1 Risk factors for peripheral artery disease Based on the Inter-Society Consensus Edited by Dr Denis Clement University Hospital, Ghent, Belgium Supported by an educational grant from Otsuka Pharmaceutical Co. Ltd. Otsuka Pharmaceutical Co. Ltd. was not involved in the development of this pocket guide and in no way influenced its contents.
2 CONTENTS Introduction 3 Importance of identifying the high-risk PAD population 4 Risk factors for PAD 5 Smoking 8 Diabetes 11 Hyperlipidemia 14 Hypertension 17 Elevated homocysteine levels 21 Antiplatelet therapy 22 Lifestyle interventions 24 Summary 25 References 26 Introduction Patients with peripheral artery disease (PAD) have multiple cardiovascular risk factors that are common to the development of other manifestations of atherothrombotic disease, such as myocardial infarction (MI) and stroke. These patients therefore constitute a high-risk population who require intensive risk factor modification and antithrombotic therapy. Early identification of this population and more effective interventions could potentially improve both morbidity and survival. 1 However, in a substantial majority of patients PAD is asymptomatic. 2 Consequently, in order to reduce the growing burden of PAD with the aging population and to reduce the risk of cardiovascular events, early recognition of the disease, as well as effective management of the risk factors, are essential. In this guide, the approach for identifying this high-risk population, the risk factors for PAD and the benefits of their management will be reviewed. 2 3
3 The systemic nature of atherosclerosis mandates a global, risk-factor driven approach to cardiovascular prevention in every patient affected with PAD. 3 Figure 1. Algorithm for use of the ABI in the assessment of systemic risk in the population 2 Cardiovascular 10-year risk score: High >20% Moderate 20 10% ABI Low <10% Importance of identifying the high-risk PAD population Secondary prevention 0.90 >0.90 Primary prevention Given that the pathology of PAD is secondary to atherosclerosis (or atherothrombosis) affecting the vascular tree, PAD is a Evaluate the patient for symptoms of PAD Manage claudication and CLI if present very useful, and early indicator of a high-risk population. 4 CLI: critical limb ischemia However, over 65% of patients with PAD are asymptomatic or Risk factors for PAD have atypical leg symptoms and approximately 50% have not yet suffered a major cardiovascular event; therefore, many patients are not identified, resulting in inadequate treatment of their risk factors. 2 The first priority in the management of patients with PAD is to modify known risk factors, in order to decrease the progression of atherosclerosis and to prevent the development of atherothrombotic complications. The initial clinical assessment for PAD is a comprehensive history and physical examination. Subsequently, PAD can be easily and inexpensively diagnosed by measuring the All patients with PAD, whether symptomatic or asymptomatic, should undergo risk factor modification. ankle-brachial index (ABI). 2 An algorithm directing the use 4 of the ABI has been developed (Figure 1). 5
4 Risk factors associated with PAD include 2 : Advanced age Other well defined atherosclerotic risk factors: Smoking Diabetes mellitus Hypertension Hyperlipidemia Elevated homocysteine level Cardiovascular risk calculators are readily available two of the most commonly used are: SCORE, for use in Europe (www.escardio.org) Framingham, for use in the USA (www.nhlbi.nih.gov/guidelines/cholesterol) Approximately 95% of individuals with prevalent PAD have at least one of the traditional cardiovascular disease risk factors, such as current smoking, diabetes, hypertension, and hypercholesterolemia. The strong impact of the predominant risk factors on the likelihood of developing PAD is demonstrated in Figure 2. Figure 2. Approximate range of odds ratios for risk factors for symptomatic peripheral arterial disease 2 Male gender (cf female) Age (per 10 years) Diabetes Smoking Hypertension Dyslipidemia Hyperhomocysteinemia Race (Asian/Hispanic/ black vs. white) C-reactive protein Odds ratio Renal insufficiency 6 7
5 Smoking Smoking is the single most important modifiable risk factor for the development of PAD and its complications. 5 Cigarette smoking is a stronger risk factor for PAD than for coronary artery disease (CAD) the risk is substantial and consistent, with a clear dose response relationship between the number of cigarettes smoked and increased risk of PAD. 6 Compared with their nonsmoking counterparts, patients who smoke 2,5 : Have poorer survival rates Are more likely to progress to critical limb ischemia Are twice as likely to progress to amputation Have a 3-fold increased risk of arterial bypass graft failure Complete and permanent cessation of smoking is by far the most clinically and cost-effective intervention in patients with atherosclerosis, including PAD. 7 A number of randomised, controlled trials have indicated that the use of pharmacological agents, such as bupropion or nicotine replacement therapies, is a highly effective intervention for smoking cessation. 2 A prospective trial evaluated the efficacy of bupropion in a population of persistent smokers with cardiovascular disease (including PAD; 33%). 8 Results indicated that: Significantly more patients receiving bupropion achieved continuous abstinence from smoking for weeks 4 7 compared with those receiving placebo (43% vs 19% p<0.001) Bupropion treatment resulted in consistently higher rates of abstinence than placebo 8 One of the most important interventions a physician can make in caring for patients with PAD is to initiate an aggressive smoking cessation effort. 9
