Clopidogrel Versus Aspirin In Patients At Risk Of Ischemic Events Research Articles

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

Impact of Smoking on Long-Term Outcomes in Patients With Atherosclerotic Vascular Disease Treated With Aspirin or Clopidogrel: Insights From the CAPRIE Trial (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events)

The goal of this study was to investigate the differential efficacy of clopidogrel or aspirin monotherapy according to smoking status in patients with atherosclerotic vascular disease. Smoking enhances clopidogrel-induced platelet inhibition, which may explain the higher relative benefit among smokers observed in trials evaluating dual antiplatelet therapy. Whether smoking has an impact on clinical outcomes in patients requiring a single antiplatelet agent remains unknown. This was a post-hoc analysis of the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial that compared clopidogrel and aspirin monotherapy in patients (N= 19,184) with atherosclerotic vascular disease. Current smokers (n= 5,688) had an increased risk of ischemic events compared with never smokers (n= 4,135; hazard ratio [HR]: 1.24 [95% confidence interval (CI): 1.08 to 1.42]) and ex-smokers (n= 9,381; HR: 1.32 [95% CI: 1.18 to 1.47]) (p< 0.001). Clopidogrel was associated with a reduction in ischemic events among current smokers (8.3% vs. 10.8%; HR: 0.76 [95% CI: 0.64 to 0.90]), whereas no benefit over aspirin was seen in the combined group of ex-smokers/never-smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI: 0.89 to 1.10]; p= 0.01 for interaction). Among current smokers, clopidogrel also reduced myocardial infarction, vascular death, and death from any cause compared with aspirin. No interaction between smoking status and study treatment was observed for bleeding events. In a post-hoc analysis of the CAPRIE population, current smokers appeared to have enhanced benefit with clopidogrel therapy for secondary prevention compared with aspirin. These results should be considered hypothesis generating for future prospective studies assessing the impact of specific platelet-inhibiting strategies according to smoking status.

Impact of Proton Pump Inhibitor Therapy on the Efficacy of Clopidogrel in the CAPRIE and CREDO Trials

BackgroundProton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.Methods and ResultsThe impact of PPI use on the 1‐year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death, MI, or urgent target vessel revascularization) and 1‐year (all‐cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non‐PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non‐PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).ConclusionsIn CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non‐PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.

High on-treatment platelet reactivity (HPR): What does it mean, and does it matter?

2013; 109: 347-355. In this issue of Thrombosis and Haemostasis, Saucedo et al. (1) demonstrate that the prevalence of high on-treatment platelet reactivity was decreased after changing clopidogrel to prasugrel. It is perhaps appealing that the patients with adverse “high on-treatment platelet reactivity (HPR)” with clopidogrel was reduced when switched to prasugrel. From a scientific point of view, the meaning of “HPR” is still unclear. This uncertainty is derived from an arguably confusing clinical development history of the thienopyridine-type antiplatelet agents (ticlopidine, clopidogrel, and prasugrel). Indeed, the use of these agents was greatly expanded based on the clinical experience, rather than on their mechanistic understanding. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)was published in 1996 (2). However, the precise mechanism of antiplatelet action exerted by clopidogrel was clarified only after cloning the target ADP receptor of P2Y12 in 2001 (3). Moreover, the extent of P2Y12 ADP receptor blockade by active metabolite of clopidogrel in an individual patient, which should be a real bio-marker for this drug, has been measured in a very limited number of studies only (4). Nonetheless, some uncertainty remains about how much percentage of P2Y12 receptor should be blocked to achieve appropriate antithrombotic effects in individual patients. Obviously, the goal is not to achieve 100% inhibition of P2Y12 because P2Y12 deficiency manifests as a bleeding disorder (5). Perhaps some focus should be on the drugs per se. Both clopidogrel and prasugrel are pro-drugs. The chemical structure of active metabolite(s) of clopidogrel was detected in 2002 (6). Since the active metabolite(s) of clopidogrel are very labile in character with a reactive thiol function, it is most likely that the majority of produced active metabolite(s) easily binds to P2Y12 receptors on platelets circulating in liver, where it is produced (▶ Figure 1A) Thus, plasma concentrations of active metabolite(s) per se would not necessarily be good pharmaco-dynamic marker(s) for the antiplatelet effects of clopidogrel (8). Thus, the extent of P2Y12 receptor blockage, once achieved in the liver circulation, would be the same in platelet circulating in peripheral blood.

Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis

Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Peripheral arterial disease is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. The primary objective in the treatment of all patients with a history of occlusive vascular events and peripheral arterial disease is to prevent the occurrence of new occlusive vascular events. To assess the clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole (MRD) alone or with aspirin (ASA) compared with ASA (and each other where appropriate) in the prevention of occlusive vascular events in patients with a history of MI, ischaemic stroke/TIA or established peripheral arterial disease. To consider the clinical effectiveness and cost-effectiveness of clopidogrel in patients with multivascular disease. This review is an update of the evidence base for the National Institute for Health and Clinical Excellence (NICE) guidance Technology Appraisal No. 90 (TA90) entitled Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (2005). Four electronic databases (EMBASE, MEDLINE, Web of Science and The Cochrane Library) were searched for randomised controlled trials (RCTs) and economic evaluations. Submissions to NICE by the manufacturers of the interventions were also considered. A systematic review of clinical effectiveness and cost-effectiveness was conducted. To manage heterogeneity between trials, indirect analysis (using a mixed-treatment methodology) was performed on selected clinical outcomes. A new economic model was developed to assess incremental costs per life-year gained [quality-adjusted life-years (QALYs)]. For evidence of clinical effectiveness, four RCTs were identified: CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events), ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial), PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) and ESPS-2 (Second European Stroke Prevention Study). In CAPRIE (patients with MI, ischaemic stroke or peripheral arterial disease), statistically significant outcomes in favour of clopidogrel were noted for the primary outcome (first occurrence of ischaemic stroke, MI or vascular death) compared with ASA [relative risk reduction 8.7%; 95% confidence interval (CI) 0.3% to 16.5%; p = 0.043]. In ESPRIT (patients with ischaemic stroke/TIA) for the primary outcome (first occurrence of death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication), the risk of event occurrence was statistically significantly lower in the MRD + ASA arm than in the ASA arm [hazard ratio (HR) 0.80; 95% CI 0.66 to 0.98], with no statistically significant difference in bleeding events between the two arms. In PRoFESS (patients with ischaemic stroke) the rate of recurrent stroke of any type (primary outcome) was similar in the MRD + ASA and clopidogrel groups, and the null hypothesis (that MRD + ASA was inferior to clopidogrel) could not be rejected. In ESPS-2 (patients with ischaemic stroke/TIA), on the primary outcome of stroke, statistically significant differences in favour of MRD + ASA were observed compared with ASA and MRD alone (relative risk 0.76; 95% CI 0.63 to 0.93). The outcomes addressed in the mixed-treatment comparisons (limited by the available data) for the ischaemic stroke/TIA population confirmed the results of the direct comparisons. The 11 economic evaluations included in the review of cost-effectiveness indicated that for patients with previous peripheral arterial disease, ischaemic stroke or MI, clopidogrel is cost-effective compared with ASA, and for patients with previous ischaemic stroke/TIA, treatment with MRD + ASA is cost-effective compared with any other treatment in patients in the secondary prevention of occlusive vascular events. The relevance of the review was limited as the economic evaluations were not based on the most current clinical data. Cost-effectiveness results generated from the Assessment Group's de novo economic model suggested that the most cost-effective approach for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA then ASA. For patients with MI, the most cost-effective approach is ASA followed by clopidogrel. For patients with established peripheral arterial disease, the most cost-effective approach is clopidogrel followed by ASA. For patients with multivascular disease, clopidogrel followed by ASA is the most cost-effective approach. Incremental cost-effectiveness ratios (ICERs) were also calculated for patients who are intolerant to ASA. Assuming that the branded price for clopidogrel is used and TA90 guidance is not applied, all of the ICERs range between £2189 and £13,558 per QALY gained. Probabilistic sensitivity analyses were fully consistent with these findings. The evidence suggests that the most cost-effective treatment for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA followed by ASA; for patients with MI, ASA followed by clopidogrel; and for patients with established peripheral arterial disease or multivascular disease, clopidogrel followed by ASA. The National Institute for Health Research Health Technology Assessment programme.

The P2Y(12) receptor as a target of antithrombotic drugs.

