MERLIN TIMI 36 METABOLIC EFFICIENCY WITH RANOLAZINE FOR
MERLIN TIMI 36 METABOLIC EFFICIENCY WITH RANOLAZINE FOR LESS ISCHEMIA IN NSTE ACS
Ranolazine in Ischemic Heart Disease Background • Anti-anginal & anti-ischemic effects without clinically significant effect on HR or BP • Approved for treatment of chronic angina – exercise time, angina in selected pts • Novel mechanism of action – Inhibition of late INa Ca 2+ overload adverse energetic, mechanical, electrical consequences • Experimental evidence – LV performance during ischemia – recovery of LV function, infarct size Morrow DA et al. JAMA 2007; 297: 1775 -83
Ranolazine in Ischemic Heart Disease Background • Ranolazine associated with an in QTc (average ~5 msec) • However, experimental data suggest suppression of pro-arrhythmic markers • Indication in chronic angina: “Because ranolazine prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other anti-anginal drugs. ” Need for additional safety information Morrow DA et al. JAMA 2007; 297: 1775 -83
Objectives Study Design MERLIN-TIMI 36 Three major aims 1) ACUTE EFFICACY 2) CHRONIC EFFICACY Acute Coronary Syndrome major CV events? Chronic Management recurrent ischemia? 3) SAFETY Morrow DA et al. JAMA 2007; 297: 1775 -83
N = 6560 UA/NSTEMI (Moderate-High Risk) Standard Therapy Ranolazine IV to PO RANDOMIZE (1: 1) Double-blind Holter Long-term Follow-up (Median 348 Days) Morrow DA et al. JAMA 2007; 297: 1775 -83 Placebo Matched IV/PO
Major Inclusion Criteria Study Design 1) Hospitalized with NSTE ACS 2) Ischemic sx at rest within 48 h 3) At least 1 indicator of moderate-high risk Ø Ø c. Tn (MI limit) or CK-MB (ULN) or ST-depression 0. 1 m. V or Diabetes Mellitus (insulin or oral rx) or TIMI Risk Score for UA/NSTEMI 3 Morrow DA et al. JAMA 2007; 297: 1775 -83
Major Exclusion Criteria Study Design • Must be enrolled prior to revascularization (if planned) • Pulmonary edema requiring intubation, sustained SBP < 90 mm. Hg or shock • Use of drugs known to QT • Clinically significant hepatic disease or end-stage renal disease Morrow DA et al. JAMA 2007; 297: 1775 -83
Endpoints Study Design Primary Endpoint composite of • Cardiovascular death • New or recurrent MI • Recurrent ischemia Major Secondary Endpoints • CVD, MI, severe recurrent ischemia, positive Holter (30 day endpoint) All elements of 1° endpoint adjudicated by blinded CEC Morrow DA et al. JAMA 2007; 297: 1775 -83
Ischemia Endpoint Definition Study Design Recurrent Ischemia defined by 2. Prompting revascularization, or 3. Rehospitalization for UA, or 4. Worsening angina/ischemia ( CCS Class) requiring intensification of rx CCS = Canadian Cardiovascular Society Morrow DA et al. JAMA 2007; 297: 1775 -83 Severe RI 1. Rest pain with ischemic ECG , or
Major Safety Endpoints Study Design • Death from any cause • Symptomatic documented arrhythmia • Clinically significant arrhythmias during Holter monitoring Morrow DA et al. JAMA 2007; 297: 1775 -83
Baseline Characteristics Enrollment October 2004 to May 2006. 9 lost to F/U Age (yrs, median) Female (%) Diabetes (%) Prior MI Prior CHF Results PLACEBO (N=3, 281) RANOLAZINE (N=3, 279) 64 36 34 33 17 64 34 34 34 16 23 51 35 46 24 51 35 45 Presentation Sx to rando (median, hrs) NSTEMI (%) ST 1 mm (%) TRS 4 (%) Morrow DA et al. JAMA 2007; 297: 1775 -83
Concomitant Treatment Results PLACEBO (N=3, 281) RANOLAZINE (N=3, 279) Aspirin (%) Heparin (UFH/LMWH) (%) Thienopyridine (%) Beta-blocker (%) Statin (%) ACEI/ARB (%) Oral nitrates (%) 96 90 65 90 82 79 31 96 91 64 89 83 78 29 Early Invasive (%) Coronary angio (%) 41 59 Hospitalization and/or discharge Morrow DA et al. JAMA 2007; 297: 1775 -83
