0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention:  The GRAVITAS Randomized Trial FREE

Matthew J. Price, MD; Peter B. Berger, MD; Paul S. Teirstein, MD; Jean-François Tanguay, MD; Dominick J. Angiolillo, MD; Douglas Spriggs, MD; Sanjeev Puri, MD; Mark Robbins, MD; Kirk N. Garratt, MD; Olivier F. Bertrand, MD; Michael E. Stillabower, MD; Joseph R. Aragon, MD; David E. Kandzari, MD; Curtiss T. Stinis, MD; Michael S. Lee, MD; Steven V. Manoukian, MD; Christopher P. Cannon, MD; Nicholas J. Schork, PhD; Eric J. Topol, MD; for the GRAVITAS Investigators
[+] Author Affiliations

Author Affiliation: Scripps Clinic (Drs Price, Teirstein, Stinis, and Topol), Scripps Translational Science Institute (Drs Price, Teirstein, Schork, and Topol), and Scripps Research Institute (Dr Schork), La Jolla, California; Geisinger Clinic, Danville, Pennsylvania (Dr Berger); Montreal Heart Institute, Montreal, Canada (Dr Tanguay); University of Florida at Shands-Jacksonville, Jacksonville (Dr Angiolillo); Clearwater Cardiovascular Consultants, Clearwater, Florida (Dr Spriggs); Trinity Medical Center, Moline, Illinois (Dr Puri); Vanderbilt University, Nashville, Tennessee (Dr Robbins); Lenox Hill Hospital, New York, New York (Dr Garratt); Laval Hospital, Quebec City, Quebec, Canada (Dr Bertrand); Christiana Hospital, Newark, Delaware (Dr Stillabower); Sansum Clinic, Santa Barbara, California (Dr Aragon); Piedmont Heart Institute, Atlanta, Georgia (Dr Kandzari); University of California at Los Angeles (Dr Lee); Sarah Cannon Research Institute and Hospital Corporation of America, Nashville, Tennessee (Dr Manoukian); and Brigham and Women's Hospital, Boston, Massachusetts (Dr Cannon).


JAMA. 2011;305(11):1097-1105. doi:10.1001/jama.2011.290.
Text Size: A A A
Published online

Context 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.

Objective To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.

Design, Setting, and Patients 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.

Interventions 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.

Main Outcome Measures 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.

Results 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).

Conclusions 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.

Trial Registration clinicaltrials.gov Identifier: NCT00645918

Figures in this Article

Current guidelines recommend treating patients undergoing percutaneous coronary intervention (PCI) and drug-eluting stent implantation with a combination of aspirin and P2Y12 antagonist for at least 1 year.1 Clopidogrel is a prodrug that requires biotransformation into an active metabolite in order to exert its inhibitory effect on platelet activation and aggregation.2 Pharmacokinetic and pharmacodynamic studies have demonstrated wide interindividual variability in the concentration of active metabolite and in the magnitude of platelet inhibition achieved by recommended loading and maintenance doses of clopidogrel.35 Although some of this variability is due to genetic polymorphisms that affect the functional activity of the CYP2C19 enzyme, most cannot be explained by genotype or other clinical characteristics.6,7

Several studies have suggested that patients with high on-treatment platelet reactivity while receiving clopidogrel are at an increased risk of cardiovascular events after PCI, including stent thrombosis.8 We conducted the Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety (GRAVITAS) trial to determine whether high-dose clopidogrel is superior to standard-dose therapy for the prevention of cardiovascular events after PCI in patients with high on-treatment reactivity according to a point-of-care platelet function assay.

Trial Design

GRAVITAS was a multicenter, randomized, double-blind, active-control trial. The details of the study design have been published previously.9 Patient flow is shown in Figure 1. An independent data and safety monitoring board monitored the trial and had access to the unblinded data. The trial was approved by the institutional ethics committee of each participating institution as well as by the appropriate national ethics committees. All patients provided written informed consent.

Place holder to copy figure label and caption
Figure 1. Trial Profile
Graphic Jump Location

PRU indicates P2Y12 reaction units.

Study Population

Patients were eligible to be enrolled if they had undergone PCI with 1 or more drug-eluting stents for the treatment of stable coronary artery disease or non–ST-elevation acute coronary syndromes. Race and ethnicity were self-identified. A protocol amendment during the conduct of the study allowed for the enrollment of patients with ST-elevation myocardial infarction. Major exclusion criteria included the use of periprocedural glycoprotein IIb/IIIa inhibitors, the planned future use of oral anticoagulant therapy, and bleeding prior to platelet function measurement. Patients were also excluded if they did not receive a clopidogrel regimen around the time of PCI that ensured that they were near to or at their steady state level of inhibition at the time of platelet function measurement. Specifically, if the patient had no prior exposure to clopidogrel, a dose of 600 mg had to have been administered no later than 2 hours after PCI; patients already treated with clopidogrel must have received 75 mg daily for at least 7 days, or, if less than 7 days, they must have received a loading dose of 300 mg or more at the time that clopidogrel was initiated. Patients could not receive an additional loading dose prior to assessment of platelet function.

