Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination

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1 Atherosclerosis Supplements 6 (2006) Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination Anthony J. Comerota Jobst Vascular Center, Conrad Jobst Tower, Suite 400, 2109 Hughes Drive, Toledo, OH 43606, USA Abstract Management of peripheral arterial disease (PAD) requires standard atherosclerotic risk management interventions. However, PAD is often complicated by walking pain (intermittent claudication [IC]), which requires symptom-specific therapies as well. Thus, all PAD patients are encouraged to take antiplatelet agents to reduce the associated risks of major cardiovascular events, and those with IC may also require treatment with cilostazol, an agent proven to increase exercise capacity and enhance quality of life in these patients. Although it was initially thought that cilostazol s antiplatelet properties might render it unsafe to use in combination with other platelet inhibitors because of possible additive effects, a recent study has dispelled such concerns. There is evidence that in a crossover trial of 21 patients with PAD and IC, aspirin alone, or clopidogrel alone, significantly increased bleeding times, but cilostazol alone did not. The combination of aspirin and clopidogrel had a greater effect on increasing bleeding time than either monotherapy, and no further bleeding time prolongation was observed, when cilostazol was added to any aspirin/clopidogrel regimen. These findings suggest that PAD patients with IC may be safely managed with both cilostazol and standard antiplatelet therapy, without increasing the risk of adverse bleeding effects Elsevier Ireland Ltd. All rights reserved. Keywords: Aspirin; Clopidogrel; Cilostazol; Peripheral arterial disease; Intermittent claudication; Bleeding time; Platelet inhibitors 1. Introduction The term atherosclerosis is derived from two Greek roots atheros, gruel, and sclerosis, hard that together refer to the necrotic debris within an arterial lesion and its hard fibrotic cap. For patients in whom such hard and gruel -filled lesions affect the lower extremities, peripheral arterial disease (PAD) is the clinical result. Because PAD is associated with a prognosis similar to that of cardiovascular ischemic events such as myocardial infarction (MI) or stroke, most clinical recommendations call for aggressive risk management, usually with aspirin, clopidogrel, or other antiplatelet therapies [1]. For much of the PAD population, however, risk factor control is not enough. Notably, it has been estimated that one-third of all PAD patients suffer from intermittent claudication (IC) [1], a debilitating condition characterized by pain when walking, that is relieved by resting. In this subgroup of patients, the phosphodiesterase Tel.: ; fax: address: acomerota@jvc.org. inhibitor cilostazol represents a safe and effective pharmacologic strategy for reducing pain, improving functioning, and enhancing quality of life [2 8]. Thus, the optimal management of such patients would seem to include cilostazol, in addition to aspirin or clopidogrel administration provided, of course, that the antiplatelet effects of cilostazol would not exacerbate the risk of increased bleeding when combined with the other platelet inhibitors. The purpose of this article is to review the risks associated with PAD and to describe the effects of treatments with aspirin, clopidogrel, and cilostazol in the PAD population. Emphasis is given to a study designed to assess the safety of antiplatelet combinations for patients with IC [9]. 2. Morbidity and mortality in peripheral arterial disease The prognosis of patients with PAD is generally poor, with approximately 20 30% of the PAD population experiencing a non-fatal MI, stroke, or vascular death within 5 years [10,11]. When considered in relation to other serious /$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi: /j.atherosclerosissup

