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Patients with high on-treatment platelet reactivity after percutaneous coronary intervention who received high-dose clopidogrel fared no better in terms of cardiovascular events than did high-reactivity patients on standard-dose clopidogrel in the GRAVITAS trial.
"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," Dr. Matthew J. Price and his coinvestigators wrote in the March 16 issue of JAMA. However, "alternative treatment strategies incorporating platelet function testing merit further investigation."
In the Gauging Responsiveness With a VerifyNow Assay – Impact on Thrombosis and Safety (GRAVITAS) trial, researchers measured platelet function with the VerifyNow P2Y12 test (Accumetrics) 12-24 hours after PCI. A greater P2Y12 reaction unit (PRU) result reflects greater P2Y12 mediated reactivity. High on-treatment reactivity was defined as 230 PRU or greater. This cutoff was chosen because it was similar to the cutoff suggested by a prior observational study.
Patients were eligible for enrollment if they had undergone PCI with at least one drug-eluting stent for the treatment of stable coronary artery disease or acute coronary syndromes. Patients with high on-treatment platelet reactivity were randomly assigned to receive either high-dose or standard-dose clopidogrel. High-dose clopidogrel was given as a total first-day dose of 600 mg followed by 150 mg daily for 6 months. Standard-dose clopidogrel involved a loading dose of placebo followed by a dose of 75 mg and placebo tablet daily.
In all, 5,429 patients from 83 sites in the United States and Canada were screened with platelet function testing. Of these, 2,214 (41%) had high on-treatment reactivity and were randomly assigned to either high-dose or standard-dose clopidogrel. An additional 586 patients without high on-treatment reactivity were selected at random and assigned to treatment with standard-dose clopidogrel (JAMA 2011;305:1097-105).
The primary efficacy end point, a composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis at 6 months, was identical in both groups with high reactivity, at 25 (2.3%).
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. That occurred in 15 (1.4%) and 25 (2.3%) of patients in the high- and low-dose groups, respectively, a nonsignificant difference.
In a 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, at 25 and 8, respectively, but this difference did not reach statistical significance.
In terms of safety, intracranial hemorrhage occurred in none of the patients with high on-treatment reactivity who were randomly assigned to high-dose clopidogrel, in two patients (0.2%) with high on-treatment reactivity on standard-dose clopidogrel, and in one patient (0.2%) without high on-treatment reactivity treated with standard-dose clopidogrel. The rate of discontinuation of study drug due to severe or moderate bleeding was similar across all three groups.
The results of GRAVITAS are of particular interest because studies have shown wide interindividual variability in the platelet inhibitory response to clopidogrel and suggested a link between a poor pharmacodynamic response to cardiovascular events after PCI.
"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," wrote Dr. Price, director of the cardiac catheterization laboratory at the Scripps Clinic in La Jolla, Calif., and his coinvestigators.
The researchers suggested several potential mechanisms that may explain the lack of a beneficial treatment effect with high-dose clopidogrel. It may be that on-treatment platelet reactivity is simply not a modifiable risk factor for thrombosis after PCI, or that the solution is to use an agent such as prasugrel, which doesn’t require metabolic transformation to reach its active form.
But the timing of the test may also play a role. Platelet reactivity resolved in nearly 40% of patients on normal-dose clopidogrel within 30 days, suggesting that the poststenting platelet activation may be temporary in a subset of patients.
"The dynamic nature of platelet reactivity that was observed underscores the importance of understanding the effect of the timing of the measurement on the level of reactivity and its association with adverse outcomes," they observed.
The GRAVITAS trial was sponsored by Accumetrics. Dr. Price said that he serves as a consultant to the company as well as to Sanofi-Aventis and Bristol-Myers Squibb, which provided the clopidogrel used in the study. Several other authors reported significant financial relationships with a number of pharmaceutical companies.
While the GRAVITAS trial is the first large randomized, prospective trial to determine whether personalization of antiplatelet therapy based on platelet function testing actually improves clinical outcomes among patients treated with stents, the results were disappointing and questions remain, Dr. Paul A. Gurbel and Udaya S. Tantry, Ph.D., wrote in an accompanying editorial (JAMA 2011;305:1136-7).
"There are several possible reasons personalizing therapy using high-dose clopidogrel was not effective. Among these are that high-dose clopidogrel had a limited effect in overcoming high platelet reactivity. The overall trial event rates were low, and the cut point for defining high on-treatment platelet reactivity may have been too high."
Importantly, the intended power of the trial’s primary analysis was reduced because only 50 events were observed but 68 events were anticipated. "Given the low event rates in GRAVITAS, only an extremely effective treatment would have had any chance to significantly influence outcomes."
