General Review

ANNALSo/ VASCULAR SURGERY --I

hteruetiunal Journal ~f Vescuhr Sufoery

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The Role of Platelets in Peripheral Arterial Disease: Therapeutic Implications M.I. Matsagas, MD, L2"J G. Geroulakos, PhD, FRCS, 2 and D.P. Mikhailidis, MD, FRCPath, t London, United K i n g d o m and Ioannina, Greece

Peripheral arterial disease (PAD) is associated with platelet hyperaggregability as well as an increase in morbidity and mortality from myocardial infarction and stroke. Enhanced platelet activation in PAD may substantially contribute to these adverse outcomes. A relative resistance to aspirin therapy has been reported in patients with PAD. Therefore, clopidogrel may be superior to aspirin in treatment of PAD. Furthermore, the aspirin + clopidogrel combination could be more effective than monotherapy but its risk-benefit ratio has yet to be evaluated. Clopidogrel is preferable to ticlopidine because of its safer profile and the convenience of once-daily administration. The glycoprotein (Gp) lib/Ilia inhibitors may also find a place as short-term therapy after peripheral angioplasty. There is a need to consider the use of clopidogrel in patients who cannot tolerate aspirin. Patients who have an event while taking aspirin also present a problem. One possibility here is to substitute aspirin with clopidogrel or to add clopidogrel to the aspirin. Although these options are currently not evidence based in patients with PAD, there is emerging evidence showing that they are realistic choices.

INTRODUCTION Peripheral arterial disease (PAD) is a c o m m o n disorder. The estimated p r e v a l e n c e of i n t e r m i t t e n t claudication is 3-6% at a b o u t the age of 60 years. ~ It is estimated that this p r e v a l e n c e increases annually by a b o u t 0.5-1% after the 65th year of age. F u r t h e r m o r e , the prevalence of a s y m p t o m a t i c PAD (a 50% or greater stenosis of the arteries supplying the legs) is at least three-fold greater t h a n that of IDepartment of Clinical Biochemistry, Royal Free and University College Medical School, University of London, London, UK. 2Department of Vascular Surgery, Charing Cross Hospital, Imperial College of Medicine, University of London, London, UK. 3Department of Surgery, University of loannina, Ioannina, Greece. Correspondence to: D.P. Mikhailidis, Department of Clinical Biochemistry, Royal Free and Universi~, CollegeMedical School, Royal Free Campus, Pond Street, London NW3 2QG, UK, E-mail: mikhailidis@ aoi.coln. Ann Vasc Surg 2002; 16:246-258 DO[: I0.I007/si0016-001-0159-8 9 Annals of Vascular Surgery Inc.

Published online: March 15, 2002

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s y m p t o m a t i c disease. L2 Patients with PAD generally h a v e widespread arterial disease and therefore h a v e an increased risk of stroke, myocardial infarction (MI), and cardiovascular death. ~3 S o m e studies reported a 1-3% a n n u a l incidence of n o n fatal MI a m o n g these patients, 3 while the 5-, i0-, a n d 15-year mortality rates f r o m all causes w e r e a p p r o x i m a t e l y 30%, 50%, and 70%, respectively; this is a b o u t 2.5 times that of the general population. ] Cardiovascular disease causes 75% of the deaths a m o n g patients with PAD, in contrast to 52% in the general population.1 Atherosclerosis is the m a j o r cause of arterial disease, but thrombosis is m a i n l y responsible for acute ischemic events. 4"5 Platelets play a key role in the t h r o m b o t i c process. 4-7 In PAD the platelets s e e m to be activated, 6"7 possibly because of the diffuse pattern of the disease. This could predispose patients to acute arterial occlusive events. This review will address the role of platelets in PAD and the efficacy of antiplatelet treatment.

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PLATELET

ACTIVATION

Although platelets contribute to maintenance of normal circulation by preserving vascular integrity after injury, they also play a key role in the initiation and extension of arterial thrombosis. 49 Platelets also contribute to the process of atherogenesis, since they release platelet-derived growth factor (PDGF) and serotonin (5-hydroxytryptamine, 5HT). 4"9 These growth factors (and others) stimulate the migration and proliferation of smooth muscle ceils leading to atherogenesis, s'9 Platelet adhesion to subendothelial collagen is an essential first step in the initiation of thrombosis. ~~ After adhesion, the platelets b e c o m e activated, other platelets stick to them, and a platelet thrombus is formed. ~~ This plug is t h e n transformed into a fibrin n e t w o r k by the action of thrombin, which causes platelet degranulation. ~~ Platelet adhesion to the vascular wall, especially u n d e r conditions of high shear stress (e.g., in medium- and small-caliber peripheral arteries), has an absolute requirement for y o n Willebrand factor (vWF). This serves as a bridge b e t w e e n receptors on the platelet cytoplasmic m e m b r a n e and the extracellular matrix, especially collagen.~l Initially, vWF molecules in the flowing blood bind to the collagen surface at the site of an arterial injury and t h e n platelets adhere, in a reversible way, to these immobilized molecules through their glycoprotein (Gp)Ib (Gp Ib-IX-V) complex receptor. 12'13 In this manner, vWF initially acts as a "rolling" receptor, supporting a slow and continuous motion at the surface, despite the high-shear stress conditions.l o's2 This m e c h a n i s m is particularly efficient at capturing platelets, which eventually bind irreversibly with the exposed s u b e n d o t h e l i u m through their collagen receptors Gp Ia/IIa and Gp VI, and their Gp IIb/IIIa (Gp IIb/IIIa) receptor that also binds irreversibly to fibrinogen and vWF.l~ Through degranulation, and the presence of thrombin and other components of the subendothelial matrix, platelets trigger the recruitment and activation of surrounding platelets. ~6 Activated platelets change shape, secrete the contents of and dense granules, and also contribute to the overall coagulation activity. ~6'17 The release of adenosine diphosphate (ADP), 5HT, and thromboxane A2 (TXA2) further activates other platelets and also induces conformational changes in the Gp IIb/ IIIa receptor, making it receptive to fibrinogen, and leading to platelet aggregation and the formation of the primary hemostatic plug. 13.~6 Platelet shape change (PSC) is an early phase of activation that precedes aggregation.~S W h e n