The P2Y(12) receptor as a target of antithrombotic drugs.

The Basis of Platelets

Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (AtheroThrombosIS). The currently available antiplatelet drugs used to prevent vascular events in patients with cardiovascular disease, including peripheral arterial disease (PAD), include aspirin and thienopyridines such as clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment. Aspirin acts by inhibiting thromboxane A2 (TXA2) formation through the inhibition (acetylation) of cyclo-oxygenase. On the other hand, thienopyridines suppress the platelet aggregation adenosine diphosphate (ADP) pathway by inhibiting the platelet P2Y12 subtype of the ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with aspirin (mixed with other antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance. Results of the large scale CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated clopidogrel in patients with cerebral infarction, myocardial infarction or PAD have found clopidogrel to be significantly more effective than aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of clopidogrel in diabetic patients with PAD, showing a significant reduction of events in clopidogrel-treated, compared with aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of aspirin resistance in aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet therapy with low-dose aspirin has been reported to prevent vascular events in high-risk patients with cardiovascular disease, recent studies in patients with PAD or diabetes mellitus have failed to support the efficacy of aspirin in preventing vascular events in these patient populations. In contrast, clopidogrel appears to be a useful antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.

Combination Antithrombotic Therapies

Atherothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke.1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications.2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis. Platelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I2, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin.3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A2 (TxA2), ADP, and thrombin. TxA2 is produced from arachidonic acid, which originates from membrane phospholipids and …

Frequency of Allergic or Hematologic Adverse Reactions to Ticlopidine Among Patients With Allergic or Hematologic Adverse Reactions to Clopidogrel

Frequency of Allergic or Hematologic Adverse Reactions to Ticlopidine Among Patients With Allergic or Hematologic Adverse Reactions to Clopidogrel

Contemporary issues on clopidogrel therapy: a critical appraisal

receptorantagonist. Following the results of the pivotal Clopidogrelversus Aspirin in Patients at Risk of Ischaemic Events(CAPRIE) trial [1], it received approval from the Food andDrug Administration in 1997 and Conformite´ Europe´ennein 1998. Subsequent studies extend on the indications forits use in the setting of acute coronary syndromes (ACS)[2], ST-segment elevation myocardial infarction [3, 4] andpercutaneous coronary intervention (PCI) [5, 6]. Despitethe robust clinical findings and indications for clopidogrelusage derived from these large-scale clinical trials per-formed over the course of the past decade, which areclearly reflected in clinical practice guidelines [7–9], thereare a large number of uncertainties regarding clopidogrelusage in daily real world practice. This is reflected by theplethora of publications dealing with clopidogrel over thecourse of the past several years. In a PubMed research, atotal of 660 citations were identified from the years 2000–2005, which is almost sevenfold higher than that of theprevious half-decade (1995–2000; n = 96). Strikingly,from years 2006 to 2008, the number of clopidogrel relatedcitations is 827 (Fig. 1). It is quite certain that these figureswill continue to increase over the course of the upcomingyears with the introduction of novel antiplatelet agents thatall have as their comparison agent clopidogrel, as this stillrepresents the ADP P2Y

The Essen Stroke Risk Score Predicts Recurrent Cardiovascular Events

Background and Purpose— Predictive scores are important tools for stratifying patients based on the risk of future (cerebro)vascular events and for selecting potential prevention therapy. Recently, the Essen Stroke Risk Score (ESRS) was derived from cerebrovascular patients in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. We aimed to validate the ESRS in a large cohort of outpatients with previous transient ischemic attack or stroke from the REduction of Atherothrombosis for Continued Health (REACH) Registry. Methods— We included 15605 outpatients with a qualifying stroke or transient ischemic attack and with clinical follow-up at 1 year. Patients with atrial fibrillation were excluded. We stratified 1-year cumulative rates for fatal and nonfatal stroke as well as combined major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) by the individually calculated stroke risk profile according to the ESRS and compared it with the 1-year event rates in the CAPRIE data subset of 6431 cerebrovascular patients. Results— The 1-year rate for recurrent stroke (or combined cardiovascular events) in the stable outpatient population of REACH increased steadily and significantly from 1.82 (2.41) in patients with ESRS 0 to 6.84 (11.48) for ESRS &gt;6. The overall as well as stratified risk of recurrent stroke and cardiovascular events was lower than for cerebrovascular patients in CAPRIE. Conclusions— In outpatients with previous stroke or transient ischemic attack, the ESRS accurately stratifies the risk of recurrent stroke or major vascular events. Patients with a high ESRS should be candidates for intensified secondary prevention strategies.

