Benefit Of Clopidogrel Research Articles

Abstract 6241: Proton Pump Inhibitors May Attenuate the Benefits of Clopidogrel among ACS Patients: Empirical Evidence from 3,311 ACS Patients

Background: A prior report showed omeprazole decreases platelet inhibitory effects of clopidogrel (clopid). However, the clinical impact of these findings is unknown. We studied outcomes of patients taking clopid alone versus clopid and proton-pump inhibitor (PPI) after acute coronary syndrome (ACS) in a national VA registry. Methods: This was a retrospective cohort study of 3,311 ACS patients discharged from 127 VA hospitals on either clopid alone or clopid+PPI based on pharmacy dispensing data. The main outcome was AMI/death. Cox proportional hazards regression models assessed the association between drug use as a time varying covariate and outcomes. Mean follow-up was >1 year. During follow-up, patients could have gaps in their treatment and thus could be categorized as “no drugs” or “PPI-only” for short durations. Results: At discharge, 34% were prescribed clopid alone and 66% clopid+PPI. Baseline characteristics were quite similar (e.g. mean age 68.1 yrs for clopid vs 68.3 yrs for clopid+PPI) except clopid+PPI patients had less diabetes and more renal insufficiency. In multivariable analyses, clopid+PPI was associated with a higher risk of AMI/death risk compared to clopid alone (HR 1.28; 95% CI 1.07–1.53) (Figure ). Findings were consistent excluding patients with bleeding event during follow-up and using a nested case-control study design. Conclusion: Concomitant use of clopidogrel and PPI after ACS is associated with higher risk of adverse outcomes than clopidogrel use without PPI. These findings, coupled with the prior mechanistic study, suggest that concomitant PPI use attenuates the benefits of clopidogrel after ACS.

Antithrombotic Therapies in Primary Angioplasty

Despite the improvement in outcome observed with primary angioplasty compared with thrombolysis, there is still room for improvement. Indeed, despite restoration of optimal epicardial flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a relatively large proportion. The aim of this article is to provide an up-to-date review of adjunctive antithrombotic therapy for primary angioplasty for ST-segment elevation myocardial infarction (STEMI).The HORIZONS trial has shown a significant reduction in mortality and major bleeding complications in patients treated with bivalirudin compared with those treated with glycoprotein (GP) IIb-IIIa inhibitors. Thus, bivalirudin may be considered as an alternative strategy to heparin plus GPIIb-IIIa inhibitors in primary angioplasty, especially in patients at high risk for bleeding complications. However, despite the negative results of the FINESSE trial, a large amount of evidence has been observed in favour of early administration of GPIIb-IIIa inhibitors, which should still be considered a reasonable strategy.Non-responsiveness to aspirin and clopidogrel is relatively common. However, future trials are needed to evaluate whether the routine assessment for non-responsiveness and a consequent change in therapy (to higher dosages of clopidogrel or a switch to another adenosine diphosphate [ADP]-receptor antagonist) may improve clinical outcome. Even though not yet demonstrated, it is conceivable that the greatest benefits of clopidogrel may come from early administration, and that this might be considered as part of a pharmacological facilitation strategy, together with early administration of GPIIb-IIIa inhibitors. As a result of better and faster inhibition of platelet aggregation, further benefits might be expected from the early administration of one of the new oral platelet ADP-receptor antagonists.As a consequence of the very low mortality currently achieved by primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, should be considered when exploring the potential benefits of adjunctive antithrombotic therapies in future randomized trials among patients undergoing mechanical revascularization for STEMI.

Is there a role for combinations of antiplatelet agents in stroke prevention?

