Clopidogrel For The Reduction Of Events During Observation Research Articles

Benefit of Long-Term Dual Anti-Platelet Therapy in Patients Treated With Drug-Eluting Stents: From the NHLBI Dynamic Registry

The optimal duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an important, unanswered question. This study was designed to evaluate the association of varying durations of DAPT on clinical outcomes after DES implantation for the treatment of coronary artery disease. Using the National Heart, Lung, and Blood Institute Dynamic Registry, patients enrolled in the last 2 waves after index percutaneous coronary intervention with DES and who were event free at the time of landmark analysis were included. Landmark analysis was performed 12 and 24 months after percutaneous coronary intervention, and patients were stratified according to continued use of DAPT or not. Subjects were evaluated for rates of death, myocardial infarction, and stent thrombosis at 4 years from their index procedures. The numbers of evaluable patients were 2,157 and 1,918 for the 12- and 24-month landmarks, respectively. In both landmark analyses, there was a significantly lower 4-year rate of death or myocardial infarction in the group that continued DAPT compared to the group that did not (12 months: 10.5% vs 14.5%, p=0.01; 24 months: 5.7% vs 8.6%, p= 0.02). Beneficial differences in the group that continued on DAPT were preserved after multivariate and propensity adjustment. There were no significant differences in definite stent thrombosis in either landmark analysis. In conclusion, at 12 and 24 months after DES implantation, continued use of DAPT was associated with lower 4-year risk for death and myocardial infarction.

Clopidogrel Efficacy and Cigarette Smoking Status

RECENT ANALYSES OF LARGE-SCALE TRIALS SUGGEST either a reduced or complete lack of clinical benefit from clopidogrel therapy in nonsmokers. Importantly, this observation is not explained by an enhanced prothrombotic state (a condition in which P2Y12 inhibitor therapy may be expected to be most effective) in smokers relative to nonsmokers as evidenced by variable event rates in smokers and nonsmokers treated with placebo. Cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2, an isoenzyme involved in the metabolic activation of clopidogrel but less recognized in importance than CYP2C19. Nonsmokers have greater platelet reactivity than smokers during clopidogrel treatment. A recent additional important analysis of the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial revealed a significant interaction based on smoking status (P=.01 for interaction). Specifically, patients in the clopidogrel-treated nonsmoker group (a combination of the neversmoker group and former-smoker group) had no reduction in the incidence of the primary outcome of ischemic stroke, myocardial infarction (MI), or vascular death compared with the aspirin-treated nonsmoker group (10.4% vs 10.6%, respectively; hazard ratio [HR], 0.98 [95% CI, 0.88-1.09]), whereas patients in the clopidogrel-treated currentsmoker group had a significantly lower incidence of the primary outcome compared with the aspirin-treated currentsmoker group (8.3% vs 10.8%, respectively; HR, 0.76 [95% CI, 0.64-0.90]). To our knowledge, the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events [N=12 562]) trial investigators have not presented a similar adjusted analysis of nonsmokers and smokers. However, an abstract based on CURE trial data reported that in the largest smoking status subgroup—never smokers—clopidogrel treatment was not associated with a significant reduction in the primary outcome (a composite of death from cardiovascular causes, nonfatal MI, or stroke) compared with never smokers treated with placebo (10.2% vs 10.9%, respectively; HR, 0.93 [95% CI, 0.79-1.11]), whereas current smokers treated with clopidogrel had a significantly lower incidence of the primary outcome compared with placebo (6.1% vs 9.4%, respectively; HR, 0.63 [95% CI, 0.48-0.83]). In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, there was no difference in the occurrence of the primary composite end point (1-year death, MI, and stroke) in clopidogrel-treated nonsmokers relative to placebo-treated nonsmokers, whereas a significant benefit was observed in clopidogrel-treated smokers compared with placebo-treated smokers (6.3% vs 13.8%, respectively; HR, 0.44 [95% CI, 0.23-0.83]). Desai et al attempted to refine the relation between smoking status and clinical outcomes based on previous pharmacodynamic findings. These investigators conducted a post hoc analysis of patients with ST-segment elevation MI, based on the quantification of the number of cigarettes smoked at baseline, in the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial. They reported an adjusted analysis based on smoking status for both the primary end point (angiographic outcome) and the secondary end point (30-day clinical outcome), revealing a significant smoking status interaction for both end points (P=.04 and P=.006, respectively, for interaction in patients who smoked at least 10 cigarettes/d). In that trial, clopidogrel therapy was associated with an overall 36% and 20% reduction in the rate of the primary and secondary end points, respectively, relative to placebo. The reduction in the primary end point was enhanced among clopidogrel-treated patients who smoked 10 or more cigarettes per day relative to placebo (adjusted odds ratio [OR], 0.49; P .0001). In addition, clopidogreltreated patients who smoked zero cigarettes per day or less than one-half pack per day had no significant benefit in 30-day clinical end point occurrence compared with patients treated with placebo (13.7% vs 14.3%, respectively; OR, 0.98 [95% CI, 0.75-1.28]), whereas clopidogrel-treated patients who smoked 10 or more cigarettes per day exhibited a 46% reduction in the 30-day clinical end point relative to the placebo group (8.0% vs 14.3%, respectively; OR, 0.54 [95% CI, 0.38-0.76]).