Study Procedures

Platelet function was measured with the VerifyNow P2Y12 test (Accumetrics, San Diego, California) 12 to 24 hours after PCI. This test has been previously described in detail.10 In brief, this test measures adenosine diphospate−induced platelet agglutination as an increase in light transmittance and uses a proprietary algorithm to report values in P2Y12 reaction units (PRU). A higher PRU result reflects greater P2Y12-mediated reactivity. Specialized software developed for the trial encrypted the platelet function results to maintain double blinding. Study drug assignment was performed centrally by an interactive voice-response system. The clopidogrel and placebo were in tablet form and identical in appearance. Patients with high on-treatment platelet reactivity according to the platelet function test were randomly assigned in a 1:1 fashion to a regimen of high-dose or standard-dose clopidogrel. High-dose clopidogrel was given as a total first-day dose of 600 mg followed thereafter by a dose of 150 mg daily for 6 months. Standard-dose clopidogrel was prescribed as a loading dose of placebo followed by a dose of 75 mg and placebo tablet daily. A random sample of patients without high on-treatment reactivity was enrolled and assigned to standard-dose clopidogrel in a blinded fashion (placebo loading dose followed by a dose of 75 mg and placebo tablet daily). A permuted block design was used to select these patients over the course of the trial. Patients without high on-treatment reactivity who were not selected by the interactive voice-response system were not followed up. Aspirin treatment was required at a dose of 75 to 162 mg daily. Study visits and platelet function testing with the VerifyNow P2Y12 test were conducted at 30 days and 6 months.

End Points

High on-treatment reactivity was defined as 230 PRU or higher. This cutoff was chosen because it was similar to the cutoff suggested by a prior observational study that used receiver-operating characteristic (ROC) curve analysis to identify the level of on-treatment reactivity that provided the maximal sensitivity and specificity for the prediction of major adverse cardiovascular events after PCI.11 The cutoff is also consistent with the suggested cutoffs derived by ROC curve analyses in several subsequent observational studies.1214 The primary efficacy variable was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. All deaths were considered cardiovascular unless an unequivocal noncardiovascular cause could be established; hemorrhagic deaths were also considered to be cardiovascular. Myocardial infarction followed the American College of Cardiology definition.15 Stent thrombosis was defined as definite or probable according to the Academic Research Consortium definitions.16 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.17 All potential events were identified by site investigators. A clinical events committee blinded to treatment assignment and independent of the trial sponsor adjudicated all suspected primary efficacy end points.

Statistical Analysis

Efficacy comparisons were performed on the basis of the time to the first event according to the intention-to-treat principle. No imputation of missing data was performed; patients lost to follow-up were censored at the date of last contact. Safety analyses were carried out on data from patients who had received at least 1 dose of the study drug. Survival curves were generated by the Kaplan-Meier method, and survival differences between groups were compared by the log-rank test stratified by acute coronary syndromes. We estimated that, assuming an event rate of 5% in patients with high on-treatment reactivity treated with standard-dose clopidogrel and a withdrawal rate of 10%, 2200 patients with high on-treatment reactivity (1100 in each group) would provide 80% power to detect a 50% relative risk reduction in the rate of the primary efficacy variable at the 2-sided .05 significance level. This would translate into the expectation of 68 events to have 82% power.9 The anticipated event rate in the active control group was based on prospective, observational studies of the relationship between high on-treatment reactivity and ischemic events.11,18 The event rate was further supported by the results of a large observational study reported after the trial began enrollment.14 The estimated relative risk reduction underlying the trial's power calculation is greater than that of traditional megatrials, but we purposefully selected the patients who would be biologically most likely to have the most powerful clinical response to the intervention that was tested.19 This estimate is also consistent with the treatment effect observed in the placebo-controlled trials of thienopyridine therapy in patients undergoing coronary intervention with bare metal stents.20,21

The principal secondary analysis was an observational comparison of the rate of the primary efficacy variable among the patients with and without high on-treatment reactivity treated with standard-dose clopidogrel. We estimated that 583 patients would provide 80% power at the 2-sided .05 significance level based on the assumptions above and an event rate of 2% in patients without high on-treatment reactivity.

Prespecified analyses included landmark analyses of the primary efficacy end point in patients event-free at 30 days. The statistical analysis plan also prespecified pharmacodynamic analyses of the randomized groups that included an assessment of the absolute level of on-treatment reactivity, the change in on-treatment reactivity, and the rate of high on-treatment reactivity at 30 days and 6 months using the Wilcoxon rank sum and χ2 tests. Analyses were performed with SAS version 9.1.3 (SAS Institute Inc, Cary, North Carolina).

