Standard-dose Clopidogrel Research Articles

Pharmacodynamic Effect of Cilostazol Plus Standard Clopidogrel Versus Double-Dose Clopidogrel in Patients With Type 2 Diabetes Undergoing Percutaneous Coronary Intervention

OBJECTIVETo determine the effect of adding cilostazol (100 mg b.i.d.) to standard-dose clopidogrel (75 mg/d) (TRIPLE) compared with double-dose clopidogrel (150 mg/d) (DOUBLE) and the influence of the cytochrome P450 (CYP2C19*2/*3, CYP3A5*3)and ATP-binding cassette subfamily B1(ABCB1 C3435T) genetic polymorphisms in type 2 diabetes (T2DM) patients.RESEARCH DESIGN AND METHODST2DM patients were treated with TRIPLE (n = 41) or DOUBLE (n = 39) after percutaneous coronary intervention. Conventional aggregometry and VerifyNow were performed at baseline and at 30 days. The primary end point was absolute change in 20-μM ADP-induced maximal platelet aggregation (ΔMPA20) between baseline and switching values.RESULTSTRIPLE versus DOUBLE showed greater ΔMPA20 (22.9 ± 11.6 vs.12.7 ± 15.5%; difference, 10.2% [95% CI 4.2–16.3]; P < 0.001). Carriage of one (β coefficient, −5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (−8.3%; P = 0.007) were associated with lower ΔMPA20 in DOUBLE–treated patients, but not in TRIPLE-treated patients.CONCLUSIONSAmong T2DM patients, adding cilostazol achieves greater platelet inhibition compared with clopidogrel (150 mg/d), which is not influenced by genetic polymorphisms.

CLOPIDOGREL LOADING WITH TIROFIBAN TO ARREST THE REACTIVITY OF PLATELETS IN PATIENTS WITH ACUTE

Objectiveswe performed a prospective randomised pharmacodynamic investigation of four antiplatelet regimens to compare different effects in arresting the reactivity of platelets by assessed the P-selectin expression on platelet membrane and...

Relation between clopidogrel active metabolite levels and different platelet aggregation methods in patients receiving clopidogrel and aspirin

Clopidogrel is a prodrug that undergoes bioconversion via cytochrome P450 system to form an active metabolite (AM) that binds to the platelet ADP receptor. The antiplatelet effect of clopidogrel is commonly assessed by measuring the aggregatory response to 5μM ADP by light transmission aggregation (LTA) or multiple electrode aggregometry (MEA) or by the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI). To determine which of these three tests of platelet ADP receptor pathway inhibition most closely correlates with clopidogrel AM levels. We analyzed blood samples from 82 patients with coronary artery disease who were randomized to receive double-dose or standard dose clopidogrel for 2weeks. We measured peak clopidogrel AM levels, platelet aggregation in response to ADP and VASP-PRI on days 1, and repeated all the measures on days 7 and 14. Linear regression analysis was used to examine the correlation between clopidogrel AM and LTA, MEA and VASP-PRI. Bland-Altman plots were used to explore the agreement between tests of the antiplatelet effects of clopidogrel. Clopidogrel AM on day 1 correlated most closely with VASP-PRI (r=-0.5767) and demonstrated weaker correlations with LTA (r=-0.4656) and MEA (r=-0.3384) (all p<0.01). Intra-class correlation (ICC) between VASP-PRI and LTA was 0.6446; VASP-PRI and MEA was 0.4720; and LTA and MEA was 0.4693. Similar results were obtained on days 7 and 14. Commonly used pharmacodynamic measures of clopidogrel response are only moderately correlated with clopidogrel AM levels and may not be suitable to measure the adequacy of clopidogrel therapy.

Using risk difference as opposed to odds-ratio in meta-analysis

In comparing cardiovascular death between patients receiving intensified antiplatelet therapy after percutaneous coronary intervention and controls given standard-dose clopidogrel, the meta-analysis by Aradi et al. [1] handled a very critical data set because only 10 randomised studies were available and more than half of the event frequencies were zero (13 out of 20).

Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: Systematic review and meta-analysis

BackgroundADP-specific platelet function assays were shown to predict thrombotic events, and might be helpful to select candidates for more potent antiplatelet therapy. We aimed to determine the efficacy and safety of giving intensified antiplatelet therapy on the basis of platelet reactivity testing for patients undergoing percutaneous coronary intervention (PCI). MethodsElectronic databases were searched to find prospective, randomized trials that reported the clinical impact of using an intensified antiplatelet protocol (repeated loading or elevated maintenance doses of clopidogrel, prasugrel or glycoprotein IIb/IIIa inhibitor) on the basis of ADP-specific platelet reactivity testing (VerifyNow, Multiplate, VASP or light transmission aggregometry) compared to standard-dose clopidogrel. Evaluated efficacy measures included cardiovascular death, non-fatal myocardial infarction and definite/probable stent thrombosis (ST), while major bleeding events were recorded as safety endpoint. ResultsBetween 2008 and 2011, 10 clinical trials comprising 4213 randomized patients were identified. Compared to standard antiplatelet therapy, the intensified protocol was associated with a significant reduction in cardiovascular mortality, ST and myocardial infarction (p<0.01 for all). There was no difference in the rate of major bleeding events between intensified and standard groups (p=0.44). Although the observed effects regarding mortality, ST and bleeding were not heterogeneous, meta-regression analysis revealed that the net clinical benefit of the intensified treatment significantly depended on the risk of ST with standard-dose clopidogrel (p=0.023). ConclusionIntensifying antiplatelet therapy on the basis of platelet reactivity testing reduces cardiovascular mortality and ST after PCI; however, the net benefit of this approach depends on the risk of ST with standard-dose clopidogrel.

Influence of Genetic Polymorphisms on the Effect of High- and Standard-Dose Clopidogrel After Percutaneous Coronary Intervention: The GIFT (Genotype Information and Functional Testing) Study

This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420).

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 …

Network meta-analysis of prasugrel, ticagrelor, high- and standard-dose clopidogrel in patients scheduled for percutaneous coronary interventions

Since novel antiplatelet treatments (prasugrel, ticagrelor, high-dose clopidogrel) have been predominantly tested against standard-dose clopidogrel, data on direct comparisons between these therapies are scarce. We therefore indirectly compared their efficacy and safety in patients undergoing percutaneous coronary intervention. Electronic databases were searched systematically to identify head-to-head randomised controlled trials (RCTs). Network meta-analysis was performed using generalised linear mixed models with adjustment for length of follow-up. Findings were corroborated by mixed treatment comparison through Bayesian methods. Fourteen RCTs were identified and included in the analysis (high- vs. standard-dose clopidogrel: 9 trials, prasugrel vs. high-dose clopidogrel: 2 trials, prasugrel vs. standard-dose clopidogrel: 2 trials, ticagrelor vs. standard-dose clopidogrel: 1 trial). No significant differences were found for efficacy outcomes except for stent thrombosis favouring prasugrel (vs. ticagrelor: odds ratio [OR] 0.63, 95% confidence interval [CI]: 0.42, 0.94; vs. high-dose clopidogrel: OR 0.70, 95%CI: 0.48, 1.01). Prasugrel exhibited a similar bleeding risk as high-dose clopidogrel, but more major (OR 1.43, 95%CI 1.07, 1.90) and major or minor bleeding (OR 1.36, 95%CI 1.09, 1.69) compared to ticagrelor. Ticagrelor was also associated with less major or minor bleeding compared to high-dose clopidogrel (OR 0.81, 95%CI 0.69, 0.96). No differences were seen for non CABG-related major bleeding between the three strategies. Results were corroborated in a subgroup analysis comprising only patients with acute coronary syndromes. In the absence of head-to-head clinical trials, network meta-analysis suggests potentially relevant differences in efficacy and bleeding risk among novel antiplatelet treatments and may thereby advance understanding of their differential therapeutic properties.

