Lepantalo M, Lindfors O. Peripheral arterial disease–natural outcome. Acta Med Scand. 1986;220:295–301
  17. Balmer H, Mahler F, Do DD, Triller J, Baumgartner I. Balloon angioplasty in chronic critical limb ischemia: factors affecting clinical and angiographic outcome. J Endovasc Ther. 2002;9:403–410
  18. Mangano DT. Perioperative cardiac morbidity. Anesthesiology. 1990;72:153–184
  19. Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. 2002;25:894–899
  20. Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk. 1994;1:333–339
  21. da Silva AF, Desgranges P, Holdsworth J, Harris PL, McCollum P, Jones SM, et al. The management and outcome of critical limb ischaemia in diabetic patients: results of a national survey. Audit committee of the vascular surgical society of Great Britain and Ireland. Diabet Med. 1996;13:726–728
  22. da Silva A, Widmer LK, Ziegler HW, Nissen C, Schweizer W. The Basle longitudinal study: report on the relation of initial glucose level to baseline ECG abnormalities, peripheral artery disease, and subsequent mortality. J Chronic Dis. 1979;32:797–803
  23. Vainio E, Salenius JP, Lepantalo M, Luther M, Ylonen K. Endovascular surgery for chronic limb ischaemia. Factors predicting immediate outcome on the basis of a nationwide vascular registry. Ann Chir Gynaecol. 2001;90:86–91
  24. Virkkunen J, Heikkinen M, Lepantalo M, Metsanoja R, Salenius JP. Diabetes as an independent risk factor for early postoperative complications in critical limb ischemia. J Vasc Surg. 2004;40:761–767
  25. AhChong AK, Chiu KM, Wong MW, Hui HK, Yip AW. Diabetes and the outcome of infrainguinal bypass for critical limb ischaemia. ANZ J Surg. 2004;74:129–133
  26. The Diabetes Control and Complications Trial (DCCT) Research Group . Effect of intensive diabetes management on macrovascular events and risk factors in the diabetes control and complications trial. Am J Cardiol. 1995;75:894–903
  27. UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853
  28. Dormandy JA, Crarbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, et al. On behalf of the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289
  29. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third joint task force of European and other societies on cardiovascular disease prevention in clinical practice. Eur Heart J. 2003;24:1601–1610
  30. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995;76:69C–77C
  31. Smith I, Franks PJ, Greenhalgh RM, Poulter NR, Powell JT. The influence of smoking cessation and hypertriglyceridaemia on the progression of peripheral arterial disease and the onset of critical ischaemia. Eur J Vasc Endovasc Surg. 1996;11:402–408
  32. Cheng SW, Ting AC. Lipoprotein (a) level and mortality in patients with critical lower limb ischaemia. Eur J Vasc Endovasc Surg. 2001;22:124–129
  33. Bismuth J, Kofoed SC, Jensen AS, Sethi A, Sillesen H. Serum lipids act as inverse acute phase reactants and are falsely low in patients with critical limb ischemia. J Vasc Surg. 2002;36:1005–1010
  34. Buchwald H, Hunter DW, Tuna N, Williams SE, Boen JR, Hansen BJ, et al. Myocardial infarction and percent arteriographic stenosis of culprit lesion: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH). Atherosclerosis. 1998;138:391–401
  35. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21:1712–1719
  36. Scandinavian Simvastatin Survival Study Group . Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4 S). Lancet. 1994;344:1383–1389
  37. Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation. 1995;92:1758–1764
  38. Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22
  39. Schillinger M, Exner M, Mlekusch W, Amighi J, Sabeti S, Muellner M, et al. Statin therapy improves cardiovascular outcome of patients with peripheral artery disease. Eur Heart J. 2004;25:742–748
  40. McDermott MM, Guralnik JM, Greenland P, Pearce WH, Criqui MH, Liu K, et al. Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease. Circulation. 2003;107:757–761
  41. Mohler ER, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation. 2003;108:1481–1486
  42. Henke PK, Blackburn S, Proctor MC, Stevens J, Mukherjee D, Rajagopalin S, et al. Patients undergoing infrainguinal bypass to treat atherosclerotic vascular disease are underprescribed cardioprotective medications: effect on graft patency, limb salvage, and mortality. J Vasc Surg. 2004;39:357–365
  43. O'Neil-Callahan K, Katsimaglis G, Tepper MR, Ryan J, Mosby C, Ioannidis JP, et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: the Statins for Risk Reduction in Surgery (StaRRS) study. J Am Coll Cardiol. 2005;45:336–342
