Prasugrel Effective in Stable Patients With Poor Response to Clopidogrel

CHICAGO, IL—Prasugrel effectively decreases platelet reactivity compared with high dose clopidogrel in stable patients who respond poorly to the older antiplatelet agent after percutaneous coronary intervention (PCI), according to results presented March 24, 2012, at the annual American College of Cardiology/i2 Scientific Session.

Researchers led by Gennaro Sardella, MD, of “Sapienza” University of Rome (Rome, Italy), looked at 32 patients with stable CAD who received elective PCI with DES implantation but responded poorly to clopidogrel (600-mg loading dose or 75-mg/day maintenance) on multiple electrode platelet aggregometry (Multiplate analyzer; Dynabyte Medical, Munich, Germany). The patients, all of whom had high on-treatment platelet reactivity (> 450 area under the curve [AUC] of AU/min) were randomized to double-dose clopidogrel (150 mg/day; n = 16) or prasugrel (10 mg/day; n = 16). After 15 days, each arm crossed over to the alternate therapy. In addition, patients were genotyped to determine the influence of the loss-of-function CYP2C19*2 variant allele, which contributes to poor clopidogrel response.

Baseline mean AUC was equivalent between the prasugrel and clopidogrel groups (576 ± 97.20 vs. 573.33 ± 87.10; P = 0.957), but after 15 days of treatment, patients in the prasugrel group showed a much better platelet response compared with clopidogrel in terms of the primary endpoint (mean AUC) and other measures (table 1).

Table 1. Platelet Reactivity Outcomes

 

 

Prasugrel

Clopidogrel High Dose

P Value

Mean AUC at 15 Days

325.82 ± 104.70

478.52 ± 208.54

0.028

Inhibition of Platelet Aggregation

49.69 ± 42.88%

9.31 ± 5.19%

0.036

Difference in AUC from Baseline to 15 Days

251.18 ± 102.10

94.48 ± 150.62

0.0017

 

Poor responders were more common in the clopidogrel group as defined by AUC > 450 (28.1% vs. 0; P = 0.0012), while inhibition of platelet aggregation of more than 20% was more common in the prasugrel group (62.5% vs. 37.5%; P = 0.045).

Prior to the crossover phase, prasugrel was more effective in improving platelet response than clopidogrel (AUC 180.5 vs. AUC 380.5; P = 0.038). However, after patients switched agents, those changing to prasugrel continued to improve while the platelet response of those switching to clopidogrel worsened (AUC 256 in patients switched to prasugrel vs. AUC 330 in patients switched to clopidogrel).

Prasugrel Unaffected by Variant Alleles

In the genetic analysis, 43% of all patients had at least 1 variant CYP219*2 allele. In carriers, prasugrel was more effective than clopidogrel in improving platelet response after 15 days of treatment (AUC 205.1 vs. AUC 520.3; P = 0.045). In noncarriers, both drugs were equally effective in improving response (AUC 171.6 with prasugrel vs. AUC 106.6 with clopidogrel; P = 0.575).

Among carriers, prasugrel did a better job in lowering the proportion of patients with high platelet reactivity (AUC > 450) compared with clopidogrel (0 vs. 43.7%; P = 0.003), while in carriers, both drugs showed similar efficacy (0 with prasugrel vs. 12.5% with clopidogrel; P = 0.274).

At 3-month clinical follow-up, there were no MIs, deaths, strokes, or major bleeding events (BARC criteria) in any patient. Other adverse events were low and equivalent between groups. The trial numbers were too small to determine statistically significant differences in clinical outcomes.

Cutoff for Carrier Status

In an additional analysis, Dr. Sardella and colleagues determined an AUC cutoff for platelet reactivity of 600, above which patients are more likely to have a CYP219*2 variant allele. The sensitivity and specificity of the cutoff was 75% and 72%, respectively.

“Compared with high‐dose clopidogrel, prasugrel significantly decreased platelet reactivity in patients with high on-clopidogrel platelet reactivity after elective PCI,” Dr. Sardella concluded, leading to “fewer patients remaining non-responsive after prasugrel than after high-dose clopidogrel.” He added that in those patients with CYP2C19*2 allelic variants, “high clopidogrel dose, in contrast to prasugrel, is frequently ineffective,” while in noncarriers, “both drugs have similar effects.”

Panel co-chair George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY) commented that the results are a good example of how small studies have shown a relationship between genotype and clopidogrel response while larger studies have failed in this regard.

“I think it has to do with size and power,” noted Matthew J. Price, MD, of the Scripps Translational Research Institute (La Jolla, CA), and lead author of GRAVITAS, a large trial that failed to show an effect of altering clopidogrel dose based on genotype. “With the bigger studies, it’s clear there’s an influence of carrier status but there’s a lot of unknowns. There’s still a lot of variability or nonresponsiveness in patients who are ‘wild type’ for CYP219.”

Regardless, he called the AUC cutoff to determine carrier status based on clopidogrel nonresponsiveness, a “provocative approach.”

 

Source:

Sardella G. Pharmacodynamic effects of switching therapy in PCI patients with high on treatment platelet reactivity and genotype variation: High clopidogrel dose versus prasugrel (RESET study). Presented at: American College of Cardiology Scientific Session; March 24, 2012; Chicago, IL.

Disclosures:

  • Dr. Sardella reports no relevant conflicts of interest.

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