Genetic, Drug-Related Factors May Play Role in Early Stent Thrombosis

Cayla G. JAMA. 2011;306:1765-1774.

Issue: January/February 2012

Three genes involved in clopidogrel metabolism and platelet receptor function and two clopidogrel-related factors were independently associated with early stent thrombosis in a French study.

In the study, Jean-Sébastien Hulot, MD, PhD, associate professor of medicine at Mount Sinai School of Medicine, N.Y., and colleagues examined patients (n=123) from 10 centers in France who had undergone PCI and had definite early stent thrombosis and DNA samples available for analysis, and matched them with 246 stent thrombosis-free controls.

Results indicated that early stent thrombosis was significantly linked to CYP2C19 metabolic status (OR=1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (OR=2.16; 95% CI, 1.21-3.88) and ITGB3 PLA2 carriage (OR=0.52; 95% CI, 0.28-0.95).

Several non-genetic independent factors were also associated with early stent thrombosis, including acuteness of PCI (OR=3.05; 95% CI, 1.54-6.07); complex lesions (ACC/AHA type C; OR=2.33; 95% CI, 1.40-3.89); left ventricular ejection fraction less than 40% (OR=2.25; 95% CI, 1.09-4.70); diabetes (OR=1.82; 95% CI, 1.02-3.24); use of proton pump inhibitors (OR=2.19; 95% CI, 1.29-3.75); and higher loading doses of clopidogrel (Plavix, Sanofi-Aventis; OR=0.73; 95% CI, 0.57-0.93).

“Genetic testing has been criticized because of its low predictive value and its potential redundancy with other markers, including clinical characteristics,” Hulot told Cardiology Today Intervention. “In our study, the genetic variables were as predictive as the clinical and procedural variables. In other words, the invisible part of the iceberg is as big as its visible part. As a consequence, the combination of genetic and clinical risk factors allows a better discrimination of patients at risk as compared with a clinical-only or a genetic-only strategy.”

Disclosure: Dr. Hulot reports receiving research grant support from Biotronik, Federation Francaise de Cardiologie, Fondation de France, INSERM and Medco Research Institute; consulting fees from Biotronik and Medco Health Solutions; and lecture fees from Daiichi Sankyo, Eli Lilly and Sanofi-Aventis.

The study by Cayla et al confirms the association of three genetic polymorphisms with early definite stent thrombosis. The authors present a mixed genetic-clinical model with increased predictive accuracy as compared with the genetic model alone or the clinical model alone.

Major concerns of the study are the following: the focus on early definite stent thrombosis with underestimation of the effect of abnormal genotyping on the risk of thrombotic events, including late and very late stent thrombosis; a very incomplete clinical multivariable model that did not include crucial procedural variables such as the use of glycoprotein IIb/IIIa inhibitors or final stent inflation pressure, number of stents, etc; the small number of patients in the case-control analysis, which prevented a robust statistical analysis; and the lack of phenotyping the effective platelet aggregation inhibition on clopidogrel treatment.

Genetic studies on platelet reactivity are of crucial importance, but, although the pharmacogenetic approach in drug development will still be continued, individualized medications based on genomics remain a challenge for the future.

And in regards to antiplatelet therapy, potential individualized treatment based on phenotyping is already a realistic and effective approach and allows for the identification of high-risk patients with a higher predictive value.

– David Antoniucci, MD
Cardiology Today Intervention Editorial Board member
Disclosure:Dr. Antoniucci reports no relevant financial disclosures.