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Role of Antiplatelet Therapy in Cardiovascular Disease Ill: Peripheral Arterial Disease

Posted on: Friday, 7 January 2005, 03:00 CST

SUMMARY

Peripheral arterial disease (PAD) is a common manifestation of the atherosclerotic disease process, typically affecting vascular beds in the lower extremities. In its most severe form PAD may lead to limb amputation. Patients with PAD are also at increased cross- risk of thrombosis at coronary and cerebrovascular sites. However, despite its prevalence and severity, PAD is underdiagnosed and undertreated. In this collection of case studies, the role of the antiplatelet agent clopidogrel in current treatment strategies for the management of PAD is highlighted.

Introduction

Peripheral arterial disease [PAD] is a significant cause of morbidity and mortality in Western countries. Current epidemiological projections indicate that approximately 27 million people in North America and Europe have PAD. The majority of these cases (~16.5 million) are asymptomatic. In the USA, the prevalence of PAD in those aged 65 years or older is estimated to be 12-20%; this corresponds to 4.5 to 7.6 million affected people1,2. By 2050, as many as 19 million Americans may be expected to suffer from this disease.

PAD is a distinct manifestation of the atherosclerotic disease process that is characterized by stenosis (narrowing) and occlusion (obstruction) of peripheral arterial beds, typically those in the lower extremities. Patients with either form of PAD, symptomatic or asymptomatic, are at an increased risk of thrombosis. Due to the generalized nature of atherothrombosis, this elevated risk is not limited to the peripheral vasculature, but also includes an increased likelihood of coronary artery disease (such as acute coronary syndromes) or ischemic stroke. In an evaluation of over 1800 elderly patients in a long-term care facility, a significant proportion of PAD patients also had coexistent coronary artery disease (68%) or ischemic stroke (42%)3. As such, patients with PAD are at 4 times greater risk of a myocardial infarction (MI)4 and at 2-3 times greater risk of stroke or transient ischemic attack than those without PAD5.

The most common symptom of PAD is intermittent claudication, characterized by aching pain, numbness or fatigue typically affecting the calf area; these symptoms usually develop during exercise and are relieved by rest. Depending on the extent of vascular occlusion, severe peripheral limb ischemia may lead to limb amputation. Despite the prevalence, mortality and cross-risk of PAD for other cardiovascular events, only 25% of patients are currently undergoing treatment6. Evidence from the PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) program7 demonstrates that PAD is underdiagnosed in primary care (up to 95% of cases may be missed). In this program, the prevalence of PAD in a high-risk population (those >50 years old with diabetes and/or smoking, or those > 70 years old) was 29%. These findings indicate that physical examination alone is insufficient to detect PAD; the most accurate and reliable method to detect PAD and determine its severity is the measurement of ankle-brachial index8. Moreover, PAD has not received adequate attention in terms of risk factor modification and aggressive therapeutic approaches.

The management of PAD involves two precepts: (1) risk factor modification to reduce progression of underlying atherothrombosis and subsequent ischemic vascular complications, and (2) the alleviation of symptoms using exercise therapy, pharmacotherapy or surgery. For the treatment of symptomatic PAD, exercise therapy9 and treatment with the type III phosphodiesterase inhibitor cilostazol10 have proven to be most effective. In patients with limb-threatening ischemia or those who are disabled with functional ischemia, surgical revascularization or angioplasty may be indicated. Reduction of atherothrombotic risk can be achieved by managing the modifiable risk factors associated with PAD (Table 1)2. In addition to lifestyle modifications, another strategy is to target the platelet which plays a key role in the atherothrombotic process through the use of long-term antiplatelet therapy with aspirin or clopidogrel11,12. Other antiplatelet agents such as ticlopidine13 or dipyridamole14 appear to be of limited benefit due to safety or efficacy concerns. However, data from PARTNERS indicate that antiplatelet agents are underutilized in PAD patients (used in 33% of new PAD cases) versus patients with other cardiovascular diseases (used in 71% of cases)7.

