When a major trial is published in a top clinical journal, the accompanying editorial often serves to set the agenda for discussion about the trial. With the publication in JAMA of the GRAVITAS (Gauging Responsiveness With A VerifyNow Assay– Impact on Thrombosis and Safety) trial, presented last November at the American Heart Association meeting, fresh questions are being raised about this issue, sparked by the selection of Paul Gurbel as the editorialist. Gurbel is a senior and highly-respected researcher in the field who has received large amounts of support from industry.
Dr Gurbel reported receiving research grant support from AstraZeneca, Accumetrics, Bayer, Lilly, Portola, Novartis, Pozen, sanofi-aventis, Daiichi Sankyo. Dr Gurbel also reported being a consultant or receiving honoraria from AstraZeneca, Accumetrics, Portola/ Novartis, Pozen, sanofi-aventis, Boehringer Ingleheim, Bayer, Lilly, Daiichi Sankyo, and Merck.
In a post on CardioExchange, Rick Lange and David Hillis ask the question: “Why Invite the Fox into the Henhouse?” They write:
We commend the author for disclosing his potential conflict of interest but have difficulty understanding why JAMA invited a major proponent of this platelet-reactivity test to write the editorial. Rather than acknowledging that the test has a negligible impact on risk prediction, the editorial simply calls for different platelet-function cutpoints to be used.
I spoke with Paul Gurbel about these issues. He made an impassioned defense for his suitability as editorialist. Standing on his many credentials, he stated that “we created the field” and asked, “who has brought more insight into the field?” and “who knows the field better than we know it?” He also pointed out that all the other experts in the field are also “conflicted with industry.” Finally, he noted that his recommendations are largely in accord with current guidelines, which state that platelet function testing should be reserved for high risk patients: “we leave it up to the doctor to determine who’s the high risk patient,” said Gurbel.
When asked for a comment about this issue, JAMA’s editors declined to comment.
Sanjay Kaul provided the following comment to CardioBrief:
Specific comments
- HPRA is a correlate of poor outcomes post-stenting, not a major cardiovascular risk factor as claimed by the editorialists. Association should not be confused with causation!
- The editorialists failed to mention the null effect with respect to the primary endpoint as the major finding of the study, but instead focused on secondary endpoints.
- I fail to see how lower cut points for platelet function test will improve the poor to modest prognostic utility of VerifyNow assay for ischemic endpoints post-stenting. Data from the nonrandomized comparison between HPRA vs non-HPRA suggests a sensitivity of 75%, specificity of 36% PPV of 2% and NPV of 99% and AUC of 0.59 indicating tiny impact on MACE risk prediction. Furthermore, how do lowering cut points overcome the possibility of HPRA not being a modifiable variable?
- It is possible that a more potent antiplatelet agent (such as prasugrel) will be effective, but it is important to keep in mind that this treatment advantage might come at a price of significant bleeding, including fatal bleeding.
- The GRAVITAS investigators’ assumption of 50% risk reduction with high-dose vs. standard-dose clopidogrel for sample size estimation was on the generous side, driven perhaps by trial feasibility considerations.
General comments
The VerifyNow test fulfills only 1 out 4 requisite attributes for a screening test to have clinical utility. While the test is practical in the clinical setting due to availability of a point of care assay, it fails to characterize low- and high-risk patients, it fails to identify at-risk individuals that should lead to a treatment that improves outcome, and it is unclear whether the process is cost-effective.To quote one of the editorialists, “The bottom line is we have no prospective studies at this time that alteration of therapy based on platelet function testing or genetic testing really affects patient outcomes. Until the results of large scale trials of personalized antiplatelet therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended.”
Trial Summary
GRAVITAS enrolled 2,214 patients with high residual platelet reactivty, as assessed by the VerifyNow P2Y12 Test measured 12 to 24 hours after the procedure. (The manufacturer of the test, Accumetrics, sponsored the trial.) Patients in the trial were randomized to either high dose clopidogrel (additional loading dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily thereafter). The primary endpoint, a composite of CV death, MI, or stent thrombosis at 6 months occurred in 2.3% of patients in each group. Bleeding complications also occurred at similar rates in the groups.
“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,” conclude the GRAVITAS investigators in the JAMA paper.
In the accompanying editorial, Paul Gurbel and Udaya Tantry speculate about several possible explanations for the negative result, and conclude:
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.
