JACC: Two studies added to platelet function testing mix
Two studies this week in the Journal of the American College of Cardiology: Cardiovascular Interventions explored both the use of prasugrel (Effient) and higher doses of clopidogrel to evaluate genetic responses, adding to the extensive database of research surrounding patients’ responses to clopidogrel (Plavix).

In the first study, Jean-Philippe Collet, MD, PhD, and the CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2) trial investigators set out to determine whether responses to high or standard loading doses of clopidogrel differ according to the CYP2C19*2 allele, a loss-of-function allele shown to be associated with reduced clopidogrel responsiveness.

To do so, the researchers randomized patients to receive either a 300 mg or 900 mg loading dose of clopidogrel and then compared the reduction in residual platelet aggregation and area under plasma concentration time curve of active metabolite from baseline to six hours after loading. Higher loading doses of clopidogrel have been known to result in higher platelet inhibition.

The authors wrote that “the ‘one size fits all’ treatment strategy with clopidogrel therapy does not take into account the large degree of interindividual pharmacodynamic (PD) responses, and patients with lesser degrees of platelet inhibition and/or higher residual platelet reactivity on clopidogrel are at increased risk of cardiovascular events.”

Forty-three heterozygous carriers were matched at a 1:1 ratio with 43 homozygous patients, and eight homozygous carriers were matched at a 1:2 ratio with 16 homozygous patients—110 coronary patients were randomized to receive the 300 mg (n=55) or 900 mg dose of clopidogrel (n=55).

The researchers found the CYP2C19*2 variant to be associated with:

  • A gene-dose response to a standard 300 mg loading dose of clopidogrel and 75 mg maintenance dose (MD); and
  • A correction of the genetic trait effect by using the 900 mg dose of the drug (limited to heterozygous patients).

“The labeled 300 mg LD [loading dose] appears adequate in the majority of patients with the wt/wt genotype but appears insufficient in carriers of at least one reduced-function CYP2C19*2 allele,” the authors wrote. “The 900 mg LD was chosen because it was shown to be superior to both 300 and 600 mg to reduce poor clopidogrel response, in both naïve patients and patients already taking 75 mg/day clopidogrel.”

The researchers said that the study demonstrated that genetic resistance to clopidogrel can be overcome in carriers already administered clopidogrel by a 900 mg dose of the drug.

“CLOVIS-2 also demonstrates that *2/*2 carriers responded poorly to both LDs suggesting a profile of complete resistance to clopidogrel. This further supports that a strategy of an increased clopidogrel-dose regimen is ineffective, as previously reported in patients who survived a stent thrombosis and who have both persistent HOPR and a genetic profile of resistance,” the authors noted.

The researchers concluded that these data confirm that an individualized approach to treatment is necessary in patients administered clopidogrel. And while they said that the evidence base for these treatments doesn’t currently exist, these results could help interpret ACC/AHA recommendations on pharmacogenetic testing to identify patients’ altered clopidogrel metabolism.

“The CLOVIS-2 investigation answers many of the concerns raised by the FDA and may help interpreting the American College of Cardiology/American Heart Association recommendations on pharmacogenetic testing to identify patients’ altered clopidogrel metabolism,” the authors concluded.

“A high clopidogrel dose can overcome poor response to the drug in heterozygous carriers of the CYP2C19*2 genetic variant but not in homozygous carriers, who probably deserve alternative therapy.”

In the second study, Dimitrios Alexopoulos, MD, of Patras University Hospital in Patras, Greece, and colleagues studied the effects of 10 mg/day dose of prasugrel (Effient, Eli Lilly/Daiichi Sankyo) vs. a high, 150 mg/day dose of clopidogrel in 71 patients with high on-treatment platelet reactivity post-PCI.

The researchers used the VerifyNow assay to determine platelet function and used platelet reactivity as the study’s primary endpoint.

Results showed that platelet reactivity was lower in patients treated with prasugrel (36 patients) compared with clopidogrel (35 patients). The high on-treatment platelet reactivity (HTPR) rates were also lower for prasugrel when compared with clopidogrel, 7.5 percent vs. 35.8 percent, respectively, in all patients. These rates in carriers were 5.3 percent vs. 47.4 percent and in non carriers were 8.8 percent vs. 29.4 percent, respectively.

While the researchers said that switching from the conventional 75 mg/day dose of clopidogrel to 150 mg/day can overcome low responsiveness in a proportion of patients, prasugrel “seems to be an attractive choice to overcome HTPR.”

However, the authors noted that even with prasugrel, suboptimal platelet inhibition may occur. And while prasugrel was more effective in patients carrying one loss-of-function CYP2C19*2 allele, “genotyping guidance might be helpful only in case an increased clopidogrel maintenance dose is considered.”

“Measurement of platelet function in a post-PCI patient and subsequent treatment with prasugrel—if found with HTPR—seems to be the most effective strategy to overcome low responsiveness,” the researchers concluded.

While these study results bolster data, questions still remain as to whether patients should undergo genetic testing or whether other antiplatelets like prasugrel or ticagrelor (Brilinta, AstraZeneca) should be considered.