Between July 2008 and April 2010, 5429 patients from 83 sites in the United States and Canada were screened with platelet function testing 12 to 24 hours after PCI. Of these, 2214 (40.8%) had high on-treatment reactivity and were randomly assigned to either high-dose or standard-dose clopidogrel (Figure 1). The treatment groups were generally well balanced with regard to baseline demographic, clinical, and procedural characteristics (Table 1). An additional 586 patients without high on-treatment reactivity were selected at random and assigned to treatment with standard-dose clopidogrel. Demographic and clinical characteristics were similar between patients who were or were not selected, except more patients with prior myocardial infarction were in the selected cohort (189 [32%] vs 711 [27%], P = .01). As shown in Table 1, there were several differences in the baseline demographics, medical history, and concomitant medications of the selected patients without high on-treatment reactivity compared with the patients in the randomized groups with high on-treatment reactivity. Clopidogrel exposure prior to enrollment was similar across all 3 treatment groups. Four patients (0.1%) were lost to follow-up.

Table Graphic Jump LocationTable 1. Baseline Clinical and Procedural Characteristics of the Study Patients, According to Treatment Group
Efficacy End Points

The rate of death from cardiovascular causes, nonfatal MI, or stent thrombosis was not different with high-dose compared with standard-dose clopidogrel in the patients with high on-treatment reactivity (25 [2.3%] vs 25 [2.3%]; hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97; Table 2 and Figure 2). The event rates in the 2 groups after 30 days were not different by landmark analysis (20 [1.9%] vs 17 [1.6%]; HR 1.19; 95% CI, 0.62-2.27; P = .60).

Table Graphic Jump LocationTable 2. Major Efficacy and Safety End Points at 6 Months in Randomized Patients With High On-Treatment Platelet Reactivitya
Place holder to copy figure label and caption
Figure 2. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point
Graphic Jump Location

The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Data were analyzed according to the intention-to-treat principle.

In the secondary, observational comparison of patients with and without high on-treatment reactivity treated with standard-dose clopidogrel, the rate of death from cardiovascular causes, nonfatal MI, or stent thrombosis was numerically greater in the patients with high on-treatment reactivity than in those without high on-treatment reactivity, but this difference did not reach statistical significance (25 [2.3%] vs 8 [1.4%]; HR, 1.68; 95% CI, 0.76-3.72; P = .20; Table 3 and Figure 2). Landmark analysis at 30 days also demonstrated a greater, but not significant, risk of events in patients with high on-treatment reactivity (17 [1.6%] vs 4 [0.7%]; HR, 2.27; 95% CI, 0.76-6.74; P = .13).

Table Graphic Jump LocationTable 3. Major Efficacy and Safety End Points at 6 Months for the Nonrandomized Comparison of Patients With or Without High On-Treatment Platelet Reactivity Treated With Standard-Dose Clopidogrela
Safety End Points

The frequencies of bleeding events are shown in Table 4. Intracranial hemorrhage occurred in none of the patients with high on-treatment reactivity randomly assigned to high-dose clopidogrel, in 2 patients (0.2%) with high on-treatment reactivity randomly assigned to standard-dose clopidogrel, and in 1 patient (0.2%) without high on-treatment reactivity treated with standard-dose clopidogrel. The rate of discontinuation of study drug due to GUSTO severe or moderate bleeding was similar across all 3 groups: 8 patients (0.7%), 11 patients (1.0%) and 6 patients (1.0%), respectively.

Table Graphic Jump LocationTable 4. Bleeding Events at 6 Months by GUSTO Criteria
Pharmacodynamic Outcomes

The pharmacodynamic effect of the study drug in patients randomly assigned to high-dose or standard-dose clopidogrel according to the intent-to-treat principle is illustrated in Figure 3. The level of on-treatment reactivity decreased significantly over the first 30 days in both groups, from 283 PRU (interquartile range [IQR], 255-321 PRU) to 250 PRU (IQR, 206-298 PRU) with standard-dose clopidogrel (P < .001) and from 282 PRU (IQR, 255-320 PRU) to 211 PRU (IQR, 155-262 PRU) with high-dose clopidogrel (P < .001). The reduction in on-treatment reactivity at 30 days and at 6 months after randomization was significantly greater with high-dose than with standard-dose clopidogrel (80 PRU; IQR, 37-128 PRU vs 37 PRU; IQR, 1-79 PRU; P < .0001 and 85 PRU; IQR, 37-138 PRU vs 44 PRU; IQR, 3.5-91 PRU; P < .001, respectively). High-dose clopidogrel led to an absolute 22% (95% CI, 18%-26% and 24%, 95% CI, 20%-28%) lower rate of high on-treatment reactivity (ie, PRU ≥ 230) compared with standard-dose clopidogrel at 30 days and 6 months (40%; 95% CI, 37%-43% vs 62%; 95% CI, 59%-65%; P < .001 and 36%; 95% CI, 33%-39% vs 60%; 95% CI, 57%-63%; P < .001, respectively).

