Clopidogrel in Secondary Ischemic Stroke Prevention - IngentaConnect

Recent Patents on Cardiovascular Drug Discovery, 2008, 3, 119-125

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Clopidogrel in Secondary Ischemic Stroke Prevention Robert Belvís1,*, Javier Pagonabarraga1, Amparo Santamaría2 and Jaime Kulisevsky1 Departments of Neurology1 and Haematology2, USP Dexeus University Institute, Barcelona, Spain Received: November 15, 2008; Accepted: April 22, 2008; Revised: May 26, 2008

Abstract: The results obtained in the CAPRIE study in 1996 led to the introduction of the clopidogrel as a new antiplatelet drug in the secondary prevention of acute myocardial infarct (AMI), ischemic stroke (IS) and symptomatic peripheral artery disease (PAD). Clopidogrel showed a similar efficacy and safety than acetylsalicylic acid (ASA). More recently, the combined use of clopidogrel with ASA has evidenced a better protection than ASA alone in some patients: patients with past history of AMI, angina pectoris, intermittent claudication or PAD, IS or TIA, coronary bypass, and diabetes mellitus, patients on treatment with statins, and patients with symptomatic carotid stenosis 50%. We review the reported evidence on the efficacy of clopidogrel in the secondary prevention of ischemic stroke.

Keywords: IS (ischemic stroke), AMI (acute myocardial infarct), PAD (peripheral arterial disease), TIA (transient ischemic attack), ASA (acetylsalicylic acid), RRR (relative risk reduction), ARR (absolute risk reduction). INTRODUCTION Stroke is the first cause of disability, the second cause of dementia and the third cause of death in developed countries. Approximately, 80-85% of strokes have an ischemic aetiology, while the rest are haemorrhagic. Five aetiologies for ischemic stroke (IS) have been described [1,2]: large-artery atheroesclerosis (21%), smallvessel disease (20%), cardioembolisms (26%), unusual causes (3%), and undetermined causes (30%). Large-artery atheroesclerosis and small-vessel disease are the underlying cause of 40-45% of all IS Figs. (1) and (2). Antiplatelet drug therapy has shown efficacy in the secondary prevention of new vascular events in both subtypes. 1. ANTIPLATELET DRUGS IN SECONDARY ISCHEMIC STROKE PREVENTION BEFORE THE STUDY CAPRIE In 1994, the Antiplatelet Trialist’Collaboration [3] showed that antiplatelet drugs reduced in 23% the incidence of non-fatal IS in patients with prior IS or TIA. Antiplatelet drugs provide a significant protection against IS, acute myocardial infarct (AMI), and vascular death in patients with high risk of aterothrombotic disease (unstable angina, prior AMI, symptomatic peripheral arterial disease -PAD and patients under vascular procedures). Acetylsalicylic acid (ASA), ticlopidine and dipyridamole were the only antiplatelet drugs available in the secondary prevention of IS before the study CAPRIE.

Fig. (1). Images on cranial CT: 1a (Right). Lacunar infarct in the left thalamus (small-vessel disease) in a diabetic woman. 1b (Left). Ischemic infarct in the territory of the left middle cerebral artery in a patient with left carotid stenosis 70%. (Large-artery atherothromboembolic disease).

Acetylsalicylic acid - ASA. The Antiplatelet Trialist’ Collaboration [4,5] showed that the use of ASA at 75 to 1300 mg/day produced a relative risk reduction (RRR) of 23% of new IS events, and of 25% of combined ischemic events (fatal or non-fatal IS, AMI or vascular death). In the subgroup of patients with IS, the use of ASA resulted in a *Address correspondence to this author at the Department of Neurology. USP Dexeus University Institute, Address: C/ Sabino Arana 5-19, cp 08028 Barcelona, Spain; Tel: 34 93 258 09 10; Fax: 34 93 254 54 02; E-mail: [email protected] 1574-8901/08 $100.00+.00

Fig. (2). Images on brain MRI: 2a (Right). Lacunar infarct in the right thalamus in a man with high blood pressure (small-vessel disease). 2b (Left). Ischemic infarct in the cerebellum in a woman with atherosclerotic occlusion of the right vertebral artery. (Largeartery atherothromboembolic disease). © 2008 Bentham Science Publishers Ltd.

