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Switching from atorvastatin to another statin that is not metabolized by the CYP3A4 pathway can decrease platelet reactivity among patients after percutaneous coronary intervention (PCI) who respond poorly to clopidogrel therapy. The clinical impact of this pharmacodynamic change, however, remains unclear, according to a study published online April 16, 2012, ahead of print in the European Heart Journal.

For the ACCEL-STATIN (Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin) trial, investigators led by Young-Hoon Jeong, MD, PhD, of Gyeongsang National University Hospital (Jinju, Korea), looked at patients with high on-treatment platelet reactivity who had been receiving dual antiplatelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) for at least 6 months. The patients were randomized to 15-day therapy with rosuvastatin 10 mg/day (n = 25) or pravastatin 20 mg/day (n = 25) in place of atorvastatin (10 mg/day). A third group (n = 25) remained on atorvastatin and served as controls.

Atorvastatin, simvastatin, and lovastatin are metabolized mostly by CYP3A4, whereas rosuvastatin and pravastatin are not.

Significant Effect of Switching

Platelet function was assessed before and after switching by conventional light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles.

Change in maximal platelet aggregation induced by 20 and 5 mM adenosine diphosphate (ADP), the primary endpoint, was measured before and after switching statins. After switching, maximal platelet aggregation in both switched groups combined decreased by 6.6% (from 66.9 ± 8.4% at baseline to 60.3 ± 15.0% at 15 weeks; P < 0.001). P2Y12 reaction units (PRUs) decreased by a value of 52 (291 ± 64 to 239 ± 76). There also was an increase in percent inhibition, or the extent of P2Y12 blockade by P2Y12 inhibitors (P = 0.001), and a decrease of 24% (P < 0.001) in the prevalence of high platelet reactivity.

There was no change in platelet function measurements in the control group that remained on atorvastatin.

The primary endpoint was similar between the rosuvastatin and pravastatin groups (P = 0.568). For the overall cohort, switching to the non-CYP3A4-metabolized statins also resulted in a significant decrease in final platelet aggregation, both for 20 (P = 0.001) and 5 µM ADP-induced aggregation values (P = 0.002).

On multivariate analysis, current smoking and carriers of the ABCB1 C3435T T allele who were not treated with calcium-channel blockers predicted a change in platelet reactivity from switching statins.

Clinical Impact Uncertain

Though there was a clear pharmacodynamic effect of switching from atorvastatin to pravastatin or rosuvastatin, the clinical import is not yet clear, Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, Texas), told TCMTD in a telephone interview.

“The truth is that we’ve written and spoken a lot about drug interactions with clopidogrel, and so far they’ve been clinical nonentities, limited to the test tube only.” Dr. Kleiman said. He added that multiple database studies have looked for interactions between clopidogrel and atorvastatin that led to worse outcomes, and found very little.

Still, the paper’s authors say they made particular efforts to eliminate potential confounders to the pharmacodynamic effects. Dr. Jeong told TCTMD in an e-mail communication that these steps included enrolling only stable patients treated for more than 6 months with a common clopidogrel/atorvastatin regimen as well as using both LTA and the VerifyNow P2Y12 assay to measure the effects.

“Enhanced platelet inhibition was more likely related to CYP3A4-related metabolism, since a similar improvement in clopidogrel-induced platelet inhibition was observed irrespective of the type of non-CYP3A4-metabolized statin,” Dr. Jeong said.

At least so far, with no strong signal of clinical outcome differences, this issue mirrors other clopidogrel interactions that have been studied recently. Proton pump inhibitors (PPIs) were also shown to have pharmacodynamic effects on clopidogrel, but the lack of clinical difference made changing recommendations difficult.

“Platelet aggregation is kind of a blunt instrument,” Dr. Kleiman said. “The point is, the differences are really pretty subtle. If you look at the atorvastatin story, the PPI story, . . . it’s probably not there. It’s good translational work, but I don’t think the clinical impact is going to be huge.”

He did note, however, that focusing on patients with the CYP2C19 loss-of-function allele could yield meaningful results; in the current study, carrying this allele did not significantly predict change in platelet aggregation.

But Dr. Jeong said he believes the study actually does offer enough evidence to make a simple change in practice in some high-risk patients. “Switching to pravastatin or rosuvastatin doesn’t [cost more] and is a simple and commendable strategy,” he said. The study authors also suggest studying larger numbers of patients to confirm the results, but Dr. Kleiman said he does not believe it would be worth following up with a big trial.

Related Stories:

• Consensus Statement Supports Judicious Use of PPIs Plus Antiplatelet Therapy
• No Adverse Platelet Aggregation Effect Seen with Statins After PCI

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