Recent developments in treatment options for peripheral arterial disease (PAD) have improved the prognosis; more patients survive longer. Newer treatment options for PAD, such as antiplatelet and claudication therapies, have aimed at preventing adverse cardiovascular events, limb loss, and the need for surgical interventions. In addition to these clinical benefits, the same treatment options enhance the quality of life (QOL) for with PAD by helping them live more productive and satisfying lives.

As the population of patients with PAD ages, QOL will be a crucial tool in the assessment of disease maintenance and therapeutic monitoring. Diagnostic measurements like the ankle-branchial index can only identify the presence or severity of PAD. They cannot provide details on patient perceptions of functioning and well-being, nor can they determine the total impact the disease has had on an individual patient. Therefore, reliable and valid QOL measurement instruments are essential for treating patients with PAD.

Liles et al¹ recently reviewed current disease-specific QOL measurement tools for PAD. Only 3 instruments were identified as responsive, valid, and interpretable for determining QOL in patients with PAD. These instruments are as follows:

• Intermittent Claudication Questionnaire (ICQ)²
• For use in patients with intermittent claudication and rest pain
• Measures symptom severity and walking distance
• Vascular Quality of Life Questionnaire (VascuQoL)³
• For use in patients with lower limb ischemia
• Measures pain, symptoms, activities, emotion, and social functioning
• Theoretically possesses greater sensitivity to detect treatment effects
• The Claudication Scale (CLAU-S)⁴
• For use in patients with intermittent claudication
• Measures pain, emotional health, psychological status, daily living, and social limitations (all within the time frame of the past week)
• English version has not yet been validated

These instruments have supplemented traditional clinical outcome measures with information from the patient’s point of view. Because of the use of such tools, a recent meta-analysis on medical treatment of PAD was able to demonstrate that patient QOL was improved by lifestyle modifications (eg, smoking cessation, exercise) and medical therapies (eg, nicotine replacement therapy, bupropion, antihypertensive agents, statins, antiplatelet drugs).⁵

As current research in PAD seeks to establish how this disease affects the individual’s health status and well-being, additional tools are needed to better measure psychosocial characteristics, such as mental health and mood. In fact, patients with both symptomatic and asymptomatic PAD are at an increased risk for emotional and social impairments, such as depressive symptoms and impaired social role functioning.6 When assessing disease impact in the clinical setting, the clinician should listen carefully to the patient because self-reported and objective measures of QOL may differ substantially. With the increasing number of treatment choices for patients with PAD, the clinician should consider the impact of the treatment on patient QOL and thoughtfully review the literature to look for information regarding this impact in clinical trials.

References

1. Liles DR, Kallen MA, Petersen LA, Bush RL. Quality of life and peripheral arterial disease. J Surg Res. 2006 Dec;136(2):294-301.
2. Chong PF, Garratt AM, Golledge J, et al. The intermittent claudication questionnaire: a patient-assessed condition-specific health outcome measure. J Vasc Surg. 2002;36:764-71.
3. Morgan MB, Crayford T, Murrin B, Fraser SC. Developing the vascular quality of life questionnaire: a new disease-specific quality of life measure for use in lower limb ischemia. J Vasc Surg. 2001;33:679-87.
4. Boccalon H, Lehert P, Comte S. Intermittent claudication and quality of life. Psychometric validation of the French version of the CLAU-S questionnaire. J Mal Vasc. 2000;25:98-107.
5. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA. 2006;295:547-53.
6. McDermott MM, Greenland P, Guralnik JM, et al. Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med. 2003;18:461-7.

Peripheral Arterial Disease and Diabetes: Studies Reveal More Answers

Cardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus; up to 80% of deaths in patients with diabetes are closely associated with vascular disease.¹ The development of new collateral arteries is significantly reduced in patients with diabetes who also have coronary or peripheral arterial disease (PAD). This is one of many factors that contribute to the often progressive and critical course of limb ischemia in patients with diabetes. Foot ulceration and lower extremity amputation are 2 complications of PAD that are significantly more common in patients with diabetes than in those without diabetes.

The association between diabetes, PAD, and coronary disease continues to be highlighted in the following recent studies:

• Fremantle Diabetes Study: Patients with diabetes were recruited between 1993 and 1996 for this prospective, community-based observational study.²
• Both prevalent and incident PAD were strongly and independently associated with increasing age, systolic blood pressure, and total serum cholesterol level, and, especially, with smoking.
• An ankle-brachial index (ABI) less than or equal to 0.90 was independently associated with an increased risk of cardiac death of 67%.

• ARIC (Atherosclerosis Risk in Communities): This was a prospective, community-based cohort study of 1,894 patients with diabetes.³
• During a mean follow-up of 9.8 years, a positive, graded, and independent association between glycosylated hemoglobin A1c (HbA1c) levels and PAD risk was demonstrated in adults with diabetes.
• This association was stronger for clinical (symptomatic) PAD, the manifestations of which may be related to microvascular insufficiency, than for low ABI.
• The results also suggested that efforts to improve glycemic control in persons with diabetes may substantially reduce their risk of PAD.

• PAD-SEARCH: This was the first international study to investigate the prevalence of PAD in Asian patients with type 2 diabetes.⁴
• A total of 6625 patients aged 50 years and older who had type 2 diabetes were enrolled from Korea, China, Taiwan, Hong Kong, Indonesia, Thailand, and the Philippines.
• Of these patients, 1172 (17.7%) were determined to have PAD by an ABI less than or equal to 0.9, suggesting that PAD is a common complication in Asian patients with type 2 diabetes.
• Compared with patients with diabetes but without PAD, patients with both diabetes and PAD had significantly longer duration of diabetes and hypertension and had higher HBA1c levels.

