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clinical evaluation of ranolazine efficacy and safety

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clinical evaluation of ranolazine efficacy and safety

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    1. Clinical Evaluation of RanolazineEfficacy and Safety Andrew A. Wolff, MD, FACC Sr VP, Clinical Research and Development CV Therapeutics, Inc.

    2. CE-2 Demonstrated in 5 double-blind, randomized, placebo-controlled studies Dose and plasma concentration dependent Observed in a broad population with severe coronary disease Not dependent upon decreases in blood pressure or heart rate At least as great as atenolol 100 mg qd In patients on atenolol or diltiazem at doses considered optimal by their physicians

    3. CE-3 Studies Demonstrating Efficacy of Ranolazine Two pivotal Phase 3 studies of ranolazine SR MARISA: monotherapy, 191 randomized CARISA: combination, 823 randomized 1° efficacy variable: trough exercise duration Three supportive studies of ranolazine IR

    4. CE-4 MARISA and CARISA Enrolled a Broad Population of Chronic Angina Patients

    5. CE-5 Baseline Duke Score at Trough—All Randomized PatientsMARISA (CVT 3031) and CARISA (CVT 3033) Is Rand stand for All Randomized Patients?Is Rand stand for All Randomized Patients?

    6. CE-6 Monotherapy Assessment of Ranolazine In Stable AnginaMARISA (CVT 3031) Patients withdrawn from other anti-anginals(N = 191 randomized) Randomized, double-blind, 4-period crossover 1-wk treatment periods Placebo vs 500, 1000, and 1500 mg bid Exercise tests after each week of treatment At trough (12 hr after dosing) At peak (4 hr after dosing)

    7. CE-7 Monotherapy With Ranolazine Increases Exercise Performance at Trough and Peak MARISA (CVT 3031)

    8. CE-8 Combination Assessment of Ranolazine In Stable AnginaCARISA (CVT 3033) Randomization criteria identical to MARISA except for background therapy Atenolol 50 mg qd (n = 354), or Amlodipine 5 mg qd (n = 256), or Diltiazem CD 180 mg qd (n = 213) Three parallel groups for 12 wk of treatment Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid Exercise testing At trough after 2, 6, and 12 wk of treatment At peak after 2 and 12 wk of treatment

    9. CE-9 Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times at Trough and Peak CARISA (CVT 3033)

    10. CE-10 Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin ConsumptionCARISA (CVT 3033)

    11. CE-11 Ranolazine SR Dose Predicts Concentration Combined Data From MARISA and CARISA

    12. CE-12 Ranolazine Concentration Predicts ResponseAcross the Chronic Angina Population—Population-Based Analysis of Exercise Duration Four double-blind, placebo-controlled studies MARISA, CARISA and 2 IR studies 1397 patients (1073 men, 324 women) 10,998 ETT-plasma concentration pairs No influence on concentration-response Demographic factors: age, weight, and race Concurrent diseases: CHF class, diabetes Background anti-anginal therapy Men and women respond differently Women: 6.4 sec/1000 ng/mL, 95% CI (3.1, 9.7) Men: 16.8 sec/1000 ng/mL, 95% CI (14.6, 19.0)

    13. CE-13 Anti-Anginal Effects of Ranolazine SR in Women Significant increase in exercise duration 6.4 sec per 1000 ng/mL, 95% CI (3.1, 9.7)

    14. CE-14 Exercise Duration by Subgroup—Borderline Vital Signs or AV Conduction†MARISA (CVT 3031) and CARISA (CVT 3033)

    15. CE-15 Ranolazine Is Effective Across a Broad Spectrum of Chronic Angina PatientsSubgroups Often Intolerant of Other Anti-Anginals Subgroups in which the effect of ranolazine appears consistent with the effect demonstrated in all patients: Borderline vital signs or AV conduction† Reactive airway disease Congestive heart failure Diabetes

    16. CE-16 Ranolazine Is at Least as Effective as Atenolol 100 mg DailyRAN080

    17. CE-17 Different Anti-Anginal Pharmacodynamics of Ranolazine vs AtenololEffects on RPP in RAN080

    18. CE-18 Ranolazine With Atenolol or DiltiazemRAN072 “… patients … receiving an optimal dose of … beta blocker or diltiazem and stabilised at this optimal regimen for at least 7 days.” 2-period, double-blind, crossover design Exercise tests 2.5 to 3 hr after dosing Both ranolazine and background Rx at peak Efficacy with 240 mg IR single dose (N = 25) 15 on atenolol (90 ± 21 mg qd) 10 on diltiazem (186 ± 19 mg qd)

    19. CE-19 Exercise Performance 3 hr After Single Dose of Ranolazine 240 mg With Atenolol or DiltiazemRAN072

    20. CE-20 Summary—Anti-Anginal and Anti-Ischemic Efficacy of Ranolazine Dose and plasma concentration dependent Consistent throughout a broad population of chronic angina patients Not dependent on decreases in blood pressure or heart rate At least as great as atenolol 100 mg qd (RAN080) In patients on atenolol or diltiazem at doses considered optimal by their physicians (RAN072)

    21. Ranolazine Safety

    22. CE-22 Safety of Ranolazine Extent of exposure 2783 subjects/patients 1714 subject/patient yr Adverse events are generally dose dependent and manageable by typical dose titration No evidence for an adverse effect of ranolazine on survival

    23. CE-23 Extent of Ranolazine Exposure

    24. CE-24 Duration of Exposure† 1714 subject/patient yr 1275 angina patient yr on SR Mean exposure of angina patients to SR = 495 days 850 for > 30 days 503 for > 1 yr 259 for > 2 yr

    25. CE-25 Ranolazine Was Well ToleratedAdverse Events Reported in = 2% of Patients and More Frequently on Ranolazine Than on Placebo

    26. CE-26 Incidence per Patient Yr of Death and Sudden Death

    27. CE-27 Mortality in Controlled Studies

    28. CE-28 Summary— Ranolazine Efficacy and Safety Efficacy demonstrated in 5 double-blind, randomized, placebo-controlled trials Safe and well tolerated Adverse events are generally dose dependent and manageable by typical dose titration No evidence for an adverse effect of ranolazine on survival

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