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platelets are initially stimulated, the first event is a r e a r r a n g e m e n t of the cytoskeletal proteins (actin and myosin), and these normally discoid cells become spherical, resulting in an increase in their surface area. ls'~9 During PSC platelets also present pseudopodia; these spike-like projections participate in the aggregation process. ]9'2~ It has been recently s h o w n the PSC can be induced by ADP via the P2YI2 (P2TeLc) platelet receptor. ]s'21'22 The activation of the Gq-coupled 5HT2A platelet receptors can also induce P S C . I8'21"22 Circulating extracellular ADP, which originates from damaged red blood and endothelial cells and also from platelet-dense granules, plays a major role in platelet activation, iv ADP from the plateletdense granules is released w h e n platelets are stimulated by other agents (e.g., t h r o m b i n and collagen) and thus contributes to and reinforces (amplifies) platelet aggregation. 23 ADP activates platelets, resulting in PSC, aggregation, TXA2 production, and the further release of granule contents. 24 Other mediators stored in platelet granules (e.g., 5HT) amplify this process by activating surrounding platelets. ~6 ADP-induced platelet activation involves three distinct surface receptors2~: (1) the P2X~ receptor, which causes a rapid calcium influx but not internal Ca 2+ mobilization; (2) the Gi protein-coupled P2TAc receotor, which inhibits adenylyl cyclase and induces aggregation w i t h o u t PSC; and (3) the P2Y12 receptor coupled to protein Oq, which activates phospholipase C (PLC) and mobilizes cytosolic Ca 2+, leading to PSC and aggregation. 22'24-27 ADP-induced aggregation results from concomitant signaling from both the P2Y~2 and P2Y~2 receptors, while the P2X~ receptor does not play a significant role in aggregation. 22 W h e n platelets are exposed to agonists such as ADP, thrombin, and collagen, they liberate arachidonic acid (AA) stored as phospholipid in the platelet plasma m e m b r a n e . 28 AA is converted into TXA2 by cyclooxygenase and TXA 2 synthase. 2s The r e l e a s e d TXA 2 acts as a positive feedback mediator by activating and recruiting more platelets. TXA 2 exerts its actions in h u m a n platelets via the protein Gq pathway, 29 causing intracellular calcium mobilization and PSC. TXA 2 induced platelet aggregation also depends on the secretion of other platelet agonists (mainly ADP). 2s Platelet activation by most agonists causes PSC and conformationat changes in GplIb/IIIa receptors (inside-out signaling), transforming t h e m from a ligand-unreceptive to a ]igand-receptive state, t6 The GplIb/IIIa receptor is the most a b u n d a n t integrin on the platelet surface (approximately 50,000 to 80,0_00 copies per cell), 3~ Ligand-receptive

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GplIb/IIIa receptors bind fibrinogen, which forms bridges between adjacent platelets and facilitates aggregation. 3~ Although the binding fibrinogen to GpIIb/IIIa receptors is the principal mechanism for aggregation, other adhesive glycoproteins, including fibronectin, vWF, and vitronectin, also bind to these receptors, but they appear to play a greater part in platelet adhesion to subendothelial structures. 32 In particular, interactions b e t w e e n the vWF and GpIIb/IIIa receptors seem to be important in platelet aggregation u n d e r conditions of high shear stress. 33 GpIIb/IIIa receptor occupancy leads to aggregation and to signals back to the platelet (outside-in signaling). 34

