New Therapies

Heather Kertland, PharmD

• Eplerenone• Ultrafiltration• CRT

Outline

New Agents

Rales StudyPopulation NYHA Class III and IV heart failure and LVEF≤35%

Comparator spironolactone target dose 50 mg/day vs. placebo

Outcome n = 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

Safety Hyperkalemia ≥ 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

Eplerenone (Inspra)• A chemical derivative of spironolactone,

• enhanced selective binding to the mineralocorticoid receptor

• minimizing binding to progesterone and androgen receptors

Ephesus trialPopulation 3 to 14 days post-MI with either symptoms of HF or diabetes

without HF symptoms; NYHA classes I-IV; LVEF≤40%

Comparator eplerenone target dose 50 mg/day vs. placebo

Outcome n = 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:

Ephesus

Safety Hyperkalemia ≥ 6.0 μmol/L:

5.5% eplerenone vs. 3.9% placebo

Gynecomastia in men:

0.5% eplerenone vs. 0.6% placebo

Other DI: substrate for CYP3A4 (concomitant use of strong CYP3A4 inhibitors is contraindicated)

New Engl J Med 2004;351:542-51

Hyperkalemia

Rx info• Monitoring K+

– 48 hours post 1st 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.

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

SMH experienceEndpoint N=8

Age 66.1 yrs

Duration of UF 36 hrs (15 – 65 hrs)

UF rate 50 – 250 mL/hr

Average weight loss 7.5 kg

SMH Experience

0

50

100

150

200

250

300

350

baseline Cr Post UF Cr

a

b

c

d

e

f

g

i

j

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

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

New Engl J Med 2010

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