2 14 A.J. Comerota / Atherosclerosis Supplements 6 (2006) Fig. 1. Kaplan Meier survival curves based on mortality from all causes among normal subjects and subjects with symptomatic or asymptomatic large-vessel PAD. * Large-vessel PAD. Reprinted with permission from Criqui et al., Copyright 1992 Massachusetts Medical Society. All rights reserved [13]. diseases, this 5-year morbidity and mortality rate places PAD midway between localized breast cancer (2%) and Hodgkin s disease (15%) on one side, and colorectal cancer (37%) and lung cancer (85%) on the other [12]. As the disease progresses beyond 5 years, survival decreases accordingly. In one study [13], 21 of 34 men (61.8%) and 11 of 33 women (33.3%) with PAD died during a 10-year follow-up period. When compared with subjects who had no evidence of PAD, the relative risks of all-cause and cardiovascular death for PAD patients were 3.1 and 5.9, respectively. Not surprisingly, these risks increased as symptom severity increased. For cardiovascular mortality, relative risks increased from 4.7 in individuals with asymptomatic PAD to 11.2 in patients with IC, and were higher in patients with severe PAD (8.4) than in those with more moderate disease (4.8). Similar trends were noted for deaths due to coronary artery disease (CAD) and for all-cause mortality (Fig. 1). To further address the effects of disease progression on mortality and morbidity, a separate study followed a group of 247 PAD patients for a period of 6 years [14]. Using the ankle brachial index (ABI) as a measure of disease severity, this study yielded two important results. First, it demonstrated that patients with very severe PAD (ABI 0.30) were more likely than those with less severe disease (ABI = ) to require limb amputation during follow-up (32% versus 13%, respectively). Secondly, it found that the 6-year mortality rate for the most severe PAD patients (64%) greatly exceeded their rate of limb amputation. Thus, it appears that individuals with very severe PAD are more likely to die than undergo a major amputation. This difference may be at least partially attributable to the use of revascularization procedures in severe PAD, as such techniques tend to obviate the need for amputation (5-year limb salvage rates, 81 86%) without significantly improving long-term survival (5-year mortality rates, 29 31%) [15]. In fact, in a study of 82 patients who underwent repeat lower-extremity bypass surgeries for severe PAD [16], mortality rates (38, 72, and 88% at 1, 3, and 5 years post-surgery, respectively) appeared to be even higher than in the general PAD population. Notably, 26% of this population died within 6 months of the repeat bypass procedure. Fig. 2. The prevalence of coexistent vascular disease in patients with PAD, CAD, and stroke. CAD, coronary artery disease; PAD, peripheral arterial disease. Reprinted from Journal of the American Geriatric Society, Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in a academic hospitalbased geriatrics practice. Ness & Aronow, Copyright 1999, with permission from Blackwell Publishers [18]. According to the morbidity associated with a PAD diagnosis, the data clearly indicate that PAD patients have a high rate of systemic atherosclerotic involvement. In fact, a diagnosis of PAD seems to be more predictive of concomitant vascular disease than other atherosclerotic diagnoses. Dormandy et al. [17] reported that as many as 58% of PAD patients meet criteria for CAD based on history and electrocardiography alone, with a high of 90% showing evidence of CAD on angiography and up to 52% exhibiting signs of cerebrovascular disease, when assessed by ultrasonographic techniques. Supporting these data, a study conducted in 1998 [18] found that patients with PAD (n = 236) were more likely to be subsequently diagnosed with CAD (68%) or stroke (42%) than stroke patients (n = 351) were to be diagnosed with CAD (56%) or PAD (28%), or CAD patients (n = 612) to be diagnosed with PAD (26%) or stroke (32%) (Fig. 2). More recently, researchers studied a group of 497 patients undergoing coronary angiography for suspected CAD [19] and found that patients with PAD were more likely than those without PAD to have left main CAD (18% versus <1%), three- or four-vessel CAD (63% versus 11%), or obstructive CAD (98% versus 81%). Similarly, in a follow-up evaluation of 700 men, a diagnosis of PAD at age of 55 years was associated with a four-fold increase in the rate of cardiac events, compared with no leg pain (64.2 events per 1000 person-years versus 14.5 events per 1000 person-years; P < 0.001) [20]. In summary, these data lead to two conclusions: (1) the prognosis in PAD is at least equivalent to that of other forms of cardiovascular disease and (2) a diagnosis of PAD may be the single best indicator of a large atherosclerotic burden. The substantial morbidity and mortality imposed by PAD requires an aggressive risk management approach. In effect, a patient with PAD must be treated as if subject to an imminent ischemic event.