120 Recent Patents on Cardiovascular Drug Discovery, 2008, Vol. 3, No. 2

13-17% reduction of combined ischemic events (non-fatal IS, non-fatal AMI and vascular death) at doses of 75 to 150 mg/day. In clinical situations with a higher probability of recurrence of ischemic events (angina, AMI, acute IS) the use of greater doses of ASA up to 150-300 mg/day could be better [3-5]. Ticlopidine. In the CATS (Canadian American ticlopidine study) study [6], the use ticlopidine 500 mgr/day in a prospective sample of 1072 patients was associated with a reduction of 30-33% of IS, AMI or vascular death. The TASS study (Ticlopidine aspirin stroke study) [7] compared the efficacy of ASA (1.300 mg/day) with ticlopidine (500 mg/day) in 3069 patients. Comparative analyses showed ticlopidine to display a RRR of 21% versus ASA after a 3year follow-up period. Dipyridamole. The ESPS-2 (European stroke prevention study 2) [8] recruited 6602 patients in three parallel groups (ASA 50 mg/day, dipyridamole 400 mg/day, and both, ASA plus dipyridamole). Both, ASA and dipyridamole, resulted in a similar efficacy when administered in monotherapy (RRR of IS of 18% for ASA, and 16% for dipyridamole), but a better efficacy was observed with ASA plus dipyridamole (RRR of IS of 24%). The ESPRIT (European/Australian stroke prevention in reversible ischaemia trial) [9] is a recent open-label randomised controlled study that compared longterm treatment of patients with a TIA or a minor IS. It randomized two groups of patients: ASA 30-325 mg daily with (n = 1363) or without (n = 1376) dipyridamole 200 mg twice daily. As results, 13% of patients on ASA plus dipyridamole, and 16% on ASA in monotherapy suffered a new ischemic event (vascular death, non-fatal IS, non-fatal AMI, or major bleeding). Finally, it will be interesting to know the results of the PROFESS (Prevention regimen for effectively avoiding second strokes trial) study. It is an ongoing randomized, double-blind, controlled trial that aimed to compare the efficacy of extended-release dipyridamole plus ASA versus clopidogrel, telmisartan, and placebo in the secondary prevention of IS. The PRoFESS has prospectively recruited 20333 patients from 720 sites in 35 countries. The patients will be followed during 4 years, and first preliminary results will be available in 2010. 2. THE CAPRIE STUDY (CLOPIDOGREL VERSUS ASPIRIN IN PATIENTS AT RISK OF ISCHEMIC EVENTS) Clopidogrel is a thienopyridine derivative related to ticlopidine. It blocks activation of platelets by ADP inhibiting the binding of ADP to its receptor on platelets. The result is an inhibition of the activation of the GpIIb-IIIa complex that is the major receptor of fibrinogen. These effects were studied in animal models, in volunteers and in patients with symptomatic atherosclerotic disease [10]. CAPRIE [11] was the first trial that investigated the efficacy and safety of an antiplatelet drug in patients with recent IS, AMI and symptomatic PAD. The combined endpoint was the risk reduction of IS, AMI and vascular death, This randomised clinical trial, performed in 384 centres of 16 countries, enrolled 19185 patients between 1992 and

Belvís et al.