Aspirin is the mainstay of treatment to manage the progression of cardiovascular disease. This drug inhibits platelet aggregation by initiating the thromboxane A2 pathway. In a meta-analysis of over 100000 patients14, aspirin reduced the combined risk of vascular death, MI or stroke by 27%. In a subgroup of patients with claudication, aspirin reduced the risk of this combined endpoint by 18%, although this effect was not statistically significant. Aspirin is not indicated to reduce thrombotic risk in patients with PAD. The efficacy of clopidogrel, an ADP receptor antagonist, has been demonstrated in the large-scale (-20 000 patients) CAPRIE trial15 that involved patients with established PAD, recent stroke or recent MI. Clopidogrel produced a significant risk reduction of 8.7% versus aspirin in the combined endpoint of vascular death, MI or stroke; this benefit was additional to the 23% risk reduction with aspirin alone. In the subgroup of PAD patients, the risk reduction of these events with clopidogrel compared with aspirin was 24%.

Table 1. Risk factors associated with peripheral arterial disease2

The following collection of case studies is the final of a three- part set illustrating the role of antiplatelet therapy in current approaches for the treatment of atherothrombotic diseases. The focus of the case reports in this articles is PAD, with case reports on acute coronary syndromes16 and ischemie stroke17 presented in the accompanying articles.

Case studies

1. Concomitant Unstable Angina and Right Arm Claudication* in a 62-Year-Old Woman

A 62-year-old woman recently diagnosed with new-onset asthma was evaluated for hypertension. Over the preceding months, she had experienced multiple 'asthma' exacerbations, which had been treated with prednisone and inhalers. She complained of intermittent chest tightness, shortness of breath and dyspnea on exertion. She also had severe aches in her right arm. Her physical examination was notable for poorly controlled hypertension in the left arm (170/85mmHg), but in the right arm her systolic blood pressure was 80 mmHg. Her right carotid, right brachial and right radial pulses were all markedly diminished. Cardiac catheterization and aortic arch angiography were recommended.

Coronary angiography showed a very severe stenosis in the proximal left anterior descending artery (LAD). Subsequent aortic arch angiography revealed 90% stenosis of the innominate artery. Combined angioplasty and stenting of the LAD and innominate arteries was undertaken. A heparin bolus of 3000units was given and tirofiban bolus and infusion was started. Angioplasty and stenting of the LAD was successfully performed with deployment of a 3.0 18mm Penta stent (Guidant, Temecula, CA) which was post-dilated with a 3.5 20mm NC Ranger balloon (Boston Scientific, Natick, MA). Post- procedural angiography demonstrated an excellent result. Angioplasty and stenting of the innominate artery was then performed with placement of an 8.0 18mm Omnilink stent (Guidant). The stent was post-dilated with a 10 20 mm Agiltrac balloon (Guidant) to a diameter of 11.0mm. Excellent results were demonstrated on the post- stent angiogram.

The patient showed immediate improvements with regard to pulse and sensation in her right arm. She was monitored overnight and discharged the next day. The patient had been taking, and will continue to take, aspirin chronically. Aspirin did not exacerbate her 'asthma'. She was given 375 mg of clopidogrel orally at the end of the procedure and will continue with clopidogrel 75 mg per day indefinitely and her other outpatient medications.

At the patient's 1-month follow-up, her right arm claudication and asthma/dyspnea had completely resolved. At the 1-year follow-up examination, she continued to do well and had no recurrence of symptoms; clopidogrel was therefore discontinued. The patient remained on aspirin, statin and angiotensin converting enzyme inhibition therapy.

2. Optimizing Care of PAD with Combined Use of Stenting and Long- term Antiplatelet Therapy

An 83-year-old man with history of aspirin hypersensitivity, hypertension, hyperlipidemia, and PAD presented with increasing claudication. The patient reported that his walking capacity was gradually decreasing and that walking was accompanied by increasing pain in both legs, particularly the right lower extremity. On physical examination, the lower extremities showed no clubbing, cyanosis, or edema. The peripheral pulses were diminished bilaterally, and only audible by Doppler (worse on the right than the left side). His current medications included cilostazol lOOmg PO bid, and dipyridamole 50 mg PO tid for the last 2 months, in addition to atorvastatin 20 mg before bedtime, captopril 25 mg PO tid, and nifedipine XL 60 mg PO qd.