Drug evaluation of clopidogrel in patients with ischemic stroke

Clopidogrel is an effective antiplatelet medication used for the secondary prevention of ischemic events in patients with various cardiovascular, cerebrovascular and peripheral vascular disease conditions. The objective of this paper is to discuss the role of clopidogrel in ischemic stroke patients and to review the existing data from randomized trials supplemented by pilot and mechanistic studies that supports these indications for its use. An analysis of the mechanism of action and pharmacology of clopidogrel is provided. After Phase III trials, such as the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trials, the role of clopidogrel in secondary prevention is well defined. The role of clopidogrel in acute ischemic stroke and neurointerventional procedures is evolving based on new pilot trials. At present, there is insufficient data to recommend the use of clopidogrel in acute ischemic stroke. Clopidogrel may be a valuable alternative to aspirin. However, more studies are required to assess the role of clopidogrel in selected patient groups with respect to acute ischemic stroke.

Stroke and the statistics of the aspirin/clopidogrel secondary prevention trials

Four randomized trials have investigated the combination of clopidogrel plus aspirin for secondary prevention of vascular outcomes in 54,949 patients. Here we argue that attempts to translate the results of these trials into clinical practice have proven frustrating because of the following statistical considerations: differences in study populations and study design make comparisons difficult (comparisons of 'apples and oranges'), incomplete factorial designs prevent proper contrasts (examining 'bits and pieces' of a larger picture), results concern widely different vascular diseases ('puzzling subgroups'), and negative results are easily misinterpreted. Between 1996 and 2004 three major randomized trials assessed combinations of aspirin and clopidogrel, finding: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) in favor of clopidogrel alone versus aspirin alone, Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) in favor of clopidogrel plus aspirin versus aspirin alone, and Management of Atherothombosis with Clopidogrel in High-risk Patients (MATCH) in favor of clopidogrel plus aspirin versus clopidogrel alone. A recently completed fourth trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CHARISMA) was a 'negative study' comparing aspirin alone to aspirin plus clopidogrel. Even after four large randomized trials we still do not know the optimal treatment for secondary prevention of stroke. We suggest that subsequent trials should focus on a particular vascular disease and test hypotheses that relate to a specific mechanism.

Prevention of Venous Thromboembolism, Recurrent Stroke, and Other Vascular Events After Acute Ischemic Stroke: The Role of Low-Molecular-Weight Heparin and Antiplatelet Therapy

Patients with stroke or transient ischemic attacks (TIAs) are at increased risk of vascular events, such as recurrent stroke or venous thromboembolism (VTE), and thus the secondary prevention of such events is an important element of managing these patients. Current guidelines recommend that patients with acute stroke, restricted mobility, and no contraindications to anticoagulants receive thromboprophylactic therapy with low-dose unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or heparinoids to prevent VTE. This recommendation is based on clinical trial evidence that UFH is effective in reducing the incidence of deep vein thrombosis (DVT) after stroke. LMWHs have been shown to be at least as effective as UFH in preventing VTE, and offer advantages in terms of a more predictable anticoagulant effect, lower risk of bleeding, and ease of administration. However, adequately powered trials are needed to confirm their relative benefits and risks; the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study with enoxaparin, currently in progress, should provide valuable information in this context. Antiplatelet therapy has been shown to be effective in preventing recurrent vascular events, as evidenced by the results of studies such as the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. In contrast, evidence for the efficacy of LMWH in this situation is contradictory. Given the potential benefits of LMWH in preventing VTE in stroke patients, a potential rationale exists for combination therapy with antiplatelet agents and LMWHs. Clinical trials with such combinations are warranted.