3 A.J. Comerota / Atherosclerosis Supplements 6 (2006) Antiplatelet therapy Among the many pharmacotherapeutic options for risk reduction in PAD patients, platelet inhibitors stand out as the primary strategy for preventing arterial thrombosis [21]. As the prototype and reigning gold standard of all antiplatelet therapies, aspirin works to counteract formation of arterial thrombi by inhibiting the cyclo-oxygenase pathway, which subsequently reduces platelet thromboxane A 2 synthesis and partially blocks the final step of platelet aggregation [21]. By contrast, the thienopyridines (e.g., ticlopidine or clopidogrel) inhibit platelets by blocking the adenosine diphosphate (ADP) receptor, and cilostazol blocks platelet cyclic adenosine monophosphate (camp) phosphodiesterase, thereby providing a third, albeit weaker [9], form of platelet inhibition. Over the years, a large body of literature has been generated to demonstrate the protective effects of platelet inhibitors in systemic forms of atherosclerosis. Reflecting this wealth of clinical information, the Antiplatelet Trialists Collaboration published a comprehensive meta-analysis [22] in which they studied over 73,000 high-risk patients from 142 randomized trials of antiplatelet medications. Their primary finding was that platelet inhibition significantly reduced the risk of major ischemic events (i.e., MI, stroke, and vascular death) by 27% in the total population, and produced significant vascular event reductions in subgroups with PAD and other vascular disorders as well. Eight years later, this same group of collaborators published a follow-up analysis [23] incorporating an even larger number of studies (n = 195) with an even greater patient population (n = 135,640). Among the issues addressed in this analysis, the researchers sought to determine the optimal dose of aspirin for patients requiring secondary prevention. To this end, they looked at only those trials that studied varying dosages of aspirin, and found that there was no significant difference in reduction in cardiovascular risk between a dosage of mg/day (32%) and higher dosages of mg/day (26%) or mg/day (19%). The effect of dosages <75 mg/day (13%) were less certain. Beyond the reduction of MI, stroke, and vascular death, aspirin has demonstrated additional benefits for PAD patients undergoing peripheral vascular reconstruction [24]. Thus, the pre-operative administration of aspirin has been objectively associated with improved patency of infrainguinal bypass grafts, particularly for patients receiving artificial prostheses, as well as protection against cardiovascular events following reconstructive procedures. It is therefore recommended that patients with PAD receive aspirin at standard dosages before presenting for vascular surgery. Despite the many benefits provided by aspirin therapy, new evidence suggests that second-generation platelet inhibitors may offer even greater preventive efficacy, at least for certain populations of vascular patients. In the largest trial to address this issue to date [25], researchers from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events Table 1 CAPRIE trial: mean follow-up results (1.9 years) Group Rate per year n ASA (%) Clop (%) RRR (%) P-value Stroke MI PAD Total Reprinted from The Lancet, volume 348, CAPRIE Steering Committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), , Copyright 1996, with permission from Elsevier [25]. ASA, aspirin; Clop, clopidogrel; RRR, relative risk reduction; MI, myocardial infarction; PAD, peripheral arterial disease. (CAPRIE) study randomized over 19,000 patients at high risk of secondary ischemic events, to treatment with clopidogrel 75 mg/day or aspirin 325 mg/day for a mean follow-up period of 1.9 years. Like the members of the Antiplatelet Trialists Collaboration, the CAPRIE investigators selected a composite of stroke, MI, or vascular death as the primary outcome measure, and assessed the risks associated with antiplatelet therapy in patients with different vascular diagnoses. By stratifying patients into pre-defined subgroups with recent MI, recent stroke, and chronic PAD, the CAPRIE study group sought to determine whether pathophysiologic differences between acute versus chronic disease would impact the outcomes of the two drug therapies. The final data indicated that clopidogrel reduced the risk of major cardiovascular events by 8.7% compared with aspirin therapy, a small but statistically significant difference (P = 0.043). Importantly, however, the added benefits of clopidogrel over aspirin in the total population did not derive from the patients who had had a recent MI or a recent stroke, but rather from the patients with chronic PAD diagnoses (Table 1). Within the first two subgroups, clopidogreland aspirin-treated patients had similar rates of ischemic events per year. Among patients with PAD, however, the annual event rates were 3.71% with clopidogrel versus 4.86% with aspirin, a reduction that reached nearly 24% in relative cardiovascular risk (P = ) and may correspond to an incremental cost-effectiveness ratio of US $25,100 per quality-adjusted life-year gained [26]. In addition to the relative benefits of clopidogrel over aspirin in the PAD population, subsequent analyses of the CAPRIE database found that clopidogrel was also significantly superior to aspirin among patients with previous cardiac surgery (relative risk reduction, 36.3%; P = 0.004) [27] and those with pre-existing symptomatic atherosclerosis (relative risk reduction, 14.9%; P = 0.045) [28]. The CAPRIE researchers thus concluded that clopidogrel and aspirin are equally effective in the overall population of patients with acute stroke or MI, but that PAD patients and other high-risk subgroups derive a far greater benefit from clopidogrel than from aspirin administration. To further investigate the differences between aspirin and clopidogrel, and to explore the consequences of combining the two platelet inhibitors, a recent study [29] evaluated

