Platelet Inhibitory Effect Of Clopidogrel Research Articles

Right Ventricular Dysfunction in Myocardial Infarction: A New Risk Factor for Clopidogrel Resistance?

Aims: Mortality in acute coronary syndroms (ACS) complicated by right ventricular dysfunction (RVD) still remains high. The aim of this study was to determine the association between RVD in ACS and the platelet inhibitory effect of clopidogrel. Methods: In this single center observational study 50 patients with ACS were investigated, 38 with normal right ventricular function and 12 with RVD as determined by echocardiography and electrocardiography. The effect of clopidogrel was determined by the PRI/VASP-Index 24 hours after loading dose of 600 mg. PRI/VASP-Indices above 50% were claimed as clopidogrel non-responder. Results: PRI/VASP-Index was significant higher in the RVD-group compared to control (Median: 74.5% ± 12.3 vs. 26.5% ± 23.3, p<0.01). The percentage of patients with unsatisfactory effect was significantly higher in the RVD group compared to control (83.3% vs. 23.7%, p<0.01). There were no increased rates of adverse cardiac events in both groups. Conclusions: Patients with RVD complicating myocardial infarction show a significantly impaired response to clopidogrel. These patients suffer from congestive gastro- and enteropathy and liver dysfunction, in consequence resorption and metabolization of orally administered drugs including platelet-inhibitors like clopidogrel might be compromised.

Prasugrel, but not clopidogrel, is effective in platelet inhibition in patients treated by therapeutic hypothermia after cardiac arrest for acute myocardial infarction

Background: Therapeutic hypothermia (TH) is currently recommended in comatose patients after out-of-hospital cardiac arrest (OHCA). Acute myocardial infarction (AMI) is the most common cause of OHCA and survivors receive dual antiplatelet therapy (DAPT) after PCI. TH can attenuate the effectiveness od P2Y12 inhibitors due to reduction of gastrointestinal absorption, reduction of metabolic activation of prodrugs and due to increased platelet aggregation. The combined effect of these conditions on platelet inhibition efficacy of P2Y12 inhibitors is unknown. The aim of this study was to compare platelet inhibitory effect of clopidogrel and prasugrel in patients after OHCA for AMI treated with therapeutic hypothermia. Methods: In single center, prospective study were enrolled 51 patients after OHCA for AMI. The subgroup of 22 pts. who underwent PCI, receive DAPT, underwent TH (32-34oC for 24 h) and survived more than 3 days was analyzed. Group A (n=11 pts.) receive clopidogrel (LD 600mg + MD 150mg daily) and group B (n=11 pts.) receive prasugrel (LD 60mg + MD 5/10mg daily) via nosogastric tube. Platelet reactivity index (PRI-VASP) was measured on day 1, 2 and 3 after administration. A PRI-VASP under 50% is defined as effective platelet inhibition. Results: In the group A was median values PRI-VASP significant higher compared to the group B in all monitored days (79,3% vs. 25,9% on day 1; 81,8% vs. 18,2% on day 2; 76,0% vs. 19,5% on day 3; p< 0,001). The number of patients with effective platelet inhibition (PRI-VASP under 50%) was in group A vs. B 18% (2/11) vs. 91% (10/11) on day 1, 18% (2/11) vs. 91% (10/11) on day 2, 9% (1/11) vs. 100% (11/11) on day 3. Conclusion: New antiplatelet inhibitor prasugrel is very effective in terms of therapeutic hypothermia in patients after cardiac arrest for AMI. Clopidogrel is not effective in platelet inhibition even at an increased dose. Futher studies are needed to confirm the clinical context of these laboratory measurements.

Platelet Inhibitory Effect of Clopidogrel in Patients Treated With Omeprazole, Pantoprazole, and Famotidine: A Prospective, Randomized, Crossover Study

Concerns about an inhibitory effect of proton pump inhibitors (PPIs) on clopidogrel metabolism have been raised. Because the pharmacological effect of clopidogrel is dependent on genetically determined activity of the hepatic cytochrome P450 isoenzymes system, it is important to examine the interaction between different PPIs and high on-treatment platelet reactivity (HPR) after controlling for genetic variability. The aim of the study was to assess the effect of 2 PPIs and a histamine-2 (H2) receptor-blocker on platelet reactivity in a crossover trial where each patient was alternately treated with each drug. Omeprazole reduces HPR more than other PPI or H2 blockers. Patients treated with aspirin and clopidogrel for at least 1 month were assigned to 3 consecutive 1-month treatment periods during which they were treated with each of the 3 study medications twice daily: omeprazole 20 mg, famotidine 40 mg, and pantoprazole 20 mg. At the end of each treatment phase, platelet function was evaluated with the Verify Now system using 2 cutoff values (>208 P2Y12 reaction units [PRUs] and >230 PRUs) for the definition of HPR. Patients with HPR were older than those without HPR (62 ± 10 vs 55 ± 8 years, respectively, P = 0.03). HPR was more prevalent during omeprazole therapy compared to famotidine or pantoprazole (48%, 33%, and 31%, respectively, for the 208 PRU cutoff, P= 0.04; and 37%, 17%, and 23%, respectively, for the 230 PRU cutoff, P= 0.003). After eliminating the effects of interindividual variability in clopidogrel metabolism, omeprazole therapy was associated with substantially more HPR than famotidine or pantoprazole.

