600-mg Loading Research Articles

Pharmacodynamic study of prasugrel or clopidogrel in non-ST-elevation acute coronary syndrome with CYP2C19 genetic variants undergoing percutaneous coronary intervention (PRAISE-GENE trial)

BackgroundThe CYP2C19*2 or *3 loss-of-function (LOF) allele is associated with high platelet reactivity (HPR) on clopidogrel treatment. East Asians may benefit from a lower dose of prasugrel due to their more potent platelet inhibitory response. The impact of LOF alleles on the pharmacodynamic response to half-dose prasugrel in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) is unknown. MethodsSeventy patients with the LOF alleles were assigned to half-dose prasugrel (n = 35, 30-mg load followed by 5 mg daily) or clopidogrel (n = 35, 600-mg load followed by 75 mg daily). The primary endpoint was the rate of HPR, defined as VerifyNow-P2Y12 reaction unit (PRU) >235, at 24 h post loading. ResultsPrasugrel achieved a lower PRU compared to clopidogrel after loading (119 [56–175] vs. 245 [189–299]), at 24 h (34 [8–58] vs. 196 [122–244]), and at 30 days (134 [98–189] vs. 203 [144–248]). Prasugrel had a lower rate of HPR after loading (5.7% vs. 57.1%, p <0.001), at 24 h (2.9% vs. 28.6%, p=0.006), and at 30 days (11.4% vs. 34.3%, p=0.004). Prasugrel had a similar rate of optimal platelet reactivity at 30 days (71.4% vs. 60.0%, p=0.450). There was no significant difference in the occurrence of periprocedural myonecrosis within 48 h after PCI with clopidogrel and prasugrel (22.9% vs. 17.1%, p>0.960). ConclusionsHalf-dose prasugrel provided potent platelet inhibition in NSTE-ACS patients that were carriers of the CYP2C19*2 or *3 allele, with a lower rate of HPR. Periprocedural myonecrosis was not significantly different in the 2 groups.

Influence of rabeprazole and famotidine on pharmacodynamic profile of dual antiplatelet therapy in clopidogrel-sensitive patients: The randomized, prospective, PROTECT trial

Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 μM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 μM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 μM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P= .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P= .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.

Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone.

In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268.

Pharmacokinetic, Pharmacodynamic, and Safety/Tolerability Profiles of CG100649, a Novel COX-2 Inhibitor: Results of a Phase I, Randomized, Multiple-dose Study in Healthy Korean Men and Women

BackgroundCG100649 is a novel anti-inflammatory drug that is currently under development. CG100649 demonstrates a dual mechanism of action on cyclooxygenase-2 and carbonic anhydrase that may result in favorable treatment effects and few adverse gastrointestinal and cardiovascular events. ObjectiveThe objective of this study was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of administering multiple oral doses of CG100649 to healthy Korean volunteers. MethodsThis was a randomized, double-blind, placebo-controlled, multiple ascending oral dose study that was performed on 8 male and 8 female subjects per dose cohort. Each subject was randomly selected to receive either a single loading dose followed by 6 days of once-daily placebo (n = 4; 2 male and 2 female subjects) or CG100649 (n = 12; 6 male and 6 female subjects). Each subject was administered 1 of 3 sequential dose levels (8-mg loading dose + 2 mg/d, 10-mg loading dose + 4 mg/d, or 12-mg loading dose + 8 mg/d). Blood samples for pharmacokinetic analysis were obtained ≤480 hours after the last dose. Blood samples for measuring serum thromboxane B2 (TXB2) and ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2) (markers of cyclooxygenase-1 and cyclooxygenase-2 activity, respectively) and urine samples for measuring prostanoid metabolites were collected ≤21 days after the last dose. ResultsDuring steady state, the median Tmax in blood and plasma after the last dose ranged from 3 to 10 hours and 3.5 to 7.3 hours, respectively. Mean terminal t½ values in blood and plasma ranged from 121 to 203 hours and 100 to 167 hours, respectively. Whole blood concentrations were 50 to 70 times higher than plasma concentrations in all 3 dose cohorts in both male and female subjects. Compared with baseline, serum TXB2 diminished by 68% to 91% at 8 hours after the administration of the last dose in all 3 cohorts (P < 0.001). Ex vivo lipopolysaccharide-stimulated PGE2 was maximally inhibited (89%–96%; P < 0.001) by all 3 dose levels on day 7. Urinary prostacyclin metabolite was inhibited by 64% (P < 0.001) on day 7 (12–24 hours) but only by the highest CG100649 dose. There were no clinically significant drug-related changes in blood pressure between treatment groups. The most frequently encountered adverse events were aphthous stomatitis and dyspepsia. ConclusionsCG100649 was well tolerated and demonstrated a whole blood concentration that is ~50 to 70 times higher than in plasma in these healthy subjects. CG100649 suppressed TXB2 and PGE2 at all 3 doses, and only the highest dose suppressed the urinary excretion of the urinary prostacyclin metabolite.