The patient was referred for magnetic resonance angiogram which showed significant right iliac artery stenosis. Cilostaz\ol and dipyridamole were discontinued. He was started on clopidogrel 75 mg PO qd to reduce the risk of a thrombotic event. The patient was then scheduled for elective angiography of the abdominal, renal, and bilateral lower extremity arteries. The angiogram confirmed the proximal right iliac artery stenosis with a 45 to 50 mmHg gradient. The patient underwent percutaneous transluminal angioplasty (PTA) and stenting of this artery, resulting in resolution of the pressure gradient.

The patient was discharged the same day on a regimen of clopidogrel (75 mg/day) and asked to continue his lipid- and blood pressure-lowering medications. During follow-up visits at 7 days, 1 and 3 months post-procedure, the patient showed improved pulses to the right lower extremity; he also reported a slow and steady increase in his walking distance with minimal pain. The patient has not reported any complaints suggestive of arterial thrombosis since his PTA. He is overdue for his 6-month follow-up visit.

3. Treatment of Severe Aorto-iliac Occlusive Disease in a 59- Year-Old Woman

A 59-year-old woman with new-onset atrial fibrillation, chest pain, orthopnea, paroxysmal nocturnal dyspnea and progressive claudication underwent coronary and lower extremity angiography. Her coronary arteries had mild atherosclerosis. However, her left common iliac artery was occluded proximally and the right common iliac artery had a proximal 90% stenosis. Distally from the external iliacs, she had mild diffuse atherosclerosis with excellent three- vessel run-off to each foot. She opted for medical management of her PAD, underwent transesophageal echocardiography and cardioversion of her atrial fibrillation and was discharged on cilostazol, aspirin and clopidogrel. Over the next year, she had no improvement in her claudication despite cilostazol therapy and after 18 months her symptoms were severely limiting. Ankle-brachial indices were 0.5 on the left side and 0.7 on the right side. Percutaneous revascularization was then attempted.

Figure 1. Aortogram illustrating complete occlusion of the left common iliac artery (depicted by the white arrow) and high-grade stenosis of the right common iliac artery (depicted by the white arrow head) before (a) and after (b) angioplasty and stenting

A 6 French sheath was placed in the right common femoral artery. Repeat distal aortography demonstrated occlusion of the left common iliac artery and high-grade stenosis of the right common iliac artery (Figure 1a). A 6 French sheath was then placed in the left common femoral artery. Recanalization was ultimately achieved with a 0.035 inch glidewire (Boston Scientific) and a glide catheter (Boston Scientific). Angiography through the glide catheter confirmed that the catheter was positioned in the distal aorta. A heparin bolus of 4000 units was then given to increase the activated clotting time to 270 sec.

Balloon angioplasty of the left common iliac artery was performed with a 4.0 30 mm Stormer balloon (Medtronic AVE, Minneapolis, MN) followed by a 5.0 40mm Agiltrac balloon (Guidant). The Agiltrac balloon was then used to predilate the right common iliac artery stenosis. Reconstruction of the aorto-iliac junction was completed by deployment of two self-expanding Dynalink (Guidant) stents from the distal aorta into the distal common iliac arteries. A 7.0 56mm Dynalink stent was placed on the left side and post-dilated with a 6.0 20 mm Agiltrac balloon, while an 8.0 56 mm Dynalink stent was placed on the right side and post-dilated with a 7.0 20mm Agiltrac balloon. There was a stenosis in the very distal right common iliac artery that was treated with a 7.0 18mm Omnilink (Guidant) balloon expandable stent overlapping with the Dynalink stent. Excellent results were seen on the final aortogram (Figure 1b).

Immediately following the procedure the patient had bounding pulses bilaterally in the dorsalis pedis and posterior tibial arteries. At her two-week follow-up examination she showed complete resolution of her claudication. Six months after the procedure she remained completely asymptomatic, walking up to two miles a day. Secondary to her diffuse atherosclerotic disease, she will remain on aspirin and clopidogrel indefinitely and continue with her other outpatient medications for hypertension and lipid lowering.

Conclusions

Patients with PAD typically have co-existing cardiovascular and cerebrovascular disease, which collectively increases their risk of morbidity and death. Despite the high prevalence of PAD and association with the atherosclerotic disease process, the awareness of PAD by both primary care staff and the public is generally quite low. As a result, PAD remains underdiagnosed and undertreated. The overall burden of PAD on individuals and society can be reduced by better identification of affected patients, particularly those that are asymptomatic and at risk, such as diabetics and tobacco abusers. This can be achieved through improved screening techniques and education about diagnostic procedures.