Platelet Function Testing and Tailored Antiplatelet Therapy

Dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor inhibitor, has dramatically reduced the incidence of atherothrombotic events for patients with acute coronary syndrome and those undergoing a percutaneous coronary intervention (PCI). However, the platelet inhibitory effect of clopidogrel, the most commonly used P2Y12 inhibitor, is variable between patients. Patients exhibiting high platelet reactivity (HPR) despite clopidogrel treatment are at higher risk of recurrent atherothrombotic events after PCI. In order to reduce the incidence of HPR, the more potent P2Y12 receptor inhibitors prasugrel and ticagrelor are used. However, these drugs increase the risk of bleeding. As there is evidence of a therapeutic window for platelet inhibition, platelet function tests could be helpful for tailoring antiplatelet therapy based on the patient's thrombotic and bleeding risk. In the present article, we review the most commonly used platelet function tests and the current evidence for tailoring of antiplatelet therapy in PCI patients.

Antiplatelet Therapy and Proton Pump Inhibition

A 77-year-old man with history of diabetes mellitus and coronary artery disease presented with angina and evidence of ischemia despite maximal medical therapy. He underwent a percutaneous coronary intervention with a drug-eluting stent and was started on long-term dual antiplatelet therapy with aspirin and clopidogrel. His medical history was significant for an episode of gastrointestinal (GI) bleeding in the setting of using nonsteroidal antiinflammatory drugs. Dual antiplatelet therapy, typically the addition of an ADP receptor antagonist to aspirin, has become the cornerstone of management of patients with acute coronary syndromes and after percutaneous coronary intervention. However, along with the reduction of thrombotic outcomes, this therapeutic strategy has the untoward effect of increasing the risk of bleeding events, including GI bleeding.1 The use of gastroprotective strategies, most notably proton pump inhibitors (PPIs), has become a widely adopted and recommended practice in this patient population.2 Currently, the most commonly prescribed ADP receptor antagonist is clopidogrel, a prodrug that undergoes activation by the cytochrome P450 system, in particular CYP2C19. The importance of this reaction on the overall platelet inhibitory effects of clopidogrel is highlighted by the fact that patients with reduced-function CYP2C19 alleles exhibit a reduced response to clopidogrel compared with those with the wild-type alleles. This finding might translate into increased risk of adverse events after acute coronary syndromes and percutaneous coronary intervention. Given that PPIs are inhibitors of CYP2C19, coupled with reports suggesting a clinically significant interaction,3 regulatory agencies issued a cautionary statement advising against the combined use of PPIs (specifically omeprazole and esomeprazole) and clopidogrel.4 Aspirin causes direct damage to the gastric epithelium and inhibits prostaglandin production by the gastric mucosa, leading to ulcerations and an estimated 2-fold increased risk of GI bleeding with low-dose aspirin alone.1 The risk increases with the additional use of …

Effect of esomeprazole versus famotidine on platelet inhibition by clopidogrel: A double-blind, randomized trial

Previous studies showed that esomeprazole does not interfere significantly with the platelet inhibitory effect of clopidogrel. It is unknown whether famotidine, a histamine 2 receptor antagonist, interacts with clopidogrel. This double-blind, randomized study aimed to compare the influence of esomeprazole and famotidine on the platelet inhibitory effect of clopidogrel. Patients with acute coronary syndrome or elective percutaneous coronary interventions treated with aspirin and clopidogrel cotherapy were randomized to receive esomeprazole 20 mg daily or famotidine 40 mg daily. Platelet reactivity units (PRUs) were measured at baseline and on day 28. The primary analysis involved the PRU values on day 28. There were 44 patients in the esomeprazole group and 44 in the famotidine group. The baseline PRUs of the 2 groups were comparable (esomeprazole vs famotidine, 229.1 ± 85.6 vs 220.4 ± 83.0, P = .63). The PRUs on day 28 were 242.6 ± 89.7 and 237.5 ± 79.2 in the groups receiving esomeprazole and famotidine, respectively (mean difference 5.1, 95% CI -30.8 to 41.0, P = .78). The platelet inhibitory effect of clopidogrel was not significantly different between patients receiving esomeprazole and those receiving famotidine. Neither esomeprazole nor famotidine reduced the platelet inhibitory effect of clopidogrel. (Clinicaltrial.gov Identifier NCT01062516).

Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited. To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking. A search of the published literature combined with the authors' knowledge of the field. There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11,000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18,000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking. Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven.

Beyond Platelet Functional Testing: Value in the Aggregate

In a review of functional testing methods for the antiplatelet effect of P2Y 12 antagonists, featured in this issue of Biomarkers in Medicine, Price and Barker succinctly summarize several pharmacodynamic (PD) tests of platelet reactivity/function, namely light transmission aggregometry (LTA), vasodilator-stimulated phosphoprotein (VASP), VerifyNow P2Y12 and multiple electrode platelet aggregometry [1]. The article largely focuses on the application of these PD assays to the evaluation of a registered antiplatelet agent, clopidogrel, in the postapproval clinical arena. An important finding that has been established utilizing these tests is the substantial inter individual variation in the platelet inhibitory effect of clopidogrel and the resultant consequences on clinical outcome. Beyond clopidogrel, these, and alternative assays, have played an important role in the identification and preclinical and clinical pharmaco logical evaluation of novel antiplatelet agents. Recent reports on ticagrelor and elinogrel, novel direct-acting P2Y 12 antagonists, have utilized the aforementioned assays to provide important data on the PD profile of these agents compared with clopidogrel [2,3]. Similarly, platelet function testing, supplemented by a variety of complementary assays, has played a critical role in the identification and clinical development of prasugrel, a thirdgeneration thienopyridyl P2Y 12 antagonist [4–6]. Prasugrel, like clopidogrel, is a prodrug that must be converted to an active metabolite (AM) that binds to and inhibits platelet P2Y 12 ADP receptors and, therefore, inhibits ADP-mediated platelet aggregation, and a variety of other prothrombotic and proinflammatory activities [7]. Early preclinical evaluation of prasugrel using LTA documented that it provides approximately equivalent levels of platelet inhibition as clopidogrel but at a tenth of the dose [4]. Numerous

Treatment with clopidogrel and proton pump inhibitors in combination: a review of emerging evidence

Proton pump inhibitors often are prescribed in combination with clopidogrel to decrease risk of gastrointestinal bleeding after acute coronary syndrome. Clopidogrel is a prodrug that has to be metabolized in the liver to generate the active metabolite. Both medications are metabolized largely by the CYP2C19 enzyme; therefore, concerns exist that a drug-drug interaction during concomitant treatment with clopidogrel and a proton pump inhibitor may result in reduction of platelet inhibition. We have reviewed observational and randomized control studies that have evaluated the potential influence of proton pump inhibitors on the platelet inhibitory effect of clopidogrel, along with cardiovascular outcomes. We also have summarized regulatory and academic guidelines for treatment of patients in which concomitant therapy with clopidogrel and proton pump inhibitors may be indicated. Confounding issues, including differential effects of individual proton pump inhibitors on the pharmacodynamics of clopidogrel and variation in clopidogrel metabolism mediated by CYP2C19 gene polymorphisms, also are discussed.

ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning”

The recent US Food and Drug Administration (FDA) “boxed warning” on clopidogrel raises important questions for practitioners and patients. The warning addresses the need for pharmacogenomic testing to identify patients’ altered clopidogrel metabolism and thus their risk for a suboptimal clinical response to clopidogrel. Although there is an expanding database on genetic polymorphisms that may affect clopidogrel metabolism and thus clinical outcomes, there are no evidence-based data upon which todevelop specific recommendations on the role of genetic testing in routine care nor strategies proven to improve the safety/efficacy of specific pharmacologic approaches. To provide guidance on this issue, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. The ACCF and AHA adhere to a rigorous policy regarding relationships with industry and other entities (RWI) of authors and peer reviewers for clinical document development (see http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx). This policy requires that a majority of writing committee members have no relevant relationships with industry to this topic, a standard that has been achieved for this document as indicated in Appendix 1. In the spirit of full disclosure, comprehensive RWI (RWI not relevant to this document) for all authors is available online for public view. RWI …

Abstract 5010: Is Impact of Proton Pump Inhibitor on Platelet Reactivity to Clopidogrel A Class Effect?