Fatal dabigatran-associated bleeding

We read with great interest the case presented by Schaeffer and Conway1 describing a fatal outcome with the use of dabigatran and would like to address several points about the patient’s medical management. We find it peculiar that the patient received the medications she did in the first place, given her advanced age, comorbidities, and high risk of major bleeding. We are surprised that there did not seem to be a pharmacist intervention at any point in the care of the patient. After the patient developed paroxysmal atrial fibrillation, she was prescribed warfarin sodium 10 mg daily for three days while in the hospital. Harrison et al.2 found that patients given a 10-mg loading dose of warfarin sodium had more above-target International Normalized Ratio (INR) values than patients receiving 5 mg. On the third day, the INR for the current patient was 1.3, which prompted the physician to prescribe dabigatran 150 mg twice daily. However, given warfarin’s slow onset, responding to an INR of 1.3 was likely premature. Warfarin exhibits a long half-life of approximately 20–60 hours,3 and it is likely that much of the INR of 8.3 arising eight days later was due to warfarin as well as dabigatran. Hylek et al.4 found that INR decay back to baseline was significantly delayed in patients of advanced age, especially those age 80 years or older (the current patient was 78 years old).

Relation between the vasodilator-stimulated phosphoprotein phosphorylation assay and light transmittance aggregometry in East Asian patients after high-dose clopidogrel loading

We analyzed the relation between platelet aggregation measured by light transmittance aggregometry (LTA) and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. It has been suggested that LTA and VASP-P assay correlate differently according to the level of P2Y12 receptor blockade by thienopyridines. We simultaneously measured platelet function by LTA and VASP-P assay in 466 East Asians undergoing elective percutaneous coronary intervention after a 600-mg clopidogrel loading. High on-clopidogrel platelet reactivity (HPR) was defined by published consensus criteria. The degree of correlation between LTA and the VASP-P assay was different according to PRI levels. The correlation was lower in patients with poor responsiveness (PRI >60%) (n = 216) (0.035 ≤ r(2) ≤ 0.047), which was greater in responsive patients (PRI ≤60%) (n = 250) (0.315 ≤ r(2) ≤ 0.526). Despite a 600-mg loading, East Asians had a high prevalence of HPR (40.1%-63.5%), and the prevalence of HPR also differed between LTA and VASP-P assay. A PRI cutoff of >58% (area under curve, 0.829; 95% confidence intervals, 0.792-0.862; P < .001) corresponded to the published HPR cutoff by 5-μM adenosine diphosphate-induced maximal platelet aggregation >46%. This is the largest study correlating platelet reactivity measured by LTA and VASP-P assay in a percutaneous coronary intervention-treated cohort. The correlation is dependent on the level of responsiveness. Future investigations are needed to better define the optimal cutoffs of HPR measured by LTA and VASP-P assay for personalized antiplatelet therapy.