Several important questions cannot be answered based on the data, they pointed out. Was the platelet reactivity before the ischemic event greater than the platelet reactivity in patients without ischemic events? Were ischemic events clustered among patients whose platelet reactivity was lower than the cut point used to define high on-treatment reactivity?
"Answers to these questions will be useful in addressing the hypothesis that ischemic event occurrence increases markedly above a critical cut point. However, the possibility also exists that ischemic events occurred in the presence of low platelet reactivity in GRAVITAS. The latter finding would suggest that high on-treatment platelet reactivity identified early after stenting is only a marker of risk and that the level of risk cannot be modified by intensification of antiplatelet therapy," they wrote.
While more work is needed before personalized antiplatelet therapy can be recommended, one idea is that a more potent P2Y12 receptor blocker may be a more effective intervention. Future studies of personalized antiplatelet therapy will also consider whether a different optimal P2Y12 cutoff and serial platelet function measurements can better identify patients at risk."
"Even though GRAVITAS demonstrated that platelet function testing after drug-eluting stent placement does not improve outcomes if high-dose clopidogrel is used as the remedy, it is hoped that future studies evaluating different platelet function cut points and more potent P2Y12 inhibitors will be effective."
Dr. Gurbel is the director of the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. He reported significant financial relationships with several pharmaceutical companies. Dr. Tantry is the laboratory director at the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. Dr. Tantry reported no financial disclosures.
While the GRAVITAS trial is the first large randomized, prospective trial to determine whether personalization of antiplatelet therapy based on platelet function testing actually improves clinical outcomes among patients treated with stents, the results were disappointing and questions remain, Dr. Paul A. Gurbel and Udaya S. Tantry, Ph.D., wrote in an accompanying editorial (JAMA 2011;305:1136-7).
"There are several possible reasons personalizing therapy using high-dose clopidogrel was not effective. Among these are that high-dose clopidogrel had a limited effect in overcoming high platelet reactivity. The overall trial event rates were low, and the cut point for defining high on-treatment platelet reactivity may have been too high."
Importantly, the intended power of the trial’s primary analysis was reduced because only 50 events were observed but 68 events were anticipated. "Given the low event rates in GRAVITAS, only an extremely effective treatment would have had any chance to significantly influence outcomes."
Several important questions cannot be answered based on the data, they pointed out. Was the platelet reactivity before the ischemic event greater than the platelet reactivity in patients without ischemic events? Were ischemic events clustered among patients whose platelet reactivity was lower than the cut point used to define high on-treatment reactivity?
"Answers to these questions will be useful in addressing the hypothesis that ischemic event occurrence increases markedly above a critical cut point. However, the possibility also exists that ischemic events occurred in the presence of low platelet reactivity in GRAVITAS. The latter finding would suggest that high on-treatment platelet reactivity identified early after stenting is only a marker of risk and that the level of risk cannot be modified by intensification of antiplatelet therapy," they wrote.
While more work is needed before personalized antiplatelet therapy can be recommended, one idea is that a more potent P2Y12 receptor blocker may be a more effective intervention. Future studies of personalized antiplatelet therapy will also consider whether a different optimal P2Y12 cutoff and serial platelet function measurements can better identify patients at risk."
"Even though GRAVITAS demonstrated that platelet function testing after drug-eluting stent placement does not improve outcomes if high-dose clopidogrel is used as the remedy, it is hoped that future studies evaluating different platelet function cut points and more potent P2Y12 inhibitors will be effective."
Dr. Gurbel is the director of the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. He reported significant financial relationships with several pharmaceutical companies. Dr. Tantry is the laboratory director at the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. Dr. Tantry reported no financial disclosures.
While the GRAVITAS trial is the first large randomized, prospective trial to determine whether personalization of antiplatelet therapy based on platelet function testing actually improves clinical outcomes among patients treated with stents, the results were disappointing and questions remain, Dr. Paul A. Gurbel and Udaya S. Tantry, Ph.D., wrote in an accompanying editorial (JAMA 2011;305:1136-7).
"There are several possible reasons personalizing therapy using high-dose clopidogrel was not effective. Among these are that high-dose clopidogrel had a limited effect in overcoming high platelet reactivity. The overall trial event rates were low, and the cut point for defining high on-treatment platelet reactivity may have been too high."
Importantly, the intended power of the trial’s primary analysis was reduced because only 50 events were observed but 68 events were anticipated. "Given the low event rates in GRAVITAS, only an extremely effective treatment would have had any chance to significantly influence outcomes."
Several important questions cannot be answered based on the data, they pointed out. Was the platelet reactivity before the ischemic event greater than the platelet reactivity in patients without ischemic events? Were ischemic events clustered among patients whose platelet reactivity was lower than the cut point used to define high on-treatment reactivity?