Background: Concomitant administration of clopidogrel and proton pump inhibitor (PPI) is associated with the reduced effect on platelet response to clopidogrel, and increased risk of adverse outcome after stent placement in patients with acute coronary syndrome. However, it remains unknown whether all PPIs may reduce platelet inhibitory effects of clopidogrel. The aim of this study was to examine the impact of rabeprazole, which is one of PPIs and mostly not metabolized by CYP2C19, on platelet response to clopidogrel. Methods: Adenosine diphosphate (ADP) induced platelet aggregation (PA) using light transmission aggregometer (MCM HEMA TRACER 313) was measured as response to clopidogrel in 127 patients (male 64%, age68 years) with coronary artery disease (CAD), and CYP2C19 polymorphism, which is involved with metabolism of clopidogrel and PPI, is also examined using PCR. Results: CYP2C19 genotypes were divided into 3 groups such as homozygous extensive metabolizer (homoEM, n=46, CYP2C19*1/*1), heterozygous EM (heteroEM, n=52, *1/*2, *1/*3), and poor metabolizer (PM, n=29, *2/*2, *2/*3, *3/*3). In contrast to distribution of CYP2C19 polymorphism in Caucasian, the rate of CYP2C19 loss of function was higher in Japanese. ADP induced PA decreased significantly in homoEM, subsequently heteroEM, and was not well inhibited in PM (PA; 3250+/−1800, 4250+/−1300, and 5010+/−1370, respectively). However, ADP induced PA was not significantly different between patients treated with (n=29; PA=4637 +/−1800) and without rabeprazole (n=98; PA=3980 +/−1159). Moreover, there were no differences in ADP induced PA between groups with and without rabeprazole, in each subgroup categorized according to the genotype of CYP2C19. As to clinical events, the intake of PPI was not associated with increased risk of mortality and stent thrombosis in patients treated with stent delivery. Conclusion: In contrast to the reported negative PPI-clopidogrel drug interaction, the intake of rabeprazole is not associated with impaired response to clopidogrel and increased risk of mortality and stent thrombosis in patients with CAD.

Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome

Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear. To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS). Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006. All-cause mortality or rehospitalization for ACS. Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13). Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.

Upper Gastrointestinal Bleeding in Patients Receiving Dual Antiplatelet Therapy after Coronary Stenting

We investigated the risk of upper gastrointestinal (UGI) bleeding and the protective effect of concomitant anti-secretory drugs during dual antiplatelet therapy administered following implantation of drug-eluting stents (DES) for coronary heart disease. Because proton pump inhibitors (PPIs) are reported to decrease the platelet inhibitory effects of clopidogrel, we also assessed cardiovascular outcomes in patients taking thienopyridine derivatives with or without anti-secretory drug. We retrospectively analyzed 243 patients, who underwent DES implantation between January 2006 and December 2007 and were receiving dual anti-platelet therapy post-surgery. The main outcome measurement was the presence of UGI bleeding. Cardiovascular outcomes were assessed by follow-up coronary angiography (CAG) findings. Data were collected from medical records. Eight cases of UGI bleeding were observed during the follow-up period, none of whom were taking anti-secretory drugs. Among the 243 cases, 108 cases were taking anti-secretory drugs: a PPI (67 cases), and an H2 receptor antagonist (41 cases). No UGI bleeding was observed among patients who were taking concomitant anti-secretory drugs. The 1- and 2-year cumulative incidences of UGI bleeding among patients who were not taking anti-secretory drugs were 4.5% and 9.2%, respectively. When CAG findings were compared between patients not taking any anti-secretory drug, taking PPI, or taking H2RA, significantly more stenotic lesions of the coronary artery were observed in the PPI-treatment group. Concomitant use of an anti-secretory agent was associated with a reduced risk of UGI bleeding. Use of PPI may be associated with an attenuation of the effect of dual antiplatelet therapy.

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 &gt;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.

Potent low dose platelet inhibitory effects of clopidogrel and aspirin on coronary thrombus formation in an animal model of acute unstable angina