6 A practical approach to maximizing the success of smoking cessation efforts would include: Physician counseling Referral to a structured smoking cessation program Pharmacotherapy, e.g. bupropion or nicotine replacement Diabetes Diabetes increases the risk of PAD approximately 3- to 4-fold, and the risk of claudication 2-fold. 2 There is a strong positive association between the duration of diabetes and the development of PAD, even after adjusting for major risk factors (Figure 3). 9,10 Figure 3. Prevalence of PAD increases as the duration of diabetes increases 9 25 Smoking cessation advice should be tailored according to the individual patient s smoking habits. It is important to note that patients should be encouraged to stop smoking primarily to reduce their risk of cardiovascular events, as well as their risk of amputation and disease progression, but should not be promised improved symptoms immediately upon cessation. 2 Prevalence (%) n= Years from diagnosis of diabetes Copyright 2002 American Diabetes Association. From Diabetes Care, Vol. 25, 2002; Reprinted with permission from The American Diabetes Association
7 Compared with patients without diabetes, those with diabetes 11 : Have a significantly higher mortality rate (51.7 vs 25.6%; p<0.002, during a mean follow-up of 4.5 years) Are significantly younger at the time of death (64.7 ± 11.4 vs 71.2 ± 8.7 years; p<0.04) Are five times more likely to have undergone an amputation (41.4 vs 11.5%; p<0.0001) The main parameter for evaluating long-term glycemic control is glycosylated hemoglobin (HbA 1c ), which is a more accurate and stable measure than fasting blood glucose levels. A positive, graded association independent of known risk factors between HbA 1c and PAD risk in persons with diabetes was identified in a large-scale, community-based study (Figure 4). 12 Compared with those with good glycemic control (HbA 1c <6%), individuals with poor glucose control (HbA 1c >7.5%) were 12 : More than five times as likely to develop IC Five times as likely to be hospitalized for PAD Figure 4. Risk of PAD-related hospitalizations by tertile of HbA 1c (%) in people with diabetes during 10 years of follow-up (N=1894) 12 Probability of PAD-related hospitalization st tertile 2nd tertile 3rd tertile Years of follow-up Copyright 2002 American Diabetes Association. From Diabetes Care, Vol. 29, 2006; ( ). Reprinted with permission from The American Diabetes Association. For each 1% point increase in HbA 1c, the risk of PAD increases by 28% in patients with type 1 diabetes 12 and 32% in those with type
8 In terms of management, the role of blood glucose lowering agents in patients with PAD remains to be clarified. Studies of both type 1 and type 2 diabetes have shown that aggressive blood glucose lowering can prevent microvascular complications (particularly retinopathy and nephropathy). However, this has not been demonstrated for PAD, primarily because the studies conducted to date examining glycemic control in patients with diabetes were neither designed nor powered to examine PAD endpoints. 2 Diabetes is associated with peripheral neuropathy and decreased resistance to infection, which leads to an increased risk of foot ulcers and foot infections. Therefore, foot care is pivotal in reducing the risk of skin ulceration, necrosis and subsequent amputation. Hyperlipidemia Treatment of hyperlipidemia is a vital component of risk factor modification for patients with PAD (Figure 5). Figure 5. Alterations in the plasma lipid levels are independent risk factors for PAD Total cholesterol Low-density lipoprotein cholesterol (LDL-C) Triglycerides Strong evidence in favor of reducing cholesterol levels in patients with PAD comes from the Heart Protection Study (HPS). The study included 6748 patients with PAD (33% of the study population). 14 High-risk patients were randomly allocated to treatment with simvastatin (40 mg daily) or placebo for a mean follow-up of 5 years. Treatment with simvastatin resulted in reductions of 14 : 17% in vascular mortality 38% in MI Independent risk factors for PAD High-density lipoprotein cholesterol (HDL-C) Apolipoprotein (a-1) 14 25% in all strokes 15
9 A reduction of 1 mmol/l in LDL-C levels, regardless of threshold, results in a 25% reduction in cardiovascular morbidity and mortality. A meta-analysis of 14 randomized statin trials found a 12% proportional reduction in all-cause mortality per mmol/l reduction in LDL-C, and 19% reduction in coronary mortality. 15 The meta-analysis also confirmed an approximately linear relationship between the absolute reductions in LDL-C achieved in the trials and the proportional reductions in the incidence of coronary and other major vascular events. Again, this benefit was not dependent on the initial lipid levels (even patients with lipids in the normal range responded), but did depend on the baseline assessment of cardiovascular risk. All symptomatic PAD patients should have their LDL-C lowered to <2.59 mmol/l (<100 mg/dl). 2 Given that patients with PAD are considered high-risk, there is a strong likelihood that they will benefit from statin therapy. An additional benefit of statin use in patients with PAD is the apparent improvement in the symptoms of intermittent claudication (IC): Statin use is associated with less annual decline in walking speed among patients with PAD, independent of cholesterol level and other confounders 16 The use of atorvastatin over a 12-month period resulted in a significant improvement in pain-free walking time 17 Hypertension Almost every relevant epidemiologic study has shown an association between hypertension and PAD. 5 It is estimated to increase the risk of developing PAD 2- to 3-fold. 2 Based on these observations, guidelines developed for the management of hypertension support the aggressive treatment of elevated blood pressure in patients with atherosclerosis, including PAD