1995 with a mean follow-up of 1.9 years. The Tables 1 and 2 show inclusion and exclusion criteria of the study. Patients received blister packs containing either 75 mg tablets of clopidogrel plus ASA placebo (9599 patients) or 325 mg tablets of ASA plus clopidogrel placebo (9586 patients). Both groups were comparable regarding age, sex, race and cardiovascular risk factors. Inclusion ischemic events were IS (6431 patients), AMI (6302 patients) and PAD (6452 patients). All patients were treated between 1 week and six months after the ischemic event: Primary Analysis Primary analysis of efficacy by intention-to-treat was based on the first occurrence of IS, AMI or vascular death. Finally, 2800 events were collected (1669 fatal y 1131 nonfatal). In the clopidogrel group, 939 patients reached the primary event (32.8% were fatal), with an average rate of 5.3% per year; and 1021 in the ASA group (31.4% were fatal), with an average rate per year of 5.8%. The more frequent event was IS (46%), followed by AMI (31%) and vascular death (23%). The majority of IS (73%) occurred in the IS group. Only 9% of AMI group and 18% of PAD group patients present a IS as event. The RRR was 8.7% favourable to clopidogrel (p=0.043). Therefore, in a population similar to the CAPRIE study, ASA would be expected to prevent about 19 major clinical events versus 24 with clopidogrel, for each 1000 patients treated for 1 year. The RRR was respectively for IS, AMI and PAD of 7.3%, 3.7% and 23.8% [11]. Table 1.

Inclusion Criteria of the CAPRIE Study

Brain infarct (including retinal and lacunar infarction) •

Focal neurolgical deficit likely to be of aterothrombotic origin.

•

Onset 1 week and 6 months before randomisation.

•

Neurological signs persisting 1 week from stroke onset.

•

CT or MRI ruling out haemorrhage or non-relevant disease.

Myocardial infarction •

Onset 35 days before randomisation.

•

Two of: - Characteristic ischemic pain for 20 min. - Elevation of CK, CK-MB or AST to 2x upper limit of the laboratory normal with no other explanation. - Development of new 40 Q waves in at least two adjacent ECG leads or new dominant R wave in V1 (R>1 mm > S in V1).

Atherosclerotic peripheral arterial disease.

• Intermittent claudication (WHO:leg pain on walking, disappearing in < 10 min on standing) of presumed atherosclerotic origin;and ankle/arm systolic BP 0.85 in Esther leg at rest (two assessments on separate days);or history of intermittent claudication with previous leg amputation, reconstructive surgery, or angioplasty with no persisting complications from intervention).

Clopidogrel in Stroke

Table 2.

Recent Patents on Cardiovascular Drug Discovery, 2008, Vol. 3, No. 2

Tolerability

Exclusion Criteria of the CAPRIE Study

•

Age < 21 years.

•

Severe cerebral deficit likely to lead to patient being bedridden or demented.

•

Carotid endarterectomy after qualifying stroke.

•

Qualifying stroke angiography.

•

Patient unlikely to be discharged alive after qualifying event.

•

Severe co-morbidity likely to limit patient´s life expectancy to less than 3 y.

•

Uncontrolled hypertension.

•

Scheduled for major surgery.

•

Contraindications to study drugs:

induced

by

carotid

endarterectomy

121

or

- Severe renal or hepatic insufficiency. - Haemostatic disorder or systemic bleeding. - History of Haemostatic disorder or systemic bleeding. - History of thrombocytopenia or neutropenia. - History of drug-induced haematologic or hepatic abnormalities. - Known to have abnormal WBC, differential, or platelet count - Anticipated requirement for long-term anticoagulants, non-study Antiplatelet drugs or NSAIDs affecting platelet function - History of ASA sensitivity. Women of childbearing age not using reliable contraception. Currently receiving investigation drug. Previously entered in other clopidogrel studies. Geographic or other factors making study participation impractical.

Secondary Analysis (Secondary Variables) All RRR were favourable to clopidogrel in the analyses of secondary variables, alone or associated, in front to ASA patients: 1) IS, AMI, amputation or vascular death 7.6% (p=0.076); 2) vascular death 7.6% (p=0.29); 4) any cerebrovascular disease, AMI or death of any cause 7.0% (p=0.081); and 5) death of any cause 2.2% (p=0.71) [11]. Analysis by inclusion disease prior to the study: This was not the original objective of the study. However, in patients with prior IS the RRR was 7.3% favourable to clopidogrel; in patients with PAD the RRR was 23.8% favourable to clopidogrel; and in patients with prior AMI RRR was 22.7% favourable to clopidogrel. Moreover, patients who presented more than one event prior to study, RRR was 15.4% favourable to clopidogrel [11,12]. Analysis by clinical response: This study was performed after finishing CAPRIE. All the events, alone or combined, presented better results in the clopidogrel group [11,13]. Analysis by re-hospitalization: This variable was not studied in the original study but the RRR were also favourable to clopidogrel [11,14].