Antiplatelet medications are the agents of choice for secondary prevention of noncardioembolic ischemic strokes. Multiple clinical trials have proven their reliable albeit modest clinical benefits and relatively good safety profile. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are aspirin, clopidogrel, and the combination of aspirin and extended-release dipyridamole. Because of the multiple pharmacologic mechanisms available for platelet inhibition, combination antiplatelet agents have the potential for synergistic effects. However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases. Combination antiplatelet therapy with clopidogrel and aspirin has established clinical benefits, particularly in coronary disease and in patients who have undergone coronary stenting. Although it is tempting to extrapolate the benefits of clopidogrel and aspirin to the setting of secondary stroke prevention, recent clinical trials have failed to document significant clinical benefits in cerebrovascular patients. This failure has occurred because of a lack of significant efficacy for prevention of vascular events and a substantial increase in bleeding risk. Therefore, the clopidogrel and aspirin combination is not recommended for recurrent stroke prevention. In general, when clopidogrel is used for cerebrovascular patients, the addition of aspirin should be avoided unless there is a specific cardiac indication such as recent acute coronary syndrome or a coronary stent. The combination of aspirin and extended-release dipyridamole is supported by Class I data from two large studies demonstrating superiority over aspirin alone for recurrent stroke prevention. Although dual antiplatelet therapy with clopidogrel and aspirin has never been directly compared with the combination of aspirin and extended-release dipyridamole, clinical trial results favor the latter for secondary stroke prevention. Currently, there are no data for primary stroke prevention with dual antiplatelet agents regarding aspirin and extended-release dipyridamole. Limited data from the recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial indicate that the combination of clopidogrel and aspirin may be harmful, compared with aspirin alone.

Abstract 3539: Low Inflammatory Activity Evidenced By hsCRP Predicts A Benefit From Clopidogrel Treatment In Patients With High Risk For Cardiovascular Events. - A Substudy From The CHARISMA Trial

Aims We investigated the impact of clopidogrel treatment on the inflammatory activity as evidenced by a change of hsCRP levels in a broad population of high risk for atherothrombotic events. Further, the prediction of hsCRP levels for a treatment benefit of clopidogrel was explored. Methods This study included 8021 patients with overt atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomized either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28 months). The predefined primary endpoints were myocardial infarction, stroke and death from cardiovascular causes. Results There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP (4.0%, 6.1%, 7.4% and 8.7% in the highest quartile). In both treatment groups the changes of hsCRP levels over time were identical. In patients with low hsCRP levels (<3 mg/l) clopidogrel treatment was associated with a lower event rate as compared to placebo (4.0% vs. 6.0%, Log-rank p=0.005). In contrast no treatment effect could be observed in patients with high hsCRP levels (8.1% vs. 8.0%, ns). Conclusions Surpisingly, the reduction of cardiovascular events by antiplatelet treatment with clopidogrel occurred in patients with low levels of hs-CRP

Clopidogrel and risk for acute coronary events

Clopidogrel bisulfate is a potent adenosine diphosphate receptor blocker that irreversibly inhibits platelet aggregation by preventing the activation of the glycoprotein IIb/IIIa pathway. This helps to prevent thrombus formation and resultant ischemic or thrombotic complications. Clopidogrel was proven to be superior to aspirin in the treatment of atherothrombotic diseases. Clopidogrel plus aspirin, known as dual antiplatelet therapy, is highly effective in patients with acute coronary syndromes or undergoing percutaneous coronary intervention. There is no apparent benefit of dual antiplatelet therapy in primary prevention. In this article, we review the benefits of clopidogrel as an antiplatelet agent and its role in the management of acute coronary syndromes and following percutaneous coronary intervention.

Prise en charge du syndrome coronaire aigu à la phase aiguë

The clinical benefit of the combination of aspirin plus clopidogrel over aspirin alone to prevent recurrent events after acute coronary syndrome is obviously a key step of the past few years in the management of coronary artery disease. The extended benefit of this combination among patients undergoing stent implantation is another key message for clinician. The consistent benefit of the dual oral antiplatelet therapy in all clinical trials is reassuring for clinicians. However, all well designed clinical trials generate new hypothesis and unsolved clinical issues. The loading dose of clopidogrel and whether we should monitor the biological response to clopidogrel in order to improve its clinical benefit are the next clinical challenges for clinicians dealing with acute coronary syndromes. Providing adequate answers to these relevant clinical issues should improve the clinical benefit of clopidogrel. All these important points are discussed in the following manuscript.