"Answers to these questions will be useful in addressing the hypothesis that ischemic event occurrence increases markedly above a critical cut point. However, the possibility also exists that ischemic events occurred in the presence of low platelet reactivity in GRAVITAS. The latter finding would suggest that high on-treatment platelet reactivity identified early after stenting is only a marker of risk and that the level of risk cannot be modified by intensification of antiplatelet therapy," they wrote.
While more work is needed before personalized antiplatelet therapy can be recommended, one idea is that a more potent P2Y12 receptor blocker may be a more effective intervention. Future studies of personalized antiplatelet therapy will also consider whether a different optimal P2Y12 cutoff and serial platelet function measurements can better identify patients at risk."
"Even though GRAVITAS demonstrated that platelet function testing after drug-eluting stent placement does not improve outcomes if high-dose clopidogrel is used as the remedy, it is hoped that future studies evaluating different platelet function cut points and more potent P2Y12 inhibitors will be effective."
Dr. Gurbel is the director of the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. He reported significant financial relationships with several pharmaceutical companies. Dr. Tantry is the laboratory director at the Sinai Center for Thrombosis Research at Sinai Hospital of Baltimore. Dr. Tantry reported no financial disclosures.
Patients with high on-treatment platelet reactivity after percutaneous coronary intervention who received high-dose clopidogrel fared no better in terms of cardiovascular events than did high-reactivity patients on standard-dose clopidogrel in the GRAVITAS trial.
"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," Dr. Matthew J. Price and his coinvestigators wrote in the March 16 issue of JAMA. However, "alternative treatment strategies incorporating platelet function testing merit further investigation."
In the Gauging Responsiveness With a VerifyNow Assay – Impact on Thrombosis and Safety (GRAVITAS) trial, researchers measured platelet function with the VerifyNow P2Y12 test (Accumetrics) 12-24 hours after PCI. A greater P2Y12 reaction unit (PRU) result reflects greater P2Y12 mediated reactivity. High on-treatment reactivity was defined as 230 PRU or greater. This cutoff was chosen because it was similar to the cutoff suggested by a prior observational study.
Patients were eligible for enrollment if they had undergone PCI with at least one drug-eluting stent for the treatment of stable coronary artery disease or acute coronary syndromes. Patients with high on-treatment platelet reactivity were randomly assigned to receive either high-dose or standard-dose clopidogrel. High-dose clopidogrel was given as a total first-day dose of 600 mg followed by 150 mg daily for 6 months. Standard-dose clopidogrel involved a loading dose of placebo followed by a dose of 75 mg and placebo tablet daily.
In all, 5,429 patients from 83 sites in the United States and Canada were screened with platelet function testing. Of these, 2,214 (41%) had high on-treatment reactivity and were randomly assigned to either high-dose or standard-dose clopidogrel. An additional 586 patients without high on-treatment reactivity were selected at random and assigned to treatment with standard-dose clopidogrel (JAMA 2011;305:1097-105).
The primary efficacy end point, a composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis at 6 months, was identical in both groups with high reactivity, at 25 (2.3%).
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. That occurred in 15 (1.4%) and 25 (2.3%) of patients in the high- and low-dose groups, respectively, a nonsignificant difference.
In a 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, at 25 and 8, respectively, but this difference did not reach statistical significance.
In terms of safety, intracranial hemorrhage occurred in none of the patients with high on-treatment reactivity who were randomly assigned to high-dose clopidogrel, in two patients (0.2%) with high on-treatment reactivity on standard-dose clopidogrel, and in one patient (0.2%) without high on-treatment reactivity treated with standard-dose clopidogrel. The rate of discontinuation of study drug due to severe or moderate bleeding was similar across all three groups.
The results of GRAVITAS are of particular interest because studies have shown wide interindividual variability in the platelet inhibitory response to clopidogrel and suggested a link between a poor pharmacodynamic response to cardiovascular events after PCI.
"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," wrote Dr. Price, director of the cardiac catheterization laboratory at the Scripps Clinic in La Jolla, Calif., and his coinvestigators.
The researchers suggested several potential mechanisms that may explain the lack of a beneficial treatment effect with high-dose clopidogrel. It may be that on-treatment platelet reactivity is simply not a modifiable risk factor for thrombosis after PCI, or that the solution is to use an agent such as prasugrel, which doesn’t require metabolic transformation to reach its active form.
But the timing of the test may also play a role. Platelet reactivity resolved in nearly 40% of patients on normal-dose clopidogrel within 30 days, suggesting that the poststenting platelet activation may be temporary in a subset of patients.
"The dynamic nature of platelet reactivity that was observed underscores the importance of understanding the effect of the timing of the measurement on the level of reactivity and its association with adverse outcomes," they observed.
