Dual Antiplatelet Therapy in Peripheral Arterial Disease and After Peripheral Percutaneous Revascularization

Abstract: Peripheral arterial disease (PAD) is common and is associated with a high cardiovascular mortality. While dual antiplatelet therapy (DAT) does not appear superior to antiplatelet monotherapy in preventing myocardial infarction, stroke, and death in the general PAD population, a subgroup of patients with peripheral percutaneous revascularization, particularly superficial femoral artery (SFA) stenting, may benefit from prolonged DAT (>3 months). One to 3 months of DAT appears reasonable after percutaneous revascularization of SFA in low-risk settings, and 1 month of DAT appears reasonable after iliac stenting or carotid stenting, but definite randomized trial data are lacking. Individualized therapy, taking into account the diffuseness of the disease, the quality of the inflow and the outflow, the presence of critical limb ischemia, the extent of stenting, the use of covered stents, and the stent fracture risk is reasonable.

J INVASIVE CARDIOL 2012;24(12):679-684

Key words: peripheral arterial disease, dual antiplatelet therapy, stent, percutaneous intervention, superficial femoral artery, iliac, carotid

_______________________________________________

Peripheral arterial disease (PAD) is common, with a 12% prevalence in the general adult population and a 20%-30% prevalence in the diabetic population.^1,2 Percutaneous revascularization therapies have evolved dramatically, yet the long-term success of these therapies remains modest and the morbidity and mortality associated with PAD remains high, with up to 30% mortality risk at 5 years.³ Research has mainly focused on improving interventional devices and techniques, and in contrast to the field of percutaneous coronary revascularization, antiplatelet strategies, particularly dual antiplatelet therapy (DAT) with aspirin and clopidogrel, remain largely unstudied in the field of peripheral revascularization. An understanding of the current antiplatelet data, along with the inherent benefits and limitations of antiplatelet therapy, is imperative for physicians treating PAD. 

DAT in patients with PAD

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial randomized 15,603 patients with either clinically documented atherothrombotic disease or multiple risk factors but without documented atherothrombotic disease to either clopidogrel (75 mg/day) plus low-dose aspirin or placebo plus low-dose aspirin for a median of 28 months.⁴ DAT did not significantly reduce the rate of the primary efficacy endpoint of myocardial infarction (MI), stroke, or cardiovascular death (6.8% in the clopidogrel plus aspirin group and 7.3% in the aspirin alone group; P=.22). Furthermore, treatment with clopidogrel plus aspirin led to a significant increase in moderate bleeding (2.1% vs 1.3%; P<.001), and a non-significant increase in rates of severe bleeding (1.7% vs 1.3%; P=.09). A post hoc analysis suggested that patients with a history of MI or ischemic stroke may have a reduction of the primary efficacy endpoint with long-term aspirin plus clopidogrel as compared to aspirin plus placebo, at the price of a significant increase in moderate bleeding.⁵ Patients with disease in multiple vascular locations (that is, 2 or 3 of MI, stroke, or symptomatic PAD) derived the largest benefit. Patients who only had symptomatic lower extremity PAD, however, did not derive any significant benefit from DAT.^5,6 

DAT in patients with a prior stroke

While the post hoc analysis of the CHARISMA trial suggested a benefit in patients with a history of ischemic stroke, the Management of Atherothrombosis with Clopidogrel in High Risk Patients (MATCH) randomized trial included a much larger stroke population than the CHARISMA trial and did not show any benefit of DAT in comparison to clopidogrel monotherapy in patients with a recent stroke (<3 months).⁷ Moreover, DAT was associated with a significant increase in the rates of major and intracranial bleeding. Thus, DAT is preferably avoided in patients with a recent stroke. On the other hand, initiation of DAT very early after a transient ischemic attack or a stroke (within 24 hours) proved beneficial in reducing the risk of recurrent stroke in a pilot trial, potentially through the inhibition of platelet function during the period of highest risk for stroke.⁸ Larger trials are needed to confirm this finding.