PLATELET HYPERACTIVITY IN PAD E n h a n c e d platelet reactivity has been reported in PAD. 7'3>38 A shortening of platelet survival, increased platelet aggregation, and the e n h a n c e d release of intraplatelet products (e.g., [3-thromboglobulin, 5HT and TXA2) have also been observed. 7"3s Patients with PAD have significantly e n h a n c e d spontaneous platelet aggregation (SPA) in vitro as compared with healthy individuals. <7 Patients with PAD also exhibit significantly enhanced platelet aggregation in comparison with controls, after the addition, in vitro, of various agonists (e.g., ADP, 5HT, and adrenaline). 7 In addition, the hyperactivity of platelets in PAD has been detected in vivo by the m e a s u r e m e n t of urinary 1 1 dehydro-TXA2; this demonstrates an increased platelet TXA2 release. 35 There is no clear explanation for this platelet hyperactivity, but it m a y be attributed to the diffuse pattern of atherosclerotic disease. There are usually several affected arteries in PAD, with stenoses that lead to an increase in shear stress; in turn, shear stress can activate platelets. 39,40 W h a t e v e r the mechanisms involved, platelet hyperactivity in PAD m a y contribute to the increased vascular morbidity and mortality in these patients. 41'42 For example, SPA predicts the risk of acute coronary events and mortality. 43 Platelet hyperactivity may also explain w h y the plasma levels of 5HT are markedly raised in PAD. 44 Probably there is excessive release from hyperactive platelets (approximately 95% of the 5HT in the blood is stored in platelets). 44 This bioamine amplifies the reponse of other platelet agonists (like ADP); 5HT is also a vasoconstrictor 4s and a growth f a c t o r . 44'45 Furthermore, its growth-promoting activity is e n h a n c e d by PDGF. 44"45

Annals of Vascular Surgery

Along with platelet hyperactivity, other hemostatic abnormalities have been reported in patients with PAD. 37 For example, blood viscosity and fibrinogen levels are higher in patients with PAD and these " m a r k e r s " are associated with a poorer prognosis and disease progression. <45'45 Furthermore, platelet activity is e n h a n c e d by fibrinogen 47 and raised levels of this coagulation factor have been reported to predict the risk of death in patients with intermittent claudication. 4s'49 The platelets of patients with PAD also demonstrate a hypersensitive response to unfractionated heparin (UH). 5~ In contrast, low-molecular weight heparins (LMWHs) seem to be weaker platelet activators. 5~ This is of potential relevance because UH is frequently used as an anticoagulant during and after surgical and endovascular procedures in patients with PAD. 5~ Platelet hyperactivity in PAD m a y play a role in the process that leads to complications and disease progression. 55 Thus, antiplatelet t r e a t m e n t in these patients m a y be essential.

ANTIPLATELET TREATMENT

IN PAD

The natural history of patients with PAD is a relative benign local evolution. Approximately 75% of patients presenting with intermittent claudication n e v e r require any intervention and less than 5% eventually undergo an amputation. I'54 Nevertheless, these patients have a high prevalence of coronary artery disease (CAD) and cerebrovascular disease (CVD). 1,56 CAD was present in 40-60% of patients with PAD w h e n the diagnosis was made by history, clinical examination, and electrocardiography; the incidence was 90% w h e n coronary angiography was performed. 1,56 Carotid disease was also found in 25-50% of PAD patients following duplex examination.~ Thus, it is not surprising that PAD is associated with a high cardiovascular mortality rate (almost 2.5 times that of the general population); this is mainly due to MI and stroke. ~ These figures emphasize that the real danger for these patients is not the deterioration of local disease but p r e m a t u r e cardiovascular complications or even death. Nevertheless, some patients with PAD will require surgical or endovascular revascularization. ~3 These patients will then face the possibility of failure of the intervention due to acute thrombosis or late reocclusion.l-3 Acute thrombosis is usually due to the injury of the vessel wall at the time of intervention 54-Sr'Sa while late occlusion is often the result of myointimal hyperplasia or the progression of atheromatous disease in the native

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arteries. 54'59 Prophylactic therapy with antiplatelet drugs aims to improve both the general prognosis and the local disease progression in PAD. This t r e a t m e n t has b e e n proved to be of clinical benefit in reducing adverse o u t c o m e s in cardiovascular disease. 6~ It also represents a rational prophylactic a p p r o a c h to i m p r o v e the patency of revascularization procedures. 6~'62 Several antiplatelet drugs h a v e b e e n used in patients with PAD.

Aspirin Acetylsalicylic acid (ASA, aspirin) irreversibly acetylates cyclooxygenase. 63 Endothelial cells can regenerate cyclooxygenase and thus m a i n t a i n PGIx production that induces vasodilatation and inhibits platelet aggregation. In contrast, this is not possible in platelets because t h e y do not h a v e a n u cleus. 64"65 Thus, ASA irreversibly inhibits the production of TXA2 (a stimulator of platelet aggregation and a vasoconstrictor) by platelets. 66 Other ASA-mediated actions h a v e also b e e n prop o s e d - - f o r example, the inhibition of platelet activation by neutrophils 67 a n d antioxidant effects on lipoproteins a n d fibrinogen. 68'69 However, these effects m a y be less relevant t h a n inhibiting TXA2 production. 65,7~ ASA only partially inhibits platelet aggregation. 65 However, it is well established that ASA is effective in the secondary p r e v e n t i o n of CAD and CVD (i.e., w h e n administered after a MI or stroke). 6~ ASA also offers w o r t h w h i l e protection against MI, stroke, and death in asymptomatic patients at high risk for cardiovascular disease. 6~ Antiplatelet t r e a t m e n t with ASA alone or in c o m b i n a t i o n with dipyridamole (see below) delayed the progression of PAD in one randomized study. 73 ASA also i m p r o v e d b o t h graft p a t e n c y and mortality in patients with PAD after revascularization procedures. 61 However, in most studies ASA was used in c o m b i n a t i o n with dipyridamole and the benefit after angioplasty was not very clear, in terms of p a t e n c y . 61"62"74 R e c e n t w o r k also suggests that the effectiveness of ASA depends on the " i n f l a m m a t o r y " status of the patients. For example, the effectiveness of ASA in preventing MI in healthy subjects was significantly greater a m o n g those in the highest quartile of baseline C-reactive protein levels. 75 The effectiveness of ASA therapy is not dependent on large d o s e s . 60'76"77 Most authors recomm e n d a dose of 75-160 m g / d a y in an a t t e m p t to reduce the adverse effects that are most frequently related to gastrointestinal (GI) toxicity. 6~176

