PharmacOdynamic compaRison of piTavastatin Versus atOrvastatin on Platelet Reactivity

Phase 4

• Conditions: Coronary Artery Disease
• Interventions: Drug: Atorvastatin; Drug: Pitavastatin

• Registration Number: NCT01648829
• Lead Sponsor: University of Roma La Sapienza

Brief Summary

Levels of platelet reactivity in patients on Dual Antiplatelet Therapy (DAPT) can be influenced by concomitant treatment with medications (i.e. statins) that inhibit the CYP3A4 system involved in the activation of clopidogrel. Atorvastatin and simvastatin are metabolized by CYP3A4. Pitavastatin, unlike other statins, is little metabolized, most of the dose being excreted unchanged in bile, and biotransformation through the cytochrome P450 system is minimal. Indeed, pitavastatin's cyclopropyl group diverts the drug away from metabolism by CYP3A4 and allows only a small amount of clinically insignificant metabolism by CYP2C9.

The primary objective of this study is to compare the pharmacodynamic effects of a CYP3A4-metabolized statin (atorvastatin) versus a non-CYP3A4-metabolized statin (pitavastatin) in patients showing high platelet reactivity while on DAPT.

Detailed Description

Patients with coronary artery disease (CAD) are often treated with dual anti-platelet therapy (DAPT), including aspirin and clopidogrel, to prevent from recurrent atherothrombotic events.

Levels of platelet reactivity in patients on DAPT can be influenced by concomitant treatment with medications (i.e. statins) that inhibit the CYP3A4 system involved in the activation of clopidogrel.

Atorvastatin and simvastatin are metabolized by CYP3A4. Pitavastatin, unlike other statins, is little metabolized, most of the dose being excreted unchanged in bile, and biotransformation through the cytochrome P450 system is minimal. Indeed, pitavastatin's cyclopropyl group diverts the drug away from metabolism by CYP3A4 and allows only a small amount of clinically insignificant metabolism by CYP2C9.

At least 1 month after starting DAT (clopidogrel 75 mg and aspirin 100 mg), patients will receive randomly atorvastatin (20 mg day, N=50) or pitavastatin (4 mg day, N=50) for 30 days (until T-1).

At this time-point, there will be a wash-out period of 15 days after the first treatment with atorvastatin or pitavastatin in order to avoid any carry-over effect.

Afterwards, a cross-over will be performed, and patients will be switched to the other drug which will be continued for further 30 days (until T-2).

No previous studies have evaluated the influence of pitavastatin as compared with other statins on platelet reactivity in patients receiving DAPT.

The primary objective of this study is to compare the pharmacodynamic effects of a CYP3A4-metabolized statin (atorvastatin) versus a non-CYP3A4-metabolized statin (pitavastatin) in patients showing high platelet reactivity while on DAPT.

Study Timeline

• Study First Submitted: 2012-07-19
• Study First Submitted QC: 2012-07-23
• Study First Posted: 2012-07-24
• Status Verified: 2013-03
• Last Update Submitted: 2013-03-06
• Last Update Posted: 2013-03-07
• Study Start: 2014-01
• Primary Completion: 2015-12
• Study Completion: 2017-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Angiographically-proven coronary artery disease
• Class I indication to DAT because of recent (< 12 months) percutaneous coronary intervention and/or recent acute coronary syndrome (< 12 months)
• Stable clinical conditions
• Able to understand and willing to sign the informed CF

Exclusion Criteria

• Use of other drug interfering with CYP activity such as proton pump inhibitors
• Women of child bearing potential patients must demonstrate a negative pregnancy test performed within 24 hours before CT

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Atorvastatin	Atorvastatin	os, 20 mg, once per day, for 30 days
Pitavastatin	Pitavastatin	os, 4 mg, once per day, for 30 days

Primary Outcome Measures

Name	Time	Method
Assessment of platelet reaction units	After 30 days of treatment with each drug	Absolute changes in platelet reactivity (expressed as P2Y(12) reaction units by the point-of-care VerifyNow assay \[Accumetrics, San Diego, California\])

Secondary Outcome Measures

Name	Time	Method
Frequency of high platelet reactivity	After 30 days of treatment with each drug	Frequency of high platelet reactivity with the 2 study treatments (as defined by a Platelet Reaction Unit value\>208)

Trial Locations

Locations (1)

Sapienza University; 🇮🇹 Rome, Italy