GRAVITAS Published: No Benefit from High-Dose Clopidogrel in Poor Responders

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Results of the largest randomized trial of personalized antiplatelet therapy to date do not support using high-dose clopidogrel therapy to curb high on-treatment platelet reactivity. The findings, from the much awaited GRAVITAS trial, appear in the March 16, 2011, issue of Journal of the American Medical Association and were first presented last year at the American Heart Association Scientific Sessions 2010.

For the GRAVITAS (Gauging Responsiveness with A VerifyNow assay - Impact on Thrombosis And Safety) trial, researchers led by Matthew J. Price, MD, of the Scripps Translational Research Institute (La Jolla, CA), looked at platelet reactivity using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in 5,429 stable or unstable CAD patients who had received DES.

Among them, 2,214 subjects were found to have high residual platelet reactivity (defined as platelet reactivity unit [PRU] values ≥ 230) between 12 and 24 hours after DES implantation. This group was randomized to either high-dose (n = 1,109; 600-mg initial dose and 150 mg daily thereafter) or standard-dose (n = 1,105; no additional loading dose and 75-mg daily thereafter) clopidogrel.

No Difference Between Doses

At 6 months, the rate of the primary endpoint (composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis) and its individual components were similar in high-dose and standard-dose patients (table 1).

Table 1. Outcomes at 6 Months

 

High Dose
(n = 1,109)

Standard Dose
(n = 1,105)

HR
(95% CI)

P Value

Primary Endpoint

2.3%

2.3%

1.01
(0.58-1.76)

0.97

CV Death

0.3%

0.7%

0.38
(0.10-1.43

0.14

Nonfatal MI

1.8%

1.6%

1.12
(0.59-2.12)

0.72

Stent Thrombosis

0.5%

0.7%

0.63
(0.21-1.93)

0.80


In addition, severe or moderate bleeding was not increased by the high-dose regimen (1.4% vs. 2.3%; HR, 0.59; 95% CI 0.31-1.11; P = 0.10).

Compared with standard-dose clopidogrel, the increased dose led to a reduction in the prevalence of high on-treatment reactivity at 30 days (40% vs. 62%) and at 6 months (36% vs. 60%; P < 0.001 for both comparisons).

A secondary analysis, meanwhile, looked at patients who had high on-treatment reactivity and were assigned to receive the standard dose. This subgroup was compared with 583 randomly chosen controls from the original cohort who had normal clopidogrel response and also received the standard dose. The rate of the primary endpoint was numerically greater in the high on-treatment reactivity group than in controls. Despite a lack of statistical significance, the finding hints at an association between on-treatment reactivity and late outcomes (table 2).

Table 2. Secondary Analysis

 

High Reactivity Patients
(n = 1,105)

Controls
(n = 586)

HR
(95% CI)

P Value

Primary Endpoint

2.3%

1.4%

1.68
(0.76-3.72)

0.20


Lessons Learned

Despite the negative nature of the trial, Dr. Price told TCTMD that there are still lessons to be learned.

“I think it’s important for clinicians to take away the key messages from GRAVITAS, which are that a strategy of high-dose clopidogrel in clopidogrel non-responders does not improve clinical outcomes and also that other strategies to incorporate platelet function testing within clinical practice need to be studied,” he commented in a telephone interview. “That may include either using more potent P2Y12 antagonists or targeting a certain level of reactivity.”

But the benefit of high-dose clopidogrel should not be completely ruled out, since the overall cardiovascular mortality was lower in the 150-mg group, Dr. Price stressed.

“It needs to be taken as an interesting observation at this point,” he said, adding that the researchers are currently conducting a subanalysis to see whether patients who had a “more dramatic pharmacodynamic” response to the higher dose also obtained better outcomes.

Questions Raised Concerning Cutpoint

In an accompanying editorial, Paul A. Gurbel, MD, and Udaya S. Tantry, PhD, both of Sinai Hospital of Baltimore (Baltimore, MD), suggest that one reason personalizing therapy was not effective in GRAVITAS may be that the cutpoint used to define clopidogrel response (PRU ≥ 230) was too high.

They say future trials such as TRIGGER-PCI, which is evaluating a lower cutpoint for defining at-risk patients and is testing the more potent P2Y12 receptor blocker prasugrel, may provide more definitive answers. In addition, TARGET-PCI is focusing on genotyping and serial platelet function testing, while the TRILOGY ACS platelet function substudy, which uses serial measurements, is being conducted in medically managed patients with ACS randomized to clopidogrel or prasugrel.

“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 cutpoints and more potent P2Y12 inhibitors will be effective,” Drs. Gurbel and Tantry write.

Future Research Expected to Use Broader Scope

“The platelet hypothesis is still alive and well,” said Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), in a telephone interview with TCTMD. “We still need to figure out how intensely to inhibit the platelets and what that means not just for efficacy but for safety. That being said, GRAVITAS is a great study because it is the first attempt to try and individualize antiplatelet therapy. It does provide some lessons for future studies, particularly that we need to study a higher risk population and a strategy that separates the 2 treatment groups a little more in terms of platelet inhibition.”

But the main lesson from GRAVITAS, Dr. Rao added, is that using a platelet function assay such as VerifyNow to guide treatment is probably a big mistake.

“We don’t know yet how to tailor therapy, and if anything GRAVITAS should provide more caution for instituting that in a clinical setting,” he noted. “I think GRAVITAS answered the broad question. A lot of people probably don’t like the answer, but it did answer it. Now we need to get a little bit more specific in terms of figuring out who will benefit most. Reporting negative trials is an incredibly important thing to do because it helps credibility in the field and it tells us what we should not be doing.”

 


Sources:
1. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs. high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: The GRAVITAS randomized trial. JAMA. 2011;305:1097-1105.

2. Gurbel PA, Tantry US. An initial experiment with personalized antiplatelet therapy: The GRAVITAS trial. JAMA. 2011;305:1136-1137.

 

 

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Disclosures
  • GRAVITAS was funded by Accumetrics. The study drug was provided by an investigator-initiated grant from Bristol-Myers Squibb/Sanofi-Aventis.
  • Dr. Price reports receiving consulting fees from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, Daiichi Sankyo/Eli Lilly, and Medicure; speaker’s fees from Daiichi Sankyo/Eli Lilly; and grant support from Bristol-Myers Squibb/Sanofi-Aventis.
  • Dr. Gurbel reports receiving research grant support from AstraZeneca, Accumetrics, Bayer, Daiichi Sankyo, Lilly, Novartis, Portola, Pozen; and Sanofi-Aventis and serving as a consultant or receiving honoraria from Accumetrics, AstraZeneca, Bayer, Boehringer Ingleheim, Daiichi Sankyo, Lilly, Merck, Novartis, Portola, Pozen, and Sanofi-Aventis.
  • Dr Tantry reports no relevant conflicts of interest.
  • Dr. Rao reports consulting fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis.

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