Download Neprilysin Inhibitors – The Mainstay for Heart Failure?

Neprilysin Inhibitors –
The Mainstay for Heart Failure?
Alison M. Walton, PharmD, BCPS
Associate Professor of Pharmacy Practice – Butler University
Clinical Pharmacy Specialist, Ambulatory Care – St. Vincent
Indianapolis, IN
Email: [email protected]
Disclosure Statement
• No conflicts of interest to disclose.
• I work for Butler University and St.
Vincent in Indianapolis, Indiana.
Learning Objectives
• Define the mechanism of action of neprilysin
inhibitors in the management of heart failure.
• Explain the monitoring and toxicity of neprilysin
inhibitors.
• Discuss the place of neprilysin inhibitors in the
heart failure treatment algorithm.
3
Treatment Guidelines for Heart Failure
2013 ACCF/AHA Guideline for the Management of
Heart Failure
2016 ACC/AHA/HFSA Focused Update on New
Pharmacological Therapy Heart Failure: An
Update of the 2013 ACCF/AHA Guideline for the
Management of Heart Failure
2016 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure
Circulation 2013;128;e240-e327.
Circulation 2016. DOI: 10.1161/CIR.0000000000000435
4
European Heart Journal 2016. DOI: 10.1093/eurheartj/ehw128
Goals of Heart Failure Therapy
Reduce
mortality
Reduce
hospitalizations
Relieve
symptoms
Slow
progression of
disease
Improve quality
of life
5
Types of Heart Failure
Classification
EF
Description
I. HF with reduced
ejection fraction
(HFrEF)
<40%
Systolic HF; Primary patients in
randomized clinical trials;
Efficacy data for therapies
II. HF with
preserved ejection
fraction (HFpEF)
a. HFpEF,
borderline
>50%
Diastolic HF; Challenging
diagnosis; Efficacy data for
therapies not identified to date
Intermediate group;
Characteristics, treatment
patterns, outcomes similar to
HFpEF
Recovery in EF; Further
research needed
b. HFpEF,
improved
EF = Ejection fraction
41-49%
>40%
6
Circulation 2013;128;e240-e327.
Classifications of Heart Failure
NYHA Functional
Classification
ACCF/AHA Stages of HF
A At high risk for HF but None
without structural heart
disease or symptoms
B Structural heart disease
I
but without signs or
symptoms of HF
I
C Structural heart disease
with prior or current
II
symptoms of HF
III
D Refractory HF requiring
specialized intervention
IV
Asymptomatic
Asymptomatic
Symptomatic: moderate
exertion
Symptomatic: minimal
exertion
Symptomatic
at rest
7
Circulation 2013;128;e240-e327.
Non-Pharmacologic Therapy
•
•
•
•
•
•
•
•
Patient education and close follow-up
Daily weight measurement
Sodium restriction
Exercise training
Weight loss in obese patients
Alcohol, illicit drug avoidance
Fluid restriction in patients with severe HF
Avoidance of offending medications
(e.g. NSAIDs)
Circulation 2013;128;e240-e327.
8
Circulation 2016. DOI: 10.1161/CIR.0000000000000426
Pearls of Drug Therapy for HFrEF
Therapeutic
Key Clinical Pearls
Class
ACE Inhibitor • Attempt to achieve target doses (At a
minimum, achieve intermediate doses)
ARB
• Utilize if ACE Inhibitor intolerance (i.e.
cough) and attempt to achieve target doses
• Initiate switch but caution if previous ACE
Inhibitor angioedema
• Routine combined use of ACE Inhibitor,
ARB, and Aldosterone Antagonist
potentially harmful
Pearls of Drug Therapy for HFrEF continued
Therapeutic
Key Clinical Pearls
Class
Beta-blocker
• Initiate clinical trial-proven agent
(metoprolol succinate, carvedilol, bisoprolol)
and achieve target doses
• For patient on low dose ACE Inhibitor,
addition of beta-blocker produces greater
improvement in symptoms and reduction in
risk of death than increase in ACE Inhibitor
dose
• Continue in most patients experiencing
symptomatic exacerbation
Vasodilator
• Benefits African American patients on
optimal therapy
Pearls of Drug Therapy for HFrEF continued
Therapeutic
Class
Aldosterone
Antagonist
Loop Diuretic
Key Clinical Pearls
• Avoid if sCr >2.5mg/dL in men or
>2mg/dL in women (CrCl<30mL/min)
and/or K >5mEq/L
• Evaluate risk vs benefit if close monitoring
not feasible
• Stop or reduce potassium supplements with
initiation
• No benefit on mortality thus never used as
monotherapy
• Optimal use of diuretics is cornerstone of
symptom management and successful HF
treatment
Dosing Recommendations for Common Agents
Therapeutic
Drug
Class
ACE Inhibitor lisinopril
ARB
losartan
valsartan
Beta-blocker metoprolol
succinate (XL)
carvedilol
Initial Dose
Target Dose
2.5-5mg daily
25-50mg daily
20-40mg BID
12.5-25mg
daily
3.125mg BID
20-40mg daily
150mg daily
160mg BID
200mg daily
Aldosterone
Antagonist
12.5-25mg
daily
spironolactone
12
<85kg: 25mg
BID
>85kg: 50mg
BID
25mg daily
Stage C HFrEF Pharmacologic Therapy
13
Circulation 2013;128;e240-e327.