These recent data further support the role of regular screening for PAD in patients with diabetes, intensive management of PAD, foot care to avoid ulceration, and patient education to prevent critical limb ischemia. Consequently, early diagnosis and treatment of PAD in patients with diabetes is critically important to reduce the risk of cardiovascular events, minimize the risk of long-term disability, and improve quality of life. A diagnosis of PAD in patients with diabetes requires a multifaceted treatment approach, involving aggressive risk-factor modification, antiplatelet therapy, education in foot care and injury prevention, and, potentially, revascularization.

References
1. Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol. 2006;47:921-29.
2. Norman PE, Davis WA, Bruce DG, Davis TM. Peripheral arterial disease and risk of cardiac death in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. 2006;29:575-80.
3. Selvin E, Wattanakit K, Steffes MW, et al. HbA1c and peripheral arterial disease in diabetes: the Atherosclerosis Risk in Communities study. Diabetes Care. 2006;29:877-82.
4. Rhee SY, Guan H, Liu ZM, et al; the PAD-SEARCH Study Group. Multi-country study on the prevalence and clinical features of peripheral arterial disease in asian type 2 diabetes patients at high risk of atherosclerosis. Diabetes Res Clin Pract. 2006 Sep 1; [Epub ahead of print].

Overcoming Aspirin Resistance in Patients With Peripheral Arterial Disease: Are We Getting Any Closer?

Aspirin has been shown to reduce the odds of an arterial thrombotic event in high-risk patients by more than 25%, but 10-20% of these patients do experience an ischemic event during long-term follow-up.¹

Aspirin resistance (the inability of aspirin to reduce platelet activation and aggregation) has been blamed for a proportion of arterial thrombotic events.² A possible correlation has been postulated between increasing degrees of aspirin resistance and increasing risk for cardiovascular events. Potential causes of aspirin resistance include the following:

• Inadequate dose
• Drug interactions
• Genetic polymorphisms of cyclooxygenase-1 (COX-1) and other genes involved in thromboxane biosynthesis
• Up-regulation of nonplatelet sources of thromboxane biosynthesis
• Increased platelet turnover

Aspirin resistance can be detected by laboratory tests of platelet function that depend on platelet thromboxane production, but patients demonstrate a marked variability in their laboratory responses to aspirin.³ To better understand this variability of response, a recent study in 700 aspirin-treated patients undergoing cardiac catheterization measured COX-dependent arachidonic acid–induced platelet function before and after the ex vivo addition of aspirin or indomethacin.⁴

Using serum thromboxane B₂ and flow cytometric measures, the authors reported that a residual arachidonic acid–induced platelet activation was caused by underdosing, noncompliance, or both, in only 2% of patients. In the remaining patients, the residual arachidonic acid–induced platelet activation occurred via a COX-1–independent and COX-2–independent pathway, in direct proportion to the degree of baseline platelet activation, which was mediated in part by adenosine diphosphate–induced platelet activation.

A multivariate analysis in the same study showed that arachidonic acid–induced platelet activation was less in patients receiving clopidogrel, which suggests that dual antiplatelet therapy with a thienopyridine, in addition to its direct antiplatelet effect via the P2Y12 adenosine diphosphate receptor, may decrease aspirin resistance. A recent clinical study confirmed this hypothesis in patients who are resistant to aspirin and have peripheral arterial occlusive disease (PAOD).⁵

Using the PFA-100^TM platelet function analyzer, this study defined the prevalence of aspirin resistance as patients who had a normal platelet function (closure time collagen/epinephrine <158 s) despite treatment with aspirin. Fifty patients with PAOD were treated with aspirin therapy (100 mg/d) for 2 weeks. PFA-100 analysis revealed 9 patients resistant to aspirin. These patients were then treated with combined aspirin 100 mg/d and clopidogrel 75 mg/d for 2 weeks, followed by 2 weeks of 300 mg/d of aspirin.

After aspirin and clopidogrel treatment, 6 of the 9 patients resistant to aspirin showed increased platelet inhibition. Combination antiplatelet therapy also prolonged closure time in patients who had submaximal platelet inhibition with 300 mg aspirin. However, combination therapy did not overcome all cases of laboratory aspirin resistance, suggesting that antiplatelet therapy, including aspirin dosage, may need to be individualized.

The findings from these recent studies have brought us a few steps closer to overcoming aspirin resistance in patients with peripheral arterial disease. Additional research is needed to further define aspirin resistance and assess reliable measuring tests and treatments.

References
1. Patrono C, Coller B, FitzGerald GA, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2004;126:234S–264S.
2. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet. 2006;367:606–17.
3. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation. 2004;110:e489–93.
4. Frelinger AL 3rd, Furman MI, Linden MD, et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation. 2006;113:2888-96.
5. Wong S, Morel-Kopp MC, Chen Q, et al. Overcoming aspirin resistance: increased platelet inhibition with combination aspirin and clopidogrel and high dose aspirin therapy in aspirin resistant patients with peripheral vascular disease. Thromb Haemost. 2006;95:1042-3.

Treatment with antiplatelet agents has become an essential therapeutic strategy for the management of atherothrombotic disease and its manifestations. However, monitoring platelet activity is not yet conventional in clinical practice. The ideal monitoring test would evaluate the effects of antiplatelet strategies, identify high-risk vascular patients who would benefit most from antiplatelet therapy, and distinguish between patients who do or do not respond to antiplatelet therapy.

Platelet aggregometry, developed in the 1960s, revolutionized the ability to identify and diagnose alterations in platelet function. Although it has become the mainstay and criterion standard of the clinical coagulation laboratory, aggregometry is an expensive and labor-intensive technique that requires highly specialized technicians to perform the tests and interpret test results.

Recent advances in antiplatelet therapy have mandated a perceived need to better assess drug efficacy by measuring platelet activity. Numerous new monitoring devices currently under investigation have shown promising results.