Application of clopidogrel before percutaneous coronary intervention in patients with acute coronary syndrome reduces the risk of cardiac events. Clopidogrel administration before surgery increases bleeding complications after CABG. Therefore,the antithrombotic effect of the low-dose combination of clopidogrel and aspirin was investigated in an in vivo pig model of coronary artery thrombus formation with cyclic flow reductions. The platelet inhibitory effect was determined by platelet aggregation and CFR, according to the methodology described by Folts. CFR were initiated by endothelial damage and placement of a constrictor around the LAD. 30 min after CFR were established, clopidogrel (0. I mg/kg or 5 mg/kg), aspirin (I mg/kg or 7 mg/kg) or LDC (0. I mg/kg clopidogrel and I mg/kg aspirin) were administered orally. CFR-frequency was determined for further 240 min.CFR-frequency (CFR/30 min) was significantly reduced at 60 min in response to aspirin (7 mg/kg, -48%, p<0.05), and at 120 min in response to clopidogrel (5 mg/kg,-65%, p<0.05) but not at low doses of either compound. In contrast, LDC of clopidogrel (0. I mg/kg) plus aspirin (I mg/kg) resulted in a complete and rapid abrogation of CFR at 90 min (-70%, p<0.05 y. Furthermore, LDC led to reduction of platelet aggregation when CFR-frequency was already significantly decreased. In contrast, high dose groups presented a significant reduction of platelet aggregation prior to CFR-frequency decrease. Low dose combination of clopidogrel plus aspirin demonstrates a potent over additive anti-thrombotic effect in vivo with a significant reduction in thrombus formation early after drug application. The effect occurs before inhibition of platelet aggregation is detectable.

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial

We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease. The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01]. The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.

Results and follow‐up after implantation of four or more sirolimus‐eluting stents in the same patient

The aim of this study was to assess the safety and effectiveness of > or =4 sirolimus-eluting stent (SES; Cypher, Cordis, Johnson and Johnson) implantation. The safety of implantation of > or =4 SESs in the same patient and setting has not been established. Furthermore, it has been hypothesized that sirolimus administration with the use of multiple stents may diminish the platelet inhibitory effects of clopidogrel and may trigger drug-drug interactions. We identified 96 consecutive patients (96 procedures) who underwent implantation of > or =4 SESs in 365 lesions (438 stents) during the same procedure. All patients received aspirin indefinitely and clopidogrel or ticlopidine for at least 1 year postprocedure; 57% and 47% of the patients were on calcium channel blocker and statin therapy, respectively. All stents were successfully deployed and glycoprotein IIb/IIIa inhibitors were used in 50% of the procedures. There were no in-hospital deaths, Q-wave myocardial infarction (MI), urgent bypass surgery, or repeat percutaneous coronary intervention; 18 patients (19%) suffered non-Q-wave MI (defined as CK-MB elevation >3 times the upper limit of normal). At 30-day follow-up, there was one (1%) subacute thrombosis resulting in target lesion revascularization. At mean follow-up time of 15.4 +/- 6.2 months, the frequency of target lesion revascularization, target vessel revascularization, and major adverse cardiac event rates were 12%, 16%, and 18%, respectively. No other notable clinical events that might have been attributed to the possible drug-drug interactions or discontinuation of concomitant antithrombotic, statin, or calcium channel blocker therapy were reported. Multiple (> or =4) SES implantation appears safe with no increase in major adverse cardiac events.

Existence of a Clinically Relevant Interaction between Clopidogrel and HMG‐CoA Reductase Inhibitors? Re‐evaluating the Evidence

Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well-defined surrogate ex vivo parameter should be performed.

Effect of 300- and 450-mg clopidogrel loading doses on membrane and soluble P-selectin in patients undergoing coronary stent implantation

Background After coronary artery stent implantation patients are treated with the adenosine diphosphatase (ADP) receptor antagonist clopidogrel to prevent subacute stent thromboses. Today these patients initially receive a loading dose of 300 mg of clopidogrel to accelerate the complete drug effect. In the current study we investigated whether a higher loading dose can shorten the time until the maximum platelet inhibitory effect of clopidogrel is achieved. Methods P-selectin expression of nonstimulated and ADP-stimulated platelets was flow cytometrically measured before the clopidogrel loading dose and on 3 consecutive days in 52 patients with coronary artery disease: 21 patients in group 1 received 300 mg of clopidogrel after stent implantation and 11 patients in group 2 received the higher 450-mg clopidogrel loading dose followed by a daily dose of 75 mg of clopidogrel for both groups. The control group consisted of 20 patients who were monitored over 2 days before coronary intervention. Soluble P-selectin levels in plasma were determined by an enzyme-linked immunosorbent assay. Results Inducible P-selectin expression on ADP-stimulated platelets was significantly reduced (P =.05) on days 1 and 2 in patient group 2 (450-mg loading dose) compared with group 1 (300-mg loading dose). No influence of clopidogrel on the P-selectin levels in plasma was observed. Conclusions In our study the application of 450 mg of clopidogrel as the loading dose in patients undergoing coronary stenting shortens the period until the maximum effect of the ADP receptor antagonist is achieved and thus may lead to a more successful prevention of subacute coronary stent thromboses. (Am Heart J 2002;143:118-23.)