A RTICLES. Key Articles and Guidelines in the Management of Peripheral Arterial Disease

Transcription

1 K EY A RTICLES Key Articles and Guidelines in the Management of Peripheral Arterial Disease Zachary A. Stacy, Pharm.D., Paul P. Dobesh, Pharm.D., FCCP, toby C. trujillo, Pharm.D., William e. Dager, Pharm.D., FCSHP, FCCP, FCCM, FASHP, toni Ripley, Pharm.D., and Kari l. Olson, B.Sc.(Pharm.), Pharm.D. Peripheral arterial disease (PAD) affects approximately 8 million people in the united States, with less than half of these patients experiencing symptoms. the frequent asymptomatic presentation, combined with a lack of disease awareness by patients and health care practitioners, may result in missed diagnoses and inadequate treatment. Clinicians should recognize PAD as a marker of systemic atherosclerosis and appreciate the increased cardiovascular morbidity and mortality associated with the disease. Furthermore, intermittent claudication can significantly affect the quality of life of patients with acute and chronic leg ischemia. Consequently, a comprehensive treatment approach is needed, targeting both cardiovascular risk reduction and treatment of claudication pain. Although peripheral atherosclerosis can affect arterial beds throughout the body, our focus is on the key articles and guidelines addressing lower limb disease. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with PAD. Key Words: peripheral arterial disease, intermittent claudication, peripheral arterial occlusive disease, atherosclerosis, key articles, treatment guidelines. (Pharmacotherapy 2011;31(9):176e 206e) Outline Clinical Guidelines incidence/prevalence/impact of Disease Detection, Diagnosis, Prognosis Antiplatelet therapy Risk Factor Reduction Cilostazol Pentoxifylline Other intermittent Claudication therapy Fibrinolytics Percutaneous transluminal Angioplasty (PtA) Pharmacotherapy Post-Operative Anticoagulation for Graft Patency Vitamin K Antagonists (VKA) for Graft Patency Antiplatelet therapy for Graft Patency Peripheral arterial disease (PAD) is an obstructive disease of the upper and lower extremities resulting in reduced arterial blood flow at rest and with exertion. While nearly 8 million patients in the united States (u.s.) have been diagnosed with PAD, it remains largely underappreciated and underdetected. Peripheral atherosclerosis can be an early signal for vascular complications in patients at risk for coronary heart disease. therefore, PAD management should include two distinct therapeutic goals. All patients should receive therapy to prevent complications such as myocardial infarction (Mi), stroke, and vascular death. this preventive therapy can consist of risk factor modification and antiplatelet therapy. the second goal involves the prevention or reduction of claudication symptoms. evaluation of therapy can be challenging as the evidence has grown and evolved slowly over the past 25 years.

2 GuiDelineS in the MAnAGeMent OF PAD Stacy et al 177e the Cardiology Practice and Research network (PRn) of the American College of Clinical Pharmacy has taken the initiative to assemble a list of key articles and guidelines in major focus areas of cardiology. examples of these collections of annotative bibliographies include acute coronary syndromes, heart failure, and venous thromboembolism. 1 3 this document incorporates significant manuscripts and guidelines published in the area of PAD and ic. the authors provide a brief summary of the results, along with their insights on the implications on clinical practice and research. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with PAD. CLINICAL GUIDELINES Working Party on Thrombolysis in the Management of Limb Ischemia. thrombolysis in the management of lower limb peripheral arterial occlusion a consensus document. Am J Cardiol 1998;81: While over a decade old, these guidelines issued by the Working Party on thrombolysis in the Management of limb ischemia still retain clinical relevance to this day. Published in 1998, this consensus document represented the first effort at providing guidance for the appropriate use of thrombolysis in patients with lower extremity PAD. Many recommendations that can be found here can be characterized as no more than expert consensus, reflecting the lack of strong scientific evidence that was available at the time. However, in the subsequent decade, there has been what some may characterize as minimal progress in the emergence of well-designed From the Division of Pharmacy Practice, St. louis College of Pharmacy, St. louis, MO (Dr. Stacy); Saint luke's Hospital, Chesterfield, MO (Dr. Stacy); the Department of Pharmacy Practice, university of nebraska Medical Center College of Pharmacy, Omaha, ne (Dr. Dobesh); the Department of Clinical Pharmacy, university of Colorado School of Pharmacy, Aurora, CO (Drs. trujillo and Olson); the Department of Pharmaceutical Services, uc Davis Medical Center, Sacramento, CA (Dr. Dager); the university of Oklahoma Health Sciences Center, College of Pharmacy, Oklahoma City, OK (Dr. Ripley); and Department of Pharmacy, Kaiser Permanente Colorado, Aurora Colorado (Dr. Olson). For reprints, visit loi/phco. For questions or comments, contact Zachary A. Stacy, Pharm.D., BCPS, St. louis College of Pharmacy, Division of Pharmacy Practice, 4588 Parkview Place, St. louis, MO 63110; zachary.stacy@stlcop.edu. randomized clinical trials investigating the use of thrombolysis in patients with PAD. in fact, many recommendations that can be found in more contemporary documents such as the 2008 American College of Chest Physicians (ACCP) guidelines are based on small studies that often are simply descriptive in nature. As such, this consensus document from 1998 still has clinical relevance as many recommendations that were developed then are still used today, including the various dosing strategies that can be employed with thrombolytic agents in patients with lower extremity PAD. Additional guidance can be obtained regarding the definition of successful thrombolysis, appropriate patient selection, various administration techniques (ranging from intravenous (iv) to intra-arterial (ia) administration), as well as adjunctive treatment with anticoagulant and antiplatelet medications. Hirsch AT. Haskal ZJ, Hertzer NR, et al. ACC/AHA guidelines for management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and interventions, Society of