Place holder to copy figure label and caption
Figure 3. Pharmacodynamic Effect of High- and Standard-Dose Clopidogrel in Randomized Patients With High On-Treatment Platelet Reactivity
Graphic Jump Location

High-dose clopidogrel resulted in significantly lower levels of on-treatment platelet reactivity at 30 days and 6 months than standard-dose clopidogrel (P < .001, respectively, not corrected for multiple comparisons). The horizontal line in the middle of each box indicates the median; the top and bottom borders of each box indicate the interquartile range (IQR). The whiskers above and below the box indicate plus/minus 1.5 IQRs, respectively.

Pharmacodynamic studies have demonstrated wide interindividual variability in the platelet inhibitory response to clopidogrel, and observational studies have linked a poor pharmacodynamic response to cardiovascular events after PCI.8,22 We found that compared with the standard maintenance dose of 75 mg daily, prolonged high-dose clopidogrel therapy in a population of patients with high on-treatment reactivity after PCI provided a modest pharmacodynamic effect but did not reduce the rate of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.

Several potential mechanisms may explain the lack of a beneficial treatment effect with high-dose clopidogrel. The possibility that on-treatment platelet reactivity is not a modifiable risk factor for thrombotic events after PCI cannot be excluded. However, undertreatment may explain our findings because high-dose clopidogrel resulted in only a modest reduction in the level of on-treatment reactivity and in the rate of high on-treatment reactivity compared with standard-dose clopidogrel. This observation is consistent with previous smaller studies demonstrating that clopidogrel 150 mg daily provides only a moderate increase in platelet inhibition above that provided by 75 mg daily in patients with high on-treatment reactivity, and that heightened platelet reactivity persists in a large proportion of patients.2327 Carriers of a reduced function CYP2C19 allele are at greater risk for high on-treatment platelet reactivity while taking clopidogrel,6 and higher-dose clopidogrel may have only a marginal pharmacodynamic effect in these patients, especially in homozygotes.25,28,29 It is possible that other more potent inhibitors of platelet aggregation may have been beneficial. Prasugrel has a strong and consistent pharmacodynamic effect in clopidogrel nonresponders30 and is not affected by genetic variation of the CYP2C19 enzyme.31 The clinical impact of prasugrel in patients with high reactivity while receiving clopidogrel is currently being examined in an ongoing clinical trial (clinicaltrials.gov, NCT00910299).

The relative benefit of high-dose clopidogrel may also have been diluted by the decrease in the frequency of high on-treatment reactivity in both randomized groups over the initial 30 days after PCI. High on-treatment reactivity measured 12 to 24 hours after PCI resolved at the 30-day follow-up in 38% of the patients randomly assigned to standard-dose clopidogrel. A possible explanation for this decrement in reactivity in the post-PCI period may be that early high on-treatment reactivity is a manifestation of poststenting platelet activation in a subset of patients.32 The clinical, procedural, and genetic predictors of the early resolution of high on-treatment reactivity after PCI deserve further evaluation. The dynamic nature of platelet reactivity that was observed underscores the importance of understanding the effect of the timing of measurement on the level of reactivity and its association with adverse outcomes.

In a secondary, nonrandomized, observational comparison within the current trial, there was a numerically greater rate of the composite end point in patients with high on-treatment reactivity 12 to 24 hours after PCI. However, the low event rates and modest sample size reduced the power of the study to identify statistically significant differences. Many prior studies have documented a consistent and significant association between on-treatment reactivity and early and late cardiovascular events, and several studies have demonstrated the prognostic utility of the platelet function test used in the current study.8,1214,18,22,3337 The prognostic strength of a single measurement of platelet reactivity after PCI may be weakened by the diminution of platelet reactivity that we observed at 30 days after PCI. This observation, combined with the variable pharmacodynamic response to high-dose clopidogrel, suggests that rather than prescribing a fixed, higher dose of clopidogrel based on a single post-PCI platelet function test, a strategy of repeated platelet function testing may have merit, and this hypothesis should be explored further.

The duration of treatment with high-dose maintenance clopidogrel in the present trial is substantially longer than previously examined. We found that treatment with a 6-month post-PCI regimen of high-dose clopidogrel did not appear to be accompanied by an excess of severe or moderate bleeding events or intracranial hemorrhage compared with a standard-dose regimen. This clinical finding is consistent with our pharmacodynamic observation that high-dose clopidogrel provided only a modest amount of incremental platelet inhibition in patients with high on-treatment reactivity. The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial evaluated a 600-mg clopidogrel loading dose followed by 7 days of 150 mg of clopidogrel in patients with acute coronary syndromes not selected by platelet function testing and found an increased risk of bleeding that required blood transfusion.38 The discordant findings between that study and GRAVITAS may in part be explained by differences in the study populations: in the current trial, we enrolled patients with high on-treatment reactivity and excluded those with major bleeding around the time of the index PCI, while CURRENT-OASIS 7 enrolled patients prior to PCI without regard to the level of on-treatment reactivity.