Cardiac oxalosis: a rare cause of diastolic dysfunction

1. McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med 2002; 136:873–883. 2. Murabito JM, D’Agostino RB, Silbershatz H, Wilson WF. Intermittent claudication. A risk profile from The Framingham Heart Study. Circulation 1997;96:44–49. 3. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 4. Lamina C, Meisinger C, Heid IM, Lowel H, Ranter B, Koenig W, Kronenberg F, for the KORA Study Group. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J 2006;27:2580–2587. First published on September 4, 2006, doi:10.1093/eurheartj/ehl228. 5. Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, Haberl RL, Allenberg JR, Dasch B, Trampisch HJ. Association of low ankle brachial index with high mortality in primary care. Eur Heart J 2006;27:1743–1749. 6. Schroder F, Diehm N, Kareem S, Ames M, Pira A, Zwettler U, Lawall H, Diehm C. A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease. J Vasc Surg 2006;44:531–536.

Case report: An unusual complication of clopidogrel

Various clinical trials [ 1 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996; 348: 1329-1339 Abstract Full Text Full Text PDF PubMed Scopus (6061) Google Scholar , 2 Peters R.J. Mehta S.R. Fox K.A. et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003; 108: 1682-1687 Crossref PubMed Scopus (677) Google Scholar ] have confirmed the important role of clopidogrel in the pharmacological treatment of patients presenting with an acute coronary syndrome (ACS) as well as those undergoing percutaneous coronary intervention (PCI) with stent deployment. In ACS and with the use of intra coronary stents the current consensus favours combination anti-platelet treatment (clopidogrel together with aspirin) for 1 year [ [3] Bhatt D.L. Topol E.J. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J. 2004; 148: 263-268 Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar ].

Gastrointestinal Complications of Dual Antiplatelet Therapy

Case presentation: A 59-year-old man with a history of hypertension, dyslipidemia, and smoking was hospitalized with acute coronary syndrome requiring emergency percutaneous coronary intervention with 4 drug-eluting stents. His discharge medications included dual antiplatelet therapy with aspirin 325 mg/d and clopidogrel 75 mg/d. Three weeks after discharge, he returned to the Emergency Department with bloody stools and a hematocrit of 23% (previously 36%) and required 3 U of packed red blood cells. Endoscopy showed a bleeding duodenal ulcer with adherent clot (Figure). Endoscopic image of bleeding duodenal ulcer with clot on top. This image was taken in a patient with a history similar to that of our patient. Arrow points to the base of duodenal ulcer with active bleeding. Picture contributed by Sarathchandra Reddy, MD, and Edwin Chun Ouyang, MD, PhD, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Mass. We prescribe dual antiplatelet therapy with aspirin and clopidogrel to prevent and treat cardiovascular, cerebrovascular, and peripheral arterial disease. According to American Heart Association statistics, 700 000 patients had stroke, 13 million had coronary artery disease, and 8 to 12 million suffered from peripheral arterial disease in 2002. Each year, 1.2 million patients in the United States receive dual antiplatelet therapy with aspirin and clopidogrel after percutaneous coronary intervention with drug-eluting stents. The number of patients in the United States who receive dual antiplatelet therapy for various vascular conditions such as coronary artery disease, transient ischemic attack, thrombotic stroke, and peripheral vascular disease probably exceeds several million. The use of aspirin compared with placebo reduces the risk of myocardial infarction, stroke, or death from vascular causes by ≈25%.1 In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, administration of clopidogrel decreased the relative risk of vascular events by 8.7% compared with aspirin.2 The …

A Multi-Country Economic Evaluation of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease

Low-dose aspirin (acetylsalicylic acid) is standard care in patients with a history of cardiovascular disease (CVD). The use of low-dose aspirin in primary prevention is not yet fully established, although meta-analyses and US and European guidelines support its use in people at increased risk of CVD. The primary objective of this study was to assess the economic consequences of the use of low-dose aspirin in the primary prevention of CVD in four European countries (UK, Germany, Spain and Italy). Based on results (benefits and harms) reported in meta-analyses, a state-transition model was developed to predict the cost effectiveness of low-dose aspirin in the primary prevention of CVD. The model consists of five health states: no history of CVD, history of stroke, history of myocardial infarction (MI), history of stroke and MI, and death. A 10-year time horizon and 1-year cycles were used. Secondary prevention data were derived from the aspirin arm of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study. Direct costs from the public healthcare payer's perspective were used (euro, 2003 values). Effects were expressed in life-years (LY) and QALYs gained. Quality weights were obtained from published data.Country-specific discounting was applied on effects and costs (3.5% for the UK, 5% for Germany and 3% for Spain and Italy). Univariate sensitivity analysis and Monte Carlo simulation were performed to assess uncertainty in the results. For patients with an annual risk of coronary heart disease (CHD) of 1.5%, the model resulted in 10-year savings with low-dose aspirin of on average euro 201 (95% CI 81, 331), euro 281 (95% CI 141, 422), euro 797 (95% CI 301, 1331) and euro 427 (95% CI 122, 731) per patient in the UK, Germany, Spain and Italy, respectively. Average total cost was almost 3- to 4-fold higher in Spain and Italy than in the UK and Germany. Savings (non-significant) start in the first year of treatment in all countries. Sensitivity analyses on cost of complications, utility, discounting, stroke rate and gastrointestinal bleeding rate showed the robustness of the results. From an annual risk of CHD of 0.236% for the UK, 0.324% for Germany, 0.244% for Spain and 0.560% for Italy, low-dose aspirin was cost saving compared with placebo. Monte Carlo analysis showed aspirin dominance in about 97% of cases for the three studied annual risks of CHD (0.6%, 1.0% and 1.5%) in the UK, Germany and Spain. In Italy, aspirin dominance in > 95% of cases was seen at annual risks of 1% and 1.5%. Administering low-dose aspirin to patients with an annual risk of CHD of > or = 1% appears to be significantly cost saving from the healthcare payer's perspective in all countries analysed. Sensitivity analyses (CHD risk and bleedings) suggested the results were robust.

Clopidogrel: cardiologists’ Panacea Or neurologists’ headache?

Clopidogrel (Plavix) is a potent platelet inhibitor that has been demonstrated to be significantly more effective than aspirin for the prevention of atherothrombotic events in patients with established atherosclerotic disease in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study. Furthermore, the benefit of clopidogrel compared with placebo in patients with acute coronary syndromes, as well as those undergoing percutaneous coronary intervention receiving a standard therapy including aspirin, has been largely demonstrated by the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO), CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis In Myocardial Infarction (CLARITY-TIMI)28, and Clopidogrel and Metoprolol in Myocardial Infarction Trial/Secon Chinese Cardiac Study (COMMIT/CCS-2) trials. However, in the Management of Atherothrombosis with Clopidogrel in High-risk patients with recent transient ischemic attack or ischemic stroke (MATCH) trial, there was no clinical benefit of adding aspirin versus placebo to a standard therapy of clopidogrel in patients with cerebrovascular disease. The implications of these findings, as well as future perspectives from upcoming trials, shall be discussed herein.

Loading, Pretreatment, and Interindividual Variability Issues With Clopidogrel Dosing

Clopidogrel, a thienopyridine, decreases adenosine diphosphate (ADP)–induced platelet aggregation. Clopidogrel is an inactive prodrug that requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system to an active metabolite that exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y12.1 The 75-mg once-daily dose was approved by the US Food and Drug Administration (FDA) in November 1997 after the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial2 showed superior reduction of adverse cardiovascular events with clopidogrel versus aspirin. The 75-mg once-daily dose had been used in CAPRIE because it produced inhibition of platelet aggregation equivalent to that produced by ticlopidine 250 mg administered twice daily. FDA approval for the 300-mg loading dose in patients with acute coronary syndromes was granted in February 2002 after the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial3 demonstrated a reduction of adverse cardiovascular events with dual antiplatelet therapy versus aspirin. Clopidogrel is not approved by the FDA for adjunctive antiplatelet therapy in percutaneous coronary intervention (PCI), although it has become the standard of care. It is curious that investigations into the optimal loading and maintenance doses of clopidogrel have been pursued only recently. See p 2560 In this issue of Circulation , Hochholzer et al4 performed optical platelet aggregometry and flow cytometry before and after a 600-mg oral dose of clopidogrel in 1001 potential PCI candidates undergoing cardiac catheterization. The findings are consistent with previous observations from small studies with regard to the 600-mg clopidogrel loading dose: Maximal inhibition of ADP-induced platelet aggregation was achieved ≈2 hours after ingestion,5 interindividual variability of platelet response was considerable,6 and there was no significant effect of concomitant statin therapy on platelet inhibition.7,8 Although …