  44. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:1317–1324
  45. Meijer WT, Grobbee DE, Hunink MG, Hofman A, Hoes AW. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med. 2000;160:2934–2938
  46. Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis. 2004;172:95–105
  47. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755–1762
  48. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med. 2000;342:145–153
  49. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413–2446
  50. Narins CR, Zareba W, Moss AJ, Marder VJ, Ridker PM, Krone RJ, et al. Relationship between intermittent claudication, inflammation, thrombosis, and recurrent cardiac events among survivors of myocardial infarction. Arch Intern Med. 2004;164:440–446
  51. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. a meta-analysis of randomized controlled trials. Arch Intern Med. 1991;151:1769–1776
  52. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-blockers. Eur Heart J. 1994;15(Suppl. C):2–7
  53. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106
  54. Antiplatelet Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86
  55. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ. 1994;308:159–168
  56. CAPRIE Steering Committee . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339
  57. Clagett GP, Sobel M, Jackson MR, Lip GY, Tangelder M, Verhaeghe R. Antithrombotic therapy in peripheral arterial occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(Suppl. 3):609S–626S
  58. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA. 2004;292:1867–1874
  59. The clopidogrel in unstable angina to prevent recurrent events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502
  60. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331–337
  61. Willigendael EM, Teijink JA, Bartelink ML, Kuiken BW, Boiten J, Moll FL, et al. Influence of smoking on incidence and prevalence of peripheral arterial disease. J Vasc Surg. 2004;40:1158–1165
  62. Jonason T, Ringqvist I. Factors of prognostic importance for subsequent rest pain in patients with intermittent claudication. Acta Med Scand. 1985;218:27–33
  63. Hirsch AT, Treat-Jacobson D, Lando HA, Hatsukami DK. The role of tobacco cessation, antiplatelet and lipid-lowering therapies in the treatment of peripheral arterial disease. Vasc Med. 1997;2:243–251
  64. Ameli FM, Stein M, Provan JL, Prosser L. The effects of postoperative smoking on femoropopliteal bypass grafts. Ann Vasc Surg. 1989;3:20–25
  65. Quick CR, Cotton LT. The measured effect of stopping smoking on intermittent claudication. Br J Surg. 1982;69(Suppl.):S24–S26
  66. Jonason T, Bergström R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand. 1987;221:253–260
  67. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med. 1990;322:214–217
  68. Ingolfsson IO, Sigurdsson G, Sigvaldason H, Thorgeirsson G, Sigfusson N. A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968–1986: a strong relationship to smoking and serum cholesterol–the Reykjavik Study. J Clin Epidemiol. 1994;47:1237–1243
  69. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004;(Issue 3):pub2. Art. No.: CD000146.
  70. Dale LC, Glover ED, Sachs DP, Schroeder DR, Offord KP, Croghan IT, et al. Bupropion for smoking cessation: predictors of successful outcome. Chest. 2001;119:1357–1364
  71. Mukherjee D, Lingam P, Chetcuti S, Grossman PM, Moscucci M, Luciano AE, et al. Missed opportunities to treat atherosclerosis in patients undergoing peripheral vascular interventions: insights from the University of Michigan Peripheral Vascular Disease Quality Improvement Initiative (PVD-QI2). Circulation. 2002;106:1909–1912
  72. Ness J, Aronow WS, Newkirk E, McDanel D. Prevalence of symptomatic peripheral arterial disease, modifiable risk factors, and appropriate use of drugs in the treatment of peripheral arterial disease in older persons seen in a university general medicine clinic. J Gerontol A Biol Sci Med Sci. 2005;60:255–257
  73. Bismuth J, Klitfod L, Sillesen H. The lack of cardiovascular risk factor management in patients with critical limb ischaemia. Eur J Vasc Endovasc Surg. 2001;21:143–146
  74. Barani J, Mattiasson I, Lindblad B, Gottsäter A. Suboptimal treatment of risk factor for athero-sclerosis in critical limb ischemia. Int Angiol. 2005;24:59–63

PII: S1078-5884(06)00160-2

doi:10.1016/j.ejvs.2006.03.007

European Journal of Vascular & Endovascular Surgery
Volume 32, Issue 5 , Pages 478-483, November 2006

Article Tools