Although GRAVITAS is the largest randomized trial to date of individualized antiplatelet therapy based on ex vivo platelet function testing, the desired power of our primary analysis was reduced because we observed only 50 events, yet anticipated 68 events to have greater than 80% power to detect a 50% relative risk reduction with our intervention. A treatment effect of high-dose clopidogrel therefore cannot be excluded.

Our trial has several limitations. Although eligible to be enrolled, few patients in the trial had high-risk acute coronary syndromes (biomarker-positive non–ST-elevation and ST-elevation myocardial infarction); accordingly, the results may not apply to such patients. We measured platelet reactivity and assigned study drug after PCI, and therefore could not assess the effectiveness of high-dose clopidogrel in reducing the incidence of periprocedural myocardial infarction. Our therapeutic intervention was a higher, fixed dose of clopidogrel, rather than a strategy of iterative-dose adjustment to “normalize” platelet reactivity to a specific target. The baseline characteristics of patients with and without high on-treatment reactivity differed greatly, as noted in previous, smaller studies.7,3941 We did not adjust our analyses for these differences because of the large number of independent variables compared with the relatively small number of events.42 Therefore, the current study cannot address whether on-treatment reactivity is an independent predictor of thrombotic risk.14

In conclusion, high-dose clopidogrel for 6 months in patients with high on-treatment platelet reactivity 12 to 24 hours after PCI with drug-eluting stents did not reduce the rate of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis compared with standard-dose clopidogrel. The results of GRAVITAS do not support a uniform treatment strategy of high-dose clopidogrel in patients with high on-treatment reactivity identified by a single platelet function test after PCI. Alternative treatment strategies incorporating platelet function testing merit further investigation.

Corresponding Author: Matthew J. Price, MD, 10666 N Torrey Pines Rd, Maildrop S1056, La Jolla, CA 92037 (price.matthew@scrippshealth.org).

Author Contributions: Dr Price 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: Price, Berger, Cannon, Angiolillo, Topol

Acquisition of Data: Price, Berger, Teirstein, Tanguay, Angiolillo, Spriggs, Puri, Robbins, Garratt, Bertrand, Stillabower, Aragon, Manoukian

Analysis and Interpretation of the data: Price, Berger, Cannon, Teirstein, Angiolillo, Schork, Topol

Drafting of the manuscript: Price

Critical revision of the manuscript for important intellectual content: Price, Berger, Cannon, Teirstein, Tanguay, Angiolillo, Topol, Schork, Spriggs, Puri, Robbins, Garratt, Bertrand, Stillabower, Aragon, Stinis, Kandzari, Lee, Manoukian

Statistical analysis: Price, Schork

Obtained funding: Price, Topol

Study supervision: Price, Berger, Cannon, Tanguay, Teirstein, Topol

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Price reported receiving consulting fees from Bristol-Myers Squibb/sanofi-aventis, Daiichi Sankyo/Eli Lilly & Co, Accumetrics, AstraZeneca, and Medicure; speakers fees from Daiichi Sankyo/Eli Lilly & Co; and grant support from Bristol-Myers Squibb/sanofi-aventis. Dr Tanguay reported receiving consulting and speakers fees from Bristol-Myers Squibb/sanofi-aventis, Daiichi Sankyo/Eli Lilly & Co, GlaxoSmithKline, Abbott Vascular, and AstraZeneca and speakers fees from Boehringer Ingelheim. Dr Angiolillo reported receiving consulting fees from Bristol-Myers Squibb/sanofi-aventis, Daiichi Sankyo/Eli Lilly & Co, AstraZeneca, The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, and Merck; and speakers fees from Bristol-Myers Squibb/sanofi-aventis and Daiichi Sankyo/Eli Lilly & Co; Dr Garratt reported receiving consulting fees from The Medicines Company; speakers fees from Boston Scientific, The Medicines Company, sanofi-aventis, Daiichi Sankyo/Eli Lilly & Co, Medtronic, and Abbott Vascular; and serving on the advisory board of Boston Scientific. Dr Aragon reported receiving consulting and speakers fees from The Medicines Company, and speakers fees from Bristol-Myers Squibb/sanofi- aventis. Dr Kandzari reported receiving consulting and speakers fees from Daiichi Sankyo/Eli Lilly & Co. Dr Lee reported receiving speakers fees from Bristol-Myers Squibb/sanofi-aventis. Dr Cannon reports receiving consulting fees from Bristol-Myers Squibb/sanofi-aventis, Alynlam, and Novartis and grant support from Intekrin Therapeutics; and serving on the advisory board for GlaxoSmithKline and Merck. Dr Topol reported receiving consulting fees from Bristol-Myers Squibb/sanofi-aventis and Daiichi Sankyo/Eli Lilly & Co. The other authors reported no disclosures.