Benefits of clopidogrel in patients undergoing coronary stenting significantly depends on loading dose: evidence from a meta-regression

Benefits of clopidogrel in patients undergoing coronary stenting significantly depends on loading dose: evidence from a meta-regression

Benefits of clopidogrel in patients undergoing coronary stenting significantly depend on loading dose: Evidence from a meta-regression

Clopidogrel is an established alternative to ticlopidine in addition to aspirin after coronary stenting because of its safety, but its optimal initial dosing is unclear. We performed a systematic review and meta-regression of randomized clinical trials comparing clopidogrel versus ticlopidine, focusing on clopidogrel front-loading. PubMed was searched for pertinent studies (updated August 2006). Random-effect odds ratios (ORs) with 95% CIs were computed for death or nonfatal myocardial infarction, and weighted least squares random-effect meta-regression was performed to explore the impact of loading versus nonloading clopidogrel scheme. We retrieved 7 trials (3382 patients, average follow-up of 7 months). In 5 studies, both clopidogrel and ticlopidine were started with a loading dose, in 1 trial clopidogrel was administered without loading, and in 1 trial clopidogrel could be administered with or without loading. Overall analysis (P for heterogeneity = .02) showed similar results for clopidogrel and ticlopidine (OR 0.90, 95% CI 0.44-1.84, P = .77). In studies administering clopidogrel with loading, this treatment was, however, significantly better than ticlopidine (OR 0.60, 95% CI 0.36-0.99, P = .05). This significant interaction between clopidogrel loading and its superiority in comparison with ticlopidine was also formally confirmed by meta-regression (beta = -0.64, P = .012). This work supports the superiority of a clopidogrel regimen including an initial loading dose in comparison with ticlopidine in patients undergoing coronary stenting.

Myocardial infarction: contemporary management strategies

Myocardial infarction (MI) is a common clinical diagnosis, associated with significant morbidity and mortality, not only in the short term, but also years following the index event. A more complete understanding of the pathophysiology of MI has ushered the era of multipronged treatment approach, with a combination of goal-directed revascularization, a broad adjunctive pharmacological therapy and aggressive secondary prevention measures. The goals of this article are to review the basic pathophysiological processes, which lead up to a clinical diagnosis of MI, to highlight the essential elements of clinical presentation and to summarize the evidence for comprehensive therapy. Emphasis has been placed on the choice of primary reperfusion therapy for ST-elevation MI, on risk-stratification of patients with non-ST elevation MI, and on rationale behind the selection of anti-ischaemic and antithrombotic therapy. Finally, evidence-based approach to secondary prevention is outlined.

Identification of and Management Approaches for the High-Risk Patient

Atherothrombosis is a systemic disease that often involves the coronary, cerebrovascular, and peripheral arterial circulations. The presence of multiple risk factors, even in asymptomatic patients, greatly increases the risk of future cardiovascular disease. Antiplatelet therapy potentially has a valuable role across the full spectrum of atherothrombotic disorders. The role of aspirin is well established, and the benefits of clopidogrel have been demonstrated in clinical trials. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial is currently under way to determine whether the combination of clopidogrel plus aspirin is superior to aspirin plus placebo in >15,000 patients with stable atherothrombosis. The results of the CHARISMA trial are expected to provide further information on the optimal management of patients with stable atherothrombosis with respect to both antiplatelet therapy and overall management.

Clopidogrel in ST-elevation myocardial infarction

Platelet adhesion, activation, and aggregation are central to the pathophysiology of the acute coronary syndromes (ACS). Clopidogrel, an oral thienopyridine derivative, is a platelet adenosine diphosphate (ADP)-receptor antagonist capable of inhibiting platelet activation. The benefits of clopidogrel in patients with stable coronary artery disease undergoing elective percutaneous coronary interventions (PCI) and in patients presenting with non-ST-elevation ACS are well established. This article will review the results of recent clinical trials in which the utility of clopidogrel in patients with ST-elevation myocardial infarction was evaluated.