Duration of DAT after percutaneous lower-extremity revascularization

No trial has addressed the clinical benefit or the duration of DAT following lower-extremity percutaneous revascularization. Notably, the two initial randomized trials that demonstrated comparable success with angioplasty and surgical revascularization for the treatment of iliac or femoropopliteal disease did not mandate any long-term antiplatelet therapy.^9,10 

Iliac interventions. Early studies, including the only randomized trial of angioplasty versus stenting for iliac disease, recommended aspirin monotherapy and reported favorable long-term patency rates with stenting and angioplasty. However, rates of stent thrombosis are not readily available from these studies.^11-13 Later on, major studies that addressed iliac transluminal angioplasty and stenting recommended DAT with aspirin and a thienopyridine for a duration of 1 month after the procedure (Table 1).^14,15 In COBEST, a randomized trial that addressed the use of covered balloon-expandable stents in aorto-iliac disease, DAT was recommended for at least 1 month after the procedure (Table 1).¹⁶ 

Femoropopliteal interventions. The BASIL trial, the only randomized trial of percutaneous versus surgical revascularization for femoropopliteal disease in patients with severe limb ischemia, established the non-inferiority of percutaneous revascularization in this subgroup of patients; angioplasty without stenting was performed and aspirin monotherapy was used.¹⁷ On the other hand, studies that have shown a long-term benefit with femoropopliteal stenting have generally recommended a DAT duration of 1 to 3 months after the intervention, and the largest two randomized trials of stenting vs angioplasty have recommended a DAT duration of 3 months (Table 2).^18-25A prospective study addressing Silverhawk atherectomy of femoropopliteal lesions recommended a DAT duration of 1 month.²⁶

Drug-eluting stents. Two major randomized trials compared the use of bare-metal nitinol stent with drug-eluting nitinol stent in the treatment of femoropopliteal disease. The SIROCCO trial failed to show any clinical superiority of the polymer-based sirolimus stent over the long-term follow-up;²³  the ZILVER PTX trial, on the other hand, showed  improved long-term patency with the polymer-free paclitaxel stent.²⁴ These studies recommended the use of thienopyridine for 1 month (the SIROCCO trial) or 2 months (the ZILVER PTX trial) after stenting. It is plausible that a longer duration of antiplatelet therapy, ie, 12 months, similar to the minimal duration of DAT necessary with coronary DESs, would have shown further improvement of outcomes with the peripheral DESs.

The duration of DAT used in all of the above studies, ie, 1 to 3 months, has been adopted in practice. However, the optimal duration of DAT after percutaneous lower extremity intervention, particularly stenting, has not been established and randomized trials addressing this issue are needed, similar to the studies performed in the coronary field. In fact, a longer duration of antiplatelet therapy (>3 months) may be more appropriate in patients presenting with critical limb ischemia, poor runoff, diffuse disease, or long occlusion >15 cm, factors associated with higher long-term rates of occlusion (Table 3).^20,27 The latter patient subgroups are poorly represented in the randomized trials (Table 2).

Rationale for a more prolonged DAT after superficial femoral artery stenting

The superficial femoral artery (SFA) is exposed to relevant external forces, including compression, torsion, and elongation, implying a high rate of restenosis. As opposed to coronary in-stent restenosis, which is due to intimal hyperplasia, the SFA shear forces likely lead to a combination of thrombosis and intimal hyperplasia as an underlying mechanism of stent failure, explaining the potential role of a more prolonged DAT. 

Stent restenosis and reocclusion in the SFA are also partly related to the high rate of stent fractures (37% in one study,²⁸ 15% and 18% in 2 other studies^20,29), half of which are major fractures. Fracture rate increases with the length of the stented segment (>8 cm, especially >16 cm) and the number of overlapping stents (≥2 stents). Stent fracture is strongly associated with a 50% reduction of the 12-month stent patency rate; furthermore, about half of stents with severe fracture are occluded at 1 year.²⁷ In a landmark pathological analysis in the coronary field, severe coronary stent fracture was associated with stent thrombosis in 67% of the cases.³⁰ The stent distorsion or acquired underexpansion associated with fracture may lead to stent thrombosis. A similar mechanism, ie, stent thrombosis rather than just restenosis, may partly explain peripheral stent failure after stent fracture. One may speculate that prolonged DAT in patients at risk of stent fracture may reduce the risk of thrombosis, but this remains to be established in a randomized trial. 

Another mechanism of long-term failure of SFA stenting is the progression of inflow and outflow disease. Therefore, TASC C and D lesions that correspond to a more advanced atherosclerosis are associated with a gradual decrease in long-term stent patency.²⁷ In this case, stent failure may not just be related to intimal hyperplasia and likely has a flow-related thrombotic component. It remains to be seen whether a longer duration of DAT in patients with long and diffuse disease reduces the rate of stent failure.