interventional Radiology, Society for Vascular Medicine and Biology, and the American College of Cardiology/American Heart Association task Force on practice guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease). J Am Coll Cardiol 2006;47: the 2005 guidelines for the management of patients with PAD from the American College of Cardiology (ACC)/ American Heart Association (AHA) represent the first focused effort by these organizations at addressing the appropriate management of patients with PAD. As such, they represented a paradigm shift in how patients with PAD should be viewed. Previously, the overall level of risk for cardiovascular morbidity and mortality present in patients with PAD was to some degree unappreciated. With the publication of these guidelines there was an effort to educate the healthcare community that the management of PAD should not be limited to symptomatic treatment of lower limb ischemia, but also to the reduction of hard cardiovascular endpoints such as Mi, stroke and death. Readers can find information not only on the epidemiology, prognosis and clinical presentation of lower extremity PAD, but also specific recom-

3 178e PHARMACOtHeRAPY Volume 31, number 9, 2011 mendations for both the management of atherosclerotic risk factors [which mirror those for patients with coronary artery disease (CAD) or cerebrovascular disease] and the reduction of cardiovascular risk (lifelong antiplatelet therapy). As with other guidelines on PAD, recommendations for the appropriate use of cilostazol and pentoxifylline for ic, as well as revascularization procedures are addressed. One distinguishing feature of the ACC/AHA guidelines is that specific arterial beds, such as renal, mesenteric, and abdominal, are recognized and discussed. these guidelines are well referenced with over 1300 references to the primary literature supporting the recommendations. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkers FGR, on behalf of the TASC II Working Group. inter-society consensus for the management of peripheral arterial disease (tasc ii). J Vasc Surg 2007;45(suppl S):S5A S67A. the transatlantic Atlantic Society Consensus (tasc) document on the management of PAD was first developed and published in this document represented the collaboration of 14 medical societies ranging from vascular radiology, cardiology, and vascular surgery in europe and north America this current document represents an abbreviated update of the 2000 guidelines for the diagnosis and management of PAD, and was developed with broad international representation. Readers who may be unfamiliar with the development group and resulting guidelines can rest assured that the methodology for grades of recommendations follow similar processes and standards in better known guideline documents such as the ACCP guidelines. the guideline provides an excellent overview of the epidemiology, risk factors, and typical clinical course of PAD. in addition, there is extensive discussion on the ramifications for management when PAD co-exists with CAD or cerebrovascular disease. the diagnosis of ic is discussed, as well as methods for the appropriate determination of prognosis in patients with PAD. the comprehensive treatment of ic, from modification of risk factors to medication management with cilostazol, is laid out in a structured and step by step manner. the remainder of the guideline discusses the treatment of patients with critical and chronic limb ischemia, including specific recommendations for revascularization procedures based on the nature and extent of peripheral atherosclerosis, as well as recommendations for the appropriate use of antithrombotic agents in these patients. Of note, recommendations on the appropriate use of thrombolysis, anticoagulant and antiplatelet agents largely coincides with recommendations that can be found in the 2008 ACCP guidelines. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease. American College of Chest Physicians evidence-based Clinical Practice Guidelines (8th edition). Chest 2008;133:815S 843S. the 8 th edition of the ACCP guidelines, published in the summer of 2008, provides recommendations on the use of antithrombotic therapy in a variety of patient scenarios. While these guidelines are the most up-to-date reference discussed in this bibliography, the recommendations only address the use of antithrombotic therapy, and do not discuss other general measures for the management of PAD or ic. Significant highlights include the recommendation of lifelong antiplatelet therapy in patients with PAD to reduce the risk of the risk of atherothrombotic events, regardless of the presence of concomitant CAD or cerebrovascular disease. A further discussion of the merits of different oral antiplatelet agents such as ASPiRin and clopidogrel is included the data demonstrating a lack of benefit for chronic anticoagulation in patients with PAD and ic is reviewed with a subsequent recommendation that they not be used. Agents used for the symptomatic treatment of ic are also discussed, with cilostazol being recommended while the authors recommend against the use of pentoxifylline. Specific recommendations for the use of thrombolytic agents, as well as iv ufh can be found in patients presenting with acute limb ischemia. Additional recommendations are also available regarding the use of acute and chronic anticoagulants in various revascularization procedures for patients with lower limb ischemia. these guidelines provide 208 references to the primary literature. Olin JW, Allie DE, Belkin M, et al. ACCF/AHA/ACR/SCAi/SiR/SVM/SVn/SVS 2010 performance measures for adults with peripheral artery disease: a report of the American College of Cardiology Foundation/American Heart Association task Force on Performance Measures, the American College of Radiology, the Society for Cardiac Angiography and