PFA-100 Platelet Function Analyzer (Dade Behring, Deerfield, Ill) - The PFA-100 is a screening device for the evaluation of primary hemostasis capacity in the citrated whole blood. The instrument measures the closure time of an aperture in a collagen/epinephrine-coated membrane (cartridge) under shear stress conditions. In an observational study of 150 patients with documented peripheral arterial disease (PAD), collagen plus epinephrine (CEPI) closure times were similar (P > 0.05) among the patients who received aspirin alone and those who received aspirin plus clopidogrel. In contrast, both of those patient groups exhibited prolonged CEPI values (P < 0.001) compared to patients who did not receive antiplatelet therapy and patients who were treated with clopidogrel alone. The authors concluded that while the PFA-100 device may be a suitable tool for monitoring aspirin therapy, it is not an appropriate tool for the detection of clopidogrel administration in its current setup. (Mueller, 2006)

Retention Index Test Homburg (RTH-II) - The RTH-II is quoted to detect effects of shear stress on platelets, which involve ADP receptor signaling. An ADP (2 microM) triggered RTH-II was studied in parallel with light-transmittance aggregometry and flow cytometry in subjects before and after treatment with clopidogrel. Correlation analysis showed that the ADP-stimulated retention index (RI) corresponded significantly to P-selectin expression (P < 0.01) but not to aggregation. A strong correlation (P < 0.01) also existed between the ADP-stimulated RI and the expression of CD62P after stimulation with 2 microM ADP, whereas no correlation was observed for RI vs binding of PAC-1 or aggregation. (Klinkhardt, 2006)

VerifyNow P2Y12 assay (Accumetrics, San Diego, Calif) - This assay tests platelet activity over 3 minutes and uses of the combination of ADP and prostaglandin E₁ (PGE₁) to directly measure the effects of clopidogrel on the P2Y12 receptor. The instrument reports results in P2Y12 Reaction Units (PRU). The VERIfy Thrombosis risk ASsessment (VERITAS) study was a prospective study designed to measure platelet response to clopidogrel therapy in subjects with multiple risk factors or history of vascular disease using the VerifyNow P2Y12 assay. Data from 147 participants demonstrated that clopidogrel therapy resulted in a mean PRU reduction of 64.0±25.3%. No participant reached PRU inhibition below 10% of baseline, validating that VerifyNow P2Y12 is a reliable, fast, and sensitive device suitable for monitoring platelet inhibition during clopidogrel therapy. (Malinin, 2006)

References

1. Klinkhardt U, Wenzel E, Harder S. The Retention Index Test Homburg (RTH-II): Response to clopidogrel and comparison with aggregometry and CD62P-expression. Platelets. 2006;17:42-8.
2. Malinin A, Pokov A, Spergling M, et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: The VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res. 2006 Mar 22; [Epub ahead of print].
3. Mueller T, Haltmayer M, Poelz W, Haidinger D. Monitoring aspirin 100 mg and clopidogrel 75 mg therapy with the PFA-100 device in patients with peripheral arterial disease. Vasc Endovascular Surg. 2003;37:117-23.

Patients with lower extremity peripheral arterial disease (PAD) have significantly impaired lower extremity functional performance compared with persons without PAD.¹ Current evidence-based treatment guidelines support the efficacy of supervised walking exercise programs to improve treadmill walking performance in patients with PAD and intermittent claudication.² A meta-analysis of 10 randomized studies showed that maximal walking time increased in claudication patients who underwent exercise training; the overall improvement in walking ability was 150%.³ In addition to the benefits of regular exercise on limb ischemic symptoms, sustained increases in physical activity have the potential to improve cardiovascular risk factors, thereby reducing the risk of cardiovascular ischemic events and improving survival rates in this population.⁴ Garg and colleagues⁵ just published their findings from a study of 460 men and women with lower-extremity PAD who were monitored for 57 months. Higher baseline physical activity levels measured by vertical accelerometer were associated with lower all-cause mortality (P = 0.003), demonstrating that patients with PAD who are more physically active during daily life have lower mortality rates than PAD patients who are less active.

Despite the demonstrated benefits of supervised walking exercise programs, few patients with PAD participate in supervised exercise programs. Barriers such as cost, lack of medical insurance coverage, and lack of transportation prevent wider participation in supervised exercise programs by patients with PAD. Recent data, however, suggest that self-directed walking exercise may protect against functional decline in patients with PAD.⁶ In a prospective observational study, 417 patients with PAD were classified at baseline and annually according to the number of times they reportedly walked for exercise each week (median follow-up of 36 mo). Compared with those who walked for exercise 1-2 times per week or not at all, patients who walked for exercise 3 or more times per week had smaller average annual declines in 6-minute walking distance (P = 0.029), usual-paced 4-meter walking velocity (P = 0.004), and fast-paced 4-meter walking velocity (P = 0.010). Similar associations between more frequent walking exercise and less functional decline were observed in the subset of asymptomatic patients.

Studies are currently under way to determine whether increased physical activity, other therapeutic interventions, or both are associated with improved outcomes in patients with PAD. These studies include the following:

• Study in Leg Circulation (SILC): This randomized controlled clinical trial (sponsored by the National Heart, Lung, and Blood Institute [NHLBI]) was designed to determine whether lower extremity resistance training and supervised treadmill walking exercise, respectively, improve functional performance in both symptomatic and asymptomatic patients with PAD.
• Reducing Risk Factors in Peripheral Arterial Disease: The investigators of this randomized controlled clinical trial (sponsored by the NHLBI) hope to determine whether a telephone behavioral counseling intervention achieves lower LDL cholesterol levels and increases physical activity in patients with PAD.
• Claudication: Exercise Versus Endoluminal Revascularization (CLEVER): This phase III interventional study (sponsored by the NHLBI) will test if a combination of aortoiliac stenting and pharmacotherapy improves maximum walking duration better than a combination of supervised exercise rehabilitation, exercise maintenance, and pharmacotherapy for those with aortoiliac artery obstruction.
• The Effects of Physical Training, Aspirin and Clopidogrel on the Walking Capacity of Patients With Stage II PAD: This randomized, controlled study plans to evaluate the change in walking capacity after a well-organized and structured intensive physical training program with supportive pharmacotherapy (clopidogrel or aspirin).

