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Body platelet testing to guide antiplatelet therapy: Implications of the GRAVITAS trial
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Antiplatelet therapy with aspirin and clopidogrel has been the cornerstone of medical therapy for acute coronary syndrome and percutaneous coronary intervention, and it is a class I indication in the American College of Cardiology/American Heart Association guidelines.
Despite the proven effectiveness of antiplatelet therapy, studies have suggested that between 5% and 50% of patients either do not respond or have a minimal antiplatelet response to clopidogrel (Plavix, Sanofi-Aventis) as measured by ex vivo platelet function tests. Numerous studies have shown that when platelet function is inadequately inhibited (referred to as “high on-treatment” platelet reactivity), outcomes are significantly worse.
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The most commonly used platelet function assay is the VerifyNow (Accumetrics) P2Y12 point-of-care test, and at least seven studies of more than 3,000 patients have shown that high on-treatment platelet reactivity is associated with a poor outcome. Studies have also shown that increasing the dose of clopidogrel can reduce the number of patients who do not respond.
Learning from CURRENT-OASIS 7 and GRAVITAS
The CURRENT-OASIS 7 trial randomly assigned 25,086 patients with ACS and intended PCI to standard-dose clopidogrel or double-dose loading-dose (600 mg) and maintenance dose (150 mg) for 1 week. The overall trial showed no benefit, but in those patients undergoing PCI, the combined endpoint of death, MI and stroke at 30 days was reduced significantly by 14%.
Impressively, definite stent thrombosis was reduced by 46%. Major bleeding was increased slightly, however. The limitation of this strategy is that all patients must be treated with high-dose clopidogrel, and in some, either no benefit or an increased bleeding risk occurs. A strategy using platelet-testing may make more sense by targeting those who need the higher dose.
The GRAVITAS trial was presented at the AHA Scientific Sessions 2010 in November. It addressed this issue by randomly assigning patients with high on-treatment platelet aggregation as measured by the VerifyNow P2Y12 test to either standard-dose clopidogrel or to double-dose clopidogrel. This is the first large randomized clinical trial to test a treatment strategy in patients with high on-treatment platelet aggregation. The study randomly assigned the 2,214 patients with high on-treatment platelet aggregation (P2Y12 reactivity units [PRU] >230) and followed the 59% of patients who had a PRU <230 as another control group. The primary endpoint of CV death, MI or stent thrombosis was not different between the study groups (2.3% vs. 2.3%, HR=1.01). Likewise, there was no difference in bleeding. The trial was sized for a 5% incidence of the primary endpoint that was not achieved. It is unlikely, however, that even if the trial were much larger a different outcome would have occurred, given the identical event rate in both groups.
The outcomes in those without high on-treatment platelet aggregation were much better than those with high on-treatment, confirming again that the platelet-testing is a marker for a better outcome. One of the limitations of the study was that doubling the dose of clopidogrel resulted in modest improvement in platelet inhibition. Perhaps larger doses would be needed for adequate inhibition in all patients. Upon examining all of the adverse events, it is apparent that they occurred in patients with PRU values more than 180 units, a cut-point much lower than that adopted by the trial. This, again, raises concerns about the adequacy of double-dose clopidogrel in these patients.
Potential viability of testing-guided therapy
Platelet testing-guided therapy with individualized dosing to achieve adequate platelet inhibition may make more sense. In a nonrandomized study, Bonello and colleagues have shown that in patients with high on-treatment platelet function, escalating doses of clopidogrel can result in most patients achieving adequate platelet inhibition. A preliminary report of the randomized DOSER trial presented at the European Society of Cardiology Congress 2010 meeting in September suggests that this strategy may be of benefit.
In this study, 196 patients were randomly assigned to titration of the maintenance dose for 28 days to attain adequate inhibition using the VerifyNow assay or to no escalation. Titration resulted in a significantly lower primary endpoint (CV death, MI and target vessel revascularization) without a significant increase in bleeding. There are also two other ongoing trials, the ARCTIC trial and the DANTE trial, that are both testing platelet function-guided therapy using the VerifyNow P2Y12 assay.
Although these studies have used the VerifyNow assay, there are many other tests that have been used and appear to predict outcomes, including light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The lack of single standardized test and consensus concerning the optimal cutoff points for adjusting the dose of clopidogrel has limited the field. Although these tests are highly predictive of adverse events, they lack adequate sensitivity. In one study, for example, the negative predictive value was high, but the positive predictive value was only 12%. With the availability of prasugrel (Effient, Daiichi Sankyo/Eli Lilly) and perhaps ticagrelor (Brilinta, AstraZeneca) in the near future, use of these more powerful agents in place of clopidogrel would be a reasonable strategy.
GRAVITAS has led the way in properly testing the role of platelet-guided therapy, and the concept is an attractive one. At the moment, however, benefit for this strategy remains to be shown, and more trials are clearly needed before this strategy can be adopted into practice.
David P. Faxon, MD, is the director of strategic planning and a professor of medicine at Brigham and Women’s Hospital in Boston. He is also a member of the Vascular Medicine section of the Cardiology Today Editorial Board.
Disclosure: Dr. Faxon reports no relevant financial disclosures.
For more information:
- Aradi D. Abstract 31. Eur Heart J. 2010 (supplement):970.
- Bonello L. J Am Coll Cardiol. 2008;51:1404-1411.
- CURRENT-OASIS 7 Investigators. N Engl J Med. 2010; 363:930-942.
- Marcucci R. Circulation. 2009;119:237-242.
- Price M. Abstract 21791. Presented at: American Heart Association Scientific Sessions 2010; Nov. 13-17; Chicago.