4 GuiDelineS in the MAnAGeMent OF PAD Stacy et al 179e interventions, the Society for interventional Radiology, the Society for Vascular Medicine, the Society for Vascular nursing, and the Society for Vascular Surgery (Writing Committee to Develop Performance Measures for Peripheral Artery Disease). Circulation. 2010;122: eight organizations have partnered to create the first set of performance measures for PAD. this document is intended for adult patients seen in the outpatient setting for lower extremity and abdominal aortic disease. the committee created seven final performance measures of which six directly relate to lower extremity disease including (1) measurement of the ABi in at-risk patients, (2) statin use for lowering low-density lipoprotein cholesterol, (3) smoking cessation, (4) antiplatelet therapy for cardiovascular risk reduction, (5) supervised exercise programs for patients with ic, and (6) ABi and ultrasound on vein bypass site. two test measures were also created including (1) vascular review of systems for lower extremity PAD and (2) population pulse measurement in at-risk patients. these performance measures should be acknowledged by any clinician managing patients with cardiovascular disease. the detailed appendices outlining the measure specifications will be essential for any individual involved in quality assurance, but may also be helpful for any clinician who cares for patients with PAD. INCIDENCE/PREVALENCE/IMPACT OF DISEASE Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. the prevalence of peripheral arterial disease in a defined population. Circ 1985;71: this prospective investigation, often referred to as the San Diego Study, assessed the prevalence of PAD in 613 men and women who were members of a lipid research clinic. the study participants ranged in age from 38 to 82 years (mean age 66). the authors used several objective non-invasive tests to determine both large vessel and small vessel disease prevalence. Claudication was also assessed by standardized Rose questionnaire. Claudication symptoms were present in 2.2% of men and 1.7% of women. Abnormalities in femoral or posterior tibial pulse were present in 20.3% of men and 22.1% of women. However, the noninvasive tests revealed that 11.7% of the cohort had large vessel PAD, with half of that population also having evidence of small vessel PAD (5.2%). the authors concluded that relying on symptoms of ic may underestimate the true prevalence of PAD, while palpation of peripheral pulses may overestimate the prevalence. this analysis was conducted in a very limited population with the cohort described as white, upper-middle-class residents in a community in Southern California. As such, the prevalence of PAD reported in this study may not apply to other regional or ethnic groups. this study provides some information about the possible prevalence of large and small vessel PAD in a specific population. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. n engl J Med 1992;326: this was a prospective study to investigate the rates of mortality from coronary heart disease (CHD) and cardiovascular disease among patients with large vessel PAD. Sixty-seven patients with PAD and 408 patients without PAD were followed for ten years. the relative risk (RR) of all-cause death in men with PAD was 3.3 (95% Ci 1.9 to 6.0) and in women with PAD was 2.5 (95% Ci, 1.2 to 5.3). Men with PAD experienced a significant increase in cardiovascular [5.1 (95% Ci 2.4 to 10.8)] and CHD [5.8 (95% Ci 2.4 to 14.3)] death. Similarly, women with PAD experienced cardiovascular [4.8 (95% Ci 1.6 to 14.7)] and CHD [4.8 (95% Ci 1.0 to 22.3)] death significantly more than women without PAD.. the RR of all-cause death among all patients with PAD continued to be high after adjustment for known cardiovascular risk factors (3.1 95% Ci 1.9 to 4.9). the overall RR of death in patients with large vessel PAD was 5.9 (95% Ci 3.0 to 11.4) from cardiovascular causes and 6.6 (95% Ci 2.9 to 14.9) from CHD causes. Kaplan-Meier survival curves demonstrated that patients with asymptomatic large vessel PAD were associated with a reduction in survival compared to the group without PAD. However, the Kaplan-Meier survival curves show that severe symptomatic large vessel PAD had the worst prognosis, with only 1 in 4 patients surviving 10 years. this study demonstrated that patients with large vessel PAD, regardless of the severity or presence of symptoms, have a higher risk of death from cardiovascular or CHD than patients without PAD. Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler thromb Vasc Biol 1998;18:

5 180e PHARMACOtHeRAPY Volume 31, number 9, 2011 this publication was part of the Rotterdam study, which was a prospective study to determine the occurrence and progression of chronic diseases in the elderly. this specific analysis was to determine the age- and sexspecific prevalence of PAD and ic in 7715 subjects 55 years of age or older (mean age for men was 69.0 and the mean age for women was 71.7). the presence of PAD and ic was assessed using the ankle-brachial index (ABi) and World Health Organization (WHO)/Rose Questionnaire, respectively. Overall, PAD was present in 19.1% of the cohort. the prevalence in women was 20.5% and the prevalence in men was 16.9 %. the age difference between the women and men in the cohort accounted for the apparent difference in prevalence. A clear association with age was observed with the prevalence of PAD in men (6.6%) and women (9.5%) age years compared to men (52.0%) and women (59.6%) older than 85 years. intermittent claudication was reported in 1.6% of the overall cohort. the prevalence of ic in men was 2.2% and in women was 1.2%. Among those with PAD, the prevalence of ic was higher at 6.3%. these data were used to establish the ACC/AHA PAD screening criteria for patients greater than 70 years old in the absence of other risk factors. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the united States: Results from the national Health and nutrition examination Survey, Circulation 2004;110: this study is from the national Health and nutrition examination Survey , which is an ongoing cross-sectional survey of noninstitutionalized patients across the united States (us). this analysis was done to assess the prevalence of PAD among the general us population, to assess the prevalence of cardiovascular risk factors among individuals with PAD, and to determine the associations between hypothesized PAD risk factors and the prevalence of PAD in the us adult population. Among the 2174 participants aged 40 years and older, the prevalence of PAD was 4.3%. the prevalence increases with age as the overall prevalence of PAD among individuals 70 years was 14.5%. in age- and gender-adjusted odds ratios (OR), non-hispanic black race (OR 2.83, 95% confidence interval (Ci) ), current smoking (OR 4.46, 95% Ci ), hypercholesterolemia (OR 1.68, 95% Ci, ), DM (OR 2.71, 95% Ci ), and reduced