4 16 A.J. Comerota / Atherosclerosis Supplements 6 (2006) the effects of clopidogrel 75 mg/day, aspirin 75 mg/day, and their combination on indices of platelet function in 20 PAD patients. Results indicated that clopidogrel was a more potent inhibitor of ADP-induced platelet activation compared with aspirin monotherapy, and that combination treatment was more effective than either drug alone in reducing spontaneous platelet aggregation, inhibiting serotonin-induced aggregation, and decreasing soluble P-selectin. Similarly, research involving a human model (ex vivo) of arterial thrombosis [30] has shown that adding clopidogrel to aspirin therapy exerts a more potent effect on platelet and fibrin deposition compared with aspirin alone, and a 14-day randomized study involving CAD patients [31] found that platelet aggregation was significantly impaired with clopidogrel compared to aspirin and the combination of aspirin/clopidogrel maximized platelet disaggregation. Taken together, these data support a potential synergistic effect of aspirin and clopidogrel on platelet function in vascular, including PAD, populations [30,31]. 4. Cilostazol As shown by the previous data, there is strong evidence to support the management of PAD with aspirin [24], and perhaps even stronger evidence supporting clopidogrel [25] or combination therapy [9]. Despite their established efficacy in secondary prevention, neither of these drugs has exhibited added benefits in treating the most common symptom of PAD, namely IC. For PAD patients with IC, the use of aspirin or clopidogrel may be expected to improve cardiovascular outcomes, but is nonetheless unlikely to enhance functioning or improve quality of life. These patients will thus require treatment beyond risk factor control. It is in this context that cilostazol has emerged as a treatment of choice for the PAD population. The efficacy of cilostazol in the symptomatic treatment of PAD-associated IC has been firmly established in a series of eight randomized, controlled trials [2 8]. Analyses of the cilostazol clinical trial database indicate that cilostazol 50 mg bid significantly improves walking distance relative to placebo, and that the walking benefits of cilostazol 100 bid are even greater than those of the lower dosage [2,8] or of pentoxifylline, the only other FDA-approved claudication therapy [3]. Importantly, cilostazol has also demonstrated superiority over placebo on the bodily pain, physical function, role-physical, and physical summary domains of the Short Form-36 questionnaire, indicating that the cilostazolassociated improvements in exercise capacity are indeed accompanied by meaningful improvements in functioning and health-related quality of life [7]. With the establishment of cilostazol as a first-line therapy for IC, the question arises whether this drug can be safely added to ongoing antiplatelet regimens in PAD patients who require both symptomatic and cardiovascular risk management interventions. More specifically, the question is whether the antiplatelet effects of cilostazol will increase the risk of bleeding in patients already receiving stronger platelet inhibitors. Acting on the assumption that the best test to measure platelet function should be performed in vivo, a group of investigators set out to assess the bleeding effects of multiple platelet inhibitors in a well-performed standardized trial in which each PAD patient served as his or her own control [9]. 5. Effects of multiple platelet inhibitors on bleeding times As criteria for inclusion in the trial, 26 patients (71.4% males; mean age 65.9 years) were identified who had PAD with IC, an ABI < 0.90, and no contraindications to the study drugs. After the exclusion of 5 subjects, 21 of the identified patients were offered sequential 2-week regimens of aspirin (325 mg/day), clopidogrel (75 mg/day), and cilostazol (100 mg bid), each alone, and in every combination. At the end of each regimen, bleeding times were evaluated by trained clinicians in accordance with a standardized protocol. This was not a randomized trial. Patients did not receive the treatment regimens in a varying order, but rather in a carefully defined sequence designed to allow adequate washout periods and full analyses of platelet function. In essence, each patient was started out with one drug for 2 weeks, then given an additional drug for 2 weeks, and finally taken off platelet inhibitors for 2 weeks before starting the sequence again with a different initial medication. The complete protocol is shown in Fig. 3. For the primary data analysis, patients bleeding times following each treatment phase were compared with baseline values. Results, as depicted in Fig. 4, indicated that the mean baseline bleeding time of 4.29 min increased significantly after aspirin only (+55%; P 0.05) and clopidogrel only (+137%; P 0.05), but not after cilostazol monotherapy (+26% P = NS). Furthermore, the combination of aspirin and clopidogrel was associated with a 305% increase in mean bleeding time from baseline (P 0.05), a change that was significantly greater than that produced by either agent alone (P 0.05), and the combination of all three agents produced a 318% increase (P 0.05), which greatly exceeded those observed with each individual therapy (P 0.05). Perhaps the most important finding from this small, crossover trial was that the addition of cilostazol to aspirin or clopidogrel did not significantly further affect bleeding times, compared with aspirin alone or clopidogrel alone. On average, bleeding times following cilostazol/aspirin and cilostazol/clopidogrel dual therapy remained significantly higher compared with baseline values (+93 and +196%, respectively; P 0.05), but the differences between aspirin versus cilostazol/aspirin and clopidogrel versus cilostazol/clopidogrel were not statistically significant. Based on these data, the authors of the study came to four primary conclusions: (1) treatment with aspirin or clopidogrel alone prolonged bleeding time in PAD patients; (2) the com-

