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Original Contribution |

Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease FREE

Jessica L. Mega, MD, MPH; Willibald Hochholzer, MD; Andrew L. Frelinger, PhD; Michael J. Kluk, MD, PhD; Dominick J. Angiolillo, MD; Dean J. Kereiakes, MD; Steven Isserman, MD; William J. Rogers, MD; Christian T. Ruff, MD, MPH; Charles Contant, PhD; Michael J. Pencina, PhD; Benjamin M. Scirica, MD, MPH; Janina A. Longtine, MD, PhD; Alan D. Michelson, MD; Marc S. Sabatine, MD, MPH
[+] Author Affiliations

Author Affiliations: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Drs Mega, Ruff, Scirica, and Sabatine); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (Dr Hochholzer); Center for Platelet Research Studies, Children's Hospital Boston, Boston (Drs Frelinger and Michelson); Center for Advanced Molecular Diagnostics, Department of Pathology, Brigham and Women's Hospital, Boston (Drs Kluk and Longtine); University of Florida College of Medicine, Jacksonville (Dr Angiolillo); Heart and Vascular Center and Lindner Research, The Christ Hospital, Cincinnati, Ohio (Dr Kereiakes); Clinical Trials of America, Hickory, North Carolina (Dr Isserman); University of Alabama at Birmingham Medical Center (Dr Rogers); TIMI Study Group, Boston (Dr Contant); and Harvard Clinical Research Institute and Boston University, Boston (Dr Pencina).


JAMA. 2011;306(20):2221-2228. doi:10.1001/jama.2011.1703.
Text Size: A A A
Published online

Context Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel.

Objective To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes.

Design, Setting, and Patients ELEVATE-TIMI 56 was a multicenter, randomized, double-blind trial that enrolled and genotyped 333 patients with cardiovascular disease across 32 sites from October 2010 until September 2011.

Interventions Maintenance doses of clopidogrel for 4 treatment periods, each lasting approximately 14 days, based on genotype. In total, 247 noncarriers of a CYP2C19*2 loss-of-function allele were to receive 75 and 150 mg daily of clopidogrel (2 periods each), whereas 86 carriers (80 heterozygotes, 6 homozygotes) were to receive 75, 150, 225, and 300 mg daily.

Main Outcome Measures Platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y12 assays) and adverse events.

Results With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% CI, 66.0%-74.0%, vs 57.5%; 95% CI, 55.1%-59.9%, and VerifyNow P2Y12 reaction units [PRU]: mean, 225.6; 95% CI, 207.7-243.4, vs 163.6; 95% CI, 154.4-173.9; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity, with VASP PRI decreasing to 48.9% (95% CI, 44.6%-53.2%) and PRU to 127.5 (95% CI, 109.9-145.2) (P < .001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (≥230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 or 300 mg (P < .001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04). In CYP2C19*2 homozygotes, even with 300 mg daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) and mean PRU, 287.0 (95% CI, 170.2-403.8).

Conclusion Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition.

Trial Registration clinicaltrials.gov Identifier: NCT01235351

Figures in this Article

Clopidogrel blocks the platelet P2Y12 adenosine diphosphate (ADP) receptor, inhibition of which has been shown to reduce cardiovascular events in patients with an acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI).14 Although the standard 75-mg daily maintenance dose of clopidogrel has proven to be clinically efficacious in these settings, variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with higher platelet reactivity while receiving clopidogrel are at increased risk of adverse cardiovascular events.5 Clopidogrel, a prodrug, needs to undergo biotransformation to form an active metabolite, and interindividual differences in clopidogrel metabolism are a source of the variable response to the antiplatelet medication.

Cytochrome P450 (CYP) enzymes play a critical role in the metabolism of clopidogrel. Multiple studies have demonstrated that both heterozygotes and homozygotes for loss-of-function CYP2C19 alleles have lower levels of the active clopidogrel metabolite,6,7 diminished platelet inhibition,8,9 and higher rates of adverse cardiovascular events as compared with noncarriers in the setting of treatment with standard 75-mg maintenance doses of clopidogrel.10 Regulatory agencies, including the US Food and Drug Administration (FDA) and the European Medicines Agency, have responded to these data. In the case of the FDA, a boxed warning was added to the clopidogrel prescribing information that recommends considering alternative treatment strategies in patients with particular CYP2C19 genotypes.

As such, data are needed to offer guidance as to what might constitute optimal treatment strategies in patients with loss-of-function CYP2C19 alleles. Although newer P2Y12 inhibitors are available that are unaffected by CYP2C19 genotype, these medications can be expensive and are not accessible in all countries. In contrast, clopidogrel is widely available, already generic in some countries, and anticipated to be generic in the United States in 2012, which may influence the cost.

Therefore, we conducted ELEVATE-TIMI 56, a multicenter, randomized, double-blind trial, to test whether maintenance doses of up to 300 mg daily of clopidogrel can improve platelet reactivity in the setting of the major loss-of-function CYP2C19 genotype (CYP2C19*2), particularly among heterozygotes, who constitute approximately 25% to 45% of the population depending on racial background. We hypothesized that: (1) increasing the maintenance doses of clopidogrel in patients who carry a CYP2C19*2 allele will correspondingly reduce platelet reactivity, and (2) among carriers of CYP2C19*2, a higher maintenance dose of clopidogrel can be found that reduces platelet reactivity to the levels achieved in noncarriers treated with the established, standard 75-mg daily maintenance dose of clopidogrel.

