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No Increased Mortality Risk for DES Patients with High Platelet Reactivity on Clopidogrel

By L.A. McKeown

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High platelet reactivity on clopidogrel—but not aspirin—independently predicts 1-year stent thrombosis and myocardial infarction (MI) risk after drug-eluting stent (DES) placement, according to data from a large multicenter registry published online July 26, 2013, ahead of print in the Lancet. While high reactivity did not appear to influence mortality, it was inversely associated with clinically relevant bleeding.

The findings were first presented in October 2012 at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in Miami Beach, FL.

For the ADAPT-DES (Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents) trial, researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), prospectively enrolled an all-comers population of 8,583 patients from 11 sites in the United States and Germany between January 2008 and September 2010. All had successful and uncomplicated PCI with at least 1 noninvestigational DES (64.5% Xience V/Promus; Abbott Vascular, Santa Clara, CA/Boston Scientific, Natick, MA).

Platelet function testing for aspirin and clopidogrel response was performed approximately 20 hours after PCI using the VerifyNow assay (Accumetrics, San Diego, CA). Overall, 42.7% of patients were found to have high on-clopidogrel platelet reactivity using the cutoff of 208 platelet reactivity units (PRU), and 5.6% had poor response to aspirin. A thienopyridine, primarily clopidogrel (99.7%), was prescribed at discharge for all patients.

Protective Against Clinically Relevant Bleeding

At 1 year, most patients remained on a thienopyridine (82.1%) or aspirin (88.3%) daily without any discontinuation. Stent thrombosis occurred in 0.84% of patients (0.63% definite, 0.20% probable), MI in 3.1%, clinically relevant bleeding in 6.2%, and death in 1.9%.

In patients with PRU greater than 208, the 1-year rate of MI was increased compared with those with a PRU of 208 or below. Additionally, the risks of stent thrombosis and mortality also were increased, while major bleeding was decreased (table 1).

Table 1. Unadjusted Event Rates at 1 Year

 

PRU > 208
(n = 3,610)

PRU ≤ 208
(n = 4,839)

P Value

Definite/Probable Stent Thrombosis

1.3%

0.5%

0.001

MI

3.9%

2.7%

0.01

Major Bleeding

5.6%

6.7%

0.002

Mortality

2.4%

1.5%

0.30


On univariable analysis, 1-year all-cause mortality risk increased in patients with PRU values higher than 208. Platelet reactivity also was associated with several other known predictors of mortality, including age, diabetes, previous MI, ACS, and anemia.

However, after propensity-adjusted multivariable analysis, PRU higher than 208 was no longer significantly associated with mortality (adjusted HR 1.20; 95% CI 0.85-1.70; P = 0.30).

Among patients with high platelet reactivity on aspirin (ARU > 550), there were no increased risks of MI or death, but there was an inverse association with major bleeding (HR 0.65; 95% CI 0.43-0.99; P = 0.04). Multivariable analysis demonstrated that stent thrombosis, MI, and major bleeding were strongly associated with all-cause mortality through 1-year follow-up (P < 0.0001 for all).

Data Support Link Between Reactivity and Stent Thrombosis, MI Risk

According to the study authors, the findings confirm smaller reports linking high platelet reactivity on clopidogrel with stent thrombosis and MI, and also illustrate the central role of the ADP-P2Y12 pathway in ischemic complications after DES.

“Moreover, VerifyNow P2Y12 PRU strongly correlates with active metabolite levels of clopidogrel, and the present report validates the capability of this point-of-care assay to identify clopidogrel-treated patients at increased risk for stent thrombosis and myocardial infarction after drug-eluting stent implantation,” Dr. Stone and colleagues write. However, they also point out that most patients with high platelet reactivity on clopidogrel will not develop these complications, while many patients in whom future events will develop exhibit low platelet reactivity.

The investigators add that the absence of an association between platelet reactivity and mortality “might lie in the offsetting effects of ischemic and hemorrhagic complications on survival.”

Furthermore, they say the findings suggest “that overcoming high platelet reactivity on clopidogrel with more potent antiplatelet agents might not improve survival unless the beneficial effects of reducing stent thrombosis and myocardial infarction can be uncoupled from the potential increase in prognostically important bleeding with greater platelet inhibition.”

Devil is in the Details 

However, in an editorial accompanying the study, Matthew J. Price, MD, of Scripps Translational Science Institute (La Jolla, CA), notes that femoral access was used in 95% of cases and intraprocedural heparin in 42%. Additionally, increased bleeding in patients below the PRU cutoff was driven by groin hematomas and out-of-hospital arterial access bleeds, whereas reduction of ischemic events seemed to continue to accrue over time.

“Therefore, bleeding avoidance strategies including radial access and bivalirudin anticoagulation during PCI represent an important adjunct that could maximize net clinical benefit with intensified antiplatelet therapy,” he writes.

According to Dr. Price, the lesson of ADAPT-DES is that patients with a detectable benefit on clopidogrel “represent a lower-risk cohort than do those with no detectable effect, and therefore, simply on the basis of event rates, the absolute ischemic benefit with the newer, more expensive P2Y12 inhibitors will be smaller than that in patients without a detectable drug effect, but will potentially expose them to a greater peril of bleeding.”

Note: Dr. Stone and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

Sources:
1. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): A prospective multicentre registry study. Lancet. 2013;Epub ahead of print.

2. Price MJ. Platelet reactivity after coronary stenting. Lancet. 2013;Epub ahead of print.

 

 

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Disclosures
  • The study was sponsored by the Cardiovascular Research Foundation and funded by research grants from Abbott Vascular, Accumetrics, Biosensors, Boston Scientific, Cordis, Daiichi-Sankyo, Eli Lilly, Medtronic, The Medicines Company, and Volcano.
  • Dr. Stone reports serving as a consultant for multiple pharmaceutical companies, receiving honoraria from Edwards and Vascular Solutions, and holding stock or stock options from multiple companies.
  • Dr. Price reports serving as a consultant for Accumetrics, AstraZeneca, Boston Scientific, Daiichi Sankyo/Eli Lilly &amp; Co, Janssen Pharmaceuticals, Medicure, Medtronic,Terumo, St Jude, The Medicines Company and WL Gore; and as a speaker for AstraZeneca and Daiichi Sankyo/Eli Lilly &amp; Co.

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