The 21.2% of patients permanently discontinued the study early for reasons other than the occurrence of an outcome event without significant differences between both groups (21.3% en the clopidogrel group against 21.1% in the ASA group). Discontinuation secondary to adverse events was 11.94% in the clopidogrel group against 11.92% in the ASA group without significant differences. However, 3.21% of the clopidogrel group of patients against 4.02% of the ASA group of patients discontinued the study because of gastrointestinal symptoms (p = 0.01), gastrointestinal haemorrhage (0.52% versus 0.93%, p = 0.05), and rash (0.90% versus 0.41%, p = 0.001) [11,15]. Severe adverse effects were 1.9% in the clopidogrel group and 2.1% in the ASA group. Severe rash was infrequent but worse in the clopidogrel group against the ASA group (p = 0.017) [11,15]. Thrombocytopenia was similar in both groups. Sever neutropenia was more frequent in the clopidogrel group but differences were non significant. General haemorrhages were similar in both groups (9.27% in the clopidogrel group versus 9.28% in the ASA group). However, intracranial haemorrhages were more frequent in the ASA group but with non significant differences (including the subgroup of severe intracranial haemorrhages). Gastrointestinal bleeding was less frequent (p=0.002) in the clopidogrel group (1.99%) regarding to the ASA group (2.66%), including severe gastrointestinal haemorrhages. Three patients died because of gastrointestinal bleeding during the study: one received clopidogrel and two other received ASA [11]. Diarrhoea was more frequent in the clopidogrel group (p=0.001), including severe diarrhoea (p=0.080). However, gastrointestinal discomfort (indigestion, nausea, vomiting) were more frequent in the ASA group [16,17]. Digestive erosion seemed worse in ASA patients after 8 days of treatment, evidenced by gastroscopy, in a study performed after CAPRIE [18]. Other drugs from the patient´s previous treatment did not modify the results of the study [19]. The ASA patients treated with ACE inhibitors presented higher blood pressure (by the effect ASA-ACE inhibitors) than the clopidogrel group patients (p=0.034) [19,20]. Patients who received atorvastatin were not analysed but a recent study has sown a possible reduction of clopidogrel activity related to atorvastatin treatment [21]. The CAPRIE study concluded that clopidogrel prevents 5 vascular events and 1 gastrointestinal haemorrhage more than ASA for every 1000 patients treated for 1 year [11]. If we compare these results with the meta-analyses of the Antiplatelet TrialistĆollaboration (1994) [3], ASA shows a RRR of the 25% for 1 year and clopidogrel shows in CAPRIE a RRR of 33% without increasing adverse effects. In a recent meta-analysis that enrolled 135640 patients of 195 studies, clopidogrel reduces in a 10% more than ASA, severe vascular events, similar to the 12% of the ticlopidine [4].