In total, 335 patients from 32 sites were enrolled from October 2010 until September 2011 in the trial, which was conducted in patients with known cardiovascular disease taking 75 mg of clopidogrel daily (Figure 1). To be eligible, patients needed to have an indication for the use of clopidogrel (either a myocardial infarction [MI] and/or PCI ≥4 weeks and ≤6 months prior to enrollment) and be clinically stable. All patients took aspirin, 81 to 325 mg, daily, and they were requested to keep taking a stable dose during the study if medically indicated. Key exclusion criteria were use of anticoagulants or proton pump inhibitors (PPIs), current smoking, prior stent thrombosis, heightened risk of bleeding, end-stage renal or hepatic disease, or a procedure or hospitalization planned in the next 12 weeks.

Place holder to copy figure label and caption
Figure 1. Patient Flow Diagram
Graphic Jump Location

The number of individuals screened for eligibility is not known.

Study Protocol

At the time of enrollment, a baseline clinical evaluation was performed, and each patient underwent blood sampling for blinded genotyping and platelet function testing. A pyrosequencing assay was performed at the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital to assess for CYP2C19*2 status (National Center for Biotechnology Information [NCBI] genome build 37.1, NG_008384). Genotyping was repeated using a Nanosphere Verigene 2C19/CBS nucleic acid research-use-only assay. A total of 333 individuals were successfully genotyped and confirmed for CYP2C19*2 status.

Patients were allocated, using a central interactive voice response system (Worldwide Clinical Trials), to a blinded sequence of maintenance doses of clopidogrel for 4 treatment periods, each approximately 14 (±3) days. Patients who were carriers of CYP2C19*2 received 75, 150, 225, and 300 mg daily of clopidogrel (in various sequences). Noncarriers received 75 and 150 mg daily (2 periods of each dose) of clopidogrel (in various sequences). At the end of each treatment period, platelet function testing was performed and ischemic, bleeding, and other adverse events were ascertained. After the last study drug treatment period, patients resumed their prestudy antiplatelet medication if indicated and were contacted approximately 30 days later to assess for any adverse events.

The trial was approved by the institutional review board of each participating site, and participants provided written informed consent. An independent data and safety monitor reviewed unblinded data.

End Points

The outcome measurement was on-treatment platelet reactivity index (PRI) determined through flow cytometric assessment of phosphorylation status of vasodilator-stimulated phosphoprotein (VASP). The VASP PRI was determined from ambient blood samples sent to the Center for Platelet Research Studies (Children's Hospital Boston), which was blinded to patient treatment group.11 Platelet function testing was also conducted at each site with an encrypted point-of-care device (VerifyNow P2Y12 test; Accumetrics) and reported as P2Y12 reaction units (PRU), indicating the amount of ADP-mediated platelet aggregation specific to the platelet P2Y12 receptor. Nonresponder status was prespecified at 230 PRU or greater.12 Based on data that emerged after initiation of ELEVATE-TIMI 56,13 an additional cut point of 208 PRU or greater was also explored. Fatal, cardiovascular, cerebrovascular, and bleeding events were also assessed at each visit. These events were adjudicated by a blinded clinical event adjudicator. Adverse events and serious adverse events were collected.

Statistical Analysis

Continuous data are presented as means and 95% confidence intervals, and categorical data are presented as counts and percentages unless otherwise specified. The analytic data set consisted of all patients who were successfully genotyped, with the exception of 1 patient who was ultimately found to have a non–*2 loss-of-function CYP2C19 allele (and therefore never received the 225- or 300-mg dose of clopidogrel). No imputation was applied for missing data, and platelet function data were analyzed per-protocol.

The association of different doses of clopidogrel (test of trend) with platelet reactivity among carriers (with heterozygotes and homozygotes tested separately and combined) and noncarriers of the CYP2C19*2 loss-of-function allele was evaluated by fitting a repeated mixed model with patient as a random effect and doses as fixed effects, and, in the case of VASP PRI, adjusting for the time from sample collection to analysis. No significant carryover effects were detected for the dose sequences among CYP2C19*2 noncarriers (P = .82) or carriers (P = .46). Least square means and the differences among the means were calculated. Pairwise differences among means (ie, between individual clopidogrel maintenance doses) were assessed. Tukey-Kramer correction for multiple testing was used. Proportions of nonresponders were compared within each genotype group using a generalized linear model to account for correlated observations. A 2-sided P value of less than .05 was set as the level of significance.

The least square means from the mixed models were used to test whether higher maintenance doses of clopidogrel in carriers of a loss-of-function CYP2C19 allele could result in similar platelet inhibition as compared with a standard maintenance dose of clopidogrel in noncarriers. Differences among the least square means were calculated and reported with the 95% confidence intervals. Ratios of the means were calculated with 90% confidence intervals, and equivalence boundaries of 0.8 to 1.25 were used, extrapolating from prior FDA guidance.14

To obtain at least 80% power to detect a 7.5% difference in the paired VASP PRI means of the tested doses (which corresponds to 50% of the observed difference seen with increasing the maintenance dose of clopidogrel from 75 to 150 mg in patients of unknown genotype),15 and maintaining an overall α of .05 for the study, at least 76 CYP2C19 loss-of-function allele carriers were required. In this calculation, the standard deviation of the difference was assumed to be 20%. Based on an estimate of the proportion of patients carrying a CYP2C19 loss-of-function allele, the total sample size needed to be at least 254.