References

1. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the walking and leg circulation study. Ann Intern Med 2002;136(12):873-83.
2. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006;113(11):e463-654.
3. Leng GC, Fowler B, Ernst E. Exercise for intermittent claudication. Cochrane Database Syst Rev 2000;(2):CD000990.
4. Izquierdo-Porrera AM, Gardner AW, Powell CC, Katzel LI. Effects of exercise rehabilitation on cardiovascular risk factors in older patients with peripheral arterial occlusive disease. J Vasc Surg 2000;31(4):670-7.
5. Garg PK, Tian L, Criqui MH, et al. Physical activity during daily life and mortality in patients with peripheral arterial disease. Circulation 2006;114(3):242-8. Epub 2006 Jul 3.
6. McDermott MM, Liu K, Ferrucci L, et al. Physical performance in peripheral arterial disease: a slower rate of decline in patients who walk more. Ann Intern Med 2006;144(1):10-20.
7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44(3):720-32.
8. Kinikini D, Sarfati MR, Mueller MT, Kraiss LW. Meeting AHA/ACC secondary prevention goals in a vascular surgery practice: an opportunity we cannot afford to miss. J Vasc Surg 2006;43(4):781-7.

Clopidogrel pretreatment and continuing therapy after percutaneous coronary intervention (PCI) has been shown to reduce short-term (30 day) and long-term (8 months to 1 year) adverse cardiovascular outcomes.

• In the PCI Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI CURE) trial, 2658 patients with non–ST-elevation acute coronary syndromes were randomly assigned to double-blind treatment with either clopidogrel or placebo.¹ Overall (including events before and after PCI), the addition of clopidogrel led to a 31% reduction in cardiovascular death or myocardial infarction (MI) (P=0.002).
• The PCI Clopidogrel as Adjunctive Reperfusion Therapy (PCI CLARITY)–Thrombolysis In Myocardial Infarction (TIMI) 28 trial recently demonstrated the benefit of the addition of clopidogrel to standard fibrinolytic regimens in patients who present with acute ST-elevation myocardial infarction (STEMI).²
• In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial, a higher loading dose of clopidogrel (600 mg) was used before elective, low-risk stent procedures with favorable results over routine abciximab administration.³
• The Clopidogrel for the Reduction of Events During Observation (CREDO) trial was a randomized trial of 2116 patients. It demonstrated the effectiveness of antiplatelet therapy with clopidogrel 300 mg loading dose before PCI and 75 mg/d for 1 year afterward.⁴
• At 1 year, long-term clopidogrel therapy was associated with a 27% relative risk reduction in the combined primary endpoint of death, MI, or stroke (P = 0.02).
• In a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI had a relative risk reduction of 39% (P = 0.051) for the combined endpoint compared with no reduction in patients who received treatment less than 6 hours before PCI.
• Platelet inhibition with clopidogrel-loading before PCI followed by therapy for 1 year was highly cost-effective.⁵

Patients with PCI who have extracardiac vascular disease (ECVD), defined here as a history of either peripheral arterial disease or cerebrovascular disease, have been associated with a significantly higher risk for early⁶ and late mortality.⁷ To assess the effectiveness of long-term treatment with clopidogrel in patients with ECVD, a recent subgroup analysis of 272 patients from the CREDO trial was conducted at 99 centers in North America from June 1999 through April 2001.⁸ The main outcome measure was a 1-year incidence of the composite of death, MI, or stroke in the intent-to-treat population.

For the primary endpoint, patients with ECVD had a more than 2-fold greater relative risk reduction with clopidogrel than patients without ECVD (47.9% [95% CI = -4.2-73.9%] vs 18.2% [95% CI = -10.5-39.5%], respectively).⁸ Kaplan-Meier curves showed a significantly lower incidence of the composite of death, MI, stroke, and urgent target vessel revascularization in patients with ECVD treated with clopidogrel.

The authors of this subgroup analysis concluded that longer-term clopidogrel treatment provides added protection against thrombotic events throughout the arterial vasculature, not limited to the coronary arteries, and may be particularly effective at lowering risk in patients with more diffuse atherosclerosis such as ECVD.⁸ These results are consistent with peripheral interventional registry data, which demonstrated that clopidogrel therapy after peripheral angioplasty and stenting was associated with a significantly lower risk-adjusted composite cardiovascular event rate of death, nonfatal MI, and stroke at 6 months follow-up (OR = 0.17, 95% CI = 0.04-0.78, P = 0.02).^9,10