renal function (OR 2.00, 95% Ci, ) were all positively associated with PAD. each of these risk factors remained significantly associated with PAD when additionally adjusted for race, smoking status, body mass index, hypertension (Htn), hypercholesterolemia, diabetes (DM), and renal dysfunction. this study provides data suggesting that approximately 5 million individuals have PAD in the us. this study also confirms the risk factors associated with PAD. Hirsh AT, Murphy TP, Lovell MB, et al. Gaps in public knowledge of peripheral arterial disease: the first national PAD public awareness survey. Circ 2007;116: this is a cross-sectional, population-based telephone survey to assess public awareness of the morbidity and mortality associated with PAD. A nationally representative sample of 2501 adults 50 years old (mean age 67.2 years) were surveyed. the survey instrument was created by the investigators and was not validated, but it did undergo a cognitive pretest. Participants in the survey had Htn (52.6%), hypercholesterolemia (48.0%), and DM (18.5%). Only 1% reported a history of PAD, but 16.4% reported leg pain with ambulation. Most respondents demonstrated knowledge of atherosclerosis risk factors (Htn 89.7%, hypercholesterolemia 84.8%, and DM 77%) and cardiovascular disease (stroke 73.9% and CAD 67.1%). in contrast, only 25% of the respondents reported an awareness of PAD. Among the respondents who expressed familiarity with PAD (n=1331), knowledge of causes and consequences of PAD was low. A low percentage of respondents were aware that obesity (56%), cigarette smoking (56%), DM (50%) and Htn (47%) were important causes of PAD. Few respondents were aware that PAD was associated with stroke (27.6%), heart attack (25.3%), death (14.4%), amputation (13.6%), or disability/inability to walk (6.2%). Respondents reported their primary source of information was television (26%), with very few individuals obtaining information from health care professionals (physician 14%, nurse 2%, pharmacist 0.2%). these data demonstrate a major public knowledge gap regarding PAD exists. the authors also discuss a national PAD public awareness campaign called Stay in Circulation, which is a joint effort between the national Heart, lung, and Blood institute and the PAD Coalition, to raise awareness about PAD and the associated risks. this knowledge gap is an

6 GuiDelineS in the MAnAGeMent OF PAD Stacy et al 181e area of opportunity for health care professionals, including pharmacists, who are often easily accessed by the general public. Regensteiner JG, Hiatt WR, Coll JR, et al. the impact of peripheral arterial disease on healthrelated quality of life in the Peripheral Arterial Disease Awareness, Risk, and treatment: new resources for Survival (PARtneRS) Program. Vasc Med 2008;13: this is a cross-sectional study to evaluate the health-related quality of life (HRQOl) of patients with PAD compared to patients with other types of cardiovascular disease. this data comes from the PARtneRS database, which was a national, community-based PAD detection program that evaluated the prevalence, risk factors, and treatment of PAD and other cardiovascular disease in primary care office practices. Although the database provided 7155 patients for analysis, only 5313 provided HRQOl data and were included in the present analysis. Patients were categorized into one of four subgroups: (1) no PAD or cardiovascular disease (n=2170), which were the reference group; (2) PAD (n=727); (3) other cardiovascular disease (n=1446); (4) combined PAD plus cardiovascular disease (n=970). the investigators used three validated and one non-validated HRQOl questionnaires. One item from each of the questionnaires was chosen a priori as the primary measure: the Physical Function score from the Medical Outcomes Study SF-36, the walking distance score from the Walking impairment Questionnaire (WiQ), the present category denoting quality of life in the Cantril ladder of life, and the response to the i cannot do many of the things i like to do question in the PAD Quality of life questionnaire. Patients categorized in the PAD and other cardiovascular disease groups had significantly lower SF-36 scores on the primary measure questions compared to the reference group. the WiQ indicated patients with PAD were more likely to be limited by calf pain; those classified as other CHD were more likely to be limited by chest pain, shortness of breath, and palpitations. Patients with combined PAD and cardiovascular disease had lower quality of life scores on all the primary measures compared to patients with PAD or cardiovascular disease alone, suggesting an additive effect of PAD in combination with other cardiovascular diseases. this study demonstrates patients with PAD have a reduction in their quality of life similar to patients with other forms of cardiovascular disease. Criqui MH, Ninomiya JK, Wingard DL, Fronek A. Progression of peripheral arterial disease predicts cardiovascular disease morbidity and mortality. J Am Coll Cardiol 2008;52: this was a prospective observational study following 508 patients with PAD to examine the association of progressive versus stable disease and the risk of future cardiovascular events. Patients were initially stratified according to their ABi at baseline (ABi < 0.70, , , , and 1.40), which was retrospectively gathered from patients that had been evaluated in two hospital vascular laboratories within the ten years prior to this analysis (Visit 1). Patients identified, who agreed to participate in the current study, received repeat ABi testing to characterize disease progression (Visit 2). After Visit 2, patients were followed for six years for the occurrence of all-cause mortality, cardiovascular mortality, and combined cardiovascular morbidity and mortality. the progression of PAD was categorized as a change in ABi from Visit 1 to Visit 2 into three ranges: < 0.15, 0.15 to , and > After three years of follow-up, a decrease in ABi of at least 0.15 was associated with an all-cause mortality RR of 2.4 (95% Ci 1.2 to 4.8, p=0.01) and a cardiovascular mortality RR of 2.8 (95% Ci, 1.3 to 6.0, p=0.01). these data provide evidence that progression of PAD, as defined by a decrease in ABi of at least 0.15, is associated with clinically significant complications. Meadows TA, Bhatt DL, Hirsh AT, et al. ethnic differences in the prevalence and treatment of cardiovascular risk factors in us outpatients with peripheral arterial disease: insights from the Reduction of Atherothrombosis for Continued Health (ReACH) Registry. Am Heart J 2009;158: these are data generated from the Reduction of Atherothrombosis for Continued Health (ReACH) Registry to determine the impact of ethnicity on the risk factor profile, use of evidence-based medical therapies, and 2-year cardiovascular outcomes. Patients 45 years or older from the us with three or more cardiovascular risk factors or with established PAD, CAD, or cerebrovascular disease were enrolled. the current analysis includes 2168 patients with established PAD, with or without concomitant CAD or cerebrovascular disease, who self-identified as being white (n=1816),