Escalating Clopidogrel by Involving a Genetic Strategy-TIMI 56

Results of the EscaLating ClopidogrEl by InVolving A GeneTic StratEgy — Thrombolysis In Myocardial Infarction 56 [ELEVATE TIMI 56] trial showed that tripling the maintenance dose of clopidogrel in CYP2C19*2 heterozygote patients achieved levels of platelet reactivity that were similar to the standard-dose clopidogrel in noncarriers.

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y12 inhibitor, for 6–12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y12 inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.

Randomised comparison of adjunctive naoxintong versus standard maintenance dose clopidogrel in patients with CYP2C19*2 gene mutation

ObjectivesThe purpose of this study was to determine the impact of adjunctive Buchang Naoxintong Jiaonang (BNJ) in patients with CYP2C19*2 gene mutation undergoing percutaneous coronary intervention (PCI).BackgroundAlthough adjunctive BNJ to...

Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention

In the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial, 6 months of high-dose clopidogrel did not reduce cardiovascular events compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity (OTR) after percutaneous coronary intervention, defined as OTR ≥230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test. The aim of this analysis was to examine the relationship between outcomes and OTR over the course of the trial. OTR was measured at 12 to 24 hours and 30±7 days after percutaneous coronary intervention. Cox proportional hazards models with OTR as a time-varying covariate were used to determine the association between OTR and the primary end point of cardiovascular death, myocardial infarction, and stent thrombosis. Of the 2800 enrolled patients, 2796 (99.98%) had evaluable platelet function data. OTR <208 P2Y12 reaction units was significantly associated with a lower risk of the primary end point at 60 days (hazard ratio, 0.18; 95% confidence interval, 0.04 to 0.79; P=0.02) and at 6 months (hazard ratio, 0.43; 95% confidence interval, 0.23 to 0.82; P=0.01). After adjustment for other significant predictors of outcome, OTR <208 P2Y12 reaction units remained independently associated with the primary end point at 60 days (hazard ratio, 0.23; 95% confidence interval, 0.05 to 0.98; P=0.047) and tended to be associated at 6 months (adjusted hazard ratio, 0.54; 95% confidence interval, 0.28 to 1.04; P=0.065). In the GRAVITAS trial, achievement of on-clopidogrel reactivity <208 P2Y12 reaction units at 12 to 24 hours after percutaneous coronary intervention or during follow-up was associated with a lower risk for cardiovascular events. The efficacy of an individualized strategy to target a level of OTR below this threshold merits investigation. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00645918.

Standard- vs High-Dose Clopidogrel After Percutaneous Coronary Intervention

To the Editor: The results of the Gauging Responsiveness with a VerifyNow assay–Impact on Thrombosis and Safety (GRAVITAS) and Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENTOASIS 7) trials suggested that high-dose clopidogrel after percutaneous coronary intervention (PCI) can exhibit different clinical efficacy according to the study design. CURRENT-OASIS 7 found a reduction in cardiovascular death, myocardial infarction (MI), or stroke at 1 month with double-dose clopidogrel (adjusted hazard ratio [HR], 0.86) while GRAVITAS, after 6 months, did not (HR, 1.01). First, ischemic event occurrences may be dependent on the extent of peri-PCI platelet activation. A 600-mg loading dose before coronary angiography in CURRENT-OASIS 7 significantly reduced the primary outcome but not when given 12 to 24 hours after PCI in GRAVITAS. Second, the benefit of intensified platelet inhibition may be different depending on the risk profile, which differed between the trials. The 1-month cardiovascular death and MI rate with the standard dose was approximately 0.7% in GRAVITAS (estimated from Figure 2) vs about 4.5% in CURRENT-OASIS 7. Differences in safety may also be related to the differences in study design. More patients in the standard-dose clopidogrel group in CURRENT-OASIS 7 received heparin or glycoprotein IIb/IIIa inhibitor compared with those in GRAVITAS, and they had a higher rate of major bleeding (1.9% in 1 month in CURRENT-OASIS 7 vs 1.2%-2.3% in 6 months in GRAVITAS). Patients with high ontreatment reactivity were more likely to be women and slightly older in GRAVITAS, and double-dose clopidogrel showed greater benefits in these patients in CURRENT-OASIS 7. However, these characteristics also significantly increased bleeding risk in a meta-analysis. CYP2C19 polymorphism carriage was a main predictor of high on-treatment reactivity with high–maintenance dose clopidogrel in the Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism (ACCEL-DOUBLE) study. Differences in the genetic composition of the population in GRAVITAS could be related to the modest pharmacodynamic effect. However, despite similarly high prevalences of CYP2C19 poor metabolizers in East and South Asians (10%-20%), these groups had different clinical benefits associated with double-dose clopidogrel (19% decrease in East Asians and 40% increase in South Asians in ischemic events at 1 month in the highvs standard-dose groups). Ischemic event occurrence is a complex process in which platelets, procoagulant and fibrinolytic systems, genes, race, and environment all play a role. Rather than a single measurement of platelet function, future treatment strategies should consider all these factors in an individual patient.