Furthermore, in a small study of 31 patients with advanced PAD requiring surgery, platelet reactivity was heightened in PAD patients and, importantly, aspirin monotherapy failed to reduce platelet reactivity. Thus, while the CHARISMA trial did not show a benefit of prolonged DAT in the overall PAD population, there may be a benefit in a patient subgroup with advanced PAD, such as patients undergoing revascularization.³¹ 

Rationale for a more prolonged DAT after stent graft placement

The use of the Viabahn covered stent (Gore) for SFA disease was associated with a dramatic reduction of stent fracture and a reduction of diffuse restenosis, but the overall failure rate was comparable to the non-covered stent.²⁵ The covered stent seems an attractive therapeutic option for diffuse in-stent restenosis, as it protects from significant tissue ingrowth and therefore, it protects from neoimtimal hyperplasia.³² However, this concept did not prove true when covered stents were used to treat aortocoronary saphenous venous coronary (SVG); in the STING and RECOVERS trials, patients with SVG disease randomized to a covered stent had a trend toward a higher rate of in-stent restenosis in comparison to bare-metal stenting, particularly edge neointimal proliferation that could extend inside the stent, and a higher rate of stent occlusion.^33,34 Studies performed in the peripheral field showed that stent thrombosis may be seen in up to 30% of the covered stent-treated cases within 1-3 years of follow-up.^32,35 Covered stents are particularly prone to occlusive thrombosis in case of poor inflow, poor runoff, or progression of atherosclerosis outside the graft.³⁵ Thus, the VIBRANT stent trial recommended a minimal duration of DAT of 6 months after Viabahn stenting.²⁵ In the CASPAR trial of patients undergoing femoropopliteal bypass grafting, randomization to DAT with aspirin and clopidogrel for 6-24 months was associated with a 35% reduction of synthetic graft failure;³⁶ this superiority of DAT may be extrapolated to patients who receive a polytetrafluoroethylene-covered stent graft.

The addition of cilostazol and the role of triple antiplatelet therapy

In 1 randomized trial and 1 prospective Japanese follow-up study, the addition of cilostazol, a potent antiplatelet agent, to DAT for 24 ± 14 months reduced stent failure (15% vs 38% at 2 years; P=.02) and stent reocclusion in comparison to DAT only, with no significant increase in the risk of bleeding.^37,38 The drug was particularly effective for severe lesions such as those of TASC C/D, small vessels (<5 mm), and cases with poor runoff. This benefit of triple antiplatelet therapy is partly due to the antiplatelet effects of cilostazol, but also to its suppression of vascular smooth muscle proliferation and neointimal hyperplasia.³⁹ The efficacy of cilostazol after coronary and peripheral stenting has almost exclusively been tested in Asian populations, and it remains unclear whether this benefit can be extrapolated to other ethnic groups. However, if not contraindicated, the long-term addition of cilostazol seems reasonable, particularly after endovascular therapy for in-stent restenosis or in subgroups at high risk of clinical failure (Table 3).

DAT after carotid stenting

Studies of carotid stenting have generally recommended DAT with aspirin and a thienopyridine for at least 1 day before and 1 month after stenting; only the SAPPHIRE trial allowed a 2-week minimal duration of DAT (Table 4).^40-44 However, no trial has addressed the optimal duration of DAT after carotid stenting and the value of a longer DAT. In the CREST, EVA-3S, and SPACE trials, the rate of ipsilateral stroke beyond 30 days was low under aspirin monotherapy, similar to the stroke rate after carotid endarterectomy (2% at 4 years in the CREST trial, 1.26% at 4 years in the EVA-3S trial, and 2.2% at 2 years in the SPACE trial);^41,42,44 therefore, it is unlikely that a longer duration of DAT will be beneficial.