7 182e PHARMACOtHeRAPY Volume 31, number 9, 2011 black (n=237), or Hispanic (n=115). Risk factors varied significantly between the ethnic groups. Blacks and Hispanics were more likely to have DM and Htn, where as whites had a higher rate of hypercholesterolemia (p<0.01 for all). Blacks were more likely to have lone PAD, while whites and Hispanics were more likely to have multiple vascular diseases (p<0.01). there were no ethnic differences in all-cause mortality, cardiovascular death, nonfatal stroke, nonfatal myocardial infarction (Mi), amputation, or worsening of claudication. However, black patients were less likely to have peripheral arterial bypass graft surgery compared to white or Hispanic patients (p=0.02). ethnic differences are present in the risk factors associated with PAD and in some key treatments; however, mortality is similar among the various ethnic groups. DETECTION, DIAGNOSIS, PROGNOSIS Regensteiner JG, Steiner JF, Panzer RJ, Hiatt WR. evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vasc Med Biol 1990;2: One of the main goals of treating PAD is to improve walking ability. Prior to this study, treadmill testing was the primary mechanism to assess walking ability in patients with PAD/iC. While treadmill testing provides objective measures of walking ability, it is not practical in all practice settings and does not provide information on patient-perceived walking ability. this study developed and validated the PAD WiQ which characterized patients self-reported degree of difficulty in walking distance, speed, stair climbing, and limitations in walking ability. Validity and reliability testing was done using 26 patients. nineteen patients were enrolled in an exercise, conditioning program, had an ankle-toarm systolic blood pressure ratio < 0.95 at rest and < 0.85 after exercise, and were able to walk on a treadmill at a speed of at least 2 mph, but had claudication pain which limited leisure activities. Patients were paired according to severity of vascular disease. One member of each pair was randomized to the control or treatment group. Control patients maintained their usual activity level, while treated patients enrolled in a 12-week program of supervised treadmill walking consisting of one-hour of exercise three times per week. All patients had treadmill testing before and after completion of the program. the other seven patients were scheduled for peripheral bypass surgery and had treadmill testing performed before and 6-weeks after surgery. Questionnaire responses compared to objective treadmill performance obtained at the same time points correlated well before and after treatment. the PAD WiQ can be used to characterize the degree of walking impairment in patients with PAD and measure efficacy of interventions aimed at reducing PAD symptoms. Leng GC, Fowkes FGR. the edinburgh claudication questionnaire: an improved version of the WHO/Rose questionnaire for use in epidemiological surveys. J Clin epidemiol 1992;45: the WHO/ROSe questionnaire is an 8-item validated survey commonly used to assess and diagnose ic. Prior studies found the questionnaire to be highly specific but not very sensitive. this study explored the reasons for the poor sensitivity and good specificity of the questionnaire using 586 patients with ic and 61 with other causes of leg pain. the investigators found that over half of the false negatives with the WHO/ROSe questionnaire were produced by one question (Does the pain ever disappear while you are still walking?) and eliminating this question improved sensitivity without loss of specificity. eliminating another question What do you do if you get it when you are walking? did not affect specificity. Based on these data, a shortened 6-item self-administered questionnaire (edinburgh Claudication Questionnaire) was developed and tested on 300 subjects >55 years of age attending a general practitioner. the edinburgh Claudication Questionnaire was found to be 91.3% sensitive and 99.3% specific for diagnosing ic compared to the diagnosis made by a physician. the edinburgh Claudication Questionnaire is valuable screening tool for epidemiologic research. Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housely E, Ruckley CV. use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ 1996;313: this study was conducted to determine whether a low ABi predicts cardiovascular events and death above assessment of traditional cardiac risk factors. the study identified 1591 randomly selected men and women between 55 and 74 years of age followed for 5 years from registries of 11 general practices in Scotland. Patients with prior cardiovascular events were included. A

8 GuiDelineS in the MAnAGeMent OF PAD Stacy et al 183e World Health Organization questionnaire on smoking, diabetes status, and angina was administered at baseline. Patients had blood pressures, ankle systolic pressures, and fasting lipid profile measures recorded. Patients were followed for 5 years for cardiovascular events and death. Patients with ABi 0.9 had an nonsignificant increased risk for non-fatal Mi and significant increased risk of stroke, cardiovascular death, and all-cause mortality rates compared to patients with ABi > 1.0 after adjustment for age, sex, coronary disease and diabetes at baseline. Prediction of subsequent events improved when ABi was used in conjunction with traditional cardiovascular risk factor assessment. this trial demonstrated that an ABi measurement should be in used in combination with other cardiovascular assessment techniques rather than replace conventional cardiovascular risk factor assessments. Barletta G, Perna S, Sabba C, Catalano A, O Boyle C, Brevetti G. Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance. Vasc Med 1996;1:3 7. this study was conducted to assess overall HRQOl among patients with PAD and to evaluate how treadmill performance was related to patient perceived HRQOl. A total of 251 patients with ic were matched to 89 healthy, controls. the HRQOl was assessed using McMaster Health index questionnaire which assesses physical, social, and emotional function. Walking capacity for patients with ic was assessed using treadmill testing. Patients with ic had poorer perceived general health, physical, social, and emotional scores compared to control patients. treadmill performance did not correlate well with social or emotional scores. However, treadmill performance did correlate well with physical function scores. this study suggests that quality of life scores do not correlate well with treadmill testing, thus management of patients with ic should include an assessment of QOl in addition to usual tests of physical function. Chaudhr y H, Holland A, Dor mandy J. Comparison of graded versus constant treadmill test protocols for quantifying intermittent claudication. Vasc Med 1997;2: treadmill walking distance was the standard method for quantifying symptoms of ic. this study determined the reproducibility of maximum walking distance (MWD) and painfree walking distance (PFWD) using graded load compared to constant load treadmill testing among 14 patients with varying severity of ic. the constant testing protocol was set at 3.2 km/h and at a 10% grade while the graded protocol was set at 3.2 km/h and 0% grade increasing by 3.5% every 3 minutes. Patients were assessed two times with each protocol with at least two days in-between testing. the study found that the graded load test (R=0.84 for PFWD, R=0.98 for MWD) was more reproducible than the constant load test (R=0.68 for PFWD, R=0.93 for MWD). Furthermore, the measurement of MWD was more reproducible than PFWD using either protocol. McDermott MM, Liu K, Guralnik JM, Martin GJ, Criqui MH, Greenland P. Measurement of walking endurance and walking velocity with questionnaire: validation of the walking impairment questionnaire in men and women with peripheral arterial disease. J Vasc Surg 1998;28: Previous studies validating the WiQ included homogenous patient populations with ic. this study was designed to validate a WiQ among a heterogeneous group of patients with or without PAD or ic and multiple co-morbidities. the WiQ was mailed to 211 patients 55 years old with PAD (n=146) and without PAD (n=65) identified from a noninvasive vascular laboratory at baseline. At the study visit, patients performed the 6-minute walk test and the 4-m walking test. Correlations between the WiQ scores for walking distance and the 6-minute walk test and the WiQ scores for walking speed and the 4-m walking test were evaluated. the distance achieved in the 6-minute walk test correlated significantly with the WiQ scores for walking distance for patients with and without PAD. Similarly, WiQ scores correlated significantly with the 4-m walking tests. Correlations were not affected by comorbidities, presence of ic, or PAD severity. the study found the WiQ to be a valid measure of community walking ability in a heterogeneous group of patients with or without PAD. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286: the PAD Awareness, Risk, and treatment: new Resources for Survival (PARtneRS) program was

9 184e PHARMACOtHeRAPY Volume 31, number 9, 2011 designed to determine the feasibility of detecting PAD in primary care clinics, physician and patient awareness of PAD, and PAD treatment practices focused on risk reduction strategies. A total of 6417 patients 70 years or between 50 and 69 years of age with history of cigarette smoking or diabetes mellitus were evaluated by measurement of an ABi ( 0.9) and by patientreported history of PAD. investigators found that PAD was prevalent in primary care sites (29% overall), however the majority of PAD cases (55%) were diagnosed during the study and otherwise would have remained unrecognized. Most patients with prior PAD diagnosis were aware of the diagnosis, however only 48% of physicians were aware of the diagnosis. Patients with PAD had similar risk factor profiles compared to those with cardiovascular disease. Smoking was more frequently addressed in patients with PAD compared to those with cardiovascular disease. treatment of other cardiovascular risk factors and use of antiplatelet therapy among patients with PAD was low compared to patients with cardiovascular disease. this study highlights the importance of PAD screening using a relatively quick and easy objective method, such as the ABi, to identify patients in need of evidence-based treatment to improve long-term clinical outcomes. McDermott MM, Greenland P, Liu K, et al. leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 2001;286: Although ic is considered the most common manifestation of PAD, not all patients with PAD have ic or have symptoms other than ic. this cross-sectional study of 460 patients with and 130 without PAD was conducted to describe clinical characteristics and functional limitations associated with leg symptoms among patients with PAD. All patients had ankle-brachial index measured. the San Diego claudication questionnaire was used to characterize leg symptoms and categorize patients as having ic, leg pain on exertion and rest, atypical exertional leg pain requiring the patient to stop walking or not, and no exertional leg pain among patients active or not. Patients performed a 6-minute walk test, accelerometer-measured physical activity, repeated chair raises, standing balance, and 4-m walking velocity tests. Additionally, patients also completed a depression questionnaire and the WiQ. All patients with PAD had poorer functioning than patients without PAD. Furthermore, a large number of patients with PAD are asymptomatic (20%) or have exertional leg symptoms (29%) other than ic (32%). Co-morbidities and activity levels contribute to the variety of leg symptoms. Clinicians should be aware of both the typical and atypical leg symptoms commonly seen in patients with PAD. Breek JC, Hamming JF, De Vries J, Aquarius AD, van Berge Henegouwen DP. Quality of life in patients with intermittent claudication using the World Health Organisation (WHO) questionnaire. eur J Vasc endovasc Surg 2001;21: this prospective, open-label study of 151 patients with ic and 161 healthy controls was conducted to assess QOl in patients with ic. Quality of life was assessed using the World Health Organization quality of life instrument- 100, which consists of 6 domains (physical health, physiological health, level of independence, social relations, environment, and spirituality/religion/personal beliefs). Patients with ic scored poorly on a number of domains compared to healthy controls. Co-morbidities appear to effect QOl strongly, whereas the effect of walking distance on QOl might be small. this study suggests that invasive measures to increase walking distance should be reserved as they may have a minimal impact on a patient s quality of life. Additionally, while many clinicians may appreciate the impact wellmanaged co-morbidities have on the progression of PAD, these data underscore the impact of these co-morbidities on a patient s quality of life. Coyne KS, Margolis MK, Gilchrist KA, et al. evaluating effects of methods of administration on Walking impairment Questionnaire. J Vasc Surg 2003;38: the WiQ is a validated tool to characterize the degree of walking impairment in patients with PAD and measure effectiveness of interventions aimed at reducing PAD symptoms. in earlier validation studies, the questionnaire was administered in-person by trained individuals. the objective of this study was to determine whether a shortened version of the validated WiQ could be self-administered by patients or conducted via telephone rather than by in-person interviewers. the modified WiQ had 16 questions in four categories: pain (2 questions); walking distance (7 questions); walking speed (4 questions); and stair climbing (3 questions).

10 GuiDelineS in the MAnAGeMent OF PAD Stacy et al 185e Patients (n=60) > 40 years of age with ABi 0.90 at rest were randomized to receive a series of the WiQ self-administered or administered via telephone over a 4-week period. Group 1 patients completed a self-administered, modified WiQ at baseline, telephone-administered original WiQ at day 4 to 7, and self-administered modified WiQ at week 2. Group 2 patients completed a telephone-administered original WiQ at baseline, self-administered modified WiQ at day 4 to 7, telephone-administered modified WiQ at week 2 and again at week 4. Overall, the study found that telephone and selfadministration of the questionnaire had good internal consistency, reliability, reproducibility, and validity for the distance and speed subscales. the results of this study support administering these surveys in a more efficient manner compared to the time-intensive in-person interviews traditionally done. the modified WiQ could be useful in multicenter clinical trials comparing the effectiveness of various treatment options for ic. Resnick HE, Lindsay RS, McGrae M, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality. the Strong Heart Study. Circulation 2004;109: Prior studies demonstrated low ABi ( 0.9) increased patient risk for adverse cardiovascular outcomes. this study, conducted in 4393 American indian patients aged 45 to 74 years with follow-up out to 10 years, evaluated the risk of low ( 0.9) and high ( 1.40) ABi on all-cause and cardiovascular mortality independent of other cardiovascular risk factors. All patients had cardiovascular risk factors assessed at baseline. Deaths were ascertained through indian Health Service hospital records and by direct contact with family members. All-cause mortality rates were significantly higher among patients with low (53.8 per 1000 patient years) and high ABi (61.8 per 1000 patient years), compared to patients with a normal ABi (23.6 per 1000 patient years). this study demonstrated a high: normal ABi mortality rate ratio [2.76 (95% Ci 2.34 to 3.25)] was similar to a low: normal ABi mortality rate ratio [2.33 (95% Ci 1.87 to 2.90)] at predicting death independent of hypertension, diabetes, and renal disease at baseline. While more studies are needed to understand if these results can be expanded to a heterogeneous population, these data highlight the clinical importance of an abnormal ABi. Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systemic review. Arterioscler thromb Vasc Biol 2005;25: the ABi has been promoted as an assessment tool capable of predicting cardiovascular risk. this systematic review determines how well a low ABi ( 0.9) predicts future cardiovascular outcomes. A total of 9 studies met the inclusion criteria: 1) ABi was measured in all patients at baseline, 2) a cutoff between 0.80 and 0.90 was used to define PAD, 3) excluded patients with previous myocardial infarction and stroke, and 4) collected data on either coronary artery disease, stroke, or mortality. Overall, this study found a low ABi to be highly specific but not sensitive for predicting CHD (92.7%, 16.5%), stroke (92.2%, 16.0%), all-cause mortality (88.9%, 31.2%), and cardiovascular mortality (87.9%, 41.0%). this study demonstrated that a low ABi can be used to rule in a high-risk patient, but a normal ABi cannot be used to rule out a high risk patient. Nicolaï SPA, Kruidenier LM, Rouwet EV, Graffius K, Prins MH, Teijink JAW. the walking impairment questionnaire: an effective tool to assess the effect of treatment in patients with intermittent claudication. J Vasc Surg 2009;50: this study determined whether the WiQ, a validated questionnaire to assess walking ability with a focus on walking distance, walking speed, and ability to climb stairs, could be used to objectively assess improvement in functional ability in response to supervised exercise therapy among patients with ic. Consecutive patients (n=91) who presented to an outpatient vascular clinic with ic were included if they could walk at least 750 meters on a treadmill before treatment with supervised exercise therapy for 3 months. Patients completed a treadmill test, the WiQ, and a quality of life questionnaire at baseline and after 3 months of supervised exercise therapy. the WiQ and treadmill scores significantly increased at 3 months compared with baseline. Walking distances assessed with treadmill testing and the MWD also significantly improved. the change in WiQ correlated with changes in MWD. the results of this study suggest that the WiQ is a valid tool to evaluate the impact of exercise therapy on changes in walking ability and can be used in place of treadmill testing.