Standard- vs High-Dose Clopidogrel After Percutaneous Coronary Intervention

To the Editor: The results of the Gauging Responsiveness with a VerifyNow assay–Impact on Thrombosis and Safety (GRAVITAS) and Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENTOASIS 7) trials suggested that high-dose clopidogrel after percutaneous coronary intervention (PCI) can exhibit different clinical efficacy according to the study design. CURRENT-OASIS 7 found a reduction in cardiovascular death, myocardial infarction (MI), or stroke at 1 month with double-dose clopidogrel (adjusted hazard ratio [HR], 0.86) while GRAVITAS, after 6 months, did not (HR, 1.01). First, ischemic event occurrences may be dependent on the extent of peri-PCI platelet activation. A 600-mg loading dose before coronary angiography in CURRENT-OASIS 7 significantly reduced the primary outcome but not when given 12 to 24 hours after PCI in GRAVITAS. Second, the benefit of intensified platelet inhibition may be different depending on the risk profile, which differed between the trials. The 1-month cardiovascular death and MI rate with the standard dose was approximately 0.7% in GRAVITAS (estimated from Figure 2) vs about 4.5% in CURRENT-OASIS 7. Differences in safety may also be related to the differences in study design. More patients in the standard-dose clopidogrel group in CURRENT-OASIS 7 received heparin or glycoprotein IIb/IIIa inhibitor compared with those in GRAVITAS, and they had a higher rate of major bleeding (1.9% in 1 month in CURRENT-OASIS 7 vs 1.2%-2.3% in 6 months in GRAVITAS). Patients with high ontreatment reactivity were more likely to be women and slightly older in GRAVITAS, and double-dose clopidogrel showed greater benefits in these patients in CURRENT-OASIS 7. However, these characteristics also significantly increased bleeding risk in a meta-analysis. CYP2C19 polymorphism carriage was a main predictor of high on-treatment reactivity with high–maintenance dose clopidogrel in the Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism (ACCEL-DOUBLE) study. Differences in the genetic composition of the population in GRAVITAS could be related to the modest pharmacodynamic effect. However, despite similarly high prevalences of CYP2C19 poor metabolizers in East and South Asians (10%-20%), these groups had different clinical benefits associated with double-dose clopidogrel (19% decrease in East Asians and 40% increase in South Asians in ischemic events at 1 month in the highvs standard-dose groups). Ischemic event occurrence is a complex process in which platelets, procoagulant and fibrinolytic systems, genes, race, and environment all play a role. Rather than a single measurement of platelet function, future treatment strategies should consider all these factors in an individual patient.

Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes

Various definitions of major bleeding have been used to evaluate safety in randomized controlled trials of antiplatelet therapy. We compared the definitions and rates of major bleeding in phase III randomized controlled trials of oral P2Y(12) inhibitors in the management of patients with acute coronary syndromes (ACS). Electronic searches identified six phase III randomized controlled oral P2Y(12) inhibitor trials published between 2001 and 2010 involving 119 020 patients with ACS. The trials compared clopidogrel standard-dose (300-mg loading dose, 75-mg daily thereafter) vs. placebo (CURE, CLARITY-TIMI 28, COMMIT), clopidogrel standard-dose vs. prasugrel (TRITON-TIMI 38) or ticagrelor (PLATO) and clopidogrel standard-dose vs. clopidogrel double-dose (600-mg loading dose, 150-mg daily for 6-days, 75-mg daily thereafter) (CURRENT-OASIS 7). Using the trial definition, major bleeding rates in patients treated with standard-dose clopidogrel ranged from 0.6% in COMMIT to 11.2% in PLATO. The contrast in bleeding rates of standard-dose clopidogrel among the trials was attenuated when using the thrombolysis in myocardial infarction (TIMI) definition for major bleeding (range 1.1-7.7%) and bleeding rates in all the trials were less than 2% when comparing 30 day rates of non-coronary artery bypass graft surgery-related TIMI major bleeding (range 0.3-1.9%). Differences in major bleeding rates between trials of P2Y(12) inhibitors in patients with ACS are minimized after standardization of bleeding definitions, timing of reporting of bleeding outcomes, and procedure rates. Interpretation of the risk of bleeding associated with different P2Y(12) inhibitors would be facilitated by a consistent approach to the definition and reporting of bleeding.

Optimizing antiplatelet therapy in acute coronary syndrome and percutaneous coronary intervention

Dual antiplatelet therapy with aspirin and clopidogrel is the standard of care for patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). It is well established that inhibition of platelet aggregation reduces the risk of recurrent thrombotic events and stent thrombosis. However, some patients show a reduced antiplatelet response to standard clopidogrel loading (300 mg) and maintenance (75 mg day(-1)) doses, which has been associated with poorer patient outcomes. Pharmacodynamic and pharmacokinetic studies show that higher-than-standard clopidogrel dosing strategies facilitate more rapid platelet inhibition of a greater intensity as a result of greater plasma concentrations of the clopidogrel active metabolite. Recently completed studies suggest that in patients with ACS undergoing PCI, higher-than-standard clopidogrel dosing regimens provide greater inhibition of platelet function and improved clinical outcomes with a small but significant increase in major bleeding. Newer, more potent antiplatelet agents such as prasugrel and ticagrelor are other alternative strategies that result in more rapid, greater inhibition of platelet function and better outcomes than standard-dose clopidogrel. Whether platelet reactivity-guided therapy or genotyping for cytochrome P450 polymorphisms is useful in managing patients needs to be further defined. Most importantly, early and effective antiplatelet therapy results in the best short- and long-term outcomes for patients with ACS or those undergoing PCI.

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADP-receptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR = 0.87, 95% CI 0.79-0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR = 0.80, 95% CI 0.74-0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR = 0.52, 95% CI 0.43-0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standard-dose clopidogrel (5% vs. 4.7%, OR = 1.06 95% CI 0.96-1.17, P = 0.25). This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs.

Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention

High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined. To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI. Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months. The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days. At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001). Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. clinicaltrials.gov Identifier: NCT00645918.

An Initial Experiment With Personalized Antiplatelet Therapy

THE P2Y12 BLOCKERS PLAY A CRITICAL ROLE IN PREventing coronary thrombosis and are now widely used along with aspirin in patients undergoing coronary stent placement. Despite proven clinical efficacy, the antiplatelet effect of clopidogrel, the most widely used P2Y12 inhibitor, is highly variable as determined by ex vivo platelet function assays. Additionally, studies have demonstrated that high on-treatment platelet reactivity is a major cardiovascular risk factor for subsequent thrombotic events in patients treated with stents. This has led some to propose that patients who have received stents and were treated with clopidogrel should undergo on-treatment platelet function testing. Yet the degree to which such testing should guide therapy is not yet known. In this issue of JAMA, Price and colleagues report the results of the Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety (GRAVITAS) trial, the first large randomized, prospective trial to determine whether personalization of antiplatelet therapy based on platelet function testing actually improves 6-month clinical outcomes among patients treated with stents. In the GRAVITAS trial, patients treated with clopidogrel were screened for high on-treatment platelet reactivity 12 to 24 hours after receiving drug-eluting stents and those with high on-treatment reactivity were randomly assigned to receive either high-dose (600 mg initial dose and 150 mg/d thereafter) or standard-dose clopidogrel (no additional load, 75 mg/d). In addition, a random sample of patients without high on-treatment reactivity were observed while being treated with standard-dose clopidogrel. The major findings of the GRAVITAS trial were that the rate of ischemic events (cardiovascular death, nonfatal myocardial infarction, or stent thrombosis) was low (2.3%) in randomized patients treated with highand standard-dose clopidogrel; that bleeding risks did not differ by clopidogrel dose; that high-dose clopidogrel therapy was partially effective in eliminating high on-treatment platelet reactivity (40% prevalence at 30 days); and that in the secondary observational comparison, patients with high on-treatment reactivity treated with standard-dose clopidogrel had increased event rates compared with those who did not have high on-treatment platelet reactivity. There are several possible reasons personalizing therapy using high-dose clopidogrel was not effective. Among these are that high-dose clopidogrel had a limited effect in overcoming high platelet reactivity. The overall trial event rates were low, and the cutpoint for defining high on-treatment platelet reactivity may have been too high. The low event rate in GRAVITAS may, in part, be explained by the absence of periprocedural myocardial infarction in the primary end point as has been used in recent observational studies with higher event rates. Given the low event rates in GRAVITAS, only an extremely effective treatment would have had any chance to significantly influence outcomes. In addition, several important questions cannot be answered based on the data presented in the report by Price et al, including whether the platelet reactivity before the ischemic event was higher than the platelet reactivity in patients without ischemic events. And, whether ischemic events were clustered among patients whose platelet reactivity was lower than the cutpoint used to define high on-treatment reactivity. Answers to these questions will be useful in addressing the hypothesis that ischemic event occurrence increases markedly above a critical cutpoint. However, the possibility also exists that ischemic events occurred in the presence of low platelet reactivity in GRAVITAS. The latter finding would suggest that high on-treatment platelet reactivity identified early after stenting is only a marker of risk

Residual platelet reactivity after aspirin and clopidogrel treatment predicts 2-year major cardiovascular events in patients undergoing percutaneous coronary intervention

Background Studies on the prognostic significance of residual platelet reactivity despite the use of dual anti-platelet agents are limited and seldom extend beyond 1 year. Methods This study enrolled 144 patients treated with standard-dose aspirin and clopidogrel and undergoing percutaneous coronary intervention (PCI). Platelet reactivity was measured by the Platelet Function Analyzer-100 (PFA-100) just before PCI and presented as collagen/epinephrine closure time (CEPI-CT) and collagen/adenosine diphosphate closure time (CADP-CT). Primary endpoint included cardiovascular death, myocardial infarction, and stroke. Secondary endpoint was the primary endpoint plus hospitalization due to unstable angina or urgent target vessel revascularization. Results During the 24-month follow-up, 14 patients (9.7%) developed the primary endpoint events and 33 had the secondary endpoints. After controlling possible confounding factors, both CEPI-CT < 193 s and CADP-CT < 95 s were independently predictive of the primary endpoint (hazard ratio = 3.5; 95% confidence interval: 1.04–11.7; p = 0.044 and 5.3; 1.4–20.1; p = 0.015, respectively). Only CADP-CT < 95 s remained significantly predictive of secondary endpoints in the follow-up periods of 0–9 and 9–24 months, during which clopidogrel was mostly discontinued. Conclusion This study demonstrates that increased residual platelet reactivity measured by PFA-100 CADP-CT consistently predicts the occurrence of cardiovascular events following PCI throughout the 24-month follow-up period, irrespective of the changes in anti-platelet use.