Trial seeks to identify why stent patients respond differently to Plavix
Study stresses the understanding of platelet reactivity prior to Plavix therapy. Source: Mia Pearlman  
While the use of clopidogrel (Plavix) helps reduce thrombosis in patients implanted with drug-eluting stents (DES), its effectiveness varies among individuals. The GRAVITAS trial seeks to determine whether adjusting Plavix dose, based on individualized platelet-function monitoring, can safely improve clinical outcomes after DES implantation.

The GRAVITAS trial (Gauging Responsiveness with A VerifyNow Assay-Impact on Thrombosis And Safety) is spearheaded by the Scripps Translational Science Institute in San Diego and will use the Accumetrics’ VerifyNow P2Y12 assay to gauge anti-platelet activity. The San Diego-based Accumetrics is the sole sponsor of the trial.

Matthew J. Price, MD, director of the cardiac cath lab at Scripps Clinic, told Cardiovascular Business News that the rate of thrombotic events drastically drops in patients who receive Plavix, but not in everyone.

“There is a growing body of data showing significant variability in the inhibitory response with clopidogrel among individuals,” Price said. Using benchmark tests, “you can measure how strongly a particular drug inhibits platelets. We have found that in the case of Plavix, there is a wide spectrum of response. Some people may be low-platelet reactivity, while others have high-platelet reactivity.”

Price noted that several, small observational studies have shown that patients who have a high-platelet reactivity despite clopidogrel are at greater risk for thrombotic events after stent implantation, particularly with DES.

“If patients respond differently to an anti-platelet medication like Plavix, then why do we treat all patients the same,” he asked.

The three-arm GRAVITAS trial is seeking to enroll approximately 2,800 non-STEMI patients in 60 U.S. and Canadian centers with a six-month follow-up.

Patients who have high-platelet reactivity—“most likely about one-third,” noted Price—will be randomized to one of two groups: standard Plavix therapy of 75 mg/day along with one placebo or high-dose Plavix therapy of a one-time additional loading dose of 450 mg, followed by 150mg every day for six months.

The third arm will include a random sample of clopidogrel responders treated with a placebo loading dose and then the standard clopidogrel regimen of 75 mg and one placebo tablet every day for six months. The third arm will include patients without high-platelet reactivity.

The primary outcome is time to first occurrence of post-randomization cardiovascular death, non-fatal MI, or ARC definite/probable stent thrombosis in non-responders randomized to standard versus tailored dosage.

The researchers also will measure platelet function at 30 days and six months as one of the study’s secondary endpoints.
Price said that they are not concerned about the aggressive clopidogrel treatment in the first arm because “a number of studies have shown that repeated loading doses of Plavix are safe.” He also pointed out that several observational studies have indicated that 150 mg daily Plavix therapy appears safe.

“Moreover, we are only treating patients, who have high-platelet reactivity on standard dose Plavix, with the higher dose. The GRAVITAS study seeks to determine whether higher dosing in these non-responsive patients is safe,” Price said.

“In the future, platelet function monitoring could play an important role in both risk stratification and in choosing an anti-platelet strategy post-stent implantation. If we show that tailoring one’s therapeutic strategy based on platelet-function monitoring is effective, then that should guide us in optimizing the treatment for our patients,” he said.