Funding/Support: The GRAVITAS trial was funded by Accumetrics. The study drug was provided by an investigator-initiated grant from Bristol-Myers Squibb/sanofi-aventis.

Role of the Sponsor: The executive committee, consisting of both academic members and nonvoting representatives of the sponsor, designed and oversaw the conduct of the trial. The sponsor coordinated the data management with a contract research organization (Synteract, Carlsbad, California). Bristol-Myers Squibb/sanofi-aventis had no role in the design and management of the trial or in the analysis of the data.

GRAVITAS Investigators: D. Spriggs, S. Puri, M. Robbins, P. Teirstein, K. Garratt, O. Bertrand, M. Stillabower, J. Aragon, E.D. Nukta, J. F. Tanguay, A. Abbas, T. Mann, W. Batchelor, P. Gordon, M. Schwieger, M. Amine, P. Berger, N. Chronos, D. So, R. Stoler, S. Marshalko, R. Waksman, C. O’Shaughnessy, E. Fry, D. Angiolillo, B. McLaurin, S. Rao, R. Gammon, M. Z. Jafar, G. Wong, D. Cohen, J. Robb, M. Lucca, S. Ward, D. Rizik, J. Wang, R. Minutello, E. Mahmud, P. K. Cheung, M. Fugit, G. Mishkel, A. Jacobs, C. Meritt, M. Lurie, S. Manoukian, M. Turco, J. P. Reilly, M. Buchbinder, H. Herrmann, M. Vidovich, D. Purdy, M. Warshofsky, J. Saucedo, L. Cannon, S. Waxman, G. Goulet, H. B. Cheek, R. Applegate, D. Simon, S. Plante, H. Aronow, V. Misra, S. Mehta, A. Malik, S. Bailey, A. Cheema, J. Nappi, D. Abbott, J. Kao, O. Gigliotti, S. DeMaio, T. McGarry, A. Wu, D. Henderson, E. Schampaert, J. Joye, T. Huynh, J. P. Pelletier, D. Kereiakes, N. Kleiman, L. Bellumkonda, L. Gruberg.

Previous Presentation: This study was presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions, Chicago, Illinois, November 16, 2010.

This article was corrected for errors on May 2, 2011.