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Although some trials found that GI toxicity was related to larger doses, 79 a recent meta-analysis suggests that e v e n at low doses, l o n g - t e r m ASA use carries a significant risk of GI h e m o r r h a g e . 8~ There is also evidence that l o n g - t e r m ASA therapy increases the risk of hemorrhagic stroke. 81 Some evidence suggests that platelet activation in PAD is ASA-resistant. 6'7"82-86 Thus, w h e n ASA was added in vitro, it did not affect SPA or 5HTinduced aggregation in whole blood obtained f r o m PAD patients w h o were taking ASA. 7"83 There is also evidence that ADP released from d a m a g e d erythrocytes activates platelets and that this diminishes the antithrombotic effect of ASA. 87,88 The 1994 Antiplatelet Trialists' Collaboration report convincingly d e m o n s t r a t e d the effectiveness of antiplatelet t h e r a p y in general. 6~ However, the subgroup analysis that involved PAD patients did not s h o w a m a r k e d benefit. In this particular subgroup, the c u m u l a t e d lines, each one representing several trials, crossed the 1.0 odds-ratio b o u n d a r y , suggesting that in PAD, platelet inhibition, m a i n l y represented by aspirin, was not as effective as in o t h e r vascular diseases. 6~ F u r t h e r m o r e , a recent meta-analysis investigating the efficacy of the antithrombotic drugs in the medical m a n a g e m e n t of PAD also failed to show a clear benefit of aspirin t r e a t m e n t in these patients. 84 The a b o v e - m e n tioned "epidemiological" observations, in association with the evidence of ASA resistance in PAD, suggest that antiplatelet t r e a t m e n t with ASA alone hi this high-risk group of patients m a y be suboptimal.

Thienopyridine Derivatives Ticlopidine and its m o r e recently developed analogue, clopidogrel, are thienopyridine derivatives. 8~ Both drugs irreversibly inhibit platelet aggregation induced by ADP by binding to the P2Y~2 platelet receptor. 89'9~ By inhibiting the effects of ADP released f r o m platelet-dense granules they also inhibit platelet aggregation induced by other agonists, including TXA2, platelet activating factor (PAF), collagen, a n d low concentrations of t h r o m b i n . 87'9~ This multiplicity of actions reflects the central role of ADP in mediating aggregation induced by several agonists. 92 Thienopyridine derivatives have no effect on the cyclooxygenase p a t h w a y and therefore act i n d e p e n d e n t l y of aspirin. 89 Both ticlopidine and clopidogrel have also b e e n s h o w n to p r e v e n t platelet aggregation induced by shear stress. 93"94 Ticlopidine can reduce plasma fibrinogen levels, 95'96 an effect that m a y be

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relevant in patients with PAD in w h o m raised fibrinogen levels predict a poor prognosis and disease progression, as well as p r e m a t u r e death. 9.46,49 There is also some experimental evidence showing that ticlopidine and clopidogrel can reduce myointimal thickening after endothelial injury. 97 Ticlopidine has been widely available for some years, and several trials have demonstrated its effectiveness in the prevention of vascular events in various patient groups, including P A D . 89'9~ Thus, ticlopidine is effective, compared with placebo, in preventing MI, stroke, and vascular death in highrisk patients. 99-ml Ticlopidine m a y also be m o r e effective than aspirin, although the magnitude of the additional benefit may be modest. 9s'1~176 Furthermore, the ticlopidine + aspirin combination was more effective in preventing coronary artery stent thrombosis than aspirin + anticoagulant or aspirin m o n o t h e r a p y . ~o4-1o7 For patients with PAD, ticlopidine, apart from reducing the incidence of cardiovascular events,S4'1~ lo also increased pain-free and m a x i m u m walking distance, reduced the n e e d for vascular surgery, 1~o-112significantly improved longterm patency of peripheral autologous grafts, 62A13 and lowered the reocclusion rate after t h r o m b o e n darterectomy. 114 Ticlopidine was equally effective w h e n compared with anticoagulants in preventing reocclusion after peripheral angioplasty.74 Clopidogrel was significantly more effective than aspirin in preventing major vascular events (MI, stroke, and vascular death) in a large, randomized, double-blind trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE]; 19, 185 patients). ~15 It has also been suggested that this difference might be m u c h more in favor of clopidogrel if applied to "real-life" patients not included in a clinical trial (e.g., that of Saskatchewan, Canada). 1~6 Heterogeneity was seen a m o n g the three CAPRIE patient subgroups (patients with MI, stroke, o r PAD). 84'89'92A15 In particular, the patients with PAD showed a significantly greater benefit with clopidogrel t h a n with aspirin (about 75% of the therapeutic advantage of cIopidogrel occurred in patients with PAD, resulting in a relative-risk reduction of 23.8% in PAD, compared with 8.7% overall). 115"117 This analysis is in agreement with previous reports of e n h a n c e d platelet activation and aspirin resistance in patients with PAD. 92 Clopidogrel is equivalent to ticlopidine in inhibiting platelet aggregation in ex viw) studies.97,118 Clopidogrel has also recently been proved to be at least as effective as ticlopidine in preventing thrombosis and reocclusion after coronary artery stenting, i ~9-122

