5Chronic AnginaA condition that impairs quality of life and is associated with decreased life expectancyCurrent major drug therapiesNitratesß-blockers,Calcium antagonistsAll these affect HR and BP
6RanolazineA drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.Do not affect HR & BP.Ranolazine was approved on January 27, 2006, in the United States for use in patients with chronic angina who continue to be symptomatic on ß-blockers, calcium antagonists, or nitrates.
7Mechanisms of ActionInitially it was thought that primary mechanism of action is inhibition of fatty acid oxidation, and promotion of glucose oxidation
8Primary Mechanism of Action: Inhibition of Late Na channel NCX: Sodium-calcium exchangeEur Heart J. 2004;6(suppl I):I3–I7.
9Mechanism of actionIn ischemia, number of late Na channel (I-Na) increases which leads to calcium overload through Na-Ca exchange.Ranolazine block these late Na channel, and hence prevent the calcium overload which in turn decreases mechanical dysfunction, abnormal contraction and relaxation, and diastolic tension.
10Thus, ranolazine is a relatively selective inhibitor for late INa Ranolazine (therapeutically conc.up to 10 µmol/L) selectively inhibit late INa (IC50=5 to 21 µmol/L)No effect on either the fast sodium current responsible for the upstroke of the action potential (IC50 value of 244 µmol/L for peak INa) or the Na+-H+ and Na+-Ca2+ exchangers.Thus, ranolazine is a relatively selective inhibitor for late INaJ Cardiovasc Pharmacol Ther. 2004; 9: S65–S83
11Ranolazine & inhibition of various currents IC50 values for various currents:Late INa umol/LIKr umol/LLate ICa umol/LINa-Ca umol/LPeak ICa umol/LIKs (17%) umol/LCirculation. 2004;110:
12Pharmacokinetics Elimination Food - no effect on Bioavailability The absolute bioavailability - 35% to 50%.Elimination80% - by cytochrome P450 (CYP) 3A enzymes10-15% by CYP2D65% Glucuronidation5% Excreted unchanged in Urine.Elimination half-life7 hrs - ER formulation
13Drug–Drug Interaction Diltiazem (≥240 mg daily) - ↑ ranolazine plasma levels foldRanolazine has no significant effect on diltiazem pharmacokineticsVerapamil (≥360 mg daily) fold ↑ in ranolazine plasma levelsRanolazine increases digoxin concentrations 1.4- to 1.6-fold at trough &2-fold at peak plasma levelsRanolazine is contraindicated in patients on potent andmoderately potent CYP3A inhibitors such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice
14Drug–Drug Interaction Simvastatin Cmax is ↑ by 2-fold after ranolazine;Simvastatin - no significant effect on ranolazine pharmacokinetics.In phase II studies of ranolazine with patientson statin drugs, significant increases in creatine kinase, clinical myositis, or elevated liver function tests have not been reported.No interactions with warfarinAntiarrhythmic drugsClass Ia: quinidineClass III: dofetilide, sotalolCertain antipsychotics: Thioridazine, ziprasidone
15Monotherapy Assessment of Ranolazine In Stable Angina MARISA Patients withdrawn from other anti-anginals (N = 191 randomized)Randomized, double-blind, 4-period crossover1-wk treatment periodsPlacebo vs 500, 1000, and 1500 mg bidExercise tests after each week of treatmentAt trough (12 hr after dosing)At peak (4 hr after dosing)J Am Coll Cardiol 2004;43:
16Monotherapy With Ranolazine Increases Exercise Performance at Trough and Peak MARISA ****************************************************N = 175, All/Near Completers population; LS means ± SE.**p < 0.01 vs placebo; ***p < vs. placeboPlacebo500 mg bid1000 mg bid1500 mg bid
17Combination Assessment of Ranolazine In Stable Angina CARISA Randomization criteria identical to MARISA except for background therapyAtenolol 50 mg qd (n = 354), orAmlodipine 5 mg qd (n = 256), orDiltiazem CD 180 mg qd (n = 213)Three parallel groups for 12 wk of treatmentPlaceboRanolazine 750 mg bidRanolazine 1000 mg bidExercise testingAt trough after 2, 6, and 12 wk of treatmentAt peak after 2 and 12 wk of treatmentJAMA 2004;291:
18Change from baseline, sec Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times at Trough and Peak CARISATroughPeak*****************Change from baseline, secN = 791, ITT/LOCF; LS mean ± SE.*p < 0.05; **p ≤ 0.01; ***p ≤ vs placebo.Placebo750 mg bid1000 mg bid