3. AFTER THE CAPRIE STUDY. THE PATIENT AT RISK Not all stroke patients have the same risk of a new ischemic event. A meta-analysis [22] showed that thienopyridines (clopidogrel and ticlopidine) provide better protection than ASA in patients with high risk of IS, AMI or vascular death. Moreover, the CAPRIE study revealed that the more dangerous risk factors were previous AMI, angina pectoris, intermittent claudication, IS and TIA [23-29]. A Canadian study [30] (CAPRA) recruited 12931 patients treated with ASA after an AMI, IS and PAD between 1990 and 1995. Hospitalization for AMI, IS, intracranial haemorrhage or death were the analysed events and were compared with the same events in the clopidogrel arm of the CAPRIE study. Approximately, 15.9% of CAPRA patients presented a new event against 6.9% of clopidogrel CAPRIE patients. Therefore, it is necessary to treat 70 patients with clopidogrel to avoid an ischemic event (CAPRIE had reported 200 patients). 4. CLOPIDOGREL PLUS ASA The effect of two antiplatelet drugs with different biological targets can be complementary and synergic in thrombosis therapy. This hypothesis was demonstrated by the ESPS-2 study with the association ASA plus dipyridamole [31,32]. The association of ASA plus clopidogrel induces an 80% reduction in the platelet aggregation in monkeys. This additive effect is greater than the effect of each of these drugs alone and has also been seen in pigs and rabbits [3335]. After some pilot experiences in patients with AMI [36], the CURE study [36] was the first trial that investigated the efficacy and safety of the association ASA plus clopidogrel in patients with acute coronary syndrome. This trial recruited 12562 patients and showed a RRR of 20% and ARR of 2.1% of the association ASA plus clopidogrel in the primary endpoint (non-fatal AMI, IS and vascular death). Regarding safety, the association showed and increase of the relative risk of major bleedings. Moreover, cardiologists use the association ASA plus clopidogrel in the clinical practice for patients under coronary revascularization procedures. A meta-analysis that included 13955 patients showed a greater reduction of coronary events and mortality when ASA plus clopidogrel was used, compared to treatment with ASA plus ticlopidine [37]. Neurologists also use the combination ASA plus clopidogrel as secondary prevention after carotid revascularization procedures in IS patients [38,39]. The combination ASA plus clopidogrel seems safe, regarding peri-procedure events, intracranial bleeding and mortality in first experiences. At present, several studies that compare endarterectomy versus angioplasty (SAPPHIRE in US, CASCADE in Europe) use clopidogrel as secondary prevention The results of the CURE trial and the experiences in coronary and carotid revascularization procedures could not be extrapolated to IS patients. Therefore, a trial to analyse

Belvís et al.

the efficacy and safety of ASA plus clopidogrel in IS patients was necessary. 5. THE MATCH STUDY (MANAGEMENT OF ATHEROTHROMBOSIS WITH CLOPIDOGREL IN HIGH-RISK PATIENTS WITH RECENT TRANSIENT ISCHEMIC ATTACK OR ISCHEMIC STROKE) After some encouraging experiences [40], a trial to assess whether ASA plus clopidogrel could have a greater benefit than clopidogrel alone in secondary prevention in IS patients was proposed. The MATCH study [41,42] was a randomised, double-blind, placebo-controlled trial comparing ASA (75 mg/day) with placebo in 7599 high-risk patients with recent (previous three months) IS or TIA and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day. Additional risk factors were previous IS, previous AMI, angina pectoris, diabetes mellitus or symptomatic PAD within the previous three years. MATCH was performed in 507 centres in 28 countries and the duration of follow-up was 18 months. The primary end-point was a composite of IS, AMI, vascular death or rehospitalisation from an acute ischemic event. This primary efficacy analysis was by intention to treat. Evaluation criteria for safety included incidence of life-threatening bleeding and major bleeding [41,42]. As results, 596 patients (15.7%) reached the primary endpoint in the ASA plus clopidogrel group compared with 636 patients (16.7%) in the clopidogrel group alone (RRR 6.4% and ARR 1%). On the other hand, life-threatening bleedings were higher in the ASA plus clopidogrel versus clopidogrel alone (2.6% vs 1.3%) with an ARR of 1.3%. Therefore, adding ASA to clopidogrel in high-risk patients with recent IS or TIA does not reduce major vascular events. Moreover, the risk of life-threatening or major bleeding is increased when ASA is associated to clopidogrel [41,42]. 6. OTHER STUDIES WITH CLOPIDOGREL •

CARESS (Clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis) [43]. This randomized, double-blind study includes 107 patients with recently symptomatic 50% carotid stenosis (patients with TIA or IS within last 3 months). Patients were randomized to dual-therapy (clopidogrel plus ASA) or monotherapy (ASA alone) and studied with transcranial Doppler (TCD) on day 7. Clopidogrel was initiated with a 300-mg loading dose. The frequency of microembolic signals detected by TCD during a single hour´s recording was higher in ASA monotherapy patients (72%) than in dual-therapy patients (43.8%) with a RRR of 43.8%. As conclusion, the dual-therapy (clopidogrel plus ASA) is more effective than monotherapy (ASA alone) in reducing asymptomatic embolization.