Kushner FG, Hand M, Smith SC Jr,  et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [a published correction appears in Circulation. 2010;121(12):e257].  Circulation. 2009;120(22):2271-2306
PubMed   |  Link to Article
Kazui M, Nishiya Y, Ishizuka T,  et al.  Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.  Drug Metab Dispos. 2010;38(1):92-99
PubMed   |  Link to Article
Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.  Circulation. 2003;107(23):2908-2913
PubMed   |  Link to Article
von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial.  Circulation. 2005;112(19):2946-2950
PubMed
Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein PS. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers.  Am J Cardiol. 2006;98(5):681-684
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
Hochholzer W, Trenk D, Fromm MF,  et al.  Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.  J Am Coll Cardiol. 2010;55(22):2427-2434
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
Price MJ, Berger PB, Angiolillo DJ,  et al.  Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial.  Am Heart J. 2009;157(5):818-824
PubMed   |  Link to Article
Price MJ. Bedside evaluation of thienopyridine antiplatelet therapy.  Circulation. 2009;119(19):2625-2632
PubMed   |  Link to Article
Price MJ, Endemann S, Gollapudi RR,  et al.  Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.  Eur Heart J. 2008;29(8):992-1000
PubMed   |  Link to Article
Patti G, Nusca A, Mangiacapra F, Gatto L, D’Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study.  J Am Coll Cardiol. 2008;52(14):1128-1133
PubMed   |  Link to Article
Marcucci R, Gori AM, Paniccia R,  et al.  Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.  Circulation. 2009;119(2):237-242
PubMed   |  Link to Article
Breet NJ, van Werkum JW, Bouman HJ,  et al.  Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.  JAMA. 2010;303(8):754-762
PubMed   |  Link to Article
Cannon CP, Battler A, Brindis RG,  et al.  American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee).  J Am Coll Cardiol. 2001;38(7):2114-2130
PubMed   |  Link to Article
Cutlip DE, Windecker S, Mehran R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials: a case for standardized definitions.  Circulation. 2007;115(17):2344-2351
PubMed   |  Link to Article
 An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction: the GUSTO investigators.  N Engl J Med. 1993;329(10):673-682
PubMed   |  Link to Article
Buonamici P, Marcucci R, Migliorini A,  et al.  Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis.  J Am Coll Cardiol. 2007;49(24):2312-2317
PubMed   |  Link to Article
Schork NJ, Topol EJ. Genotype-based risk and pharmacogenetic sampling in clinical trials.  J Biopharm Stat. 2010;20(2):315-333
PubMed   |  Link to Article
Leon MB, Baim DS, Popma JJ,  et al; Stent Anticoagulation Restenosis Study Investigators.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.  N Engl J Med. 1998;339(23):1665-1671
PubMed   |  Link to Article
Bertrand ME, Legrand V, Boland J,  et al.  Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (fantastic) study.  Circulation. 1998;98(16):1597-1603
PubMed   |  Link to Article
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E,  et al.  Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.  J Am Coll Cardiol. 2007;49(14):1505-1516
PubMed   |  Link to Article
Angiolillo DJ, Shoemaker SB, Desai B,  et al.  Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.  Circulation. 2007;115(6):708-716
PubMed   |  Link to Article
Bonello-Palot N, Armero S, Paganelli F,  et al.  Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2009;104(11):1511-1515
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, Lee SW, Choi BR,  et al.  Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study.  J Am Coll Cardiol. 2009;53(13):1101-1109
PubMed   |  Link to Article
Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness.  Thromb Res. 2008;121(4):463-468
PubMed   |  Link to Article
Jeong Y-H, Kim I-S, 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
Pena A, Collet JP, Hulot JS,  et al.  Can we override clopidogrel resistance?  Circulation. 2009;119(21):2854-2857
PubMed   |  Link to Article
Jernberg T, Payne CD, Winters KJ,  et al.  Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease.  Eur Heart J. 2006;27(10):1166-1173
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
Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel.  Am J Cardiol. 2003;91(9):1123-1125
PubMed   |  Link to Article
Mangiacapra F, Barbato E, Patti G,  et al.  Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention.  JACC Cardiovasc Interv. 2010;3(3):318-323
PubMed   |  Link to Article
Migliorini A, Valenti R, Marcucci R,  et al.  High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.  Circulation. 2009;120(22):2214-2221
PubMed   |  Link to Article
Hochholzer W, Trenk D, Bestehorn HP,  et al.  Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.  J Am Coll Cardiol. 2006;48(9):1742-1750
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
Campo G, Fileti L, de Cesare N,  et al; 3T/2R Investigators.  Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.  J Am Coll Cardiol. 2010;56(18):1447-1455
PubMed   |  Link to Article
Mehta SR, Bassand JP, Chrolavicius S,  et al; CURRENT-OASIS 7 Investigators.  Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.  N Engl J Med. 2010;363(10):930-942
PubMed   |  Link to Article
Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2009;103(10):1339-1343
PubMed   |  Link to Article
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E,  et al.  Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment.  Diabetes. 2005;54(8):2430-2435
PubMed   |  Link to Article
Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel.  J Am Coll Cardiol. 2008;52(19):1557-1563
PubMed   |  Link to Article
Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models.  Ann Intern Med. 1993;118(3):201-210
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Trial Profile
Graphic Jump Location

PRU indicates P2Y12 reaction units.

Place holder to copy figure label and caption
Figure 2. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point
Graphic Jump Location

The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Data were analyzed according to the intention-to-treat principle.

Place holder to copy figure label and caption
Figure 3. Pharmacodynamic Effect of High- and Standard-Dose Clopidogrel in Randomized Patients With High On-Treatment Platelet Reactivity
Graphic Jump Location

High-dose clopidogrel resulted in significantly lower levels of on-treatment platelet reactivity at 30 days and 6 months than standard-dose clopidogrel (P < .001, respectively, not corrected for multiple comparisons). The horizontal line in the middle of each box indicates the median; the top and bottom borders of each box indicate the interquartile range (IQR). The whiskers above and below the box indicate plus/minus 1.5 IQRs, respectively.

Tables

Table Graphic Jump LocationTable 1. Baseline Clinical and Procedural Characteristics of the Study Patients, According to Treatment Group
Table Graphic Jump LocationTable 2. Major Efficacy and Safety End Points at 6 Months in Randomized Patients With High On-Treatment Platelet Reactivitya
Table Graphic Jump LocationTable 3. Major Efficacy and Safety End Points at 6 Months for the Nonrandomized Comparison of Patients With or Without High On-Treatment Platelet Reactivity Treated With Standard-Dose Clopidogrela
Table Graphic Jump LocationTable 4. Bleeding Events at 6 Months by GUSTO Criteria