11 186e PHARMACOtHeRAPY Volume 31, number 9, 2011 ANTIPLATELET THERAPY Goldhaber SZ, Manson JE, Stampfer MF, et al. low-dose aspirin and subsequent peripheral arterial surgery in the Physician s Health Study. lancet 1992;340: this publication represents one of the first studies documenting the value of long-term antiplatelet therapy in patients with PAD. the investigators retrospectively assessed data from the us Physicians Health Study, which was a randomized, double-blind placebo-controlled trial investigating the effect of primary prevention with aspirin 325 mg every other day. Patients in the study were followed up at 6 months, 12 months, and yearly thereafter with a questionnaire to assess compliance as well as for the occurrence of any cardiovascular events. After an average duration of 60 months of followup, there was significantly less need for peripheral arterial surgery in those patients randomized to aspirin as compared to those receiving placebo (RR 0.54, 95% Ci , p=0.03). there were no differences between the groups in the occurrence of new ic after study enrollment (RR 0.98, 95% Ci , p=0.92); however, significantly fewer patients in the aspirin group with ic at study entry, reported needing peripheral arterial surgery during the study duration. the authors concluded that aspirin likely reduced the occurrence of clinically significant atherothrombotic events in patients with lower extremity PAD, similar to the beneficial effects seen in patients with CAD. this paper provided some of the first evidence for the benefit of antiplatelet therapy in patients with lower extremity PAD. Bergqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results from the Swedish ticlopidine Multicentre Study (StiMS). eur J Vasc endovasc Surg 1995:10: the main results of the StiMS trial were first published in 1990 and demonstrated that ticlopidine 250 mg twice daily reduced the risk of cardiac and cerebral ischemic events, as well as total mortality in patients with ic or a reduced ABi. When further analyzed, the main effect of ticlopidine was on total mortality. this publication was a follow-up from the StiMS trial to evaluate the effect of ticlopidine on the need for peripheral vascular surgery. the rate of peripheral vascular surgery averaged 2.4% per year during the trial period. the need for peripheral vascular surgery was reduced in patients receiving ticlopidine compared to placebo (RR 0.486, 95% Ci , p<0.001). the authors also attempted to identify risk factors that would predict the need for peripheral vascular surgery; however, only the presence of previous PAD was a strong predictor for revascularization. Overall the StiMS trial supported the use of thienopyridine therapy to improve cardiovascular outcomes similar to aspirin in patients with PAD. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRie). lancet 1996;348: Patients with CAD, PAD or cerebrovascular disease were randomized to either aspirin 325 mg daily compared to clopidogrel 75 mg daily. the primary outcome was a composite of Mi, stroke, or vascular death. Analysis of the overall study population demonstrated that clopidogrel was superior to aspirin at reducing the primary endpoint over an average of 1.9 years. the absolute annual event rates were 5.83% in the aspirin group, and 5.32% in the clopidogrel group (RRR 8.7%, 95% Ci , p=0.043) Despite the statistically significant results, clinical interpretation of the CAPRie trial was that clopidogrel offered an excellent alternative for patients who could not take aspirin therapy for any reason. this clinical interpretation was based on the significant cost differential, as well as a number needed to treat of 200. An interesting finding on subgroup analysis was that the benefit of clopidogrel was not consistent among the three pre-specified subgroups of stroke, Mi, and PAD. Patients were to be stratified equally between the different vascular beds (approximately 6300 in each). Most of the benefit of clopidogrel over aspirin in the CAPRie trial was demonstrated in the PAD subgroup. the patients in the PAD subgroup had a 23.8% RRR in the primary endpoint. While the difference in clinical effect between patients with atherosclerotic disease in different vascular beds has not been further clarified, the results of the CAPRie trial provided additional evidence of the benefit of chronic antiplatelet therapy in patients with PAD, and established clopidogrel as a viable option for use. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial