ADAPT-DES: Low Response to Clopidogrel Does Not Increase Mortality Risk

Reed Miller

October 25, 2012

MIAMI — New data from the Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents (ADAPT-DES) shows that clopidogrel hyporesponsiveness does not predict one-year mortality in drug-eluting-stent recipients because the increased risk of thrombosis is offset by a lower risk of bleeding [1,2].

In light of this result, "overcoming clopidogrel hyporesponsiveness with more potent antiplatelet agents is therefore unlikely to improve survival unless the beneficial effects of reducing stent thrombosis and myocardial infarction can be uncoupled from the likely increase in bleeding with greater platelet inhibition," ADAPT-DES investigator Dr Thomas Stuckey (Moses Cone Heart and Vascular Center, Greensboro, NC) said at TCT 2012, where he and Dr Gregg Stone (Columbia University, NY) presented an analysis of the relationship between clopidogrel hyporesponsiveness and subsequent adverse events in the ADAPT-DES patients.

Commenting on the study, Dr Ajay Kirtane (New York-Presbyterian Hospital, NY) said, "We know that hyporesponsiveness is a risk factor for ischemic events, but the therapies we have to treat those ischemic events--more potent antiplatelet therapies--increase the risk of bleeding, so we do have figure out in whom should we use those therapies."

Unfortunately, these data do not identify that patient population. Commenting on the analysis, Dr Alice Jacobs (Boston Medical Center, MA) said, "This is a testament to the conundrum that we're seeing with these newer [antiplatelet] agents. We haven't gotten to that sweet spot of matching the increased efficacy and the problem of bleeding. So I don't think these data will change anything now."

Stuckey said: "We're trying to gain the advantage of newer and better agents but uncoupling them from the bleeding. There are a lot of issues related to that--the timing of the bleeding, the type of bleeding, procedure-related vs later. But if you tackle those things as separate issues, there may be a sweet spot where you can define people who are or are not at risk for bleeding and target the therapy like we have in many other areas," he predicted.

Protection From Bleeding Balances Thrombosis Risk

As reported by heartwire , the 8575-patient ADAPT-DES registry showed that absolute and relative levels of platelet inhibition independently predict stent thrombosis in patients with a DES, although the test used to measure platelet reactivity in the study, the VerifyNow (Accumetrics) assay, is not specific or sensitive enough to predict one-month stent-thrombosis risk in individual patients.

The new ADAPT-DES data released at TCT 2012 show that, at one-year postprocedure, 70 patients (0.84%) had a stent thrombosis, 224 had an MI (2.7%), 531 suffered a major bleed (6.2%), and 161 died (1.9%).

Clopidogrel hyporesponsiveness, defined as a VerifyNow score of 208 platelet reactivity units (PRU) or greater, was found in 42.7% of patients in the study. This clopidogrel hyporesponsiveness was significantly associated with stent thrombosis, as 1.3% of clopidogrel hyporesponsive patients suffered thrombosis vs only 0.5% of nonhyporesponsive patients. It was also associated with more MI, 3.9% vs 2.7%. However, clopidogrel hyporesponsiveness also predicted a lower risk of major bleeding in the study, 5.6% vs 6.7%.

Clopidogrel hyporesponsive patients had a higher one-year mortality rate than nonhyporesponsive patients in the trial, 2.4% vs 1.5%, but multivariable modeling demonstrated no independent association between clopidogrel hyporesponsiveness and mortality.

Aspirin hyporesponsiveness was defined as a score of over 550 aspirin reactive units on the VerifyNow assay. In these patients, hyporesponsiveness to aspirin predicted a slightly lower risk of bleeding but did not predict a difference in stent thrombosis, heart attack, or death. This calls into question the value of aspirin in patients treated with DES, since stent thrombosis is the most important risk associated with DES, Stuckey and Stone said.

Although the study showed no difference in mortality, Dr Matthew Price (Scripps Clinical and Translational Science Institute, La Jolla, CA) told heartwire that the significant association between clopidogrel hyporesponsiveness in the trial "strongly confirms that platelet-function testing can provide important and clinically actionable information regarding thrombotic risk in patients treated with clopidogrel."

Dr Ted Feldman (Evanston Hospital, IL) appears to be less confident in the value of platelet-reactivity testing. "These are more data in the pool, but definitely only a glimmer and not a big blast of light. . . . I've been waiting to buy a bedside platelet assay testing machine, and I won't feel guilty about waiting a little longer."

ADAPT-DES is sponsored by the Cardiovascular Research Foundation with research support from Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, the Medicines Company, Daiichi Sankyo, Eli Lilly, Volcano, and Accumetrics. Stuckey reports receiving consulting fees/honoraria from Eli Lilly and Daiichi Sankyo. Stone reported consulting fees and honoraria from Abbott Vascular, Boston Scientific, Medtronic, Volcano, the Medicines Company, Daiichi Sankyo, and Eli Lilly. Price has received research support from Accumetrics and AstraZeneca (to institution); speaker's fees from AstraZeneca and Daiichi Sankyo/Eli Lilly; and consulting fees from AstraZeneca, Sanofi, Accumetrics, and Daiichi Sankyo/Lilly, and the Medicines Company.