Grabbing the Horns of a Dilemma

Despite the overwhelming success of percutaneous cardiac interventions, the interventional practitioner is commonly faced with a number of very simple questions, the answers of which should be obvious but in truth are completely unknown. Perhaps the most common such question concerns the appropriate duration of dual antiplatelet therapy (the combination of aspirin and an inhibitor of platelet P2Y12) in patients who have received intracardiac stents. Most interventional cardiologists receive several such calls per week from patients and professional colleagues and often have to spend a considerable amount of time negotiating antithrombotic drug treatment strategies in patients who need to undergo noncardiac surgical procedures. Article see p 2015 The truth is that as we enter the third decade of stent use, we know much less about the need for antithrombotic therapy after stent implantation than we (and our patients) would like. Much of our current knowledge is derived from early studies in patients receiving bare metal stents. When stents were first implanted, the recommended antithrombotic therapy included a variety of marginally effective antiplatelet therapies and toxic doses of warfarin and heparin. In 1995, Colombo et al1 observed that optimization of stent deployment with ultrasound followed by treatment with aspirin and ticlopidine was associated with lower rates of stent thrombosis, less bleeding, and shorter hospital stays than historical reports. We probably never would have entered the modern stent era without these important observations, which were rapidly confirmed by a series of randomized trials.2 However, the appropriate duration of thienopyridine therapy after stenting was unknown. Whereas 1 report indicated that a 2-week course might be sufficient,3 the randomized Clopidogrel for the Reduction of Events During Observation (CREDO) trial showed that a year of dual antiplatelet therapy reduced the rate of a combined end point of death, myocardial infarction, or …

Is There a Clinically Significant Interaction Between Calcium Channel Antagonists and Clopidogrel?

Clopidogrel is an inactive prodrug; it is converted to its active metabolite through the cytochrome P450 (CYP3A4) pathway, which also metabolizes calcium channel blockers (CCBs). Several studies have reported that CCBs reduce the ability of clopidogrel to inhibit platelet aggregability; one suggested that CCBs reduce the efficacy of clopidogrel. We performed a post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) study to compare the treatment effect of clopidogrel in patients on CCBs versus not on CCBs. In CREDO, 2116 patients were randomly assigned to pretreatment with 300 mg clopidogrel 3-24 hours before a planned percutaneous coronary intervention followed by 1 year of 75 mg/d clopidogrel, versus 75 mg clopidogrel at the time of the procedure and continued for 28 days only. The primary end points were a combined end point of death, myocardial infarction, and stroke at 28 days and 1 year. Among the 580 patients (27%) on CCBs at enrollment, at 28 days, the combined end point was reached in 17 patients (6%) on clopidogrel versus 28 (9%) on placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.39-1.29). At 1 year, the combined end point was reached in 27 patients (10%) on clopidogrel versus 46 (15%) on placebo (HR, 0.68; 95% CI, 0.42-1.09). The treatment effect of clopidogrel was similar in patients not on CCBs at 1 year (HR, 0.78; 95% CI, 0.56-1.09). After adjustment for differences between patients on and not on CCB, there was still no evidence of an interaction between clopidogrel treatment and CCB (HR for patients not on CCBs, 0.87; 95% CI, 0.62-1.23; HR for patients on CCBs, 0.74; 95% CI, 0.45-1.21). In CREDO, there was no evidence that CCBs decrease the efficacy of clopidogrel.