5 A.J. Comerota / Atherosclerosis Supplements 6 (2006) Fig. 3. Treatment protocol for the study of multiple platelet inhibitors in PAD. Each phase required 14 days of therapy. ASA, acetylsalicylic acid; PAD, peripheral arterial disease. Reprinted from Journal of Vascular Surgery, Volume 38, Wilhite et al., Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time, , Copyright 2003, with permission from The Society for Vascular Surgery [9]. Fig. 4. Average bleeding time for each treatment phase. * P 0.05 vs. baseline. ** P 0.05 vs. all single agents and vs. ASA + cilostazol and clopidogrel + cilostazol. P < 0.05 vs. PI and baseline. P < 0.05 vs. cilostazol + other PI. Reprinted from Journal of Vascular Surgery, Volume 38, Wilhite et al., Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time, , Copyright 2003, with permission from The Society for Vascular Surgery [9]. bination of aspirin and clopidogrel had a more pronounced effect on increasing bleeding time than either agent alone; (3) administration of cilostazol alone did not significantly affect bleeding time; (4) addition of cilostazol to aspirin or clopidogrel therapy did not result in further bleeding prolongation. It thus appears that concerns regarding the additive platelet effects of cilostazol are unwarranted. Combination therapy with cilostazol plus aspirin or clopidogrel appears to be a safe strategy for the management of intermittent claudication. 6. Discussion In interpreting the data from the combined platelet inhibitor study, it is important to consider whether information on bleeding time can be extrapolated to clinical bleeding events. An exhaustive review [32], based on 1321 distinct studies involving animals (n = 238) and humans (n = 1083), addressed this question. Although the study concluded that there is no evidence to support bleeding time as a preoperative predictor of hemorrhage risk, not all researchers have accepted this assertion [33]. Specifically, they argue that many of the studies on which it was based were either incomplete [34] or were obscured by other indicators of bleeding risk [33,34]. Because most of the studies investigating the relation between bleeding time and bleeding events have been conducted in surgical settings with patients who were already at risk of bleeding complications, any conclusions regarding the predictive value of bleeding time may be inherently flawed. Regardless of its true connection with bleeding complications, the bleeding time test remains a popular method for

6 18 A.J. Comerota / Atherosclerosis Supplements 6 (2006) evaluating primary hemostasis [34] and is unquestionably useful for epidemiologic investigations and the diagnosis of congenital platelet disorders [32]. Furthermore, there are certain clinical populations (e.g., patients undergoing neuroaxial anesthesia) for whom a prolonged bleeding time might alter the course of therapy (e.g., change in choice of anesthetic), and at least one study has shown bleeding time to be a significant predictor of excessive postoperative blood transfusion [35]. Ultimately, it must be stressed that the current lack of evidence supporting a link between bleeding time and bleeding events does not prove that the link does not exist. With further study, and perhaps better testing methods and better patient selection [33], a significant relation between clinical complications and bleeding time may become apparent. 7. Conclusions A diagnosis of PAD is often indicative of a large burden of systemic atherosclerotic disease and poor survival. Because of the high risks associated with PAD, good patient management calls for aggressive secondary prevention in this population, prevention which includes aspirin, clopidogrel, or other antiplatelet therapies. Despite the proven effectiveness of aspirin and clopidogrel in preventing cardiovascular events, these agents do not improve walking distance in patients with IC, which is present in roughly one-third of PAD patients. Fortunately, there is an alternative for this indication. Based on the consistent and robust efficacy demonstrated in a large clinical trial program, the phosphodiesterase inhibitor cilostazol has emerged as a first-line therapy for increasing exercise capacity, improving walking distance, and enhancing quality of life in IC patients. Although there was some initial concern that the antiplatelet properties of cilostazol may render it unsafe in the setting of other platelet inhibitor use, a recent study has shown that the addition of cilostazol to aspirin or clopidogrel therapy does not increase bleeding compared with aspirin or clopidogrel alone. These findings suggest that the management of IC can include risk reduction and symptomatic strategies simultaneously. For patients with PAD and IC, cilostazol may be safely added to ongoing antiplatelet therapy without increasing risk of platelet inhibitor-induced bleeding effects. References [1] Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001;344: [2] Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999;159: [3] Dawson DL, Cutler BS, Hiatt WR, et al. 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