Bleeding risk associated with DAT

The reduction of ischemic events with clopidogrel has been consistently associated with an increase in major bleeding. In the CURE trial of patients with non-ST segment elevation acute coronary syndrome, the addition of clopidogrel to aspirin for up to 1 year reduced the combined endpoint of death, MI, and stroke by 2.1% in the overall population and 3% in patients undergoing PCI, but increased the major bleeding risk by 1%.⁴⁵  Similar results were found in the CREDO trial of patients undergoing elective percutaneous coronary intervention, where adding clopidogrel to aspirin for 1 year reduced the combined primary endpoint by 3%, but increased major bleeding by 2.1%, with a trend toward significance.⁴⁶ In the PRODIGY trial, randomization to DAT for 24 months vs 6 months after coronary stenting was associated with an increased risk of significant bleeding (7.4% vs 3.5%; P<.001).⁴⁷ Thus, a longer duration of clopidogrel therapy is associated with a progressive increase in bleeding risk. In the absence of data supporting long-term DAT after peripheral intervention, DAT of >3 months should be limited to specific high-risk subgroups that are judged to have a clinically low bleeding risk (Table 3).

Conclusion

While DAT does not benefit the general PAD population, a subgroup of patients with peripheral percutaneous revascularization, particularly SFA stenting, may benefit from prolonged DAT (>3 months). One to 3 months of DAT appears reasonable after percutaneous revascularization of SFA in low-risk settings, and 1 month of DAT appears reasonable after iliac stenting or carotid stenting. These recommendations are based on limited non-randomized data; randomized trials addressing the role and duration of DAT after peripheral percutaneous revascularization are needed. Individualized therapy, taking into account the diffuseness of the disease, the quality of the inflow and the outflow, the presence of critical limb ischemia, the extent of stenting, and the stent fracture risk, seems reasonable.

References

1. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71(3):510-515.
2. Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol. 2006;47(5):921-929.
3. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease. Circulation. 2006;113(11):e465-e520.
4. 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(16):1706-1717.
5. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982-1988.
6. Cacoub PP, Bhatt DL, Steg PG, et al. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J. 2009;30(2):192-201.
7. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet. 2004;364(9431):331-337.
8. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM; FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961-969.
9. Holm J, Arfvidsson B, Jivegard L, et al. Chronic lower limb ischemia. A prospective randomized controlled study comparing the 1-year results of vascular surgery and percutaneous transluminal angioplasty. Eur J Vasc Surg 1991;5(5):517-522.
10. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis. Report of a prospective randomized trial in a selected group of patients. J Vasc Surg. 1989;9(1):1-9.
11. Tetteroo E, van deer Graaf Y, Bosch JL, et al. Randomised comparison of primary stent placement versus primary angioplasty followed by selective stent placement in patients with iliac-artery occlusive disease. Dutch Iliac Stent Trial Study Group. Lancet. 1998;351(9110):1153-1159.
12. Dyet JF, Gaines PA, Nicholson AA, et al. Treatment of chronic iliac artery occlusions by means of endovascular stent placement. J Vasc Interv Radiol. 1997;8(3):349-353.
13. Rzucidlo EM, Powell RJ, Zwolak RM, et al. Early results of stent-grafting to treat diffuse aortoiliac occlusive disease. J Vasc Surg. 2003;37(6):1175-1180.
14. Henry M, Amor M, Ethevenot G, et al. Percutaneous endoluminal treatment of iliac occlusions: long term follow-up in 105 patients. J Endovasc Surg. 1998;5(3):228-235.
15. Scheinert D, Schroder M, Ludwig J, et al. Stent-supported recanalization of chronic iliac occlusions. Am J Med. 2001;110(9):708-715.
16. Mwipatayi BP, Thomas S, Wong J, et al. A comparison of covered versus bare expandable stents for the treatment of aortoiliac occlusive disease. J Vasc Surg. 2011;54(6):1561-1570.

17. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomized controlled trial. Lancet. 2005;366(9501):1925-1934.
18. Henry M, Amor M, Beyar I, et al. Clinical experience with a new nitinol self-expanding stent in peripheral artery disease. J Endovasc Surg. 1996;3(4):369-379.
19. Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med. 2006;354(18):1879-1888.
20. Sabeti S, Mlekusch W, Amighi J, Minar E, Schillinger M. Primary patency of long-segment self-expanding nitinol stents in the femoropopliteal arteries. J Endovasc Ther. 2005;12(1):6-12.
21. Lugmayr HF, Holzer H, Kastner M, Riedelsberger H, Auterith A. Treatment of complex arteriosclerotic lesions with nitinol stents in the superficial femoral and popliteal arteries: a midterm follow-up. Radiology. 2002;222(1):37-43.
22. Laird JR, Katzen BT, Scheinert DT, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery. Twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv. 2010;3(3):267-276.
23. Duda SH, Bosiers M, Lammers J, et al. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial. J Endovasc Ther. 2006;13(6):701-710.
24. Dake M, Ansel G, Jaff MR, et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare-metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4(5):495-504.
25. Ansel G. Interim results of the VIBRANT trial. Presented at Vascular Interventional Advances, Oct. 20-23, 2011; Las Vegas, Nevada.
26. Zeller T, Rastan A, Sixt S, et al. Long-term results after directional atherectomy of femoro-popliteal lesions. J Am Coll Cardiol. 2006;48(8):1573-1578.
27. Iida O, Uematsu M, Soga Y, et al. Timing of the restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses. Catheter Cardiovasc Interv. 2011;78(4):611-617.
28. Scheinert D, Scheinert S, Sax J, et al. Prevalence and clinical impact of stent fractures after femoropolpliteal stenting. J Am Coll Cardiol. 2005;45(2):312-315.
29. Duda SH, Pusich B, Richter G, et al. Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: six-month results. Circulation. 2002;106(12):1505-1509.
30. Nakazawa G, Finn AV, Vorpahl M, et al. Incidence and predictors of drug-eluting stent fracture in human coronary artery. A pathologic analysis. J Am Coll Cardiol. 2009;54(21):1924-1931.
31. Walters TK, Mitchell DC, Wood RF. Low-dose aspirin fails to inhibit increased platelet reactivity in patients with peripheral vascular disease. Br J Surg. 1993;80(10):1266-1268.
32. Bauermeister G. Endovascular stent-grafting in the treatment of superficial femoral artery occlusive disease. J Endovasc Ther. 2001;8(3):315-320.
33. Schachinger V, Hamm CW, Muzel T, et al. A randomized trial of polytetrafluoroethylene-membrane covered stent in aortocoronary saphenous venous grafts. J Am Coll Cardiol. 2003;42(8):1360-1369.

34. Stankovic G, Colombo A, Presbito P, et al. Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous veins grafts trial. Circulation. 2003;108(1):37-42.
35. 35. Fritschy WM, Kruse RR, Frakking TG, et al. Performance of ePTFE-covered endograft in patients with occlusive disease of the superficial femoral artery: a three-year clinical follow-up study. J Cardiovasc Surg. 2010;51(6):783-790.
36. Belch JJ, Dormandy J, Biasi BM, et al. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR trial). J Vasc Surg. 2010;52(4): 825-833.
37. Soga Y, Yokoi H, Kawasaki T, et al. Efficacy of cilostazol after endovascular therapy for femoropopliteal artery disease in patients with intermittent claudication. J Am Coll Cardiol. 2009;53(1):48-53.
38. Soga Y, Lida O, Hirano K, et al. Restenosis after stent implantation for superficial femoral artery disease in patients treated with cilostazol. Catheter Cardiovasc Interv. 2012;79(4):541-548. 2011, July 29 (Epub ahead of print).
39. Morishita R. A scientific rationale for the CREST trial results: Evidence for the mechanism of action of cilostazol in restenosis. Atheroscler Suppl. 2005;6(4):41-46. 
40. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med. 2004;351(15):1493-1501.
41. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355(16):1660-1671.
42. Ringleb PA, Allenberg J, Bruckmann H, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet. 2006;368(9543):1239-1247.
43. International Carotid Stenting Study Investigators. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (international carotid stenting study): an interim analysis of a randomised controlled trial. Lancet. 2010;375(9719):985-997.
44. Brott TG, Hobson RW II, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363(1):11-23.
45. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
46. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
47. Valgimigli M. PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia study. Presented at European Society of Cardiology Congress, August 2011, Paris, France.

___________________________________________

From the Cardiology Division, Louisiana State University, New Orleans, Louisiana.

Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no conflicts of interest regarding the content herein.

Manuscript submitted April 2, 2012, provisional acceptance given May 21, 2012, final version accepted June 20, 2012.

Address for correspondence: Elias B. Hanna, MD, Cardiology Division, Louisiana State University,  1542 Tulane Ave, Rm 323, New Orleans, LA, 70112. Email: ehanna@lsuhsc.edu