Benefits and risks of using clopidogrel before coronary artery bypass surgery: Systematic review and meta-analysis of randomized trials and observational studies

The benefits and risks associated with the use of clopidogrel before coronary artery bypass grafting are controversial, and these were investigated in the present meta-analysis. A systematic literature search was performed to identify studies on the use of clopidogrel before coronary artery bypass grafting. Meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews. The literature search yielded 3 prospective randomized studies and 17 observational studies with valid data. Randomized studies were post hoc analyses of the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY), Clopidogrel for the Reduction of Events During Observation (CREDO), and Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events trials. Meta-analysis based on these data showed a nonsignificant reduced risk of immediate postoperative composite end point (death, myocardial infarction, or stroke) in the clopidogrel group (risk ratio [RR], 0.77; 95% confidence interval [CI], 0.58-1.04). Data from the CREDO and CLARITY trials showed a similar risk of death (RR, 0.81; 95% CI, 0.20-3.37), myocardial infarction (RR, 0.58; 95% CI, 0.25-1.33), and major bleeding according to Thrombolysis in Myocardial Infarction criteria (RR, 1.48; 95% CI, 0.72-3.04). Meta-analysis of observational studies showed that preoperative exposure to clopidogrel was associated with an increased risk of death (RR, 1.30; 95% CI, 1.02-1.67), reoperation for bleeding (RR, 1.88; 95% CI, 1.37-2.58), blood loss (mean difference, 157.8 mL; 95% CI, 61.9-253.6), need of packed red blood cell transfusion (RR, 1.23; 95% CI, 1.10-1.37), and increased use of blood products. A significantly reduced risk of postoperative myocardial infarction was observed among patients taking clopidogrel (RR, 0.63; 95% CI, 0.48-0.82). Contrary to the findings of post hoc analyses of randomized trials, observational studies showed that recent exposure to clopidogrel before coronary artery bypass grafting is associated with increased risk of postoperative death, reoperations for bleeding, blood loss, and need of blood transfusions.

Response to Letter Regarding Article, “Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome”

To the Editor: Drs Potter and Le Lorier note that a large number of patients in our study had no recorded clopidogrel use within 7 days of hospital discharge.1 We believe the primary cause of the low use of clopidogrel is the fact that the study covered the period between 2001 and 2005. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) trials were published in 2001 and 2002, respectively, and other relevant trials (Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY], Clopidogrel and Metoprolol in Myocardial Infarction Trial [COMMIT], PCI-CLARITY) were not published until 2005. As a result, the guidelines in place during most of our study period did not recommend the routine use of …

Combination Antithrombotic Therapies

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

Relationship Between Baseline Inflammatory Markers, Antiplatelet Therapy, and Adverse Cardiac Events After Percutaneous Coronary Intervention