The following clinical outcomes were assessed by dose for CYP2C19*2 carriers and noncarriers using an intention-to-treat approach: death (cardiovascular and noncardiovascular), cardiac ischemic events (MI, unstable angina, urgent coronary revascularization), cerebrovascular events (stroke and transient ischemic attack), and bleeding (Thrombolysis in Myocardial Infarction[TIMI] scales). Analyses were conducted using SAS version 9.2.

In total, 333 patients were enrolled and underwent genotyping. Their mean (SD) age was 60.2 (9.9) years, 74.8% were male, 57.1% had a history of MI, and 97.3% had a history of PCI. A total of 247 patients were noncarriers of a CYP2C19*2 allele whereas 86 were carriers (80 heterozygotes and 6 homozygotes). Clinical characteristics did not differ between the carrier and noncarrier groups (Table 1). The adherence rates for the 75-, 150-, 225-, and 300-mg doses of clopidogrel among CYP2C19*2 carriers on study drug were 97.3%, 98.1%, 98.6%, and 98.3%, respectively.

Table Graphic Jump LocationTable 1. Patient Baseline Characteristicsa
Response to Higher Doses of Clopidogrel

When treated with a standard clopidogrel maintenance dose of 75 mg daily, both CYP2C19*2 heterozygotes and homozygotes had significantly higher on-treatment platelet reactivity than did noncarrier patients (mean VASP PRI, 70.0%; 95% CI, 66.0%-74.0%, and 86.6%; 95% CI, 80.7%-92.5%, vs 57.5%; 95% CI, 55.1%-59.9%; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, higher clopidogrel maintenance doses (up to 300 mg) produced significant reductions in platelet reactivity (P < .001 for trend) (Figure 2 and Table 2). Each 75-mg more of clopidogrel daily resulted in an approximate 8% to 9% absolute reduction in VASP PRI, with some attenuation between the 2 highest doses. Moreover, individual pairwise comparisons between the higher daily doses of clopidogrel (150, 225, and 300 mg) and the 75-mg daily dose of clopidogrel were all statistically significant (P < .001) as were comparisons between each of the higher doses (P < .001) except for the comparison between 225 and 300 mg daily.

Place holder to copy figure label and caption
Figure 2. On-Treatment Platelet Reactivity Across Genotype and Clopidogrel Daily Dose
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VASP PRI indicates vasodilator-stimulated phosphoprotein phosphorylation assay platelet reactivity index.

Table Graphic Jump LocationTable 2. On-Treatment Platelet Reactivitya

The VerifyNow results as assessed by PRU were similar to the VASP data across dose and genotype (Table 2). When treated with the standard maintenance dose of clopidogrel, 75-mg daily, both CYP2C19*2 heterozygotes and homozygotes had significantly higher platelet reactivity than did noncarrier patients (mean PRU, 225.6; 95% CI, 207.7-243.4, and 328.8; 95% CI, 247.9-409.7, vs 163.6; 95% CI, 154.4-173.9; P < .001 for both comparisons). Analogous to the VASP findings, higher doses of clopidogrel resulted in a significant reduction in platelet reactivity among CYP2C19*2 heterozygotes (P < .001 for trend).

Using a prespecified cut point for nonresponder status (defined as on-treatment platelet reactivity ≥230 PRU), 53 of 234 noncarriers (23%) were nonresponders with the 75-mg dose and 28 of 227 (12%) with the 150-mg dose. Among CYP2C19*2 heterozygotes, 40 of 76 (52%) were nonresponders with the 75-mg dose of clopidogrel. Higher maintenance doses of clopidogrel in CYP2C19*2 heterozygotes significantly reduced the proportion of nonresponders to 10% with 225 mg daily (8/75, P < .001) and 300 mg daily (7/73, P < .001) (Figure 3). The risk ratios for nonresponder status were 0.51 (95% CI, 0.37-0.69), 0.21 (95% CI, 0.11-0.39), and 0.20 (95% CI, 0.11-0.38) with 150, 225, and 300 mg daily of clopidogrel, respectively. Among the CYP2C19*2 -heterozygote nonresponders to clopidogrel, 75 mg, daily, the proportions who became responders were 49% (18/37), 79% (31/39), and 81% (30/37) when treated, respectively, with 150, 225, and 300 mg daily of clopidogrel. Similar results were obtained when a cut point for nonresponder status of 208 PRU or greater was used (eFigure 1).

Place holder to copy figure label and caption
Figure 3. Clopidogrel Nonresponders Among CYP2C19*2 Heterozygotes Across Daily Doses of Clopidogrel
Graphic Jump Location

Nonresponders were defined using the VerifyNow P2Y12 assay with a prespecified cut point of ≥230 P2Y12 reaction units (PRU).

When evaluating the CYP2C19*2 homozygotes, we saw a trend toward less platelet reactivity with higher maintenance doses of clopidogrel; however, even with 300 mg daily of clopidogrel, these individuals had a mean VASP PRI of 68.3% (95% CI, 44.9%-91.6%) and VerifyNow PRU of 287.0 (95% CI, 170.2-403.8). Similarly, the nonresponder rate (≥230 PRU) was 80% (4/5) with clopidogrel, 75 mg, daily and remained high at 60% (3/5) despite clopidogrel, 300 mg, daily.