Introduction of new oral antiplatelet drugs in myocardial infarction hospital network: initial experience

New oral antiplatelet drugs (prasugrel, ticagrelor) are recommended in the current European Society of Cardiology guidelines for the management of patients presenting with ST-segment elevation myocardial infarction (STEMI) [1]. However, in many STEMI hospital networks administration of a 600-mg clopidogrel loading dose before or during transfer to cathlab (including in ambulance administration) is a standard of care, since this strategy has been implemented for many years. Early administration of the drug may enhance antiplatelet effects of clopidogrel at the time of primary percutaneous coronary intervention (PCI), in comparison to the administration in the cathlab. On the other hand, the response to clopidogrel in patients with STEMI, especially in patients with hemodynamic compromise is impaired. Prasugrel and ticagrelor are more potent antiplatelet drugs, with faster and more profound antiplatelet effect. These agents are preferred over clopidogrel, if not contraindicated, in patients with STEMI since both are superior in comparison to clopidogrel in terms of the reduction of ischemic events [2, 3]. However, introduction of prasugrel and ticagrelor may need to change STEMI network logistics since those new drugs are predominantly administered in the cathlab, but not in ambulances or in non-PCI centers before transportation [4]. In our high-volume primary PCI center, early (before transfer to cathlab) administration of acetylsalicylic acid, unfractionated heparin and a 600-mg clopidogrel loading dose has been a well-established standard of treatment from many years. In-cathlab administration of antiplatelet drugs was a rare strategy so it was necessary to reorganize STEMI network for new antiplatelet drugs introduction in daily practice. An observational, prospective registry was designed to describe the implementation of new oral antiplatelet drugs in our network. First 100 consecutive STEMI patients (no exclusion criteria) admitted to our center after introduction of prasugrel and ticagrelor were enrolled. Registry was focused on antiplatelet therapy including type of drug, moment of administration, time from administration to PCI. Data on reason for the administration of clopidogrel instead of new drugs was also collected. Additionally, platelet aggregation inhibition was assessed at the time of PCI (guide wire introduction) with Plateletworks Aggregation Kits (Helena Laboratories, Beaumont, TX, USA) [5]. The registry analyzed the current clinical practice and did not modify patients diagnostics and treatment. A total of 100 consecutive STEMI patients entered the registry. Clinical characteristics of patient population are presented in Table 1. Registry represents real life STEMI population including elderly patients and patients in cardiogenic shock. Acetylsalicylic acid was administered before transfer to cathlab in all patients. New oral antiplatelet drugs were given after cathlab admission before or during coronary angiography only in 15 out of 100 patients (13 patients treated with a 60-mg prasugrel loading dose; 2 patients treated with a 180-mg ticagrelor loading dose). In the remaining 85 patients a 600-mg clopidogrel loading T. Rakowski (&) A. Dziewierz Z. Siudak P. Kleczynski J. S. Dubiel Second Department of Cardiology, Jagiellonian University Medical College, Kopernika 17 Street, 31-501 Krakow, Poland e-mail: mcrakows@cyfronet.pl

Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents

The only reason P2Y12 inhibitors are administered in addition to aspirin is to improve the prevention of thrombosis. The clinical efficacy of adding clopidogrel to aspirin as a secondary prevention strategy in patients with high-risk coronary artery disease is well established.1 There are no effects of clopidogrel on any receptor other than P2Y12 to explain the magnitude of the clinical benefit. All of the established clinical effects are attributed to reduced platelet responsiveness to ADP.2 Therefore, the patient with inadequate P2Y12 inhibition determined by ex vivo testing logically has an increased risk for thrombosis. Persistent ischemic event occurrence and the irrefutable demonstration of clopidogrel antiplatelet response variability are 2 potent arguments against the widely practiced nonselective or one-size-fits-all strategy of administering clopidogrel therapy. Observational studies conducted in thousands of patients have led to an international consensus that high on-treatment platelet reactivity (HPR) to ADP is a major risk factor for post–percutaneous coronary intervention (PCI) ischemic event occurrence.3,4 Moreover, the recent 2011 American and European guidelines have given a Class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management.5–7 Furthermore, the Society of Thoracic Surgeons gave a Class IIb recommendation for platelet function testing to determine the timing of surgery in patients on clopidogrel therapy (Level of Evidence C).8 These recommendations for personalizing antiplatelet therapy are unprecedented and acknowledge that a large body of data has accrued demonstrating the relation of HPR to ischemic risk in the PCI-treated patient. Finally, the evidence of diminished effectiveness of clopidogrel in poor metabolizers (those having 2 loss-of-function [LoF] cytochrome P450 [ CYP ] 2C19 alleles) has been recognized by the Food and Drug Administration (FDA) boxed warning about treatment with clopidogrel.9 Response by Krishna …

