PharmacOdynamic compaRison of piTavastatin Versus atOrvastatin on Platelet Reactivity (PORTO)

Pharmacodynamic Comparison of Pitavastatin Versus Atorvastatin on Platelet Reactivity in Patients With Coronary Artery Disease Treated With Dual Antiplatelet Therapy - The PORTO Trial

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.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Atorvastatin; Drug: Pitavastatin

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 Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00166
    • Sapienza University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atorvastatin; os, 20 mg, once per day, for 30 days	Drug: Atorvastatin; Patients will receive randomly atorvastatin (20 mg day) for 30 days; Other Names: Torvast, Pfizer, USA
Active Comparator: Pitavastatin; os, 4 mg, once per day, for 30 days	Drug: Pitavastatin; Patients will receive randomly pitavastatin (4 mg day) for 30 days; Other Names: Livalo, Kowa Pharmaceuticals, Japan

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza
• Investigators: Principal Investigator: Francesco Pelliccia, MD, Sapienza University

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: July 19, 2012
• First Submitted That Met QC Criteria: July 23, 2012
• First Posted (Estimate): July 24, 2012

Study Record Updates

• Last Update Posted (Estimate): March 7, 2013
• Last Update Submitted That Met QC Criteria: March 6, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Pitavastatin
• Other Study ID Numbers: 449/2012/D