High-Dose Clopidogrel in CYP2C19*2 Carriers vs Standard-Dose Clopidogrel in Noncarriers

In CYP2C19*2 heterozygotes, a 150-mg daily maintenance dose of clopidogrel still resulted in platelet reactivity that tended to be higher than that seen in noncarrier patients treated with 75 mg daily (Figure 4). In contrast, the 225-mg daily dose resulted in platelet reactivity at least as good as what was observed in response to standard clopidogrel dosing in noncarrier patients (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04) (eFigure 2). A 300-mg daily dose of clopidogrel resulted in superior reductions in platelet reactivity as compared with standard 75-mg clopidogrel dosing in noncarrier patients as measured both by VASP PRI and PRU (P < .001 for both). For CYP2C19*2 homozygotes, even 300 mg daily of clopidogrel did not result in platelet reactivity levels similar to standard clopidogrel dosing in noncarriers (Table 2).

Place holder to copy figure label and caption
Figure 4. Difference in Platelet Reactivity Between CYP2C19*2 Heterozygotes Treated With Increasing Doses of Clopidogrel vs Noncarriers Treated With 75 mg of Clopidogrel Daily
Graphic Jump Location

Data are reported as least squares differences and 95% confidence intervals for platelet reactivity between CYP2C19*2 heterozygotes at clopidogrel doses of 75 mg (n = 76), 150 mg (n = 73), 225 mg (n = 75), and 300 mg (n = 73) and noncarriers at 75 mg of clopidogrel (n = 237). Differences in least squares means were tested using asymptotic methods (normal z test). VASP indicates vasodilator-stimulated phosphoprotein phosphorylation assay.

Clinical Events

There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events. Among CYP2C19*2 noncarriers taking the 75 mg and 150 mg doses, 2 patients had cardiac ischemic events while taking the 75-mg dose and 3 with the 150-mg dose. There were 0 and 5 patients with bleeding events, respectively, that met criteria for bleeding requiring medical attention. Among carriers of a CYP2C19*2 allele, there was 1 patient who experienced a cardiac ischemic event at the 75-mg dose of clopidogrel. A bleeding event requiring medical attention occurred in 1 of the patients in each of the following dosing regimens: 75, 225, and 300 mg. No adverse events or serious adverse events that were not end points occurred at a frequency greater than 3% per treatment group, and there were no significant imbalances specifically for hematologic, gastrointestinal, or musculoskeletal disorders for CYP2C19*2 carriers at the different doses (eTable).

Clopidogrel, one of the most commonly prescribed cardiovascular medications in the world, is approved for a single maintenance dose of 75 mg daily. However, the response to clopidogrel is variable, and as a group, patients with either 1 or 2 loss-of-function CYP2C19 alleles have an attenuated pharmacologic response and worse clinical outcomes in the setting of treatment with the standard dose of clopidogrel. We now show that (1) higher maintenance doses of clopidogrel in patients carrying a CYP2C19*2 allele significantly reduce platelet reactivity, and (2) daily maintenance doses of 225 mg of clopidogrel or greater in CYP2C19*2 heterozygotes can achieve on-treatment platelet reactivity at least comparable with what is achieved with 75 mg daily of clopidogrel in noncarrier patients with cardiovascular disease.

Prior systematic pharmacogenetic studies have tested clopidogrel maintenance doses of 150 mg daily in carriers of a loss-of-function CYP2C19 allele and have reported mixed results. In one study of healthy individuals, a 150-mg maintenance dose of clopidogrel adequately reduced platelet reactivity in carriers of 1 or 2 loss-of-function CYP2C19 alleles16; other studies conducted in patients with cardiovascular disease with CYP2C19 loss-of-function alleles have not demonstrated as significant reductions in platelet reactivity with the 150-mg dose of clopidogrel.1721 Concordant with the latter observation, we found that increasing the maintenance dose from 75 to 150 mg did not on average inhibit platelet reactivity to the levels seen with 75 mg of clopidogrel in noncarrier patients. Rather, we found that on average, it required a tripling of the clopidogrel maintenance dose to achieve platelet reactivity that is at least as good as that observed with 75 mg of clopidogrel in CYP2C19*2 noncarriers. Interestingly, CLOVIS-2 studied the pharmacologic efficacy of different loading doses of clopidogrel based on CYP2C19 genotype and also found that a tripling of the dose (ie, a 900-mg load) achieved a degree of platelet inhibition comparable with what was observed in response to the standard 300-mg loading dose in noncarrier patients.22 Patients in our trial tolerated these higher maintenance doses of clopidogrel during the approximately 2-week duration of each therapy, with low rates of discontinuation. However, further long-term intervention trials are warranted.

Prasugrel and ticagrelor are newer P2Y12 ADP receptor blockers that achieve significantly higher levels of platelet inhibition than does clopidogrel.23,24 These agents have been shown to reduce ischemic events as compared with clopidogrel in patients with ACS, although with increased rates of nonsurgical bleeding.25,26 In contrast to clopidogrel, the effects of prasugrel and ticagrelor are unaffected by variants in the CYP2C19 gene (and correspondingly, no association between CYP2C19 genotype and clinical events has been observed in patients treated with these agents),27,28 and thus these medications represent other alternative treatment strategies in such patients. However, clopidogrel will likely continue to be used throughout the world, and it is therefore important to understand clopidogrel's effects across CYP2C19 genotypes and with higher maintenance doses.