Safety and Efficacy of Clopidogrel Reloading in Patients on Chronic Clopidogrel Therapy Who Present With an Acute Coronary Syndrome and Undergo Percutaneous Coronary Intervention

The clinical safety and efficacy of clopidogrel reloading in patients receiving long-term clopidogrel therapy who present with acute coronary syndromes and undergo percutaneous coronary intervention have not yet been evaluated. The study cohort comprised 1,368 consecutive patients receiving long-term clopidogrel therapy (75 mg/day) who had presented with acute coronary syndromes and underwent coronary artery stent implantation. In total, 926 patients were given a 600-mg clopidogrel loading dose (reload cohort) before cardiac catheterization, while 442 patients were not reloaded (no-reload cohort). Patients who had presented with cardiogenic shock or stable angina were excluded. The 2 cohorts were well matched for the conventional risk factors for coronary artery disease. The analyzed clinical end points of death (1.1% vs 0.9%, p = 0.77), death or Q-wave myocardial infarction (0.9% vs 0.9%, p = 1.0), target lesion revascularization (0.2% vs 0.8%, p = 0.45), target vessel revascularization (1.1% vs 1.1%, p = 1.0), and major adverse cardiac events (2.0% vs 1.8%, p = 0.8) were similar between the no-reload and reload groups at 30 days. The in-hospital rates of major bleeding and gastrointestinal bleeding were also similar between the 2 cohorts. There were no cases of definite stent thrombosis. In conclusion, patients receiving long-term clopidogrel therapy who present with acute coronary syndromes do not gain any clinical benefit from additional reloading with clopidogrel.

First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel

Background— The influence of cytochrome P450 (CYP) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown. Methods and Results— CYP2C19 (*1, *2, *3, *4, *5, *6, *7, *8, *17) genotyping was performed in patients with coronary artery disease treated with ticagrelor (180-mg load, 90 mg BID) (n=92) or clopidogrel (600-mg load, 75 mg/d) (n=82). All patients received 75 to 100 mg/d aspirin. Platelet function was measured by aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein-phosphorylation assay at predose, 8 hours postloading, and maintenance. In each treatment group, patients were categorized according to 2C19 genotype carrier status (loss-of-function, gain-of-function) and metabolizer status. Kruskal-Wallis test was used to compare platelet function among these categories for each treatment, and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category. There was no statistically significant influence of genotype on platelet function during aspirin therapy alone. Ticagrelor exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status ( P &lt;0.01). Loss-of-function carriers had greater platelet reactivity during clopidogrel therapy. The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow P2Y12 assay. Conclusions— This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of CYP2C19 genotype. Whereas CYP2C19 genotype influenced the antiplatelet effect of clopidogrel, there was no effect of CYP2C19 genotype during ticagrelor therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00642811 and NCT00528411.

High doses of warfarin are more beneficial than its low doses in patients with deep vein thrombosis

Background The efficacy and safety of enoxaparin in outpatient treatment of deep vein thrombosis have been well studied. The present study aimed to compare the efficacy of a 10-mg loading dose of warfarin with 5 mg of the drug and enoxaparin in achieving the international normalized ratio (INR) range. Methods This randomized clinical trial was performed in the emergency department (ED) of our study. International normalized ratio was checked daily for 7 days and on the 14th day. Based on the patient's INR on the third day, the doses were adjusted. Patients received enoxaparin (1.5 mg/kg per day) simultaneously until the therapeutic range of INR was achieved for 2 consecutive days. Result The side effects were compatible in both groups. There was a significant difference in the INR rates of the 2 groups recorded on the third, fourth, and seventh days. Conclusion The 10-mg loading dose of warfarin induces the therapeutic range of INR earlier than the 5-mg dose without causing any significant difference in the side effects. More cases in the 10-mg group had INR levels higher than 3; the very dose, therefore, is recommended as the loading dose in cases of outpatients with deep vein thrombosis referring to the ED. Tight control of INR, after the third day of treatment, is also recommended in these cases.