•

CHARISMA (Clopidogrel plus aspirin in a large population of patients with myocardial infarction, stroke, or a combination of atherothrombotic risk factors) [44]. This trial randomized 15603 patients with either clinically cardiovascular disease or multiple risk

Clopidogrel in Stroke

factors to receive dual-therapy (clopidogrel plus lowdose ASA) or placebo plus low-dose aspirin with a mean follow-up of 28 months. The primary efficacy end point was a composite of AMI, IS vascular death. Dual-therapy patients achieved the end point less frequently than placebo plus ASA group patients (6.8% vs 7.3% with RR of 0.93). As conclusion, clopidogrel plus ASA was not significantly more effective than ASA alone in reducing the rate of AMI, IS or vascular death. No differences were seen in the risk of severe bleeding. The rate of the primary end point among patients with multiple risk factors was 6.6% with clopidogrel and 5.5% with placebo (RR 1.2). Moreover, this study suggests a possible benefit of clopidogrel in patients with symptomatic atherothrombosis and multiple risk factors. •

•

•

FASTER (Fast assessment of stroke and transient ischemic attack to prevent early recurrence) [45]. This study randomized 392 patients with TIA or minor IS to clopidogrel with 300 mg loading dose (198 patients) or placebo (194 patients), and simvastatin (40 mg daily;199 patients) or placebo (193 patients) after 24 h of symptoms onset. All patients were also given ASA. The primary outcome was total stroke (ischaemic and haemorrhagic) within a 90 days follow-up. The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins. As preliminary conclusion, patients are at high risk of IS immediately after TIA or minor IS, which might be reduced by using clopidogrel plus ASA. PLUTO (Clopidogrel and aspirin versus aspirin alone in stroke patients) [46]. Seventy IS patients were randomized (clopidogrel plus ASA vs ASA alone) and platelet studies were performed: aggregometry; cartridge-based analyzers; expression of PECAM-1, Pselectin, GP IIb/IIIa, vitronectin receptor, and formation of platelet-leukocyte microparticles by flow cytometry. Platelet tests were performed at baseline and after 30 days after randomization. Dual-therapy (clopidogrel plus ASA) for 1 month resulted in a significant inhibition of platelet activity than ASA alone in patients after recent IS. ACTIVE (Clopidogrel/aspirin combination in patients with atrial fibrillation) [47] was a double-blind, placebo-controlled trial of clopidogrel plus ASA versus oral anticoagulation (INR 2.0-3.0) in patients with atrial fibrillation and at least 1 risk factor for IS. Patients have a contraindication for oral anticoagulation or they are unwilling to take an oral anticoagulant. However, the study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; RR 1.44, p=0.0003).

7. CURRENT & FUTURE DEVELOPMENTS: The CAPRIE study [11] definitely showed that clopidogrel is an effective and safe antiplatelet drug in the


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secondary prevention of ischemic events. However, CAPRIE was not designed to analyse the efficacy of clopidogrel against ASA in each subgroup (IS, AMI and PAD). WHAT IS THE FIRST-LINE ANTIPLATELET DRUG IN SECONDARY ISCHEMIC STROKE PREVENTION? It is very difficult to answer this question. First, the RRR in the AMI, IS and PAD subgroup was small (8.7%). Therefore, 1 patient treated with clopidogrel prevents an event for each 200 patients treated with ASA in the CAPRIE study [11] or for each 70 in the CAPRA study [30]. Second, the maximum benefit of clopidogrel is in the subgroups of AMI and PAD. Third, in the post hoc analysis there are not important differences between clopidogrel and ASA. Fourth, higher dose of ASA could be better than the dose of 325 mg/day of the CAPRIE study. Fifth, the average of adverse effects is similar between both antiplatelet drugs. Only gastrointestinal adverse effects were more frequent in ASA patients, but some studies show that the gastrointestinal safety of clopidogrel and low dose of ASA is similar [48]. Sixth, patients with severe IS were excluded to the CAPRIE study. Finally, the cheaper drug is the best option when we have two drugs with similar profiles regarding efficacy and safety [49,50]. At the moment, there are not enough evidence to recommend clopidogrel as first antiplatelet drug option in secondary IS prevention [51-53]. Therefore, clopidogrel is only the first antiplatelet option in patients with contraindication to ASA or in patients who receive ASA previously to the IS or TIA. The post-CAPRIE studies suggest that clopidogrel is probably a better option than ASA in patients with prior AMI or PAD, mainly in patients with diabetes mellitus, patients under statins therapy and patients with prior coronary bypass. DUAL THERAPY (CLOPIDOGREL PLUS ASA) This antiplatelet drug association is safe and effective in patients with acute coronary syndrome (CURE study) [36]. However, this dual-therapy failed to demonstrate the same results in IS patients (MATCH study) [41,42]: it does not reduce major vascular events and the risk of life-threatening or major bleeding is increased. However, in the MATCH study all IS subtypes were included but there was an overrepresentation of patients with small-vessel disease. Moreover, MATCH enrolled most patients several weeks after the acute phase of stroke when the risk of recurrences is lower. In patients with acute coronary syndrome, the CURE study enrolled patients within 24 hours of acute coronary syndrome onset. Anyway, it seems that dual-therapy is effective and safe in coronary patients after revascularization procedures. At the moment, neurologists use the same association after carotid stenting without evidences. In the near future, we will know the result of new studies: •