Clopidogrel in non-ST-segment elevation acute coronary syndromes

Platelets play a central role in the pathophysiology of arterial thrombosis in patients with acute coronary syndrome (ACS). Aspirin is superior to placebo in preventing mortality and ischemic events in patients with ACS. Clopidogrel, when added to aspirin and given daily for up to 1 year, reduces cardiovascular death, myocardial infarction and stroke by 20% in patients presenting with ACS. The benefits of long term therapy with clopidogrel are present in those patients treated medically, with percutaneous coronary intervention and with CABG surgery. There is a higher risk of bleeding with clopidogrel, but this risk may be lowered with use of lower doses of aspirin (<100 mg daily). The benefits of clopidogrel in those patients undergoing an early invasive strategy may be enhanced by increasing the loading dose to 600 mg, followed by 150 mg daily for one week, then 75 mg daily. This hypothesis is being tested in the CURRENT OASIS 7 trial involving 14000 patients with ACS undergoing an early invasive strategy with intent for PCI within 24 hours, who will be randomized to this higher dose regimen of clopidogrel versus the standard dose regimen of 300 mg loading dose followed by 75 mg daily.

Comment: Mortality Benefit of No-Load Clopidogrel in COMMIT: Not a Surprise

Myocardial Infarction Trial (COMMIT) revealed a highly significant mortality benefit of 75 mg clopidogrel when added to a fibrinolytic agent and a moderate dose of aspirin in patients who present with acute myocardial infarction (1). To be precise, 119 lives were saved in the clopidogrel arm. In a comprehensive accompanying editorial, Marc Sabatine referred to the early, first-day benefit of clopidogrel as “fascinating and unexpected” (2). In fact, these findings may be predicted and at least partly explained if we consider the following facts: First, thrombolytic agents themselves profoundly inhibit platelets in both in vitro and ex vivo settings, as shown in the platelet substudy of the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSET-2) controlled trial (3). Second, rebound platelet activation occurs not immediately, but at 3 to 6 hours after thrombolysis, matching closely with the so-called “reperfusion injury” that was observed in another platelet substudy from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial (4). Finally, clopidogrel is a pro-drug, and it takes 3 to 4 hours to metabolize and exhibit full antiplatelet potency (5). A few practical considerations seem to be justified. Combining fibrinolytic agents with aggressive fastacting antiplatelet agents such as GPIIb/IIIa inhibitors is probably not the best strategy for treatment of myocardial infarction, which is what has been proven by negative results of the GUSTO-V and ASSENT-4 trials. In contrast, delayed moderate platelet inhibition, when platelets are indeed blocked when they are excessively active, namely later at 3 to 6 hours after thrombolysis is a better alternative and ultimately resulted in the mortality benefit observed in COMMIT. Another clinical lesson which we learned from COMMIT is that the “the more—the better” postulate may no longer be valid with regard to antiplatelet regimens and, indirectly, may stop the unjustified escalations of clopidogrel loading doses exceeding 600 mg for coronary stenting. Last, but not least, the implication is that the mortality reduction observed in COMMIT makes it even more difficult for the experimental platelet P2Y12 receptor inhibitors to replace clopidogrel as a standard addition to aspirin in the treatment and prevention of vascular disease. Indeed, the COMMIT results break the tiny hopes of the competition to overcome “clopidogrel resistance” or/and “clopidogrel-atorvastatin interactions” with the novel agents because no-load clopidogrel already saves patients with acute myocardial infarction.

Clopidogrel use in coronary artery disease

Platelet adhesion, activation and aggregation are central to the pathophysiology of the acute coronary syndromes. Clopidogrel, an oral thienopyridine derivative, is a platelet adenosine diphosphate receptor antagonist capable of inhibiting platelet activation. During the last decade, the utility of clopidogrel has been evaluated in several common clinical scenarios in a large number of patients. The benefits of clopidogrel in patients with stable coronary artery disease undergoing elective percutaneous coronary interventions and in patients presenting with acute coronary syndromes are now well established. This review outlines the pharmacology of clopidogrel, highlights the results of clopidogrel trials in the setting of acute coronary syndromes, and presents areas of uncertainty and potential future work.

Is clopidogrel the antiplatelet drug of choice for high-risk patients with stroke/TIA?: Yes.

Is clopidogrel the antiplatelet drug of choice for high-risk patients with stroke/TIA?: Yes.