Studies have evaluated whether tailoring clopidogrel therapy using platelet function testing improves clinical outcomes. Bonello and colleagues29 gave patients repeated loading doses of clopidogrel (up to 2400 mg total) to achieve a target level of suppression of platelet reactivity in each patient before PCI, and this strategy resulted in a significant decrease in adverse outcomes. In contrast, in GRAVITAS and RECLOSE 2-ACS, higher maintenance doses of clopidogrel after PCI in patients with high on-treatment platelet reactivity at baseline did not improve outcomes.30,31 The higher maintenance dose in GRAVITAS was clopidogrel, 150 mg, daily, which resulted in a median PRU of 211 (interquartile range, 155-262), and therefore somewhere between 25% and 50% of the population remained nonresponders with this dose. In RECLOSE 2-ACS, despite treating with higher maintenance doses of clopidogrel or switching to ticlopidine, 38% of patients continued to be nonresponders. ELEVATE-TIMI 56, in conjunction with the important observations from GRAVITAS and RECLOSE 2-ACS, highlights that doses even higher than 150 mg of clopidogrel or other agents may be necessary when tailoring antiplatelet therapy to overcome resistance in some patients, particularly those who carry a loss-of-function CYP2C19 allele.

Patients who carry 2 CYP2C19 loss-of-function alleles, also known as poor metabolizers, face particular hurdles when it comes to generating enough active clopidogrel metabolite and platelet inhibition with standard doses of clopidogrel, as noted by the FDA. ELEVATE-TIMI 56 was not specifically powered to evaluate these individuals, as they constitute only 2% of the tested population. Nonetheless, in ELEVATE-TIMI 56, among the subset of CYP2C19*2 homozygous patients, even the 300-mg dose of clopidogrel was not able to achieve on-treatment platelet reactivity comparable with clopidogrel, 75 mg, daily in noncarriers. Similarly, in CLOVIS-2, the high clopidogrel loading dose of 900 mg was able to adequately lower on-treatment platelet reactivity among carriers of 1 loss-of-function CYP2C19 allele but not 2.22 Such patients may be better served by treatment with prasugrel or ticagrelor, or perhaps the addition of cilostazol, all of which do not appear to be affected significantly by the CYP2C19 variants.

There are some limitations to these analyses. First, treatment allocation was based on carriage of only the *2 CYP2C19 loss-of-function allele, for which we could engage in timely, validated genotyping. More comprehensive genotyping panels are available; of note though, CYP2C19*2 is the most frequent variant, accounting for greater than 95% of the loss-of-function allele carrier status. Second, each treatment period consisted of approximately 14 days. This time frame allowed for a reasonable window to achieve steady state antiplatelet effect with each regimen with no significant carryover effect from the prior treatment. However, defining the long-term tolerability of the higher-dose regimens will require gathering additional experience. Third, PPI use at baseline was an exclusion criterion. Whereas this approach allowed for a focused evaluation of higher doses of clopidogrel in patients with CYP2C19 genetic variants, further studies will be needed to address questions pertaining to possible interactions between clopidogrel dosing, PPI use, and genotype. Fourth, this study focused on achieved platelet reactivity as the primary outcome of interest. While platelet reactivity is a well-validated predictor of poor clinical outcomes, large-scale and long-term trials powered for clinical outcomes will be necessary to assess for adverse events and establish preferred treatment regimens. Until then, ELEVATE-TIMI 56 offers a framework to rationally select alternative doses and lays the foundation for future studies.

In conclusion, ELEVATE-TIMI 56 demonstrates that among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers. Even 300 mg of clopidogrel daily, however, is unlikely to result in optimal degrees of platelet inhibition in CYP2C19*2 homozygotes. These data help define how patients with different CYP2C19 genotypes respond to clopidogrel maintenance dosing strategies and provides useful information to guide further clinical studies.

Corresponding Author: Jessica L. Mega, MD, MPH, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (jmega@partners.org).

Published Online: November 16, 2011. doi:10.1001/jama.2011.1703

Author Contributions: Dr Mega had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mega, Sabatine.

Acquisition of data: Angiolillo, Kereiakes, Isserman, Rogers.

Analysis and interpretation of data: Mega, Hochholzer, Frelinger, Kluk, Angiolillo, Kereiakes, Isserman, Rogers, Ruff, Contant, Pencina, Scirica, Longtine, Michelson, Sabatine.

Drafting of the manuscript: Mega, Sabatine.

Critical revision of the manuscript for important intellectual content: Hochholzer, Frelinger, Kluk, Angiolillo, Kereiakes, Isserman, Rogers, Ruff, Contant, Pencina, Scirica, Longtine, Michelson.

Statistical analysis: Contant, Pencina.