Here is the press release from JAMA:
CHICAGO—Modifying a patient’s dosage of the antiplatelet drug clopidogrel for 6 months depending on the patient’s level of platelet reactivity did not result in combined lower rates of nonfatal heart attack, stent thrombosis (clot) and cardiovascular death in patients who had a procedure such as balloon angioplasty and received a drug-releasing coronary stent, according to a study in the March 16 issue of JAMA.
Current guidelines recommend treating patients undergoing percutaneous coronary intervention (PCI; procedure such as balloon angioplasty used to open narrowed coronary arteries) and drug-eluting stent implantation with a combination of aspirin and P2Y12 (compound found on the surface of blood platelet cells and an important regulator in blood clotting) antagonist for at least 1 year. But several studies have suggested that patients with high platelet reactivity during treatment with clopidogrel are at an increased risk of cardiovascular events after PCI. A treatment strategy for this issue has not been well defined, according to background information in the article.
Matthew J. Price, M.D., of Scripps Translational Science Institute, La Jolla, Calif., and colleagues 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. The randomized trial included 2,214 patients with high on-treatment reactivity (measured 12 to 24 hours after PCI) with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. Patients received high-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (75 mg daily) for 6 months. The primary outcome measured was the 6-month incidence of death from cardiovascular causes, nonfatal heart attack, or stent thrombosis. Safety measurements included severe or moderate bleeding.
The researchers found that the rate of death from cardiovascular causes, nonfatal heart attack, 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 percent) vs. 25 [2.3 percent]). In an analysis, the event rates in the 2 groups after 30 days were (20 [1.9 percent] vs. 17 [1.6 percent]), respectively.
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. High-dose clopidogrel was associated with an absolute 22 percent lower rate of high on-treatment reactivity compared with standard-dose clopidogrel at 30 days and 6 months (40 percent vs. 62 percent; and 36 percent vs. 60 percent, respectively).
Severe or moderate bleeding was not increased with the high-dose regimen.
“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,” the authors write.
(JAMA 2011;305[11]:1097-1105.)
Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
Paul A. Gurbel, M.D., and Udaya S. Tantry, Ph.D., of the Sinai Hospital of Baltimore, comment on the findings of this study in an accompanying editorial.
“… the GRAVITAS investigators have conducted the largest trial of personalized antiplatelet therapy thus far. The valuable information gained from the GRAVITAS trial can inform future trials. 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.”
(JAMA 2011;305[11]:1136-1137.)
Although some of the commentary presented in Dr. Husten’s article is thoughtful, it is not accurate to state that HPRA is a non-modifiable variable. Mega and colleagues have demonstrated that HPRA associated with reduced funtion CYP polymorphisms is infrequent when patients are treated with the more potent and less variable P2Y12 inhibitor prasugrel (Circulation. 2009;119:2553-2560). Furthermore, the negative outcome of the GRAVITAS trial may be attributable to the fact that many patients with HPRA on high dose clopidogrel had persistent PRUs >230, demonstrating high dose clopidogrel does not adequately reduce HPRA. It is almost certain that HPRA would be have been markedly reduced by switching patients to prasugrel. Although the strategy of switching HPRA patients to prasugrel will require validation in a randomized trial, bleeding risk with prasugrel should not be overstated because recent analysis of prasugrel in optimized patient populations (no history of stroke/transient ischemic attack, age <75 years, and weight ≥ 60 kg) demonstrates preserved efficacy and less risk of bleeding compared to the entire study cohort presented in the original TRITON trial (Circulation. 2010;122:394-403). In the absence of studies showing causality between HPRA and MACE, there is clear biologic plausibility linking HPRA with increased risk of MI and stent thrombosis. As we await additional data, rather than complacently accepting the elevated risk of CV events with HPRA, it is reasonable to risk-stratify patients with platelet function testing to assess potential benefit of switching to a more potent antiplatelet drug such as prasugrel. Our clinical protocols at the Brigham and Women’s Hospital continue to include the option of performing platelet function testing for high risk PCI patients, and we strongly consider switching to prasugrel in the setting of HPRA.
Also the Verifrenchy multi-center trial in France using Verifynow was negative. ESC slides here: http://spo.escardio.org/eslide/view.aspx?eevtid=40&fp=981
In both multi center trials, Gravitas and Verifrenchy, the Verifynow failed to identify at-risk individuals.
From a recent consensus paper which was also co-authored by Dr. Gurbel (J Am Coll Cardiol. 2010 Sep 14;56(12):919-33, table 2), you can see that this negligible impact on risk prediction is not a general class problem of platelet function tests.
Verifynow shows much weaker predictivity than other platforms, among them good old LTA and Multiplate.
http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=981