References

1. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33.
2. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005;294:1224-32.
3. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232-8.
4. Steinhubl SR, Berger PB, Mann JT 3rd, et al, for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.
5. Beinart SC, Kolm P, Veledar E, et al. Long-term cost effectiveness of early and sustained dual oral antiplatelet therapy with clopidogrel given for up to one year after percutaneous coronary intervention results: from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. J Am Coll Cardiol 2005;46:761-9.
6. Mukherjee D, Eagle KA, Smith DE, et al. Impact of extracardiac vascular disease on acute prognosis in patients who undergo percutaneous coronary interventions (data from the Blue Cross & Blue Shield of Michigan Cardiovascular Consortium [BMC2]). Am J Cardiol 2003;92:972-4.
7. Nallamothu BK, Chetcuti S, Mukherjee D, et al. Long-term prognostic implication of extracardiac vascular disease in patients undergoing percutaneous coronary intervention. Am J Cardiol 2003;92:964-966.
8. Mukherjee D, Topol EJ, Moliterno DJ, et al, for the CREDO Investigators. Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment. Heart 2006;92:49-51.
9. Mukherjee D, Dey S, Lingam P, et al. Predictors of clinical outcome in patients undergoing peripheral vascular interventions: insights from the University of Michigan Peripheral Vascular Disease Quality Improvement Initiative (PVD-QI2). J Am Coll Cardio 2003;41(suppl A):75A. (Presented at the 52nd Scientific session of the American College of Cardiology).
10. Dey S, Mukherjee D. Clinical perspectives on the role of anti-platelet and statin therapy in patients with vascular diseases. Curr Vasc Pharmaco 2003;1:329-33.

Ethnicity and Peripheral Artery Disease
The San Diego Population Study: Review and Clinical Commentary

The prevalence of peripheral artery disease (PAD) in black persons has been reported as excessive, but the reason for this finding is unknown. According to the San Diego Population Study,¹ published results of direct ethnic comparisons between non-Hispanic white (NHW) persons and black persons have appeared in only 2 studies,^2,3 and comparisons between these 2 groups and the Mexican-American Hispanic white subset have been published in only 1 other study.⁴ Because so few trials make these direct ethnic comparisons, and because the authors of the current study believe that the previous 3 studies underestimated PAD prevalence and misclassified as PAD-free some patients who actually had PAD, the present study sought to determine ethnic-specific PAD prevalence by comparing 4 ethnic groups from current and retired employees of the University of California at San Diego, including persons of NHW, black, Hispanic, and Asian descent.

In 2,343 evaluated participants aged 29–91 years, 104 (4.4%) PAD cases were found. Black persons had a higher PAD prevalence than NHW persons (odds ratio [OR] = 2.30; P <0.024). PAD prevalence in persons of Hispanic and Asian descent was somewhat lower than that found in NHW persons, but these differences were not statistically significant. The table depicts PAD prevalence results by ethnicity.

PAD Prevalence by Ethnicity

Ethnicity	PAD Cases/Total Subjects	PAD, % (95% CI)
Black	25/322	7.8
NHW	69/1401	4.9
Hispanic	6/341	1.8
Asian	4/279	1.4

A second multivariate logistic regression model that included variables such as body mass index, diabetes, and hypertension was employed to assess the degree to which ethnic-specific differences in cardiovascular disease (CVD) risk factors might account for ethnic differences in PAD prevalence. This model did not change the effect size for black ethnicity (OR = 2.34; P = 0.0480). The researchers concluded that black ethnicity is a strong and independent PAD risk factor that cannot be explained by higher CVD risk factors. They also concluded that the true cause of excessive PAD risk in black persons remains unclear.

The design of this study reflects certain refinements of the aforementioned ethnic comparison studies. The earlier studies had used ankle-brachial indexes (ABI) alone to determine PAD. The current study defined PAD as an ABI less than or equal to 0.90, an abnormal Doppler waveform, or previous revascularization for PAD. The increased complexity of this definition probably accounts for the more reliable determination of PAD in the current study. The study also adjusted for education and occupation, in consideration of a possible link between these socioeconomic factors and diagnostic and treatment differences.

While the authors must conclude that the cause of excessive PAD risk in black persons remains unknown, they suggest that newer, novel risk factors may be responsible, including atherogenic, inflammatory, and prothrombotic risk factors. These novel risk factors have previously been reported as more prevalent in black persons than in NHW persons. Genetic susceptibility to PAD is also suggested by the authors as a possible reason for increased prevalence in black persons. Finally, the authors conclude that with this research, black ethnicity itself—at a magnitude comparable to that of any other established risk factor—can now be considered a consistent and independent PAD risk factor.

References
1. Criqui MH, Vargas V, Denenberg JO, et al. Ethnicity and peripheral arterial disease: the San Diego Population Study. Circulation 2005;112:2703-7.
2. Newman AB, Siscovick DS, Manolio TA, et al. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation 1993;88:837-45.
3. Zheng ZJ, Sharrett AR, Chambless LE, et al. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 1997;131:115-25.
4. 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, 1999-2000. Circulation 2004;110:738-43.

As the use of dual antiplatelet therapy continues to expand in high-risk patients with cardiovascular disease, many clinical trials have investigated the benefits of these drug combinations in different patient populations. Large clinical trials have demonstrated that antiplatelet therapy with combined clopidogrel and aspirin significantly reduces the risk of adverse cardiac events in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention.

The CHARISMA trial was a randomized, international, multicenter, double-blinded, placebo-controlled study that set out to assess whether dual antiplatelet therapy with clopidogrel and aspirin decreased ischemic events in patients who had established vascular disease or were at risk for developing vascular disease. A total of 15,603 patients were enrolled from 32 countries and were followed for a median of 28 months. Approximately 80% of the subjects had established coronary disease, cerebrovascular disease (CVD), or peripheral arterial disease (PAD). Approximately 20% of the subjects were at high risk of developing atherothrombosis due to multiple risk factors. All patients were randomized to receive either clopidogrel or placebo, in addition to aspirin.

The primary efficacy endpoint was the first occurrence of vascular death, myocardial infarction, or stroke. The secondary efficacy endpoint evaluated hospitalization for unstable angina, transient ischemic attack (TIA), or a revascularization procedure. Although the difference in the rate of the primary event was nonsignificant (6.8% in the clopidogrel group vs 7.3% in the placebo group; P = 0.22), the rate of the principal secondary efficacy endpoint was statistically significant (16.7% in the clopidogrel group vs 17.9% in the placebo group; P = 0.04). Statistically significant differences were reported in favor of combination clopidogrel plus aspirin in the individual endpoints of nonfatal stroke (P = 0.03) and hospitalization for unstable angina, TIA, or revascularization (P = 0.02).