Background— We evaluated patients undergoing percutaneous coronary intervention to assess the predictive value of high-sensitivity C-reactive protein (hs-CRP) and pregnancy-associated plasma protein-A (PAPP-A) on adverse cardiac outcomes and the effect of antiplatelet therapy on these outcomes. Methods and Results— Baseline blood samples were available on 1468 CREDO (Clopidogrel for the Reduction of Events During Observation) patients for hs-CRP testing and 1096 patients for PAPP-A testing. The 1-year primary end point was the composite incidence of death, myocardial infarction, or stroke. Patients in the highest 2 tertiles of hs-CRP had more events compared with the lowest tertile (11.4% versus 6.4%, P =0.003). Treatment with clopidogrel reduced the 1-year composite end point for patients in the highest 2 tertiles of hs-CRP (9.1% clopidogrel versus 13.5% placebo, P =0.04) but not in the lowest tertile. Elevated PAPP-A levels were associated with a trend toward more events at 1 year that did not reach statistical significance. Patients in the highest 2 tertiles of PAPP-A randomized to clopidogrel had fewer events (7.3% clopidogrel versus 13.1% placebo, P =0.01), but no benefit was seen in the lowest tertile. A 46% risk reduction with randomization to clopidogrel was seen in patients in the highest 2 tertiles of both biomarkers (8.7% versus 16.2%, P =0.02). Conclusions— Patients undergoing nonurgent percutaneous coronary intervention who have elevated hs-CRP and PAPP-A have an increased incidence of adverse cardiovascular events. The clinical benefit of adding clopidogrel to aspirin seems greater in those with increased levels of these inflammatory biomarkers.

Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial

The optimal duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI) is unknown. Incremental reductions in the risk of major adverse cardiovascular events may be partially offset by an increased incidence of bleeding in the months after a PCI. We examined the incidence, severity, and predictors of bleeding associated with 1 year of dual antiplatelet therapy after PCI among 1,816 patients in the Clopidogrel for the Reduction of Event During Observation (CREDO) trial. We also compared bleeding in patients who received dual antiplatelet therapy for 1 year to those who did so for only 4 weeks. Bleeding was categorized as major or minor using the modified Thrombolysis In Myocardial Infarction (TIMI) Study Group criteria. Major or minor bleeding occurred in 146 patients during 1 year of follow-up. More than 80% of bleeding events were periprocedural. Multivariable predictors of any bleeding included increasing age and coronary artery bypass. Any (major or minor) bleeding occurred in 71 (8.1%) and 77 (8.9%), major bleeding in 34 (3.9%) and 49 (5.6%), and minor bleeding in 37 (4.2%) and 29 (3.3%) of placebo- and clopidogrel-treated patients, respectively; these differences were not significant. However, major gastrointestinal bleeding occurred in significantly more clopidogrel- than placebo-treated patients (13 [1.4%] vs 3 [0.3%] [P = .011]). Adding clopidogrel to aspirin beyond 4 weeks post PCI is not associated with a significant increase in the overall rate of major or minor bleeding, although it is associated with an increase in major gastrointestinal bleeding in the year after a PCI.

Duration of antiplatelet therapy following intracoronary stenting: are changes needed?

This review addresses the question of whether established guidelines for the duration of dual-antiplatelet therapy (DAT) following intracoronary stenting need to be updated. Current recommendations for the optimal duration of DAT following percutaneous coronary intervention are limited by an inadequate evidence base. While the Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) studies showed reductions in ischaemic events with prolongation of DAT out to 9–12 months, both the main CURE and CREDO studies showed an excess of major bleeding and are limited in generalizability by study design characteristics. Concerns regarding the rates of delayed acute stent thrombosis following drug-eluting stent (DES) implantation are integral to any debate on the optimal duration of DAT. The most reasonable conclusion from a number of divergent reports is that the evidence for an increased rate of stent thrombosis with DES therapy is conflicting. The Intracoronary Stenting and Antithrombotic Regimen: Safety And eFficacy of a 6-month DAT after drug-Eluting stenting (ISAR-SAFE) trial should help answer whether DAT should be routinely extended beyond 6 months post-DES implantation. Two other studies, ISAR-REBOUND and ISAR-CAUTION, are evaluating the effect of abrupt vs. tapered cessation of clopidogrel therapy on predefined in vitro and clinical endpoints and should shed further light on the existence and clinical significance of a rebound phenomenon following clopidogrel discontinuation.

