Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina
Bernard R. Chaitman, MD, FACC*,*,
Sandra L. Skettino, MD ,
John O. Parker, MD, FACC ,
Peter Hanley, MD, FACC ,
Jaroslav Meluzin, MD, PhD||,
Jerzy Kuch, MD, PhD¶,
Carl J. Pepine, MD, FACC#,
Whedy Wang, PhD,
Jeanenne J. Nelson, PhD**,
David A. Hebert, PhD**,
Andrew A. Wolff, MD, FACC MARISA Investigators
* Saint Louis University School of Medicine, St. Louis, Missouri, USA
CV Therapeutics, Palo Alto, California, USA
Kingston General Hospital, Kingston, Canada
Medical Group of Fort Wayne, Fort Wayne, Indiana, USA
|| St. Anna Hospital, Brno, Czech Republic
¶ Medical Academy Hospital, Warsaw, Poland
# The University of Florida, Gainesville, Florida, USA
** Quintiles, Inc., Research Triangle Park, North Carolina. USA.
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Figure 1 Regulation of carbohydrate metabolism by fatty acid oxidation. Predominating pathways are represented by open arrows; inhibited pathways are represented by dotted arrows. (A) When fatty acid levels are elevated, the end products of beta-oxidation reduce the activity of pyruvate dehydrogenase, the enzyme that mediates the conversion of pyruvate to acetyl CoA and permits its entry into the Krebs cycle. As a result, oxygen-wasting fatty acid oxidation predominates, pyruvate oxidation is inhibited, and lactate accumulates with deleterious consequences. (B) Inhibiting fatty acid oxidation with ranolazine should relieve the inhibition of pyruvate dehydrogenase, promoting oxidation of glucose and lactate, which phosphorylates a given amount of ATP using less oxygen than fatty acid oxidation. In addition, the coupling of pyruvate formation via glycolysis to pyruvate oxidation in the Krebs cycle is improved so that lactate accumulation is diminished.
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Figure 2 Symptom-limited exercise duration: dose and plasma concentration relationships. (A) Exercise duration versus ranolazine dose. Data are shown at trough (solid bars, primary end point) and peak (lined bars). Statistically significant increases were observed on each ranolazine dose versus placebo (*p < 0.005 vs. placebo; **p < 0.001 vs. placebo). A dose-response relationship was evident with greater increases at peak than at trough. Similar data were observed for time to onset of angina and time to 1 mm ST-segment depression (Table 2). (B) Exercise duration versus ranolazine plasma concentration. Mean exercise duration increases with mean plasma ranolazine concentrations. From left to right, values on each treatment at trough and peak, respectively, are represented by diamonds (placebo), squares (500 mg twice daily), circles (1,000 mg twice daily), and triangles (1,500 mg twice daily). Dotted lines represent the 95% confidence intervals around the fitted curve.
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Figure 3 Survival during long-term ranolazine treatment. Kaplan-Meier survival curve including 191 patients who received ranolazine during the double-blind portion of the trial; 143 patients completed the double-blind study and continued on treatment with open-label ranolazine, as described in the Methods section. The curve was constructed from the first date of ranolazine treatment during the double-blind four-period crossover study, and includes a subsequent week of placebo treatment for the 140 patients who were not randomized to begin double-blind treatment with placebo. CI = confidence interval.
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