Annals of Vascular Surgery

Ticlopidine is associated with hematological side effects. For example, n e u t r o p e n i a occurs in approximately 2.4% of patients. The neutropenia can be severe (in about 0.8% of patients treated with ticlopidine) and even fatal. 70,101,102,123 In contrast, neutropenia occurred less frequently with clopidogrel than with aspirin in the CAPRIE study, t15 Ticlopidine was also associated with an increased incidence of thrombotic t h r o m b o c y t o p a e n i c purpura (TTP). This was estimated to be 1 case/I600 to 5000 treated patients, with a mortality rate exceeding 2 0 % . 124-126 Clopidogrel has not been reported to cause TTP in randomized trials involving approximately 50,000 patients, 122 but post-marketing surveillance identified 20 cases of TTP in clopidogrel-treated patients. 127 The authors of this report calculated the incidence of clopidogrel-associated TTP as 1 case/8500 to 26,000 treated patients, with a mortality rate about 10%, 127 but it is unclear w h e t h e r clopidogrel actually caused the TTP in all these cases. ~25"12s Furthermore, the incidence of clopidogrel-associated TTP is similar to the background frequency of TTP in the general population and is approximately lO0 times less frequent than that of ticlopidine-induced T T P . 122'128"129 Other adverse effects of ticlopidine are diarrhea, nausea, vomiting, and skin rash, which are responsible for discontinuation of therapy in some 20% of patients. 89"9~176 With clopidogrel, these adverse effects seem to occur less often. 9~ In the CAPRIE study, only the freq u e n c y of severe skin rash and diarrhea was significant, but only slightly higher than with aspirin treatment, while GI discomfort and h e m o r r h a g e occurred m o r e frequently with aspirin. 115 Indeed, experience to date has s h o w n very low rates of major h e m o r r h a g e with the use of both thienopyridine derivatives. 89'115 Thus, although ticlopidine and clopidogrel appear to be very similar in terms of efficacy, clopidogrel is the thienopyridine of choice in terms of safety and because of the convenience of once-daily administration. 9s'112

Glycoprotein IIb/IIIa Receptor Blockers GIIb/IIIa receptor blockers p r e v e n t the binding of fibrinogen, thereby inhibiting aggregation, irrespective of the p a t h w a y initiating this process. 16 The GpIIb/IIIa blockers available for clinical use are administered intravenously. GpIIb/IIIa inhibitors for oral administration have been evaluated in clinical trials, but they proved to be very disappointing. 130,13l With the use of parenterally administered GpIIb/ IIIa blockers, patients undergoing p e r c u t a n e o u s

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c o r o n a r y intervention or presenting with an acute c o r o n a r y s y n d r o m e can expect a significant reduction in critical clinical events, including nonfatal MI and the n e e d for repeat procedures. ~3~ Abciximab, an i n t r a v e n o u s l y administered m o n o clonal antibody directed at GpIIb/IIIa, was associated with a significant reduction in both mortality and the need for repeat revasculanzation on longt e r m folIow-up. 130,132,133 Abcixiiilab was also used as an adjuvant to thrombolysis in patients w i t h PAD and acute arterial thrombosis. ~34'~35 This reduced the need for hospitalization, interventions, and a m p u t a t i o n s and also m a r k e d l y shortened the duration of clot lysis in comparison with aspirin.135 Although it has b e e n proposed that oral GpIIb/ IIIa inhibitors could extend platelet inhibition t h e r a p y b e y o n d the in-hospital period, this option remains highly speculative. ~36 Even t h o u g h oral GpIIb/IIIa receptor blockers inhibited platelet aggregation ex vivo, 137"138 in recently published large randomized clinical trials t h e y had no effect in reducing the incidence of m a j o r cardiovascular events. 139,~40 Instead, they u n e x p e c t e d l y increased the 30-day mortality, despite c o n c o m i t a n t aspirin administration. ~4~ It has b e e n proposed that the oral GpIIb/IIIa inhibitors m a y have a pro-aggregatory effect on platelets. It remains to be proved that n e w oral GpIIb/IIIa blockers with a longer duration of action are of clinical b e n e fit. 1 3 6 , 1 4 0 , 1 4 2 In the early trials, GpIIb/IIIa inhibitors were associated with a significantly higher rate of bleeding complications, but this proved to be largely attributable to excessive and prolonged c o n c u r r e n t heparin administration. 130,~43,J44 In later trials, incorporating reduced heparin regimens, there was no excess in m a j o r bleeding, 130,145-147 e v e n t h o u g h there was an increase in m i n o r bleeding complications. 3~176 GplIb/IIIa blockers are also associated with an increased risk of t h r o m b o c y t o p a e n i a . This complication has b e e n reported in 1.6% of a study population. ~43 However, the frequency of severe t h r o m b o c y t o p e n i a is estimated to be low, ranging from 0.1% t o 0 . 5 % . 1 3 0 ' 1 3 2 ' 1 4 8