Obtained funding: Mega, Sabatine.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mega reported receiving research grants from Bristol-Myers Squibb/sanofi-aventis, Eli Lilly, Daiichi Sankyo, and Johnson & Johnson/Bayer, and other research support from Nanosphere and Accumetrics and serving on consultant/advisory boards for Bristol-Myers Squibb, sanofi-aventis, AstraZeneca, Bayer, Novartis, and Merck. Dr Hochholzer reported serving on a consultant/advisory board for sanofi-aventis. Dr Frelinger reported receiving research grants from Bristol-Myers Squibb/sanofi-aventis, Eli Lilly, Daiichi Sankyo, GL Synthesis, and Takeda and serving on a consultant/advisory board for Eli Lilly. Dr Angiolillo reported receiving research grants from Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, Eisai, Johnson & Johnson, Bristol-Myers Squibb/sanofi-aventis, GlaxoSmithKline, and Otsuka; other research support from a James and Esther King Biomedical Research Grant; and honoraria for lectures from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, and Daiichi Sankyo and serving on consultant/advisory boards for The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Evolva, Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Daiichi Sankyo, Abbott Vascular, and AstraZeneca. Dr Ruff reported receiving a research grant from Bristol-Myers Squibb/sanofi-aventis and Merck and serving on consultant/advisory boards for Daiichi Sankyo, Beckman Coulter, and Alere. Dr Scirica reported receiving research grants from AstraZeneca, Bristol-Myers Squibb, Merck, Johnson & Johnson, Bayer Healthcare, Gilead, and Daiichi Sankyo and serving on consultant/advisory boards for Gilead and AstraZeneca. Dr Michelson reported receiving research grants from Bristol-Myers Squibb/sanofi-aventis, Eli Lilly, Daiichi Sankyo, GL Synthesis, and Takeda and serving on a consultant/advisory board for Eli Lilly. Dr Sabatine reported receiving research grants from AstraZeneca, Bristol-Myers Squibb/sanofi-aventis joint venture, Daiichi Sankyo, sanofi-aventis, and Schering-Plough and other research support from Nanosphere and serving on consultant/advisory boards for AstraZeneca, Bristol-Myers Squibb/sanofi-aventis, Daiichi Sankyo/Eli Lilly, Eli Lilly, and sanofi-aventis. No other disclosures were reported.

Funding/Support: The ELEVATE-TIMI 56 trial was funded by an investigator-initiated grant from Bristol-Myers Squibb/sanofi-aventis. Research supplies were provided by Accumetrics and Nanosphere. Dr Mega is supported in part by grant K99/R00 HL098461 from the National Institutes of Health. Dr Hochholzer is supported in part by the German Heart Foundation.

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

ELEVATE-TIMI 56 Investigators: A. Albirini, D. Angiolillo, G. Aycock, B. Bertolet, R. Bhagwat, R. Blonder, H. Chandna, J. Cole, S. Denning, D. Doty, C. Fastabend, L. Ferrier, W. Ginete, S. Gips, R. Goldberg, G. Hamroff, E. Haskel, S. Isserman, B. Iteld, S. Jones, J. Katopodis, D. Kereiakes, N. Kleiman, E. Korban, B. Peart, J. Peterson, B. Reddy, W. Rogers, C. Sotolongo, C. Staniloae, R. Vicari, F. Wefald.

Additional Contributions: The following individuals contributed to the study: Laura Grip, BA; Robert Mesa, BS; John Mattimore, BA; John Cyr, PA; and David Berg, MD (TIMI Study Group). Additional statistical support was provided by Satish Mohanavelu, MS, and Kevin Crowley, MS (TIMI Study Group), and Lanyu Lei (Harvard Clinical Research Institute) and Gheorghe Doros, PhD (Boston University). Dr Doros was compensated for his contribution by Harvard Clinical Research Institute. The other individuals were not compensated for their contributions besides their salaries.