References

Kushner FG, Hand M, Smith SC Jr,  et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [a published correction appears in Circulation. 2010;121(12):e257].  Circulation. 2009;120(22):2271-2306
PubMed   |  Link to Article
Kazui M, Nishiya Y, Ishizuka T,  et al.  Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.  Drug Metab Dispos. 2010;38(1):92-99
PubMed   |  Link to Article
Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.  Circulation. 2003;107(23):2908-2913
PubMed   |  Link to Article
von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial.  Circulation. 2005;112(19):2946-2950
PubMed
Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein PS. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers.  Am J Cardiol. 2006;98(5):681-684
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
Hochholzer W, Trenk D, Fromm MF,  et al.  Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.  J Am Coll Cardiol. 2010;55(22):2427-2434
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
Price MJ, Berger PB, Angiolillo DJ,  et al.  Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial.  Am Heart J. 2009;157(5):818-824
PubMed   |  Link to Article
Price MJ. Bedside evaluation of thienopyridine antiplatelet therapy.  Circulation. 2009;119(19):2625-2632
PubMed   |  Link to Article
Price MJ, Endemann S, Gollapudi RR,  et al.  Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.  Eur Heart J. 2008;29(8):992-1000
PubMed   |  Link to Article
Patti G, Nusca A, Mangiacapra F, Gatto L, D’Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study.  J Am Coll Cardiol. 2008;52(14):1128-1133
PubMed   |  Link to Article
Marcucci R, Gori AM, Paniccia R,  et al.  Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.  Circulation. 2009;119(2):237-242
PubMed   |  Link to Article
Breet NJ, van Werkum JW, Bouman HJ,  et al.  Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.  JAMA. 2010;303(8):754-762
PubMed   |  Link to Article
Cannon CP, Battler A, Brindis RG,  et al.  American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee).  J Am Coll Cardiol. 2001;38(7):2114-2130
PubMed   |  Link to Article
Cutlip DE, Windecker S, Mehran R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials: a case for standardized definitions.  Circulation. 2007;115(17):2344-2351
PubMed   |  Link to Article
 An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction: the GUSTO investigators.  N Engl J Med. 1993;329(10):673-682
PubMed   |  Link to Article
Buonamici P, Marcucci R, Migliorini A,  et al.  Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis.  J Am Coll Cardiol. 2007;49(24):2312-2317
PubMed   |  Link to Article
Schork NJ, Topol EJ. Genotype-based risk and pharmacogenetic sampling in clinical trials.  J Biopharm Stat. 2010;20(2):315-333
PubMed   |  Link to Article
Leon MB, Baim DS, Popma JJ,  et al; Stent Anticoagulation Restenosis Study Investigators.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.  N Engl J Med. 1998;339(23):1665-1671
PubMed   |  Link to Article
Bertrand ME, Legrand V, Boland J,  et al.  Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (fantastic) study.  Circulation. 1998;98(16):1597-1603
PubMed   |  Link to Article
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E,  et al.  Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.  J Am Coll Cardiol. 2007;49(14):1505-1516
PubMed   |  Link to Article
Angiolillo DJ, Shoemaker SB, Desai B,  et al.  Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.  Circulation. 2007;115(6):708-716
PubMed   |  Link to Article
Bonello-Palot N, Armero S, Paganelli F,  et al.  Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2009;104(11):1511-1515
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, Lee SW, Choi BR,  et al.  Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study.  J Am Coll Cardiol. 2009;53(13):1101-1109
PubMed   |  Link to Article
Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness.  Thromb Res. 2008;121(4):463-468
PubMed   |  Link to Article
Jeong Y-H, Kim I-S, 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
Pena A, Collet JP, Hulot JS,  et al.  Can we override clopidogrel resistance?  Circulation. 2009;119(21):2854-2857
PubMed   |  Link to Article
Jernberg T, Payne CD, Winters KJ,  et al.  Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease.  Eur Heart J. 2006;27(10):1166-1173
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
Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel.  Am J Cardiol. 2003;91(9):1123-1125
PubMed   |  Link to Article
Mangiacapra F, Barbato E, Patti G,  et al.  Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention.  JACC Cardiovasc Interv. 2010;3(3):318-323
PubMed   |  Link to Article
Migliorini A, Valenti R, Marcucci R,  et al.  High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.  Circulation. 2009;120(22):2214-2221
PubMed   |  Link to Article
Hochholzer W, Trenk D, Bestehorn HP,  et al.  Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.  J Am Coll Cardiol. 2006;48(9):1742-1750
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
Campo G, Fileti L, de Cesare N,  et al; 3T/2R Investigators.  Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.  J Am Coll Cardiol. 2010;56(18):1447-1455
PubMed   |  Link to Article
Mehta SR, Bassand JP, Chrolavicius S,  et al; CURRENT-OASIS 7 Investigators.  Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.  N Engl J Med. 2010;363(10):930-942
PubMed   |  Link to Article
Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2009;103(10):1339-1343
PubMed   |  Link to Article
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E,  et al.  Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment.  Diabetes. 2005;54(8):2430-2435
PubMed   |  Link to Article
Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel.  J Am Coll Cardiol. 2008;52(19):1557-1563
PubMed   |  Link to Article
Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models.  Ann Intern Med. 1993;118(3):201-210
PubMed   |  Link to Article
CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 376

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario