A drug approved to treat chest pain is being tested as a potential treatment for ventricular arrhythmias, irregular heart rhythms that are associated with increased hospitalizations and death and for which there are limited treatment options for patients with heart disease. The new nationwide clinical trial, funded with a $10.5 million grant from the National Institutes of Health, is the first major study testing a new concept – blocking late sodium currents that govern key components of the electrical activity in the heart – to combat these deadly arrhythmias.
This approach represents a new avenue of therapy after two decades of no significant developments in innovative drug treatment of ventricular arrhythmias. The two principal investigators of the new study, Wojciech Zareba, M.D., Ph.D., and Arthur J. Moss, M.D., of the University of Rochester Medical Center, are world experts on the treatment of arrhythmias.
Patients at increased risk of particularly fast heart rhythms known as ventricular tachyarrhythmias have very low survival rates. The study drug, Ranexa® (ranolazine), has been tested in animals and in pilot clinical studies, and has shown anti-arrhythmic properties. The drug was also previously tested in patients with a heart condition known as Long QT syndrome (LQTS) – a rare hereditary syndrome which makes the heart susceptible to fatal arrhythmias – with favorable results.
“This study is very important because current anti-arrhythmic agents do not offer enough protection for high-risk patients or can’t be used for long due to negative side effects, and some even cause additional heart rhythm disorders,” said Zareba, director of Clinical Cardiology Research and the Heart Research Follow-up Program at the Medical Center. “We believe ranolazine is a promising therapy and that this trial could provide a revolutionary approach to treat these difficult heart rhythm disorders.”
In the planned double-blind, randomized clinical trial, high-risk patients who already have implantable cardioverter-defibrillators or ICDs – devices that detect irregular heart rhythms and shock the heart back into a normal rhythm – will receive either ranolazine or placebo. The aim of the study, known as RAID, for Ranolazine in High-Risk Implantable Cardioverter-Defibrillator Patients, is to determine if ranolazine decreases death or cardiac arrhythmias, and also if it decreases the risk of hospitalizations from cardiac causes, including arrhythmias, heart failure or heart attack. Study investigators plan to enroll approximately 1,440 patients at 80 centers across the United States.
According to Moss, professor of Medicine at the Medical Center, “This is the right study at the right time. We know ranolazine has a good safety profile from its use to treat chest pain; early basic and clinical testing has been favorable; and we will be able to monitor precisely how patients respond to the drug by taking heart rhythm recordings directly from patients’ ICDs.” Moss will coordinate data management for the trial.
Ranolazine was tested previously in the high-profile MERLIN trial to determine if the drug reduced death rates in patients with acute coronary syndrome. While the drug was unsuccessful in reducing the risk of death in these patients, the study population was very large and researchers obtained significant data on various subgroups. They found that in people with coronary artery disease ranolazine decreased the incidence of arrhythmias.
Ranolazine works by targeting the late sodium current that moves sodium ions into the heart muscle cells with each heartbeat, regulating the electrical activity of the heart. Damage to heart cells, such as from a heart attack, can cause excess sodium to leak into heart muscle cells. This extra, unwanted sodium puts patients at greater risk for arrhythmias, and may prove to be an effective target for drugs such as ranolazine, blocking excessive inflow of sodium ions.
A new, safe and effective anti-arrhythmic drug is in high demand. While ICDs help reduce death in high-risk individuals, many patients don’t receive ICDs because they are hesitant to get a device implanted or they don’t truly understand their risk. Physicians may also prefer to manage their patients without the use of a device. Even for patients who have ICDs, the long-term death rate remains relatively high, and could be reduced by the addition of an anti-arrhythmic drug.
Zareba and Moss are widely known for their work spearheading the practice-changing MADIT clinical trial series on the use of ICDs, and furthering our understanding of the genetic underpinnings of heart disease through the study of Long QT syndrome.
The trial, which is registered on clinicaltrials.gov (#NCT01215253), is funded by the National Heart, Lung and Blood Institute at the National Institutes of Health and will begin enrolling patients in spring 2011. Gilead Sciences, Inc., the biopharmaceutical company that markets ranolazine, will donate the study drug and placebo needed for the trial.
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