Clopidogrel use after Spinal Cord Stimulator Implantation

or to neuraxial procedures (4). These recommendations are for safety and are not based on clinical trials. The available data are very limited. What about patients who have a successfully functioning SCS and then develop coronary artery stenosis requiring a stent or any of a number of other vascular diseases? After stent placement most cardiology literature states clopidogrel should be used for twelve months (5). Is this safe for patients in whom there is an SCS? At our clinic we have a 61-year-old male with spinal stenosis and radicular signs who received excellent relief from his SCS placed three years ago. He was lost to follow up for sixteen months and returned to our clinic when his internal pulse generator (IPG) had failed due to expired battery life. During that time he had a coronary artery stent placed for progressive angina and was placed on clopidogrel 75 mg per day for approximately eleven months. The battery was changed without complication. However, we were concerned that if SCS lead migration, fracture or damage occurred while he was on a thienopyridine, there may be an increased risk of epidural hematoma. After discussion with the patient and his cardiologist, it was decided that the clopidogrel could safely be discontinued because he was two weeks away from completing his post-stent antiplatelet therapy course. The clopidogrel was discontinued but the question remains. Given the paucity of data and the very low incidence of spinal hematoma with neuraxial procedures in general, would it be prudent to establish an anonymous database of complications regarding the use of clopidogrel in patients with SCS? The risk of hematoma may be negligible, but does exist. Pain physicians should consider the risks and benefits of clopidogrel in all patients with coexisting atherosclerotic disease who undergo SCS placement.

Does Clopidogrel Increase the Degree of Platelet Inhibition When a Platelet Glycoprotein IIb/IIIa Inhibitor Has Been Given? Insights From an Optical Platelet Aggregometry Study

While the CURE trial demonstrated the benefits of clopidogrel in acute coronary syndromes, patients receiving glycoprotein IIb/IIIa antagonists were excluded. Given the frequent coadministration of these two medications, we sought to examine their interaction and their combined effect on platelet inhibition. Ten patients admitted to the hospital with stable or unstable angina underwent phlebotomy prior to, three hours and six hours after administration of a standard oral loading dose of clopidogrel. The samples were then treated in vitro with incremental concentrations of tirofiban (0, 10, 20, 40, 60, and 80 ng/mL), and optical platelet aggregometry was performed utilizing ADP and TRAP as agonists. We analyzed the combined effects of these agents using a mixed effects model with time and tirofiban concentration as fixed effects, and subject and timing of phlebotomy as random effects. There was no evidence of additional inhibition of platelet aggregation due to clopidogrel regardless of the concentration of tirofiban or the study agonist (ADP 20 muM or iso-TRAP). Specifically, there was no difference in the tirofiban dose-response curves with either platelet agonist for any of the three time points (before, and three and six hours after, clopidogrel administration). There is no evidence that the combination of clopidogrel and tirofiban achieves greater inhibition of platelet aggregation than tirofiban alone.

The Value of Clopidogrel versus Aspirin in Reducing Atherothrombotic Events

Atherothrombotic disease is a growing health problem, and is increasingly more costly to manage. Clopidogrel is an advanced, specific adenosine diphosphate receptor antagonist, which has been shown to be a highly potent antiplatelet agent. Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study have demonstrated the significantly superior clinical benefit of clopidogrel over aspirin for secondary prevention of atherothrombotic disease, with a relative risk reduction in myocardial infarction, stroke or vascular death of 8.7% (95% confidence interval 0.3, 16.5; P = 0.043). Moreover, clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolaemia. On the basis of commonly accepted threshold criteria (Euros 20000 per life-year gained; LYG), clopidogrel in comparison with aspirin is cost-effective for the secondary prevention of atherothrombotic disease (cost per LYG ranging from Euros 19462 to Euros 3256). Economic analyses have demonstrated consistent cost-effectiveness results with clopidogrel in different countries. Moreover, in high-risk patient subgroups the cost-effectiveness of clopidogrel in comparison with aspirin was evenbetter (cost per LYG ranging from Euros 5900 to Euros 6310). Compared with other treatment strategies used for the prevention of ischaemic or atherothrombotic events, the cost-effectiveness of clopidogrel in comparison with aspirin based on CAPRIE is favourable, with most analyses in the intermediate range of cost-effectiveness. The available data thus support the use of clopidogrel as a clinically efficient and cost-effective option for secondary prevention of atherothrombotic disease, particularly in high-risk patients.

Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke (MATCH): Study Design and Baseline Data

Background: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. Methods: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. Results: Enrolment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. Conclusion: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.

Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?

With respect to antiplatelet therapy, randomized trials and their meta-analyses 1 indicate benefits of clopidogrel either as an alternative 2 or an adjunct 3 to aspirin in some high-risk patients. Regarding the metabolic pathways of clopidogrel, the active thiol metabolite binds rapidly and irreversibly to platelet adenosine diphosphate (ADP) receptors, thus inhibiting platelet aggregation. 4 Clopidogrel, a thienopyridine, is a platelet ADP-receptor blocker that is known to be beneficial during and after coronary stenting.2–5 Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. Results of in vitro studies in human liver microsomes and recombinant cytochromes P450 have shown that several cytochromes are involved in the oxidative metabolism of clopidogrel.6 In randomized trials of secondary and primary prevention of cardiovascular disease and their meta-analyses, 7 statins reduce risks of myocardial infarction, stroke, and cardiovascular death. Recently, in a randomized trial in patients undergoing percutaneous coronary intervention, 8 statins have been shown to reduce the incidence of major adverse coronary events, especially among the subgroups of diabetics and those with multivessel disease. In these high-risk patients, the National Cholesterol Education Program III guidelines recommend statin therapy to achieve low-density lipoprotein (LDL) goals of less than 100 mg/dL. 9 Of the 5 marketed statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), four (atorvastatin, fluvastatin, lovastatin, and simvastatin) are also metabolized by the cytochrome P450 pathway. 10 Thus, in patients receiving coronary stents, both clopidogrel and statin therapy are likely to contribute to beneficial effects on subsequent cardiovascular disease. A recent report has raised the possibility that the ability of clopidogrel to affect platelets is inhibited by atorvastatin. 11 We have a number of concerns about the validity of these findings and therefore believe the totality of evidence to be far from complete and not consistent. In that study, the sample size was small (n44), patient selection was poorly defined, no control for the presence of medications affecting CYP 450 3A4 pathway was performed before initiation, and the data were retrospective and non-randomized. Using a single method to assess platelet function was also unconventional. Furthermore, data from the larger retrospective Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial compared platelet inhibition with clopidogrel in 100 patients undergoing coronary intervention who also received statins. 12 In PRONTO, there was no evidence of any specific deleterious interaction between clopidogrel and atorvastatin in terms of platelet activity. The analysis showed that only 4 of 25 patients in the atorvastatin treated group did not exhibit sustained platelet inhibition on days 2 and 5 after treatment with clopidogrel and aspirin. A similar pattern was observed in 2 of 9 patients treated with fluvastatin and 1 of 6 patients treated with pravastatin, neither of which is metabolized by the cytochrome P450 3A4 pathway. Finally, of perhaps even greater relevance to this hypothesis, a similar pattern was observed in 12 of 75 patients who did not receive any statin. In total, about 20% of patients did not achieve profound platelet inhibition with clopidogrel, but this seemed unrelated to treatment with any statins. It is tempting to speculate that in certain patients, the burden of platelet activation is so excessive that usual treatment regimens are not sufficient to achieve even moderate platelet inhibition. Retrospective data from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and Clopidogrel Unstable angina to prevent Recurrent Events (CURE) trials among subgroups of patients concurrently administered clopidogrel and statins indicated no clinically significant adverse interactions. Further data, especially from prospective studies, are necessary to test the hypothesis of potential interactions between clopidogrel and statins. One such study, INTERACTIONs of atorvastatin and clopidogrel therapy (INTERACT), has been designed to address this issue by serial measurements of various platelet characteristics by conventional as well as whole blood aggregometry, by point of care tests with 2 rapid analyzers, and by assessment of 14 receptors on the platelet surface by whole blood flow cytometry.