10 In a subanalysis of the Heart Outcomes Prevention Evaluation (HOPE) trial, the use of the angiotensin converting enzyme (ACE) inhibitor ramipril was associated with reductions of 5.9% and 25% in the risk of a cardiovascular event in follow-up patients with asymptomatic and symptomatic PAD, respectively. 18 Results also indicated that the beneficial effect of ramipril was partly independent of lowering blood pressure. Even normotensive patients with PAD can benefit from antihypertensive therapy. 19 In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, normotensive patients with diabetes were randomized to receive intensive blood pressure lowering (with the ACE inhibitor enalapril or the calcium channel blocker nisoldipine) or placebo. 20 In the placebo group, the odds of stroke, MI, or vascular death were inversely related to the ABI, and the 5-year event rate among these very high-risk patients was 38.7%, 20 In the intensive therapy group, the odds of a major cardiovascular event were similar between those with a low ABI and those without PAD. 20 These findings highlight the important protective effect of aggressive blood pressure control in patients with PAD and diabetes. Any class of hypertensive drug may be used for the control of blood pressure in patients with PAD. 2 However, the following observations should be considered 2 : Thiazide diuretics and ACE inhibitors are first-line agents ACE inhibitors or angiotensin receptor blockers should be used in patients with diabetic renal disease or congestive heart failure Calcium channel blockers should be used for difficult-to-control hypertension Most patients will require multiple agents to achieve the desired blood pressure goals
11 Elevated homocysteine levels An elevation in the plasma level of homocysteine an amino acid by-product of the demethylation of methionine is an independent risk factor for PAD. It is possible to lower homocysteine levels with the use of vitamin B supplements and/or folate. However, currently, there is no high-level evidence indicating any benefits in terms of preventing cardiovascular events. 2 The impact of supplemental B vitamins and folic acid on cardiovascular endpoints in patients with CAD has been evaluated in two trials. The results did not demonstrate any beneficial effect; paradoxically, one study revealed a trend toward increased risk. 2 Consequently, this therapy cannot be recommended in patients with PAD, or any other cardiovascular disease. 2 Antiplatelet therapy Patients with PAD are at increased risk of generalized atherothrombotic events; therefore, in addition to aggressive risk factor modification, antiplatelet therapy is also pivotal in the prevention of ischemic events associated with PAD. 21 In a meta-analysis conducted by the Antithrombotic Trialists Collaboration, evidence from 9214 patients with PAD enrolled in 42 trials was reviewed. Results revealed a significant 23% (p=0.004) odds reduction in serious events (cardiovascular death, MI or stroke) in this population with the use of antiplatelet therapy (primarily aspirin/acetylsalicylic acid [ASA]). 22 The use of aspirin/asa can be considered in patients with PAD 2 Clopidogrel is effective in reducing cardiovascular events in patients with symptomatic PAD
12 In addition to ASA, the efficacy of the thienopyridines (ticlopidine and clopidogrel) has also been evaluated in patients with cardiovascular disease. Despite its efficacy, the clinical usefulness of ticlopidine is limited by side effects such as neutropenia and thrombocytopenia. 2 In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel was shown to reduce the risk of MI, stroke and vascular death in the symptomatic PAD population the relative risk reduction Lifestyle interventions Patients with PAD frequently have a sedentary lifestyle given the limiting effects of exertional leg symptoms and decreased functional abilities. Such a lifestyle is associated with increased cardiovascular risk. Therefore, in addition to smoking cessation, other lifestyle interventions, notably diet and exercise, are important factors in the management of PAD. Overweight patients should be given an optimal diet plan was 24% over the use of ASA (Figure 7). 23 and goal for weight loss. 1 Indeed, weight control has been Figure 7. Relative risk reduction and 95% CI by disease subgroup 23 proposed to form an essential feature of the overall management strategy in PAD. All patients with Relative risk reduction (%) symptomatic PAD should also be considered for referral Stroke to a supervised PAD exercise rehabilitation program. In addition to exercise training, PAD rehabilitation programs MI incorporate an educational component, focused on PAD optimal nutrition, weight reduction, and smoking cessation, to maximize cardiovascular risk reduction. 19 All patients In the absence of an available supervised exercise rehabilitation program, patients with PAD should be encouraged to begin Aspirin better Clopidogrel better Reprint from The Lancet, Vol 348, CAPRIE steering committee, a randomised, blinded, trial of clopidogrel versus asprin in patients at risk of ischaemic events (CAPRIE), , copyright (1996) with permission a walking program. It is important to reassure patients that walking at least twice a week, even if painful, is not harmful and gradually increases walking distance from Elsevier.