O t h e r Drugs w i t h a n A n t i p l a t e l e t Effect Other drugs with an antiplatelet activity were less extensively evaluated. 84 In addition, most of t h e m were evaluated for their ability to relieve the s y m p t o m s of PAD, rather than to reduce the risk of cardiovascular events. There is also a lack of studies directly comparing these drugs with well-established antiplatelet drugs.

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Dipyridamole. This drug is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. It probably exerts its action by inhibiting the cyclic nucleotide phosphodiesterases and blocking the uptake of adenosine, thus resulting in a reduction in platelet cytosolic calcium. ~49 Dipyridamole is considered a w e a k inhibitor of platelet adhesion and aggregation, but it m a y also modify the interaction of platelets with artificial surfaces and perhaps that with d a m a g e d blood vessels. 149 Although the clinical efficacy of dipyridamole, alone or in c o m b i n a t i o n with aspirin, has b e e n questioned on the basis of earlier randomized trials,70,149,150 the E u r o p e a n Stroke Prevention Study 2 (ESPS-2) trial showed that the c o m b i n a t i o n of aspirin with sustained-release dipyridamole significantly reduced the incidence of stroke in high-risk patients. ~51 F u r t h e r m o r e , a recent review of 15 r a n d o m i z e d trials suggested that the addition of dipyridamole to aspirin reduces the risk of vascular events by t 5 % over that expected if aspirin is used alone. 65"77 In PAD patients, p a t e n c y after revascularization procedures was significantly i m p r o v e d by the c o m b i n a t i o n of aspirin and dipyridamole as c o m p a r e d with placebo, but there are no studies comparing this effect with aspirin alone or with ticlopidine, which h a v e s h o w n similar results. 62 Overall, there is no consistent evidence to support the routine use of dipyridamole for PAD and for cardiovascular disease in general, with the possible exception of the secondary p r e v e n t i o n of stroke. Further studies are needed here. 7~ Picotamide. This antiplatelet agent inhibits 153 TXA2 synthase and antagonizes TXA2 receptors. Picotamide m a y also exert TXA2-independent actions. 1 5 4 In a r a n d o m i z e d study, t r e a t m e n t with picotamide significantly reduced the overall incidence of cardiovascular events in patients with PAD, but it did not significantly reduce mortality. 84"155 This drug is not yet widely used in clinical practice and its relative efficacy in comparison with o t h e r antiplatelet drugs has not b e e n established. 54,78 Cilostazol. This drug is a type III phosphodiesterase inhibitor. IS6 In recently published studies, cilostazol significantly i m p r o v e d the walking distance in patients with intermittent claudication, in comparison with placebo ~57 and pentoxifylline,15s but it failed to reduce overall mortality. Withdrawal rates in the cilostazol group were a p p r o x i m a t e l y 15%, mainly because of diarrhea, headache, and palpitations, t57'158 There are no data comparing

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cilostazol with established antiplatelet agents. It is of interest that cilostazol has beneficial effects on plasma lipoproteins in patients with PAD. 159

Prostaglandins. Prostaglandins with antiplatelet and vasodilatory effects, such as prostaglandin EI(PGE1) and prostaglandin Ix (PGI2), h a v e b e e n administered parenterally in patients with a d v a n c e d PAD with the aim of relieving rest pain a n d healing ischemic ulcer. 54'16~ In most studies t h e y h a d no significant beneficial i n t e r m e d i a t e and l o n g - t e r m effects w h e n c o m p a r e d with placebo. 54'16~ However, PGI2 has b e e n s h o w n to be beneficial in patients with thromboangiitis obliterans (Buerger's disease). 162 Similarly, PGEp c o m b i n e d with intensive exercise, i m p r o v e d walking distance m o r e t h a n exercise plus pentoxifylline or exercise alone.163 In current practice, the lack of available oral formulations of prostaglandins, their adverse h e m o d y n a m i c effects, and the lack of d e m o n s t r a t e d superiority o v e r c o n v e n t i o n a l agents such as aspirin h a v e resulted in limited use of these c o m p o u n d s . 54 Other drugs. Other drugs h a v e b e e n used in PAD include the antiserotonin agents ketanserin 164 and naftidrofuryl. 7'165-167 Naftidrofuryl also inhibited platelet activation induced by endothelin-1.165 This effect is of interest because endothelin- I is also a p o t e n t vasoconstrictor and a g r o w t h factor. 165 F u r t h e r m o r e , its circulating levels are elevated in patients with PAD. 165