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

Treatment patterns in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Background:The Antiplatelet Therapy Observational Registry (APTOR) is a prospective observational study of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in a ‘real world’ clinical setting. Here the authors report on the management of ACS patients in three European countries during the hospital phase and through 12-months’ follow-up, including use of antiplatelet agents, co-medications and stents, as well as clinical outcomes at 12 months.Methods:ACS patients undergoing PCI (N = 1525) from January to August 2007 were planned to be consecutively recruited in France, Spain and the UK.Results:Index diagnosis was unstable angina/non-ST-segment elevation myocardial infarction (MI) in 62% and ST-segment elevation MI in 38%. Prior to the index ACS event, 17% were prescribed both aspirin and clopidogrel. While in-hospital clopidogrel and aspirin use was similar across countries, considerable variation was observed between countries at 12 months (clopidogrel 66–75%; aspirin 86–95%). The UK most frequently used a 300-mg clopidogrel loading dose (70%) compared with France (53%) and Spain (56%), while >300 mg was used in 21%, 34% and 16% patients, respectively. Bare metal stents only were used in 42% of subjects, drug-eluting stents (DES) only in 40%, and both in 10%, with the highest rates of DES use in Spain (70%) followed by the UK (47%) and France (31%). The composite endpoint of cardiovascular (CV) death, MI or stroke occurred in 4.7% of patients by 12 months.Conclusions:APTOR shows marked variation in ACS management between countries in antiplatelet therapy, co-medications and stent use. Due to the observational design of the registry, statistical testing was not applied and data should be seen as hypothesis generating. These data provide a useful benchmark for comparison with current guidelines.

Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease

Background— Ticagrelor is the first reversibly binding oral P2Y 12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results— In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 μmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks ( P &lt;0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved &gt;50% IPA (98% versus 31%, P &lt;0.0001) and &gt;70% IPA (90% versus 16%, P &lt;0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72–hour slope [% IPA/h] −1.04 versus −0.48, P &lt;0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel ( P =NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo ( P =NS). Conclusions— Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00528411.