Risks and Benefits of Antiplatelet Therapy in Uremic Patients

Patients with renal insufficiency are at an increased risk for cardiovascular morbidity and mortality. Despite being at a substantial risk for thrombotic events, patients with renal insufficiency also experience a greater number of hemorrhagic complications associated with antiplatelet therapy than individuals with normal renal function. This review focuses on the benefits and risks of antiplatelet therapy in patients with impaired kidney function suffering from an acute coronary syndrome.

Die Kosteneffektivität von Clopidogrel in der Behandlung des akuten Koronarsyndroms ohne ST-Streckenhebung — ein pharmakoökonomischer Review

Background The randomised controlled clinical trials (RCT) Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Percutaneous Coronary Intervention substudy of CURE (PCI-CURE) and Clopidogrel for the Reduction of Events during Observation (CREDO) have demonstrated the clinical efficacy and safety of Clopidogrel for the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention. The objective of this study is to systematically review pharmacoeconomic evaluations based on data from these studies to assess the cost-effectiveness of Clopidogrel for the treatment of NSTE-ACS patients.

Cost-effectiveness of clopidogrel treatment in percutaneous coronary intervention: a European model based on a meta-analysis of the PCI-CURE, CREDO and PCI-CLARITY trials

ABSTRACTObjective: Our objective was to conduct a comprehensive cost-effectiveness analysis of pre-treatment and long-term treatment with clopidogrel in percutaneous coronary intervention (PCI) in three European countries based on a meta-analysis of the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO) and PCI-Clopidogrel as Adjunctive Therapy (CLARITY) trials. This analysis adds to existing knowledge by providing further data on the cost-effectiveness of clopidogrel in PCI across a wide spectrum of patients.Methods: A combined decision tree and Markov model was created. The relative risks of myocardial infarction, cardiovascular death and of major bleedings with clopidogrel were based on a fixed-effects meta-analysis. The risk of ischaemic events in untreated patients and long-term survival were taken from the Swedish hospital and death registers. A societal perspective was used in Sweden and a payer perspective in Germany and France. Costs are stated in €2006 and effectiveness measured in quality-adjusted life-years (QALYs).Results: The pooled effects of clopidogrel on the combined endpoint showed a relative risk of 0.711 (p = 0.003) at 30 days and 0.745 (p = 0.002) at end of follow-up (up to 1 year). Pre-treatment with clopidogrel compared with aspirin alone is a dominant strategy. Long-term treatment with clopidogrel compared with 1-month treatment leads to approximately 0.09 QALYs at an incremental cost of €393 in Sweden, €709 in Germany and €494 in France. The corresponding incremental cost-effectiveness ratios range from €4225/QALY to €7871/QALY.Conclusion: The results of this modelling analysis suggest that pre-treatment and long-term treatment in PCI with clopidogrel for up to 1 year are cost-effective in a range of patient groups and settings given commonly accepted thresholds.

The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial

Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD. Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]). Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1). Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD.

Long-Term Clopidogrel Therapy in Patients Receiving Percutaneous Coronary Intervention

