Results from an analysis of the MARISA trial demonstrates that patients with both chronic angina and a history of congestive heart failure (CHF) tolerate and respond to ranolazine at least as well as angina patients without CHF. At trough plasma concentrations, ranolazine produced statistically significant (p< 0.001) increases in exercise duration, time to angina and time to 1 mm ST segment depression compared to placebo in the angina patients without CHF. Statistically similar increases were observed at trough in the angina patients with CHF. Furthermore, at peak ranolazine plasma concentrations, patients with CHF had increases in exercise duration and time to 1 mm ST segment depression compared to placebo which were significantly greater (p < 0.01) than those observed in the patients without CHF. Adverse event rates were generally not greater in the CHF subgroup than in the patients without CHF. The results, presented at the 50th Annual Scientific Sessions of the American College of Cardiology, suggest that ranolazine, an investigational candidate in a new class of anti-anginal drugs known as pFOX (partial Fatty Acid Oxidation) inhibitors, may be a potential therapy for managing chronic angina in patients with a history of CHF.
"Many patients with chronic angina and CHF have low heart rate and blood
pressure. This can make it difficult to use several of the currently
available anti-anginal drugs, which may further depress left ventricular
function and adversely affect heart rate and blood pressure. In this study,
use of ranolazine did not result in clinically relevant changes in resting or
exercise heart rate or systolic blood pressure in either the patients with CHF
or those without," said Bernard R. Chaitman, M.D., Professor of Medicine,
Director of Cardiovascular Research, St. Louis University School of Medicine,
St. Louis, MO. "This study demonstrated that ranolazine can increase exercise
duration in angina patients both with and without heart failure, which is
significant because a sizable proportion of patients with CHF have angina."
The trial results presented represent an analysis of the Phase III MARISA
(Monotherapy Assessment of Ranolazine In Stable Angina) trial, which was a
double-blind, placebo-controlled trial of ranolazine in patients not receiving
any other anti-anginal drugs. Results from MARISA were initially presented at
the 2000 Scientific Sessions of the American College of Cardiology. These
chronic angina patients received three doses of ranolazine (500 mg, 1000 mg
and 1500 mg bid) and matching placebo, each for one week, in random order, in
a double blind, four period crossover study. Exercise tests at the time of
trough (approximately 12 hours after dosing) and peak drug levels
(approximately four hours after dosing) in 146 patients without a history of
CHF and 29 patients with New York Heart Association Class I or Class II CHF
were evaluated. Exercise times were prolonged by all three doses of
ranolazine compared to placebo in both CHF and non-CHF patients.
Side effects more common during ranolazine treatment than during placebo
treatment included dizziness, nausea, asthenia and constipation. CHF patients
did not have more adverse events than those without CHF.
Chronic angina is a debilitating cardiovascular disease affecting more
than seven million Americans, with an additional 400,000 new cases diagnosed
each year. It is estimated that by the year 2030 the number of people at risk
for developing chronic angina will increase by 50%. Chronic angina pain
develops as a result of coronary artery disease. Cholesterol deposits build
up in patients' blood vessels blocking blood flow, and therefore, oxygen
delivery to the heart muscle. The lack of oxygen causes debilitating episodes
of pain in response to physical or emotional exertion and extreme
Congestive heart failure is the condition in which a weakened heart cannot
pump enough blood to meet the body's demand, and occurs when the heart muscle
is weakened by disease. As a result of this pump failure, fluid accumulates
throughout the body; in the lungs, this results in shortness of breath.
Approximately 4.6 million people in the U.S. suffer from CHF, with an
estimated 400,000 new cases each year. CHF is the leading cause of
hospitalizations in the U.S. for people age 65 and over. In addition, the
five-year mortality rate for CHF is approximately 50%.
Ranolazine Mechanism of Action
Ranolazine represents the first of a new class of compounds for the
potential treatment of chronic angina called partial Fatty Acid Oxidation
(pFOX) inhibitors. This mechanism is different from that of currently
available drugs. Animal studies indicate that pFOX inhibitors, unlike
currently available agents, appear to work by altering the metabolism of the
heart to make it use oxygen in a more efficient manner; this in turn, reduces
the heart's oxygen requirement without reducing the work of the heart. The
MARISA data appear to be consistent with these animal studies.
Oxidation is the process of combining oxygen with the metabolic fuels,
fatty acid or glucose, to extract cardiac energy. Normally, heart muscle
cells utilize more fatty acid relative to glucose, but fatty acid is less
oxygen-efficient than glucose. pFOX inhibitors are believed to work by
partially inhibiting fatty acid oxidation causing a reciprocal increase in
glucose oxidation. Since fatty acid metabolism produces less energy per unit
of oxygen consumed than glucose metabolism, a shift from fatty acid to glucose
metabolism should allow the heart to do more work from the oxygen available to
it and may thus prevent or delay angina attacks without affecting heart rate
or blood pressure. Maintaining glucose oxidation also prevents the build-up
of toxic lactic acid.
Ranolazine has not been approved for marketing by the Food and Drug
Administration or other foreign agencies. Ranolazine is presently being
investigated in Phase III clinical trials subject to a United States IND and
applicable foreign authority submissions. CV Therapeutics has not yet
submitted an NDA to the FDA or equivalent application to any other foreign
regulatory authorities for ranolazine, and ranolazine has not yet been
determined to be safe or effective in humans for its intended use.
Ranolazine, the first in a new class of
compounds known as partial fatty acid oxidation (pFOX) inhibitors, is in Phase
III clinical trials for the potential treatment of chronic angina. CVT-510,
an A1 adenosine receptor agonist, is in Phase II clinical trials for the
potential treatment of atrial arrhythmias. CVT-3146, an A2A adenosine
receptor agonist, is in Phase I clinical trials for the potential use as an
adjunctive pharmacologic agent in cardiac perfusion imaging studies. For more
information, please visit CV Therapeutics' web site at http://www.cvt.com.