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 …

Clopidogrel Treatment Prior to Percutaneous Coronary Intervention

WORLDWIDE, MORE THAN 2 MILLION PATIENTS WILL be treated with a percutaneous coronary intervention (PCI) this year, with approximately half of these performed in the United States. For almost three fourths of these patients, the diagnosis necessitating the procedure will be an acute coronary syndrome (ACS)—eitherunstableanginaoramyocardial infarction(MI). Inhibitors of platelet function are a critical component of peri-PCI pharmacological therapy. Aspirin, although initially viewed as a weak agent with minimal potential to prevent acute thrombotic events, has been shown in a placebocontrolled trial to decrease the incidence of Q-wave MIs by 75% compared with heparin alone during coronary angioplasty. However, with aspirin alone, thrombotic complications following PCI remained unacceptably high. To address this, the platelet glycoprotein (Gp) IIb/IIIa antagonists were developed as a means to effectively prevent platelet aggregation and its associated complications. Abciximab, eptifibatide, and tirofiban were studied in several placebocontrolled trials involving nearly 17 000 patients undergoing nonemergent PCI. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) and Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trials, randomization of stented patients to receive either abciximab or eptifibatide was found to decrease rates of 30-day death, MI, or urgent target vessel revascularization by 52% and 35%, respectively, compared with placebo. Importantly, this relative risk reduction was similar for patients diagnosed with stable angina or an ACS. Since no other antiplatelet agents were available clinically that prevented platelet aggregation as completely and as quickly as the Gp IIb/IIIa antagonists, it was assumed that no other antiplatelet regimen would be as effective in preventing periPCI thrombotic events. But soon after long-term post-PCI treatment with thienopyridines—initially ticlopidine and then clopidogrel—became standard care in patients receiving stents, limited reports began to emerge suggesting that pretreatment with these agents might also protect patients from periprocedural events. Although a subsequent randomized, placebo-controlled trial failed toconfirmthis benefit, retrospective analysis suggested that adequate durations of pretreatment achieved an approximately 50% relative risk reduction in the incidence of 28-day death, MI, or urgent target vessel revascularization. This level of benefit for clopidogrel pretreatment was consistent with that found in subset analyses in both the PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) and PCI-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trials. These highly suggestive but nondefinitive results regarding the clinical benefit of clopidogrel pretreatment set the stage for a series of influential studies by the Intracoronary Stenting and Antithrombotic Regimen (ISAR) group to establish the optimal antiplatelet regimen in a broad range of patients undergoing PCI. Using a 600-mg clopidogrel loading dose given at least 2 hours prior to a PCI in all patients, the investigators systematically studied the additional benefit of adjunctive abciximab in lowto intermediate-risk patients undergoing PCI, in patients undergoing revascularization of small-diameter ( 2.5 mm) vessels, and in patients with diabetes. In all of these trials, abciximab was not found to provide even a trend toward additional benefit when given in addition to adequate pretreatment with clopidogrel. However, a large and critically important subgroup of patients was excluded from these studies—those presenting with an ACS. Not only do these patients represent the majority of patients treated with a PCI, but they are also a group of patients that most data suggest may derive the greatest benefit from adjunctive therapy with Gp IIb/IIIa antagonists. In this issue of JAMA, the ISAR investigators close this remaining gap. The ISAR-REACT 2 trial is similar in design to the previous ISAR trial, but it enrolled only patients with objective evidence of an ACS as manifest by anginal symptoms at rest or with minimal exertion accompanied by an elevated level of troponin T or by a new ST-segment deviation or bundle-branch block. Just more than half of the 2022 patients enrolled had elevated troponin levels. In contrast to previous ISAR studies, randomization to abciximab was associated with a significant 25% relative risk reduction in the 30-day combined end point of death, MI, or urgent target vessel revascularization. Interestingly, all of this benefit was con-

Initiating Warfarin Therapy: 5 mg versus 10 mg

To review the literature investigating initial dosing of warfarin at 5 or 10 mg for treatment of acute venous thromboembolism. Articles were identified through searches of MEDLINE (1966-December 2003) using the key words warfarin, oral anticoagulation, warfarin dose, warfarin initiation, venous thromboembolism, and anticoagulation. Additional references were located through review of the bibliographies of the articles cited. Studies of the initial dosing of warfarin at 5 or 10 mg were evaluated and relevant information was included, as were those that identified known factors that influence the maintenance dose of warfarin. For the treatment of acute venous thromboembolism, warfarin dosing is often provider dependent. Until recently, studies suggested that 5 mg initiation was as effective as 10 mg, without increasing the risk of bleeding. However, the most recent study comparing a 5- versus 10-mg initial dosing nomogram supports an initial dose of 10 mg. These results should be interpreted with caution, however, since patients at high risk for bleeding were excluded from the study. Several patient-specific factors will affect the maintenance dose, guiding clinicians to start with lower (<5 mg) or higher (>5 mg) doses. Although recent evidence supports a 10-mg initiation nomogram, clinicians should consider patient-specific factors prior to deciding an initial warfarin dose. If a 10-mg loading dose is utilized, strict compliance with the protocol is necessary.

American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.

### Mechanism of Action of Coumarin Anticoagulant Drugs Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1).1–6 These proteins, which include the coagulation factors II, VII, IX, and X, require γ-carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8 Figure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagulation factors II, VII, IX, and X and the anticoagulant factors protein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin-sensitive vitamin KO reductase step in the formation of vitamin KH2. Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9–11 γ-Carboxylation requires the reduced form of vitamin K (vitamin KH2). Coumarins block the formation of vitamin KH2 by inhibiting the …