The GRAVITAS trial was sponsored by Accumetrics. Dr. Price said that he serves as a consultant to the company as well as to Sanofi-Aventis and Bristol-Myers Squibb, which provided the clopidogrel used in the study. Several other authors reported significant financial relationships with a number of pharmaceutical companies.
Patients with high on-treatment platelet reactivity after percutaneous coronary intervention who received high-dose clopidogrel fared no better in terms of cardiovascular events than did high-reactivity patients on standard-dose clopidogrel in the GRAVITAS trial.
"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," Dr. Matthew J. Price and his coinvestigators wrote in the March 16 issue of JAMA. However, "alternative treatment strategies incorporating platelet function testing merit further investigation."
In the Gauging Responsiveness With a VerifyNow Assay – Impact on Thrombosis and Safety (GRAVITAS) trial, researchers measured platelet function with the VerifyNow P2Y12 test (Accumetrics) 12-24 hours after PCI. A greater P2Y12 reaction unit (PRU) result reflects greater P2Y12 mediated reactivity. High on-treatment reactivity was defined as 230 PRU or greater. This cutoff was chosen because it was similar to the cutoff suggested by a prior observational study.
Patients were eligible for enrollment if they had undergone PCI with at least one drug-eluting stent for the treatment of stable coronary artery disease or acute coronary syndromes. Patients with high on-treatment platelet reactivity were randomly assigned to receive either high-dose or standard-dose clopidogrel. High-dose clopidogrel was given as a total first-day dose of 600 mg followed by 150 mg daily for 6 months. Standard-dose clopidogrel involved a loading dose of placebo followed by a dose of 75 mg and placebo tablet daily.
In all, 5,429 patients from 83 sites in the United States and Canada were screened with platelet function testing. Of these, 2,214 (41%) had high on-treatment reactivity and were randomly assigned to either high-dose or standard-dose clopidogrel. An additional 586 patients without high on-treatment reactivity were selected at random and assigned to treatment with standard-dose clopidogrel (JAMA 2011;305:1097-105).
The primary efficacy end point, a composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis at 6 months, was identical in both groups with high reactivity, at 25 (2.3%).
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. That occurred in 15 (1.4%) and 25 (2.3%) of patients in the high- and low-dose groups, respectively, a nonsignificant difference.
In a 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, at 25 and 8, respectively, but this difference did not reach statistical significance.
In terms of safety, intracranial hemorrhage occurred in none of the patients with high on-treatment reactivity who were randomly assigned to high-dose clopidogrel, in two patients (0.2%) with high on-treatment reactivity on standard-dose clopidogrel, and in one patient (0.2%) without high on-treatment reactivity treated with standard-dose clopidogrel. The rate of discontinuation of study drug due to severe or moderate bleeding was similar across all three groups.
The results of GRAVITAS are of particular interest because studies have shown wide interindividual variability in the platelet inhibitory response to clopidogrel and suggested a link between a poor pharmacodynamic response to cardiovascular events after PCI.
"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," wrote Dr. Price, director of the cardiac catheterization laboratory at the Scripps Clinic in La Jolla, Calif., and his coinvestigators.
The researchers suggested several potential mechanisms that may explain the lack of a beneficial treatment effect with high-dose clopidogrel. It may be that on-treatment platelet reactivity is simply not a modifiable risk factor for thrombosis after PCI, or that the solution is to use an agent such as prasugrel, which doesn’t require metabolic transformation to reach its active form.
But the timing of the test may also play a role. Platelet reactivity resolved in nearly 40% of patients on normal-dose clopidogrel within 30 days, suggesting that the poststenting platelet activation may be temporary in a subset of patients.
"The dynamic nature of platelet reactivity that was observed underscores the importance of understanding the effect of the timing of the measurement on the level of reactivity and its association with adverse outcomes," they observed.
The GRAVITAS trial was sponsored by Accumetrics. Dr. Price said that he serves as a consultant to the company as well as to Sanofi-Aventis and Bristol-Myers Squibb, which provided the clopidogrel used in the study. Several other authors reported significant financial relationships with a number of pharmaceutical companies.
FROM JAMA
Major Finding: The rate of death from cardiovascular causes, nonfatal MI, or stent thrombosis at 6 months was identical, at 2.3%, in patients with high on-treatment platelet reactivity who received high-dose and in those receiving standard-dose clopidogrel.
Data Source: Randomized double-blind active control trial of 5,429 PCI patients from 83 sites in the United States and Canada.
Disclosures: The GRAVITAS trial was sponsored by Accumetrics. Dr. Price said that he serves as a consultant to the company as well as to Sanofi-Aventis and Bristol-Myers Squibb, which provided the clopidogrel used in the study. Several other authors reported significant financial relationships with a number of pharmaceutical companies.