19Nitroglycerin consumption Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin Consumption CARISA*********Angina attacksNitroglycerin consumptionN = 791, ITT/LOCF; LS mean ± SE.*p < 0.05, **p ≤ 0.01, ***p ≤ vs placebo
20ERICA: Study design Evaluation of Ranolazine In Chronic Angina History of CAD* Stable angina (≥3 angina episodes/week) Amlodipine 10 mg/day N = 565Ranolazine extended-release 500 mg bid (1 week) then 1000 mg bid n = 281Placebo n = 284Randomized Double-blind7 weeksPrimary efficacy variable: Angina frequency (weekly average)*≥60% stenosis, previous MI, and/or stress-induced perfusion defectStone PH et al. J Am Coll Cardiol. 2006;48:
21Amlodipine was to be started at least 2 weeks PRIOR to the qualification period Those taking Dig, perhexiline, trimetazidine, beta blockers, OTHER calcium channel blockers had to be withdrawn 4 weeks prior to initiation of study drug
22ERICA: Ranolazine reduces angina frequency and nitrate consumption N = 564 on amlodipine 10 mg/day654P =Mean number per weekP = 0.014321NOTE THE EFFECT OF PLACEBO ON THE NUMBER OF ANGINA EPISODES AND ALSO NITROGLYCERIN USE, THUS THE NEED FOR HAVING A PLACEBO IN ANY RANDOMIZED TRIAL IS VERY IMPORTANTAGAIN SHOWING THAT RANOLAZINE DECREASED FREQ OF ANGINA (P=.028 AND NTG USE P=.014)BaselineWeek 7BaselineWeek 7Angina episodesNitroglycerin usePlacPlaceboeboRRannanolazine 1000 mg bidStone PH et al. J Am Coll Cardiol. 2006;48:
23ERICA: No significant effect on heart rate or BP N = 564 on amlodipine 10 mg/day; Supine measurementPlaceboRanolazine 1000 bidPHeart rate (bpm)↓1.6↓2.00.66Systolic BP (mm Hg)↓1.70.72Diastolic BP (mm Hg)↓0.6↓1.00.61Stone PH et al. J Am Coll Cardiol. 2006;48:
24Ranolazine Is at Least as Effective as Atenolol 100 mg Daily RAN080 Time to onset of anginaTime to 1-mm ST-depressionExercise durationp < 0.001p = 0.006p < 0.04p < 0.001p = 0.18p < 0.001p < 0.001p = 0.86LS mean ± SE, secp < 0.001PlaceboRanolazine IR 400 mg tid(1741 ± 1026 ng base/mL)Atenolol 100 mg odAll patients analysis, N = 154.
25MERLIN-TIMI 36 Randomized, placebo controlled tiral. Subjects: 6560 patients hospitalized with NSTEMI were randomized to ranolazine or placebo, in addition to standard therapy.Initially ranolazine was given intravenous infusion followed by oral ranolazine.Median duration of cECG monitoring was 6.8 days.Circulation 2007;116:
26MERLIN-TIMI 36: SUMMARYIn more than 6300 patients admitted with NSTEMI, treatment with ranolzine resulted in significantly lower incidence ofventricular tachycardia,Supraventricular tachycardia, andSignificant ventricular pauses.Circulation 2007;116:
27Summary—Anti-Anginal and Anti-Ischemic Efficacy of Ranolazine Dose and plasma concentration dependentConsistent throughout a broad population of chronic angina patientsNot dependent on decreases in blood pressure or heart rateAt least as great as atenolol 100 mg qd (RAN080)In patients on atenolol or diltiazem at doses considered optimal by their physicians (RAN072)
28Safety Common reported adverse events are:- Dizziness:- 6.2%Headache:- 5.5%Constipation:- 4.5%Nausea:- 4.4%CARISA: the average increase in QTc was 6.1 and 9.2 ms at the ranolazine doses of 750mg and 1000mg twice daily.NO CASES OF TORSADES DE POINTES HAVE BEEN SEEN IN PATIENTS WHO RECEIVED RANOLAZINE IN CLINICAL TRIALS TO DATE
29Contraindications Preexisting QT prolongation On drugs that prolong QT intervalHepatic impairmentPatients taking drugs which inhibit CYP3A.In patients on potent and moderately potent CYP3A inhibitors such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice.
30Indications & Dosage Treatment of Chronic angina. Patients who have not achieved an adequate response with other antianginal drug.It should be used in combination with beta-blockers, amlodipine, or nitrates.500mg bid initially, can be increased to 1000 mg bid.Max. recommended daily dose is 1000 mg bid.Helps in lowering HbA1c in patients with DM
31Summary— Ranolazine Efficacy and Safety Efficacy demonstrated in 5 double-blind, randomized, placebo-controlled trialsSafe and well toleratedAdverse events are generally dose dependent and manageable by typical dose titrationNo evidence for an adverse effect of ranolazine on survival