Effect of Ranolazine on Arrhythmias and Microvolt T- Wave Alternans (MVTWA) Patients With LV Dysfunction

The Effect of Ranolazine on Cardiac Arrhythmias and Microvolt T- Wave Alternans in Patients With Significant Left Ventricular Dysfunction

The purpose this investigation is to more thoroughly investigate the effects of ranolazine on arrhythmias and microvolt t-wave alternans in patients who have an automatic implantable cardioverter defibrillator (AICD) implanted either prophylactically to prevent sudden cardiac death, as well as in patients who may have had a clinically significant arrhythmic event prompting the insertion of the automatic implantable cardioverter defibrillator. It is anticipated this study will provide valuable new insight into the potential use of ranolazine to treat arrhythmias in higher risk patients.

Study Overview

• Status: Completed
• Conditions: Sudden Cardiac Death; Ventricular Arrythmias
• Intervention / Treatment: Drug: Ranolazine; Drug: Placebo

Detailed Description

The device clinic of Aspirus Wausau Hospital follows approximately 2800 patients with pacemakers and automatic implantable cardioverter defibrillators (AICD). Approximately 300 of these patients have had an AICD inserted for primary or secondary arrhythmia prevention. From these 300 patients, approximately 20 patients who have an AICD implanted either prophylactically or for an established malignant arrhythmia will be recruited for this short study.

This is a study to investigate the effect of ranolazine on arrhythmias detected by their device to see if it will reduce abnormal beats. It will also study whether ranolazine will impact microvolt t-wave alternans (MVTWA), a measure of the tendency to have a serious arrhythmia. Approximately 10 patients with ischemic cardiomyopathy and 10 patients with a non-ischemic cardiomyopathy will be chosen. All will have an ejection fraction of 40% or less. Prior to institution of ranolazine, a MVTWA study will be performed (Cambridge Heart Inc.®). The AICD will be used to generate the increase in the heart rate needed to induce MVTWA. Each patient will have MVTWA assessed at 80 beats/minute and then again at 110 beats/minute. To eliminate interpretation bias, the auto interpretation feature of the MVTWA device will be used to determine whether the study is positive (MVTWA present) or negative (MVTWA absent) or indeterminate. In the coarse of this study, each patient will undergo a total of 3 MVTWA studies in an identical manner using the AICD to provide the needed changes in heart rate.

After informed consent is obtained the patient will begin a 10-day "ranolazine run in". Each randomized participant will be given a 10-day supply of ranolazine to make certain they tolerate the medication (constipation is by far the most common limiting side effect). Each participant will be started on 500 mg BID and after 3 days increased to 1000 mg BID. Participants able to tolerate at least 500 mg BID will then be considered eligible to participate in the study and randomly assigned to either ranolazine at 1000 mg BID (or 500 mg BID if the 1000 mg dose was not tolerated) or a comparable placebo for the next 4 weeks.

At least 3 days after the run in and prior to randomization, each patient will be brought in for or the baseline MVTWA and the device clinic will purge the AICD of data and reset the data counter. The patient will then immediately begin either placebo or ranolazine according to randomization. After 4 weeks, the MVTWA study will be repeated on either placebo or ranolazine and the arrhythmia data down loaded from the AICD, recorded and the arrhythmia counters and device operation counter again reset. Each patient will then cross over to the other therapy (ranolazine or placebo) for the next 4 weeks and the device interrogated and the MVTWA study repeated in an identical manner.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Wausau, Wisconsin, United States, 54401
      • Aspirus Wausau Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Implant of AICD for the prevention of sudden cardiac death Implant of AICD for the prevention of sudden cardiac death

Exclusion Criteria:

• Any anti-arrhythmic agent (other than beta-blockers)
• History of or intolerance to ranolazine during the run in.
• History of severe constipation defined as requiring laxatives more than 5 times a week in order to have a bowel movement.
• Because of a weak inhibitory effect of ranolazine of the cytochrome p450, CYP 3A4, certain drugs metabolized by that system could accumulate. Although clinically significant interactions of ranolazine with these agents has not been demonstrated, patients on maximum doses of simvastatin, or patients on verapamil or diltiazem will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ranolazine; Ranolazine at 1000 mg BID (or 500 mg BID if the 1000 mg dose was not tolerated) for 4 weeks	Drug: Ranolazine; Ranolazine at 1000 mg BID (or 500 mg BID if the 1000 mg dose was not tolerated) or a comparable placebo for the next 4 weeks
Placebo Comparator: Sugar pill; Placebo comparator BID for 4 weeks.	Drug: Placebo; Ranolazine at 1000 mg BID (or 500 mg BID if the 1000 mg dose was not tolerated) or a comparable placebo for the next 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The effect of ranolazine compared to placebo on MVTWA and reproducibility of MVTWA will be demonstrated. A p value of < 0.05 will be considered significant	After 4 weeks of treatment

Collaborators and Investigators

• Sponsor: Aspirus Heart and Vascular Institute-Research and Education
• Investigators: Principal Investigator: David K. Murdock, MD, Aspirus Heart and Vascular Institute-Research and Education

Publications and helpful links

General Publications

• Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res. 2004 Oct 15;95(8):754-63. doi: 10.1161/01.RES.0000145047.14691.db.
• Ebinger MW, Krishnan S, Schuger CD. Mechanisms of ventricular arrhythmias in heart failure. Curr Heart Fail Rep. 2005 Sep;2(3):111-7. doi: 10.1007/s11897-005-0018-y.
• Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM, Thomas G. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004 Aug 24;110(8):904-10. doi: 10.1161/01.CIR.0000139333.83620.5D. Epub 2004 Aug 9.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: October 16, 2009
• First Submitted That Met QC Criteria: October 19, 2009
• First Posted (Estimate): October 20, 2009

Study Record Updates

• Last Update Posted (Estimate): February 9, 2012
• Last Update Submitted That Met QC Criteria: February 8, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Sudden Cardiac Death; left ventricular dysfunction; Arrythmias; Triggered activity
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Death, Sudden; Heart Arrest; Death; Arrhythmias, Cardiac; Ventricular Dysfunction; Death, Sudden, Cardiac; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: RAN-Twave alt