Patient Case #1
74 year old white male presents to outpatient clinic to
reestablish care after moving from Ohio. He complains of
shortness of breath and fatigue when jogging at any pace
above moderate. No symptoms of systematic congestion
and concluded to be euvolemic on exam.
• PMH: HFrEF (ACCF/AHA Stage C, NYHA FC II),
Hypertension, Hyperlipidemia, Type 2 diabetes mellitus
• Vitals: BP 132/88mmHg, HR 90bpm
• Medications: unknown, son sets-up pillbox
• Labs within normal limits except BNP 240pg/mL
• Echo: LVH, estimated EF = 35%
14
Patient Case #1 Assessment – Hitting the Target
What is the best next step for heart failure management?
Current Medications
aspirin 81 mg PO daily
atorvastatin 40 mg PO QHS
lisinopril 40 mg PO daily
metoprolol succinate 50 mg PO daily
insulin detemir 20 units SC QHS
metformin ER 1000 mg PO BID
acetaminophen 325 mg q4-6h PO PRN for pain
(averages 1-2 tablets per day)
15
History of Neprilysin Inhibition
Neprilysin Inhibitors: Target for heart failure
therapy in neurohormonal model
• Neprilysin degrades natriuretic peptides and
vasoactive peptides
• Sole neprilysin inhibition likely failed due to
increased levels of angiotensin II
Dual inhibition of natriuretic peptide degradation
and activation of renin-angiotensin-aldosterone
system
• Vasopeptidase Inhibitor (Neprilysin Inhibitor and
ACE Inhibitor): omapatrilat was denied FDA
approval, increased risk of angioedema
16
Pharmacotherapy 2002;22:27-42.
New Dual Target for Heart Failure
New Drug Class: Angiotensin
receptor-neprilysin inhibitor (ARNI)
• Effects on renin-angiotensin system,
natriuretic-peptide system, and bradykinin
First New Drug in Class:
sacubitril/valsartan (Entresto®)
• Approved July 2015
17
Sacubitril/Valsartan: Mechanism of Action
http://www.nature.com/nrcardio/journal/v12/n2/images/nrcardio.2014.219-f1.jpg
New Role in Therapy: PARADIGM-HF Trial
Aim: To compare survival rates with the use of
LCZ696 or enalapril in HF
• Randomized, double blind trial
• 8442 HF patients
• 1043 sites in 47 countries
• Median follow-up 27 months
Angiotensin receptor-neprilysin inhibitor LCZ696
200mg twice daily vs. enalapril 10mg twice daily
• LCZ696 200mg = sacubitril/valsartan 97/103mg
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Entry Criteria
Inclusion Criteria
• Age > 18 yrs
• NYHA FC II, III, IV
• EF <35% (original study
design EF <40%)
• Elevated BNP (>150
pg/mL) or NT-proBNP
(>600 pg/mL)
• Stable dose for 4 weeks on
ACE Inhibitor or ARB and
beta-blocker
– Equivalent to >10 mg
enalapril
Exclusion Criteria
• Symptomatic hypotension
• Systolic blood pressure
<100 mmHg at screening
• eGFR <30mL/min/1.73m2
• Serum K+ >5.2 mmol/L
• Angioedema history
• Unacceptable side effects of
ACE Inhibitor or ARB
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Study Design
Single-blind, • enalapril 10mg
PO BID 2
run-in
weeks
period 1
Single-blind, • LCZ696 100mg PO
BID 1-2 weeks
run-in
• LCZ696 200mg PO
period 2
BID 2-4 weeks
LCZ696 200mg =
sacubitril/valsartan 97/103mg
• LCZ696 200mg
Randomized PO BID vs.