13 Summary References The importance of risk factor modification in patients with PAD is established. However, despite the availability of recommendations, recognition of PAD is poor and there is a general lack of aggressive risk factor control. 1. Khan S, et al. Life-style Modification in Peripheral Arterial Disease. Eur J Vasc Endovasc Surg 2005; 29: Norgren L, Hiatt WR, et al; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Available at: Accessed October 2007.* 3. Hackam DG. Cardiovascular risk prevention in peripheral artery disease. J Vasc Surg 2005; 41: Tomson J, Lip GYH. Peripheral arterial disease: A high risk but neglected disease population. BMC Cardiovasc Disord 2005; 5: Bartholomew JR, Olin JW. Pathophysiology of peripheral arterial disease and risk factors for its development. Cleve Clin J Med 2006; 73(Suppl 4): S Willigendael EM, et al. Influence of smoking on incidence and prevalence of peripheral arterial disease. J Vasc Surg 2004; 40: Hobbs SD, Bradbury. Smoking cessation strategies in patients with peripheral arterial disease: An evidence-based approach. Eur J Vasc Endovasc Surg 2003; 6: Tonstad S, et al. Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study. Eur Heart J 2003; 24: Adler AI, et al. UKPDS 59: Hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002; 25: Al-Delaimy WK, et al. Effect of type 2 diabetes and its duration on the risk of peripheral arterial disease among men. Am J Med 2004; 116: Jude EB, et al. Peripheral arterial disease in diabetic and nondiabetic patients. Diabetes Care 2001; 24: Selvin E, et al. HbA1c and peripheral arterial disease in diabetes. Diabetes Care 2006; 29: Selvin E, et al. Meta-Analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141: 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: Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005; 366: The use of agents that modify the risk factors e.g., statins, ACE inhibitors, aspirin, beta-blockers is associated with a reduction in long-term mortality risk in patients with PAD that is independent of clinical risk factor and adjusted for propensity scores. 25 In addition to risk factor modification, exercise and weight loss are among the most effective interventions for the management of PAD. 24 A structured exercise program should not be superseded by pharmacological intervention. 3 Even self-directed walking exercise is associated with less functional decline among persons with PAD, whether symptomatic or asymptomatic. 26 Patients who are overweight (BMI kg/m 2 ) or who are obese (BMI >30 kg/m 2 ) should receive counseling for weight reduction by inducing negative caloric balance with reduction of calorie intake, carbohydrate restriction and increased exercise. 2 25
14 16. Giri J, et al. Statin use and functional decline in patients with and without peripheral arterial disease. J Am Coll Cardiol 2006; 47: Mohler ER, et al. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 2003; 108: Yusuf S, et al. 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: Gornik HL, Creager MA. Contemporary management of peripheral arterial disease: I. Cardiovascular risk-factor modification. Cleve Clin J Med 2006; 73(Suppl 4): S Mehler PS, et al. Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation 2003; 107: Hiatt WR. Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy. J Int Med 2002; 251: Antithrombotic 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: CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: Hankey GJ, et al. Medical treatment of peripheral arterial disease. JAMA 2006; 295: Feringa HHH, et al. Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease. J Am Coll Cardiol 2006; 47: McDermott MM, et al. Physical performance in peripheral arterial disease: a slower rate of decline in patients who walk more. Ann Intern Med 2006; 144: *Also published as follows: J Vasc Surg 2007; 45(Suppl S): S5 67. Eur J Vasc Endovasc Surg 2007; 33(Suppl 1): S1 75. Int Angiol 2007; 26(2):
15 TASC II Inter-Society Consensus for the Management of PAD This pocket guide is one of a series of booklets designed to present the TASC II guidelines in a quick reference format. You can find pocket guides on other topics covered in the TASC II guidelines on the TASC II website: Discovery London and TASC II. All rights reserved.