SPS3 (Secondary prevention of small subcortical strokes) [54]. This multi-centre study will recruit 2500 patients to find out if using ASA (325 mg/day) plus


clopidogrel (75 mg/day) are more effective than using ASA alone to prevent recurrent IS and cognitive decline in patients with lacunar stroke, and if lowering a patient's blood pressure below the usual limits will also help prevent recurrent IS and maintain thinking ability. Follow-up will be every three months for a mean of 3 years. •

ARCH (warfarin versus clopidogrel plus aspirin in patients with aortic arch atherosclerosis). This openlabel, multicenter, randomized, controlled trial will recruit 644 patients with no disabling IS within 6 months and with aortic arch atheroma plaque 4 mm. It will randomize 322 patients with oral coagulation (INR 2-3) and clopidogrel (75 mg/day) plus ASA (75 mg/day). Primary outcomes are IS, AMI, peripheral embolism and vascular death.

THE LOADING DOSE OF CLOPIDOGREL This is another controversial issue. An initial and single 300-mg loading dose of clopidogrel prior to the regular dose of 75 mg/day inhibits platelet aggregation faster than clopidogrel 75 mg/day without loading dose or 500 mgr/day of ticlopidine after coronary revascularization with stenting [55]. Moreover, a 600 mg loading dose of clopidogrel seems better than 300 mg dose in patients undergoing percutaneous coronary intervention in the ARMYDA-2 (Antiplatelet therapy for reduction of myocardial damage during angioplasty) study [56]. In acute coronary syndrome the CURE study employed 300-mg loading dose of clopidogrel in all patients and it seems effective and safe. In stroke patients, the loading dose was only employed in CARESS [44] and FASTER [45] studies but it was not the aim of the study. To our knowledge, no clinical trial has been performed to analyse the efficacy and safety of the loading dose of clopidogrel in acute IS.

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CLOPIDOGREL AND TRHOMBOLYSIS The relationship between thrombolytic therapy and clopidogrel has not been analyzed in patients with AMI or acute IS. In animals and some initial experiences in humans, clopidogrel increases the thrombolytic activity of streptokinase and tPA in AMI and in acute IS [57-59]. Recently, the CLARITY TIMI 28 trial [60] has sown that early clopidogrel treatment among in patients treated with thrombolytic therapy for AMI and undergoing coronary artery bypass grafting was not associated with an increase in the rate of peri-operative bleeding and showed a trend toward reduction in 30-day ischemic events. More studies are needed to clarify the efficacy and safety of clopidogrel and thrombolysis with tPA in acute IS patients. Halfon [61] and Klaus [62] have also recently patented pharmaceutical compositions useful in the treatment of pathologies induced by platelet aggregation and related disorders. Clopidogrel formulations are also been patented for stroke prevention [63] and treating vascular diseases [64]. Combinational therapy for the treatment of patients with neurological disorders and cerebral infarction has also been patented recently [65].

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