The rate of severe bleeding was not significantly greater with clopidogrel than with placebo, but clopidogrel was associated with a significant increase in the rate of moderate bleeding.

In a subgroup analysis of symptomatic patients (ie, those with documented cardiovascular disease) and asymptomatic patients (ie, those with multiple atherothrombotic risk factors but no documented cardiovascular disease), the statistically significant results were as follows:

• Among the 12,153 symptomatic patients, those taking clopidogrel experienced a reduction in the primary endpoint (P = 0.046).
• Among the 3284 asymptomatic patients, those taking clopidogrel experienced 2 increases.
• A 20% relative increase in the rate of primary events (P = 0.20)
• A significant increase in the rate of death from all causes (P = 0.04) and from cardiovascular causes (P = 0.01)

Overall, findings from the CHARISMA trial were negative. The differing results in the predefined subgroups suggested a benefit of dual antiplatelet therapy in patients with established cardiovascular disease, while demonstrating a lack of benefit or actual harm in patients who have only multiple risk factors. This was the first trial to investigate whether long-term dual antiplatelet therapy would be of clinical value for high-risk primary prevention and secondary prevention in a broad patient population. Further investigation is needed to better understand how dual antiplatelet therapy may be optimally utilized in appropriate populations. Until then, the management of patients with PAD requires a multidisciplinary and individualized approach, especially for patients requiring intervention and for those on antitplatelet therapy.

Reference
Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-17. Mar 21; [Epub ahead of print].

The Reduction of Atherothrombosis for Continued Health (REACH) Registry: An Update

REACH is an international, prospective, observational registry designed to assess risk factor prevalence and treatment patterns for atherothrombosis throughout the world. The goal of the registry is to provide long-term, comprehensive, clinical practice data on the many manifestations of atherothrombosis in a population large enough to represent the entire spectrum of those at risk.¹ Baseline characteristics from the REACH registry population were recently published in JAMA and are summarized here.

Eligible outpatients aged 45 years or older with established coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD), or with at least 3 atherosclerosis risk factors were enrolled over an initial 7-month recruitment period (December 2003 to June 2004). Subjects were observed for up to 24 months.

A total of 67,888 patients from 5473 physician practices in 44 countries had either established arterial disease (CAD, n = 40,258; CVD, n = 18,843; PAD, n = 8273) or 3 or more risk factors for atherothrombosis (n = 12,389).

The main outcomes measured in the baseline report were prevalence of atherosclerosis risk factors, medication use, and degree of risk factor control. The authors found similar, classic risk factor profiles among atherothrombotic patients throughout the world, including the following:

• High proportion with hypertension (81.8%)
• Hypercholesterolemia (72.4%)
• Diabetes (44.3%)

Although the prevalence of overweight and obese individuals was similar in most geographic regions studies, this prevalence was significantly higher in North America than in other regions (P <0.001 vs other regions).

A key finding from this analysis was that 15.9% of subjects with symptomatic atherothrombosis also suffered from symptomatic polyvascular disease, suggesting that appropriate medications to treat cardiovascular risk in these patients are underutilized throughout the world. The baseline registry results also revealed the other following treatment patterns.

• Patients were generally undertreated with statins, antiplatelet agents, and other evidence-based risk reduction therapies.
• Current tobacco use in patients with established vascular disease was substantial.
• Undertreated hypertension, undiagnosed hyperglycemia, and impaired fasting glucose were common.

The full 1-year REACH registry results² were presented on March 12, 2006, at the American College of Cardiology 55th Annual Scientific Session in Atlanta. At 1-year follow-up, investigators observed an overall major adverse cardiovascular event (MACE) rate of 13%. However, patients with PAD were at substantially higher risk, experiencing a 1-year MACE rate of 22%. In addition, those with widespread vascular disease experienced a stepwise increase in risk (ie, the number of events increased with the number of vascular beds symptomatic for disease).

To date, no single international database has characterized the atherosclerosis risk factor profile or treatment intensity of individuals with atherothrombosis. The REACH registry has the potential to become a landmark survey as one of the largest international epidemiological registries to date. The follow-up phases of REACH will continue to allow for measurement of the cardiovascular ischemic event rates of this population as well as for an assessment of how these various risk factors affect the rates of subsequent morbidity, mortality, and cardiovascular outcomes. The knowledge gained should raise the understanding and awareness of atherothrombosis globally, contributing to the development of better preventive strategies and management regimens for at-risk patients.

References
1. Bhatt DL, Steg PG, Ohman EM, et al for the REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA. 2006;295:180-189.
2. Steg PG, Bhatt DL, Wilson PWF, et al. One-year cardiovascular event rates in a global contemporary registry of over 68,000 outpatients with atherothrombosis: the Reduction of Atherothrombosis for Continued Health (REACH) registry results. Presented at: American College of Cardiology 55th Annual Scientific Session; March 12, 2006; Atlanta, Ga.

Risk Factors for Peripheral Arterial Disease in the Community: An Update

Epidemiological research methods have traditionally been used to identify risk factors that contribute to the incidence of cardiovascular disease (CVD) ischemic events such as myocardial infarction and stroke. Over the past two decades, these studies have increasingly identified the powerful impact of the classical atherosclerosis risk factors, including hypertension, smoking, hypercholesterolemia, and diabetes, on peripheral arterial disease (PAD) incidence and associated systemic events. More recently, these predictive factors have also been linked to the prognosis of patients with PAD and to other relevant limb outcomes (ambulatory function) and non-arterial outcomes (eg, incident renal insufficiency). The pace of knowledge growth has been prodigious. New epidemiological investigations that carefully evaluate population samples now provide insights regarding the pathogenesis, incidence, and associated risk of individuals with PAD.