The PCI-CURE (Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events) and CREDO (Clopidogrel for the Reduction of Events During Observation) studies have demonstrated that, in addition to aspirin, pre-treatment with clopidogrel followed by long-term (i.e. 9-12 months) therapy significantly reduces the risk of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). To examine the economic implications, from the Dutch healthcare perspective, of the use of clopidogrel in patients undergoing PCI (elective procedures or in patients with acute coronary syndrome), comparing pre-treatment followed by long-term therapy with only 4 weeks of treatment. A lifetime Markov model was used to combine data from the PCI-CURE and CREDO trials with data from the literature concerning epidemiology, costs and quality of life. The model was run separately for each trial. Only direct healthcare costs (euro, year 2004 values) were considered. Costs and outcomes were discounted at 4% per anum. For each trial, the cost effectiveness is expressed as costs per life-year and QALY gained. Uncertainties are addressed by uni- and probabilistic multivariate sensitivity analysis. When starting with the data from the PCI-CURE trial, pre-treatment plus 9-month clopidogrel therapy was predicted to save 1119 euros and gain 0.03 life-years and 0.07 QALYs per patient compared with short-term treatment. When starting with the data from the CREDO trial, the combination of pre-treatment and prolonged clopidogrel therapy (1 year) was estimated to save 497 euros and gain 0.10 life-years and 0.14 QALYs per patient. Univariate and probabilistic multivariate sensitivity analyses suggested that the conclusions were generally robust, but that the expected gain in survival for the PCI-CURE population was very sensitive to the effects on mortality within the combined endpoint of myocardial infarction/stroke-free survival. In The Netherlands, pre-treatment plus long-term (9-12 months) therapy with clopidogrel is estimated to save costs and increase (quality-adjusted) survival in the prevention of ischaemic events among patients undergoing elective PCI (CREDO) and in patients with acute coronary syndrome (PCI-CURE) compared with short-term treatment with clopidogrel without pre-treatment.

Risk stratification for patients undergoing nonurgent percutaneous coronary intervention using N-terminal pro–B-type natriuretic peptide: A Clopidogrel for the Reduction of Events During Observation (CREDO) substudy

The utility of N-terminal pro-BNP (NT-proBNP) measurement as a prognostic marker during nonurgent percutaneous coronary intervention (PCI) has been suggested in several studies. The comparative prognostic values between NT-proBNP levels and left ventricular ejection fraction (LVEF) in the nonurgent PCI setting are unclear. CREDO was a double blind, placebo-controlled, randomized trial comparing 2 clopidogrel regimens before and after nonurgent PCI. Baseline NT-proBNP levels and LVEF were measured in 1468 subjects using the Roche Elecsys proBNP assay (Roche Diagnostics, Indianapolis, IN), and the 1-year combined end point of death/myocardial infarction (MI)/stroke was analyzed according to NT-proBNP quartiles in impaired and preserved LVEF. In this patient cohort (mean age 61.6 +/- 10 years, 22% with LVEF < 50%), the median NT-proBNP level was 131 pg/mL. Increasing quartiles of NT-proBNP were associated with a higher rate of death, MI, and the combined end point (but not stroke) at 1 year, including those with LVEF > or = 50% (P < .001 for trend). This prognostic power for death and MI remained robust even when adjusted for other clinical or biochemical markers including cardiac troponin, creatinine clearance, and high-sensitive C-reactive protein (hazard ratio 1.249, P = .006). Despite its robust prognostic value, baseline NT-proBNP levels did not identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy. In patients undergoing a nonurgent PCI, NT-proBNP levels may provide important prognostic value for death and MI, even in patients with preserved cardiac function, However, NT-proBNP levels were unable to identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy.

Clopidogrel Response Variability and Future Therapies

Case Presentation: A 75-year-old woman presents to the hospital with a non–ST-elevation myocardial infarction (MI) and is found to have a subtotal occlusion of the proximal left anterior descending coronary artery. A drug-eluting stent is successfully deployed without complication, and the patient is given a 300-mg loading dose of clopidogrel. She is started on a treatment regimen that includes aspirin 325 mg daily and clopidogrel 75 mg daily. On hospital day 4, she develops recurrent chest pain and is found to have ST-segment elevation on ECG. She is taken to coronary angiography, where she is found to have an occlusive thrombus within a well-deployed stent. After percutaneous coronary intervention (PCI), how should this patient be managed? Platelets play a central role in initiating and propagating pathological thrombosis after spontaneous or mechanical plaque rupture. Antiplatelet therapies, including aspirin and thienopyridines, are key components of pharmacotherapy in acute coronary syndromes (ACS) and PCI.1,2 As monotherapy, treatment with clopidogrel modestly reduces cardiovascular (CV) events in patients with established atherosclerotic disease compared with aspirin treatment.3 When combined with aspirin, clopidogrel provides additive reduction in the risk of ischemic events in patients with non–ST-elevation ACS and in patients undergoing PCI.4,5 In addition, clopidogrel helps to maintain infarct-related artery patency and clinical outcomes in patients with ST-elevation MI receiving fibrinolytic therapy.6,7 Clopidogrel, a prodrug, relies on cytochrome P450–dependent pathways to form its active metabolite and inhibits platelet aggregation through irreversible blockade of the platelet P2Y12 receptor (Figure 1). When a 300-mg loading dose is used, clopidogrel requires at least 4 to 6 hours to achieve its maximal effect.8 Analyses from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial suggest that clopidogrel pretreatment 6 to 15 hours before PCI is necessary to significantly reduce CV events.5,9 Clinicians …