Primary Endpoint Results CV Death, MI, or Recurrent Ischemia (%) Placebo 23. 5%* 30 (N=3, 281) 20 Ranolazine 21. 8%* (N=3, 279) 10 HR 0. 92 (95% CI 0. 83 to 1. 02) P = 0. 11 0 0 180 360 540 Days from Randomization *KM cumulative incidence (%) at 12 months Morrow DA et al. JAMA 2007; 297: 1775 -83
Components of Primary Endpoint CV Death or MI (%) Recurrent Ischemia (%) 20 Placebo 16. 1%* (N=3, 281) 20 15 15 Placebo 10. 5%* 10 Ranolazine 13. 9%* (N=3, 279) 10 Ranolazine 10. 4%* 5 HR 0. 99 (95% CI 0. 85 to 1. 15) P =0. 87 0 0 180 360 540 Days from Randomization *KM Cumulative Incidence (%) at 12 months Morrow DA et al. JAMA 2007; 297: 1775 -83 Results 5 HR 0. 87 (95% CI 0. 76 to 0. 99) P =0. 030 0 0 180 360 Days from Randomization 540
Additional Efficacy Endpoints* Results PLACEBO RANOLAZINE (N=3, 281) (N=3, 279) HR p-value CVD, MI, Severe RI Failure of therapy 19. 2 38. 3 18. 7 36. 8 0. 96 0. 94 p = 0. 50 p = 0. 16 30 -day endpoint** 25. 1 23. 1 0. 92 p = 0. 055 CV Death MI 4. 5 7. 6 4. 4 7. 4 1. 00 0. 97 p = 0. 98 p = 0. 76 *KM Cumulative Incidence (%) at 12 months CV Death, MI, RI, Holter ischemia, New/worsening HF, Early +ETT **CV Death, MI, severe RI, Holter ischemia Morrow DA et al. JAMA 2007; 297: 1775 -83
Components of Recurrent Ischemia Endpoint Results HR p-value Cardiovascular Death 1. 00 0. 98 MI 0. 97 0. 76 Recurrent Ischemia 0. 87 0. 030 with ECG 0. 88 0. 31 hospitalization w/ UA 0. 88 0. 16 revascularization 0. 84 0. 13 worsening angina 0. 77 0. 023 Hazard Ratio (95% CI) 0. 6 0. 8 FAVORS RANOLAZINE Morrow DA et al. JAMA 2007; 297: 1775 -83 1. 2 1. 4 FAVORS PLACEBO 1. 6
Assessment of Anti-anginal Effects PLACEBO (N=3, 281) % 23% P = 0. 023 Morrow DA et al. JAMA 2007; 297: 1775 -83 Results RANOLAZINE (N=3, 279) % 20% P = 0. 003 *KM Cumulative Incidence at 12 months
Efficacy Results in Major Subgroups Subgroup N Results P-interaction Primary EP (CVD/MI/RI) Sex Men Women 4, 269 2, 291 0. 12 Age <75 yo >=75 yo 5, 405 1, 155 0. 80 Diabetes No DM DM 4, 340 2, 220 0. 39 TIMI Risk 0 -3 4 -7 3, 603 2, 957 0. 16 Index Event UA NSTEMI 3, 067 3, 342 0. 85 STD ≥ 1 mm No Yes 4, 255 2, 304 0. 23 OVERALL 6, 560 Morrow DA et al. JAMA 2007; 297: 1775 -83 0. 6 0. 8 FAVORS RANOLAZINE 1. 2 1. 4 FAVORS PLACEBO 1. 6
Major Safety Endpoints Results PLACEBO RANOLAZINE (N=3, 273*) (N=3, 268*) HR P-value Death - any cause (N) Sudden cardiac death 175 65 172 56 0. 99 0. 87 p = 0. 91 p = 0. 43 Symptomatic Documented arrhythmia 102 99 0. 97 p = 0. 84 83. 1% 73. 7% 0. 89 p<0. 001 Clinically significant arrhythmia on Holter *safety analysis cohort (received at least one dose) VT ≥ 3 beats, SVT >120 bpm, new AF, brady<45 bpm, CHB or pause >2. 5 s Morrow DA et al. JAMA 2007; 297: 1775 -83
Tolerability Results Adverse events >4% PLACEBO (N=3, 273) RANOLAZINE (N=3, 268) Dizziness (%) Nausea Constipation Asthenia 7 6 3 3 13 9 9 5 Syncope* 2 3 *Includes vasovagal syncope Morrow DA et al. JAMA 2007; 297: 1775 -83 p = 0. 011
Conclusions • An 8% relative in the primary endpoint w/ ranolazine was not statistically significant • No effect on CV death or MI • Supportive evidence for efficacy as an anti-anginal in broader population than ever studied before – 23% in worsening angina – 20% in advancement of anti-anginal rx Morrow DA et al. JAMA 2007; 297: 1775 -83
Conclusions (cont. ) Conclusions • Results reassuring with respect to each of the major safety endpoints – No adverse trend in all-cause mortality or arrhythmia • Potential anti-arrhythmic effects of ranolazine (inhibitor of late Na+ current) suggested by in arrhythmias (Holter) warrant additional investigation Morrow DA et al. JAMA 2007; 297: 1775 -83
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