The Atherosclerosis Risk in Communities (ARIC) study is a long-term, community-based prospective investigation that has described the etiology and natural history of PAD and its clinical consequences in a sample of adults aged 45-64 years from 4 communities across the United States. In 12,965 subjects with no prior history of PAD, 854 developed PAD over a mean follow-up time of 9.7 years. Over the past 5 years, the ARIC project has revealed major new information regarding the pathogenesis and prognosis of PAD. The following report summarizes the most recent findings from ARIC that have improved our appreciation of the impact of risk factors for PAD in both the general community and in special at-risk populations.

• Age and risk factors predict the incidence of initial cardiovascular events, but it is less clear which factors predict subsequent ischemic events. From ARIC, it appears that a series of risk markers, including increased serum creatinine and albumin and both carotid intimal-medial thickness (IMT) and carotid plaque with acoustic shadowing, are independently associated with recurrent CVD events.¹ These factors represent circulating and arterial markers of other pathophysiologic processes that are linked to atherogenesis.
• Psychosocial factors have been demonstrated to have prognostic value as risk factors for future coronary ischemic events but had not been previously evaluated as risk factors for noncoronary atherosclerotic disease. In ARIC, anger proneness and depressive symptoms were found to be associated with an increased incidence of PAD.²
• Diabetes is known to be one of the most potent risk factors for the development of PAD in the general population. However, it has not been known which risk factors are most powerful in predicting the development of incident PAD in individuals with known diabetes. In ARIC, current smoking, prevalent coronary heart disease (CHD), elevated fibrinogen and carotid IMT, and a prior history of insulin treatment were independently associated with an increased PAD incidence, identifying a subpopulation of diabetic persons at particularly high risk for PAD.³
• Monocyte chemoattractant protein-1 (MCP-1), which mediates the recruitment of monocytes, has been suggested to play a role in atherosclerosis. In ARIC, plasma MCP-1 levels were significantly higher in subjects with PAD, independent of traditional risk factors, and were associated with other inflammatory markers, providing another potential PAD therapeutic target.⁴
• A low ankle-brachial index (ABI) (defining PAD) is associated with an increased risk of both CVD ischemic events and death. Data from ARIC now demonstrate that individuals with an ABI lower than 0.9 are more than twice as likely to experience an increase in serum creatinine level (odds ratio 2.5). Thus, PAD is now defined prospectively as a risk factor for future renal dysfunction.⁵
• Whereas a low ABI is known to be associated with a marked increase in systemic ischemic events, recent data from high risk cohorts also have demonstrated a higher rate of CV events in individuals with an ABI >1.4. Is this true in all individuals with a high ABI? Data from ARIC suggest that some populations with a high ABI, in whom classic risk factors are not elevated, do not face such an increased future CVD risk.⁶
• Chronic kidney disease (CKD) has been associated with an increased risk of CVD morbidity and mortality; however, the specific relation between CKD and incident PAD has only recently been evaluated in the general nondialysis population. ARIC data categorized 14,280 middle-aged participants based on estimated glomerular filtration rate. Over a mean follow-up of 13.1 years, 1016 participants developed PAD (multivariable adjusted relative risk of 1.56); therefore, middle-aged patients with chronic kidney disease are at increased risk of incident PAD.⁷

Both established and junior clinician-investigators can feel secure that new prospective epidemiologic investigations such as ARIC will provide new population-based insights that will continue to improve PAD prevention, diagnosis, treatment, and survival.

1. Wattanakit K, Folsom AR, Chambless LE, Nieto FJ. Risk factors for cardiovascular event recurrence in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J. 2005 Apr;149(4):606-12.
2. Wattanakit K, Williams JE, Schreiner PJ, Hirsch AT, Folsom AR. Association of anger proneness, depression and low social support with peripheral arterial disease: the Atherosclerosis Risk in Communities Study. Vasc Med. 2005 Aug;10(3):199-206.
3. Wattanakit K, Folsom AR, Selvin E, Weatherley BD, Pankow JS, Brancati FL, Hirsch AT. Risk factors for peripheral arterial disease incidence in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2005 Jun;180(2):389-397.
4. Hoogeveen RC, Morrison A, Boerwinkle E, Miles JS, Rhodes CE, Sharrett AR, Ballantyne CM. Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: Atherosclerosis Risk in Communities study. Atherosclerosis. 2005 Dec;183(2):301-7.
5. O'Hare AM, Rodriguez RA, Bacchetti P. Low ankle-brachial index associated with rise in creatinine level over time: results from the atherosclerosis risk in communities study. Arch Intern Med. 2005 Jul 11;165(13):1481-5.
6. Atherosclerosis. 2006, in press.
7. Wattanakit K, Folsom AR, Selvin E, Coresh J, Hirsch AT, Weatherley BD. Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) study. Presented at: AHA 2005 Scientific Sessions; November 13-16, 2005; Dallas, Tex.

Peripheral Arterial Disease and Adverse Cardiovascular Outcomes

Peripheral arterial disease (PAD) is a chronic, systemic condition that typically affects people older than 50 years. The morbidity and mortality associated with PAD is cardiovascular, ie, patients with PAD have a much increased rate of myocardial infarction and stroke. As the population in the United States older than 60 years increases, the prevalence of PAD and its associated adverse outcomes will also increase. Therefore, a better understanding of the management of PAD is needed to reduce adverse cardiovascular outcomes and improve the quality of care for the expanding older patient population. Understanding the relationships among risk factors, process of care, and outcomes is crucial not only to patients and clinicians, but also to policymakers and payors.

Inflammation is fundamental to the process of atherosclerosis; hence, it is not surprising that inflammatory markers such as C-reactive protein (CRP) have been linked to a higher risk of acute coronary syndromes, symptomatic and nonsymptomatic PAD, and other vascular diseases. One hypothesis suggests that the extent of atherosclerosis and the amount of systemic inflammation may measure independent aspects of disease pathophysiology.

This hypothesis was tested in a study supported by the National Institutes of Health, that was recently published in the American Journal of Cardiology.¹ One hundred and ten patients (aged 62±15 years), who were referred to a noninvasive vascular laboratory, were enrolled. According to ankle-brachial index (ABI) measurements, 55% of these patients suffered from PAD. Levels of several markers of inflammation measured at study entry, including CRP, tumor necrosis factor-alpha, and interleukin-6, were significantly higher in subjects with PAD.

After a mean follow-up period of 2.25 years, patients were prospectively evaluated. The reported results include the following:


• Forty-two percent of all patients developed an adverse cardiovascular event (myocardial infarction, stroke, unplanned coronary or lower extremity revascularization, or death).
  
  • Half of the predetermined PAD patients experienced at least 1 event.
  • Events occurred more frequently in patients with PAD than in those without PAD (50% vs 20%, respectively).
• The risk of a cardiovascular event increased threefold as CRP increased from the lowest to the highest tertile.
  
  
• The risk of an event increased as the severity of PAD worsened from the highest to the lowest ABI tertile.
  
  
• The risk of an event increased sixfold among subjects with lowest ABI (ie, with PAD) and highest CRP levels compared with subjects whose levels were normal.
  

  The findings from this study demonstrated a significant association between the severity of PAD and levels of systemic inflammation, confirming that patients who have both PAD and increased inflammation are at highest risk for adverse cardiovascular outcomes. Moreover, the authors were able to establish a graded relationship between ABI and CRP through the range of clinical values, such that the addition of ABI to CRP provides additional prognostic information.

  On a separate note, despite recommendations that advocate aggressive decreases in risk factors, the PAD patients in this study were medically undertreated, further reinforcing the need for effective preventative measures that minimize adverse events.

  1. Beckman J, Preis O, Ridker PM, Gerhard-Herman M. Comparison of usefulness of inflammatory markers in patients with versus without peripheral arterial disease in predicting adverse cardiovascular outcomes (myocardial infarction, stroke, and death). Am J Cardiol. 2005; 96(10):1374-8.

  Peripheral Arterial Disease Management Guidelines

  New practice guidelines for the management of peripheral arterial disease (PAD) have been developed and approved as a collaborative effort of the American Association for Vascular Surgery/Society for Vascular Surgery, the Society for Cardiovascular Angiography and Interventions, the Society of Interventional Radiology, the Society for Vascular Medicine and Biology, and the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines. An executive summary of the guidelines will be published in the Journal of the American College of Cardiology and in Circulation, the journal of the American Heart Association.

  More than 12 million Americans have peripheral arterial disease (PAD), which is defined within the context of the new Peripheral Arterial Disease Management Guidelines as disorders compromising the abdominal aorta, renal and mesenteric arteries, and lower extremity arteries. Among the important precepts included in the new guidelines are that PAD is a marker of systemic atherosclerosis and one component of a polyvascular disease triad that also includes coronary heart disease (CHD) and cerebrovascular disease (CVD). Regardless of the vascular bed involved, the burden of this polyvascular disease is enormous in the United States and throughout the world. With 61.8 million Americans affected by one or more of these atherosclerotic diseases, PAD is responsible for 958,775 deaths annually at a cost of about $329.2 billion. As such, patients with PAD are at increased risk for myocardial infarction, stroke, and death.

  The new guidelines draw on the experiences and recommendations of vascular specialists, including vascular medicine physicians, cardiologists, vascular surgeons, and interventional radiologists. The ACC/AHA PAD guidelines contain important principles and practice recommendations for the management of PAD, and they are a valuable resource for health care providers, including primary care physicians, nurse practitioners, and physician assistants. Early detection, treatment, and pharmacologic intervention in treating PAD are emphasized in order to decrease risks of cardiovascular events, reduce mortality, improve functional status and quality of life, and preserve limb viability.

  The guidelines committee analyzed thousands of scientific studies. The committee assigned the highest credibility to well-designed, randomized clinical trials but also took into consideration smaller studies and expert opinion. Classifications of recommendations and levels of evidence are expressed in gradations in order to clearly distinguish their strengths and weaknesses. The new guidelines divide considerations of PAD into 4 major components, including lower extremity PAD, renal artery disease, mesenteric artery disease, and abdominal aorta aneurysm. Guideline highlights include the following:

• Specific questions to identify high-risk groups and masked signs of PAD
  
  
• Descriptions, strengths, and weaknesses of ankle-brachial indices, magnetic resonance angiography, and other diagnostic and imaging procedures
  
  
• Diagnostic and therapeutic algorithms
  
  
• Cardiovascular risk reduction therapies for patients with PAD
  
  
• Therapy for intermittent claudication and critical limb ischemia
  
  
• Recommendations for abdominal aortic aneurysm surveillance
  
  
• Recommendations for endovascular and surgical treatment of abdominal aortic aneurysm
  
  
• Clinical signs and symptoms of renal artery stenosis
  
  
• Treatment guidelines for managing renal artery stenosis

  The new PAD guidelines are endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; the National Heart, Lung, and Blood Institute; the Society for Vascular Nursing; the TransAtlantic Inter-Society Consensus; and the Vascular Disease Foundation. All organizations endorsing the guidelines, including the ACC/AHA, are partners in the PAD coalition, an organization committed to raising public and clinician awareness of PAD.