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New Therapies
Heather Kertland, PharmD
New Agents
Outline
• Eplerenone
• Ultrafiltration
• CRT
Rales Study
Population
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 trial
Population
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)
Hyperkalemia
New Engl J Med
2004;351:542-51
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 experience
Endpoint
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
350
a
b
c
d
e
f
g
i
j
300
250
200
150
100
50
0
baseline Cr
Post UF Cr
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