The significant risk of PAD patients for atherothrombotic events cannot be ignored and these patients should be considered as appropriate candidates for secondary-prevention approaches. As presented in this collection of case studies, these approaches include the management of risk factors through appropriate lifestyle adjustments and drug therapy. Furthermore, in patients with severe PAD and at high risk of ischemia, intervention therapy may be necessary to restore blood flow to the affected region.

The risk of ischemic events in peripheral, coronary and cerebrovascular arteries can be reduced with antiplatelet therapy, which now plays a pivotal role in the management of PAD11,12,18,19. The results of CAPRIE15 suggest that clopidogrel is more effective than aspirin in PAD patients; these findings also formed the basis for the approval of clopidogrel by the US Food and Drug Administration for the reduction of ischemic events in PAD patients. Long-term studies addressing the combination of clopidogrel and aspirin in PAD are ongoing.

In conclusion, clopidogrel and other antiplatelet agents - in addition to other lifestyle modifications to reduce the impact of risk factors - play a key role in managing the threat of vascular events at peripheral, coronary and cerebral territories in patients with PAD.

Acknowledgements

This project was supported by Bristol-Myers Squibb/Sanofi- Synthlabo Pharmaceutical Partnership.

Case studies 1 and 3 were contributed by J.J. Cavendish and case study 2 by M. Safani.

* It should be noted that PAD most frequently manifests as femoropopliteal and aorto-iliac occlusive disease, with intermittent claudication typically affecting the calf, thigh and buttock areas. Occlusive subclavian artery disease leading to upper extremity claudication is less common.

References

1. American Heart Association. Heart Disease and Stroke Statistics - 2004 Update. Report available online at: http://www. americanheart.org/downloadable/heart/1079736729696HDSSt ats2004UpdateREV3-19-04.pdf [accessed 1 Sept 2004]

2. 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

3. Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc 1999;47:1255-6

4. 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;326:381-6

5. Wilterdink JL, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol 1992;49:857-63

6. Becker GJ, McClenny TE, Kovacs ME, et al. The importance of increasing public and physician awareness of peripheral arterial disease. J Vasc Interv Radiol 2002;13:7-11

7. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317-24

8. Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003; 163:884-92

9. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 1995;274:975-80

10. Regensteiner JG, Ware Jr JE, McCarthy WJ, et al. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials. J Am Geriatr Soc 2002; 50: 1939- 46

11. Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg 2001;88:787-800

12. Peripheral Arterial Diseases Antiplatelet Consensus Group. Antiplatelet therapy in peripheral arterial disease. Consensus statement. Eur J Vasc Endovasc Surg 2003;26:1-16

13. Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990;227:301-8

14. Antithrombotic Trialists' Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86

15. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39

16. Cavendish JJ, Fugit RY Safani M. Role of antiplatelet therapy in cardiovascular disease I: acute coronary syndromes\. Curr Med Res Opin 2004;20(11):1839-43

17. Cavendish JJ, Cramer SC, Graham GD. Role of antiplatelet therapy in cardiovascular disease II: Ischemic stroke. Curr Med Res Opin 2004;20:1845-9

18. Zusman RM, Chesebro JH, Comerota A, et al. Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection. Clin Cardiol 1999;22:559-73

19. American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003;26:3333-41

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2728C_4, Accepted for publication: 23 September 2004

Published Online: 26 October 2004

doi: 10.1185/030079904X10683

Jeffrey J. Cavendish1 and Michael Safani2

1 Department of Cardiology, Naval Medical Center, San Diego, CA, USA

2 Long Beach Memorial Medical Center, CA and Volunteer Faculty, University of California in San Francisco, Redondo Beach, CA, USA

Address for correspondence: Dr Jeffrey J. Cavendish, Department of Cardiology, Building 3, 3rd Floor, Naval Medical Center, San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134, USA.

Tel.: +1-619-532-7421; Fax: +1-619-532-9863; email: JJCavendish@nmcsd.med.navy.mil

Keywords: Antiplatelet - Claudication - Cross-risk - Peripheral arterial disease

Copyright Librapharm Nov 2004

Source: Current Medical Research and Opinion

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