1. New Therapies Heather Kertland, PharmD

2. Eplerenone Ultrafiltration CRT Outline New Agents

3. Rales Study PopulationNYHA Class III and IV heart failure and LVEF≤35% Comparator spironolactone target dose 50 mg/day vs. placebo Outcomen = 1,663; mean follow-up = 24 months; mean LVEF 25.6%; mean dose = 26 mg/day; All-cause mortality: spironolactone was associated with a 30% RRR compared to placebo (34.5% vs. 46%, p<0.001) ARR = 11%; NNT = 9 SafetyHyperkalemia ≥ 6.0 μmol/L: 2% spironolactone vs. 1% placebo (p=0.42) Gynecomastia in men: 9% spironolactone vs. 1% placebo New Engl J Med 1999

5. Eplerenone (Inspra) A chemical derivative of spironolactone, enhanced selective binding to the mineralocorticoid receptor minimizing binding to progesterone and androgen receptors

7. Ephesus trial Population3 to 14 days post-MI with either symptoms of HF or diabetes without HF symptoms; NYHA classes I-IV; LVEF≤40% Comparatoreplerenone target dose 50 mg/day vs. placebo Outcomen = 6,642; mean follow-up 16 months; mean LVEF 33%; mean dose = 43.5 mg/day; All-cause mortality: eplerenone demonstrated a 15% RRR compared to placebo (14.4% vs. 16.7%; p=0.008) ARR = 2.3%; NNT = 43 Composite endpoint of death from CV causes or first hospitalization from a CV event: eplerenone demonstrated a 13% RRR compared to placebo (26.7% vs. 30.0%, p=0.002) ARR = 3.3%; NNT = 30 New Engl J Med 2003;348:

8. Ephesus SafetyHyperkalemia ≥ 6.0 μmol/L: 5.5% eplerenone vs. 3.9% placebo Gynecomastia in men: 0.5% eplerenone vs. 0.6% placebo OtherDI: substrate for CYP3A4 (concomitant use of strong CYP3A4 inhibitors is contraindicated)

9. New Engl J Med 2004;351:542-51 Hyperkalemia

10. Rx info Monitoring K+ –48 hours post 1 st dose –1,4 and 5 weeks –1 week after any dose change Coverage –Common Drug Review (CDR) – do not cover –ODB Exceptional Access - Experience AMI, have evidence of heart failure and left ventricular systolic dysfunction (EF <40%) and tried spironolactone but experienced severe symptomatic (painful) gynecomastia.

11. Ultrafiltration Pts not responding to diuretics Clinic/inpatient setting Results 2 – 3 kg greater weight loss than diuretics, no effect on dyspnea No adverse effects on Serum Cr Anticoagulation is required

12. SMH experience EndpointN=8 Age66.1 yrs Duration of UF36 hrs (15 – 65 hrs) UF rate50 – 250 mL/hr Average weight loss7.5 kg

13. SMH Experience

14. Summary UF is an alternative to diuretics for removing fluid Well tolerated with respect to renal function, although can remove fluid too quickly/too much No known effects on drug concentrations determined to date

15. Resynchronization Therapy (CRT) Delayed conduction of electrical signal Ventricles do not contract at the same time QRS interval > 120 msec on ECG + HF symptoms + reduced EF

16. New Engl J Med 2010

17. Summary Indication is heart failure not bradycardia Can have pacing capabilities Can be combined with ICD Impact on drug therapy –Implantation – holding of anticoagulation –Post – improvement in symptoms – decrease in furosemide