DO WE NEED NEW ANTIPLATELET STRATEGIES IN PAD? M a n a g e m e n t of PAD includes the p r e v e n t i o n of all vascular events. 54"~68 Nevertheless, these patients are still less intensively treated t h a n those with CAD o r C V D . 168"t69 There is evidence that, in PAD, platelet activation is relatively aspirin resistant. 92 This p h e n o m e n o n could account for the h e t e r o g e n e i t y reported in r a n d o m i z e d studies and m e t a - a n a l y s e s that included patients with PAD.6O,7O,84,92,115 This interpretation is supported by the findings of a recent meta-analysis ~7~ in w h i c h aspirin was less effective (pooled Peto odds ratio = 0.76; 95% CI = 0.64-0.91; p = 0.003) t h a n thienopyridines or the aspirin + dipyridamole combination. ~7~ Thus, it seems reasonable to suggest that aspirin alone should no longer be considered optimal t h e r a p y for PAD. Are the thienopyridines m o r e effective than aspirin in PAD? Ticlopidine and clopidogrel inhibit platelet activation induced by several agonists

Annals of Vascular Surgery

because

they reduce the amplifying effect of This effect m a y be i m p o r t a n t in PAD and it could explain the superior efficacy of thienopyridines to that of placebo or aspirin. 84'9~' l~ 5 Since both thienopyridines h a v e similar efficacy, clopidogrel is clearly the drug of choice in terms of safety. 98A~2 On the basis of these findings, it has b e e n suggested that to achieve effective antiplatelet t h e r a p y in PAD, aspirin should be replaced by clopidogrel. 84"117'17~ However, a switch f r o m aspirin, a cheap and widely prescribed drug with an established track record, in all patients with PAD will n e e d evidence f r o m additional c o m p a r a t i v e " h e a d - t o - h e a d " studies in this patient group. Nevertheless, in light of currently available evidence, this r e p l a c e m e n t seems reasonable in PAD patients w h o h a v e a vascular e v e n t despite taking aspirin. A n o t h e r alternative in this situation is to add clopidogrel to the aspirin. Clopidogrel is also probably the drug of choice for PAD patients w h o c a n n o t tolerate aspirin. Unfortunately, n o n e of these suggestions are currently evidence based. Although m o s t patients with PAD are m a n a g e d conservatively, some still require revascularization. E n h a n c e d platelet activity in an e n v i r o n m e n t of increased surface t h r o m b o g e n i c i t y m a y lead to acute thrombosis and early failure, while the sustained release of platelet growth factors m a y contribute to restenosis. 4%54"92 Effective antithrombotic t h e r a p y w o u l d theoretically preserve patency, resulting in a reduction in overall treatment c o s t . 54 Aspirin c o m b i n e d with dipyridamole had a marginally significant benefit in p a t e n c y rates c o m p a r e d with placebo (loss of p a t e n c y odds ratio = 0.76, 95% CI = 0.58-0.99, p = 0.04). 62 Ticlopidine had a better effect in studies evaluating peripheral revascularization (loss of p a t e n c y odds ratio = 0.53, 95% CI = 0.330.85, p = 0.009), 62 while clopidogrel was as effective as ticlopidine in c o r o n a r y artery interventions.122 Therefore, clopidogrel + aspirin could be the most effective c o m b i n a t i o n for those undergoing peripheral revascularization. This c o m bination therapy is more effective than m o n o t h e r a p y in h e a l t h y volunteers and patients with CAD in ex vivo platelet aggregation studies. 172'173 Our results (unpublished data) in patients with PAD also s h o w e d the superiority of this c o m b i n a t i o n t h e r a p y o v e r m o n o t h e r a p y at inhibiting platelet activation. Nevertheless, there is a need for clinical trials to evaluate the aspirin + clopidogrel c o m b i n a t i o n in various clinical settings. Vascular surgeons h a v e used anticoagulants, with or w i t h o u t aspirin, in an a t t e m p t to achieve A D P . 9~