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345(7):494-502
PubMed   |  Link to Article
Sabatine MS, Cannon CP, Gibson CM,  et al;  CLARITY-TIMI 28 Investigators.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.  N Engl J Med. 2005;352(12):1179-1189
PubMed   |  Link to Article
Chen ZM, Jiang LX, Chen YP,  et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.  Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.  Lancet. 2005;366(9497):1607-1621
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT III,  et al; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;288(19):2411-2420
PubMed   |  Link to Article
Bonello L, Tantry US, Marcucci R,  et al; Working Group on High On-Treatment Platelet Reactivity.  Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.  J Am Coll Cardiol. 2010;56(12):919-933
PubMed   |  Link to Article
Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects.  J Thromb Haemost. 2008;6(8):1439-1441
PubMed   |  Link to Article
Brandt JT, Close SL, Iturria SJ,  et al.  Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.  J Thromb Haemost. 2007;5(12):2429-2436
PubMed   |  Link to Article
Trenk D, Hochholzer W, Fromm MF,  et al.  Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents.  J Am Coll Cardiol. 2008;51(20):1925-1934
PubMed   |  Link to Article
Shuldiner AR, O’Connell JR, Bliden KP,  et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.  JAMA. 2009;302(8):849-857
PubMed   |  Link to Article
Mega JL, Simon T, Collet JP,  et al.  Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.  JAMA. 2010;304(16):1821-1830
PubMed   |  Link to Article
Michelson AD, Frelinger AL III, Braunwald E,  et al; TRITON-TIMI 38 Investigators.  Pharmacodynamic assessment of platelet inhibition by prasugrel vs clopidogrel in the TRITON-TIMI 38 trial.  Eur Heart J. 2009;30(14):1753-1763
PubMed   |  Link to Article
Brar SS, Ten Berg J, Marcucci R,  et al.  Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data.  J Am Coll Cardiol. 2011;58(19):1945-1954
PubMed   |  Link to Article
Price MJ, Angiolillo DJ, Teirstein PS,  et al.  Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial.  Circulation. 2011;124(10):1132-1137
PubMed   |  Link to Article
 Guidance for industry: statistical approaches to establishing bioequivalence. US Food and Drug Administration site. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070244.pdf. Accessed October 28, 2011
Aleil B, Jacquemin L, De Poli F,  et al.  Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study.  JACC Cardiovasc Interv. 2008;1(6):631-638
PubMed   |  Link to Article
Simon T, Bhatt DL, Bergougnan L,  et al.  Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects.  Clin Pharmacol Ther. 2011;90(2):287-295
PubMed   |  Link to Article
Pena A, Collet JP, Hulot JS,  et al.  Can we override clopidogrel resistance?  Circulation. 2009;119(21):2854-2857
PubMed   |  Link to Article
Barker CM, Murray SS, Teirstein PS, Kandzari DE, Topol EJ, Price MJ. Pilot study of the antiplatelet effect of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on-treatment reactivity.  JACC Cardiovasc Interv. 2010;3(10):1001-1007
PubMed   |  Link to Article
Jeong YH, Kim IS, Park Y,  et al.  Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study.  JACC Cardiovasc Interv. 2010;3(7):731-741
PubMed   |  Link to Article
Alexopoulos D, Dimitropoulos G, Davlouros P,  et al.  Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping.  JACC Cardiovasc Interv. 2011;4(4):403-410
PubMed   |  Link to Article
Angiolillo DJ, Ueno M. Optimizing platelet inhibition in clopidogrel poor metabolizers: therapeutic options and practical considerations.  JACC Cardiovasc Interv. 2011;4(4):411-414
PubMed   |  Link to Article
Collet JP, Hulot JS, Anzaha G,  et al; CLOVIS-2 Investigators.  High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2).  JACC Cardiovasc Interv. 2011;4(4):392-402
PubMed   |  Link to Article
Wiviott SD, Trenk D, Frelinger AL,  et al; PRINCIPLE-TIMI 44 Investigators.  Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 trial.  Circulation. 2007;116(25):2923-2932
PubMed   |  Link to Article
Bliden KP, Tantry US, Storey RF,  et al.  The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies.  Am Heart J. 2011;162(1):160-165
PubMed   |  Link to Article
Wiviott SD, Braunwald E, McCabe CH,  et al;  TRITON-TIMI 38 Investigators.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2007;357(20):2001-2015
PubMed   |  Link to Article
Wallentin L, Becker RC, Budaj A,  et al; PLATO Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2009;361(11):1045-1057
PubMed   |  Link to Article
Mega JL, Close SL, Wiviott SD,  et al.  Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes.  Circulation. 2009;119(19):2553-2560
PubMed   |  Link to Article
Wallentin L, James S, Storey RF,  et al; PLATO investigators.  Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.  Lancet. 2010;376(9749):1320-1328
PubMed   |  Link to Article
Bonello L, Camoin-Jau L, Arques S,  et al.  Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study.  J Am Coll Cardiol. 2008;51(14):1404-1411
PubMed   |  Link to Article
Price MJ, Berger PB, Teirstein PS,  et al;  GRAVITAS Investigators.  Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.  JAMA. 2011;305(11):1097-1105
PubMed   |  Link to Article
Parodi G, Marcucci R, Valenti R,  et al.  High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.  JAMA. 2011;306(11):1215-1223
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Patient Flow Diagram
Graphic Jump Location

The number of individuals screened for eligibility is not known.

Place holder to copy figure label and caption
Figure 2. On-Treatment Platelet Reactivity Across Genotype and Clopidogrel Daily Dose
Graphic Jump Location

VASP PRI indicates vasodilator-stimulated phosphoprotein phosphorylation assay platelet reactivity index.

Place holder to copy figure label and caption
Figure 3. Clopidogrel Nonresponders Among CYP2C19*2 Heterozygotes Across Daily Doses of Clopidogrel
Graphic Jump Location

Nonresponders were defined using the VerifyNow P2Y12 assay with a prespecified cut point of ≥230 P2Y12 reaction units (PRU).

Place holder to copy figure label and caption
Figure 4. Difference in Platelet Reactivity Between CYP2C19*2 Heterozygotes Treated With Increasing Doses of Clopidogrel vs Noncarriers Treated With 75 mg of Clopidogrel Daily
Graphic Jump Location

Data are reported as least squares differences and 95% confidence intervals for platelet reactivity between CYP2C19*2 heterozygotes at clopidogrel doses of 75 mg (n = 76), 150 mg (n = 73), 225 mg (n = 75), and 300 mg (n = 73) and noncarriers at 75 mg of clopidogrel (n = 237). Differences in least squares means were tested using asymptotic methods (normal z test). VASP indicates vasodilator-stimulated phosphoprotein phosphorylation assay.