Optimal Timing for the Initiation of Pre-Treatment With 300 mg Clopidogrel Before Percutaneous Coronary Intervention

This study sought to determine the optimal timing of a 300-mg clopidogrel loading dose before percutaneous coronary intervention (PCI) in patients enrolled in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. A loading dose of clopidogrel before a PCI has become relatively commonplace, although the data supporting this practice are limited and sometimes conflicting. Patients were randomized to receive either 300 mg clopidogrel or a matching placebo administered a minimum of 3 h and a maximum of 24 h before PCI. The primary 28-day combined end point was death, myocardial infarction, or urgent target vessel revascularization. Linear splines were used to summarize the effect of the time of pre-treatment as a continuous variable. A total of 1,762 patients were evaluated. For patients randomized to placebo, there was no relationship between the duration of pre-treatment and the occurrence of the primary end point, whereas longer durations of pre-treatment in patients randomized to clopidogrel were associated with improved outcomes. The event rates diverged maximally at 24 h. The difference in outcomes between placebo and clopidogrel pre-treated patients was not significant until > or =15 h pre-treatment, with a 58.8% (p = 0.028) reduction in the primary end point in patients pre-treated with clopidogrel > or =15 h compared with placebo. When a 300-mg loading dose of clopidogrel is used, little benefit is obtained compared with just 75 mg at the time of the PCI when the treatment duration is <12 h. In patients pre-treated for longer durations, the optimal duration seems to approach 24 h.

Long-Term Cost Effectiveness of Early and Sustained Dual Oral Antiplatelet Therapy With Clopidogrel Given for Up to One Year After Percutaneous Coronary Intervention: Results From the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial

The association between objectively measured physical activity and atrial fibrillation (AF) has not been examined. Therefore, we examined the association between moderate and vigorous physical activity (MVPA) with incident AF in 5,147 participants who completed accelerometer assessment for 4 to 7 consecutive days in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. MVPA was defined as >1,065 counts/minute, and daily mean time spent in MVPA was computed. Incident AF was identified during follow-up by a study-scheduled electrocardiogram and also from self-reported medical history of a physician diagnosis. Logistic regression was used to assess the relation between daily time in MVPA and incident AF. A total of 429 (8.3%) incident AF cases were detected after a median follow-up of 3.5 years following accelerometer assessment. Participants with higher daily time spent in MVPA were less likely to develop AF than those with lower MVPA achievement (Quartile 1 = 12.4%; Quartile 2 = 8.3%; Quartile 3 = 7.1%; Quartile 4 = 5.4%; p-trend <0.001). In a multivariable model adjusted for AF risk factors, the risk of AF decreased with higher levels of daily MVPA (Quartile 1: Ref; Quartile 2: hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.58 to 1.01; Quartile 3: HR = 0.72, 95% CI 0.53 to 0.98; Quartile 4: HR = 0.62, 95% CI 0.44 to 0.87; p-trend = 0.0056). In conclusion, higher levels of objectively measured daily MVPA are protective against the development of AF suggesting that promotion of MVPA should be encouraged to reduce the risk of AF.

Clopidogrel: cardiologists’ Panacea Or neurologists’ headache?

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