Role ~zfplatelets in PAD

Vot. 16, No. 2, 2002

b e t t e r p a t e n c y rates. H o w e v e r , a clear b e n e f i t has n o t b e e n d e m o n s t r a t e d . 54'~ It m u s t also be m e n t i o n e d t h a t oral a n t i c o a g u l a n t s c a n l e a d to s e r i o u s c o m p l i c a t i o n s , e s p e c i a l l y in t h e e l d e r l y , s4 T h e use of UH d u r i n g surgical r e c o n s t r u c t i o n p r o c e d u r e s m a y f u r t h e r a c t i v a t e platelets, s~ We n e e d a m o r e efficient a n d safe a n t i t h r o m b o t i c treatment in peripheral revascularization. The a s p i r i n + c l o p i d o g r e l c o m b i n a t i o n , at least o n theoretical grounds, could become the optimal l o n g - t e r m t r e a t m e n t . This c o m b i n a t i o n h a s b e e n s h o w n to b e v e r y effective in p e r c u t a n e o u s coro n a r y a r t e r y i n t e r v e n t i o n s , t~9122 W h e t h e r t h e s e results c a n b e e x t r a p o l a t e d to p e r i p h e r a l a n g i o p l a s t y h a s y e t to b e p r o v e d . Of p a r t i c u l a r i m p o r t a n c e in r e v a s c u l a r i z a t i o n is t h e t i m i n g of a n t i p l a t e l e t t r e a t m e n t , b e c a u s e e a r l y periprocedural events may adversely influence graft p a t e n c y . 54'6~ C l o p i d o g r e l effectively i n h i b i t s p l a t e l e t a g g r e g a t i o n 2 h r after a d m i n i s t e r i n g a l o a d i n g d o s e (300 mg); a s p i r i n f u r t h e r i n c r e a s e s this effect. 172"174"175 G p l I b / I I I a i n h i b i t o r s r e d u c e a c u t e o c c l u s i o n a n d t h e n e e d for r e p e a t e d r e v a s c u l a r i z a t i o n in c o r o n a r y i n t e r v e n t i o n s . ~x~ T h e y a r e also u s e f u l as a d j u v a n t t h e r a p y d u r i n g a n d after t h r o m b o l y s i s of p e r i p h e r a l arteries. ~35 Thus, it s e e m s r e a s o n a b l e to suggest t h a t G p I I b / I I I a i n h i b i tors c o u l d b e effective at a n e a r l y stage a f t e r p e r i p h e r a l a n g i o p l a s t y . This h a s y e t to b e p r o v e d in a d e q u a t e l y d e s i g n e d trials. T h e r e is also a n e e d to e s t a b l i s h if s u c h e a r l y a n t i t h r o m b o t i c t h e r a p y c o u l d f u r t h e r i m p r o v e t h e results of surgical o r e n d o v a s c u l a r p r o c e d u r e s if u s e d t o g e t h e r w i t h l o n g e r - t e r m clopidogrel and aspirin administration. This r e v i e w has f o c u s s e d o n " d e d i c a t e d " a n t i p l a t e l e t drugs, b u t it is i m p o r t a n t to c o n s i d e r t h a t antihypertensives and lipid-lowering agents can i n f l u e n c e p l a t e l e t a c t i v i t y a n d h e m o s t a s i s . 1761sl S m o k i n g a n d d i a b e t e s also e x e r t h a r m f u l effects o n p l a t e t e t s a n d h e m o s t a s i s , xsx-~s5 F u r t h e r m o r e , lifestyle factors, s u c h t h e a m o u n t of a l c o h o l c o n s u m e d , m a y affect p l a t e l e t f u n c t i o n a n d t h e risk of d e v e l o p i n g PAD. ls6'187 F i n a l l y , t h e q u e s t i o n rem a i n s as to h o w w e s h o u l d assess p l a t e l e t f u n c t i o n . This topic is b e y o n d t h e scope of this r e v i e w . H o w e v e r , it m a y be r e l e v a n t t h a t a r e c e n t s t u d y using flow cytometry showed that P-selectin exp r e s s i o n (an i n d e x of p l a t e l e t a c t i v a t i o n ) c o r r e l a t e d w i t h PAD severity.~S8

253

t h a t this p l a t e l e t a c t i v a t i o n is r e l a t i v e l y r e s i s t a n t to a s p i r i n . T h e r e f o r e , c l o p i d o g r e l m a y be m o r e effective t h a n a s p i r i n in p a t i e n t s w i t h PAD, p r o b a b l y b e c a u s e of its a b i l i t y to i n h i b i t A D P - i n d u c e d p l a t e l e t a c t i v a t i o n . T h e c t o p i d o g r e l + aspirin c o m b i n a t i o n s e e m s to h a v e g r e a t p o t e n t i a l , b u t w e n e e d m o r e trials to assess its r i s k - b e n e f i t ratio, e s p e c i a l l y in PAD p a t i e n t s u n d e r g o i n g r e v a s c u l a r i z a t i o n . Eventually, the GpIIb/IIIa inhibitors may play a s i g n i f i c a n t role in i m p r o v i n g t h e results of p e r i p h eral a n g i o p l a s t y . C l o p i d o g r e l is a n a l t e r n a t i v e o p t i o n for p a t i e n t s who cannot tolerate aspirin and those who have an e v e n t w h i l e t a k i n g a s p i r i n . I n t h e l a t t e r case, a n o t h e r p o s s i b i l i t y is to a d d c l o p i d o g r e l to t h e a s p i r i n . A l t h o u g h these o p t i o n s a r e c u r r e n t l y n o t e v i d e n c e b a s e d in p a t i e n t s w i t h PAD, e m e r g i n g e v i d e n c e s h o w s t h a t t h e y a r e realistic c h o i c e s .

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