Tables

Table Graphic Jump LocationTable 1. Patient Baseline Characteristicsa
Table Graphic Jump LocationTable 2. On-Treatment Platelet Reactivitya

References

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345(7):494-502
PubMed   |  Link to Article
Sabatine MS, Cannon CP, Gibson CM,  et al;  CLARITY-TIMI 28 Investigators.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.  N Engl J Med. 2005;352(12):1179-1189
PubMed   |  Link to Article
Chen ZM, Jiang LX, Chen YP,  et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.  Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.  Lancet. 2005;366(9497):1607-1621
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT III,  et al; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;288(19):2411-2420
PubMed   |  Link to Article
Bonello L, Tantry US, Marcucci R,  et al; Working Group on High On-Treatment Platelet Reactivity.  Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.  J Am Coll Cardiol. 2010;56(12):919-933
PubMed   |  Link to Article
Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects.  J Thromb Haemost. 2008;6(8):1439-1441
PubMed   |  Link to Article
Brandt JT, Close SL, Iturria SJ,  et al.  Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.  J Thromb Haemost. 2007;5(12):2429-2436
PubMed   |  Link to Article
Trenk D, Hochholzer W, Fromm MF,  et al.  Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents.  J Am Coll Cardiol. 2008;51(20):1925-1934
PubMed   |  Link to Article
Shuldiner AR, O’Connell JR, Bliden KP,  et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.  JAMA. 2009;302(8):849-857
PubMed   |  Link to Article
Mega JL, Simon T, Collet JP,  et al.  Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.  JAMA. 2010;304(16):1821-1830
PubMed   |  Link to Article
Michelson AD, Frelinger AL III, Braunwald E,  et al; TRITON-TIMI 38 Investigators.  Pharmacodynamic assessment of platelet inhibition by prasugrel vs clopidogrel in the TRITON-TIMI 38 trial.  Eur Heart J. 2009;30(14):1753-1763
PubMed   |  Link to Article
Brar SS, Ten Berg J, Marcucci R,  et al.  Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data.  J Am Coll Cardiol. 2011;58(19):1945-1954
PubMed   |  Link to Article
Price MJ, Angiolillo DJ, Teirstein PS,  et al.  Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial.  Circulation. 2011;124(10):1132-1137
PubMed   |  Link to Article
 Guidance for industry: statistical approaches to establishing bioequivalence. US Food and Drug Administration site. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070244.pdf. Accessed October 28, 2011
Aleil B, Jacquemin L, De Poli F,  et al.  Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study.  JACC Cardiovasc Interv. 2008;1(6):631-638
PubMed   |  Link to Article
Simon T, Bhatt DL, Bergougnan L,  et al.  Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects.  Clin Pharmacol Ther. 2011;90(2):287-295
PubMed   |  Link to Article
Pena A, Collet JP, Hulot JS,  et al.  Can we override clopidogrel resistance?  Circulation. 2009;119(21):2854-2857
PubMed   |  Link to Article
Barker CM, Murray SS, Teirstein PS, Kandzari DE, Topol EJ, Price MJ. Pilot study of the antiplatelet effect of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on-treatment reactivity.  JACC Cardiovasc Interv. 2010;3(10):1001-1007
PubMed   |  Link to Article
Jeong YH, Kim IS, Park Y,  et al.  Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study.  JACC Cardiovasc Interv. 2010;3(7):731-741
PubMed   |  Link to Article
Alexopoulos D, Dimitropoulos G, Davlouros P,  et al.  Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping.  JACC Cardiovasc Interv. 2011;4(4):403-410
PubMed   |  Link to Article
Angiolillo DJ, Ueno M. Optimizing platelet inhibition in clopidogrel poor metabolizers: therapeutic options and practical considerations.  JACC Cardiovasc Interv. 2011;4(4):411-414
PubMed   |  Link to Article
Collet JP, Hulot JS, Anzaha G,  et al; CLOVIS-2 Investigators.  High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2).  JACC Cardiovasc Interv. 2011;4(4):392-402
PubMed   |  Link to Article
Wiviott SD, Trenk D, Frelinger AL,  et al; PRINCIPLE-TIMI 44 Investigators.  Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 trial.  Circulation. 2007;116(25):2923-2932
PubMed   |  Link to Article
Bliden KP, Tantry US, Storey RF,  et al.  The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies.  Am Heart J. 2011;162(1):160-165
PubMed   |  Link to Article
Wiviott SD, Braunwald E, McCabe CH,  et al;  TRITON-TIMI 38 Investigators.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2007;357(20):2001-2015
PubMed   |  Link to Article
Wallentin L, Becker RC, Budaj A,  et al; PLATO Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2009;361(11):1045-1057
PubMed   |  Link to Article
Mega JL, Close SL, Wiviott SD,  et al.  Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes.  Circulation. 2009;119(19):2553-2560
PubMed   |  Link to Article
Wallentin L, James S, Storey RF,  et al; PLATO investigators.  Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.  Lancet. 2010;376(9749):1320-1328
PubMed   |  Link to Article
Bonello L, Camoin-Jau L, Arques S,  et al.  Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study.  J Am Coll Cardiol. 2008;51(14):1404-1411
PubMed   |  Link to Article
Price MJ, Berger PB, Teirstein PS,  et al;  GRAVITAS Investigators.  Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.  JAMA. 2011;305(11):1097-1105
PubMed   |  Link to Article
Parodi G, Marcucci R, Valenti R,  et al.  High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.  JAMA. 2011;306(11):1215-1223
PubMed   |  Link to Article
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