double-blind
• enalapril 10mg
period
PO BID
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Key Baseline Characteristics
Characteristic
Age (years)
Female sex (%)
White/Black/Asian (%)
EF (%)
NYHA FC II/III (%)
Systolic blood pressure
(mmHg)
Heart rate (beats/min)
Serum creatinine (mg/dL)
Sacubitril/
Valsartan
(n=4187)
Enalapril
(n=4212)
63.8 +/- 11.5
63.8 +/- 11.3
21%
22.6%
66%/5.1%/18.1% 66%/5.1%/17.8%
29.6 +/- 6.1
29.4 +/- 6.3
71.6%/23.1%
69.3%/24.9%
122 +/- 15
121 +/- 15
72 +/- 12
1.13 +/- 0.3
73 +/- 12
1.12 +/1 0.3
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Key Baseline Characteristics
Characteristic
Sacubitril/
Valsartan
(n=4187)
Medical History (%)
Hypertension
70.9%
Diabetes
34.7%
Myocardial infarction
43.4%
Atrial fibrillation
36.2%
HF hospitalization
62.3%
Stroke
8.5%
Enalapril
(n=4212)
70.5%
34.6%
43.1%
37.4%
63.3%
8.8%
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Key Baseline Characteristics
Characteristic
Sacubitril/
Valsartan
(n=4187)
Treatment at Randomization (%)
Diuretic
80.3%
Beta-blocker
93.1%
Aldosterone antagonist
54.2%
Digoxin
29.2%
Implantable defibrillator
14.9%
Cardiac resynchronization
7%
therapy
Enalapril
(n=4212)
80.1%
92.9%
57%
31.2%
14.7%
6.7%
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Endpoints
Primary
Outcomes
no. (%)
Composite of
CV death or
first HF
hospitalization
Death from CV
causes
First HF
hospitalization
Sacubitril/ Enalapril
Valsartan (n=4212)
(n=4187)
Hazard
Ratio
(95% CI)
914 (21.8%)
1117
(26.5%)
0.80 (0.73- <0.001
0.87)
558 (13.3%)
693
(16.5%)
658
(15.6%)
0.80 (0.71- <0.001
0.89)
0.79 (0.71- <0.001
0.89)
537 (12.8%)
P
Value
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Safety
Adverse Event
no. (%)
Symptomatic
hypotension
Symptomatic with
systolic blood pressure
<90 mmHg
Elevated serum
creatinine >2.5 mg/dL
Elevated serum
creatinine >3 mg/dL
Sacubitril/
Valsartan
(n=4187)
588 (14%)
Enalapril
(n=4212)
P Value
388 (9.2%)
<0.001
112 (2.7%)
59 (1.4%)
<0.001
139 (3.3%)
188 (4.5%)
0.007
63 (1.5%)
83 (2%)
0.10
N Engl J Med 2014;371:993-1004.
PARADIGM-HF Trial: Safety continued
Adverse Event
no. (%)
Sacubitril/
Valsartan
(n=4187)
674 (16.1%)
Elevated serum
potassium >5.5 mmol/L
Elevated serum
181 (4.3%)
potassium >6 mmol/L
Cough
474 (11.3%)
10 (0.2%)
Angioedema
(no treatment or use of
antihistamines only)
Enalapril
(n=4212)
P Value
727 (17.3%)
0.15
236 (5.6%)
0.007
601 (14.3%)
5 (0.1%)
<0.001
0.19
N Engl J Med 2014;371:993-1004.
Sacubitril/Valsartan (Entresto®)
FDA Indication
• To reduce risk of cardiovascular death and HF
hospitalization in patients with chronic heart failure
(NYHA FC II-IV) and reduced EF
• Administered in conjunction with other HF therapies,
in place of ACE Inhibitor or other ARB
Contraindications
• History of angioedema with ACE Inhibitor or ARB
• Concomitant use of ACE Inhibitor
– Do not administer within 36 hours of switching from or to
an ACE Inhibitor due to angioedema risk
• Concomitant use with aliskiren in patients with
diabetes
28
Product Information for Entresto. Novartis Pharmaceuticals. 2015.
Sacubitril/Valsartan: Dosing
Fixed combination product
• Starting dose 49/51mg by mouth twice daily
• Utilize reduce starting dose as appropriate
• Double the dose every 2-4 weeks to achieve target
dose of 97/103mg twice daily
• Administer with or without food
Dosage Strengths
• 24/26mg; 49/51mg; 97/103mg
29
Product Information for Entresto. Novartis Pharmaceuticals. 2015.
Sacubitril/Valsartan: Dosing continued
Criteria for Dosage Adjustment
- Not currently taking ACE Inhibitor/ARB
- Low doses of ACE Inhibitor/ARB
(enalapril total daily dose <10mg,
lisinopril <10mg; valsartan total daily
dose <160mg, losartan <50mg)
- Severe renal impairment
(eGFR <30mL/min)
- Moderate hepatic impairment
- Severe hepatic impairment
Initial Dose
24/26mg twice daily
24/26mg twice daily
Use not
recommended
30
Product Information for Entresto. Novartis Pharmaceuticals. 2015.
Sacubitril/Valsartan: Warnings
Warnings/Precautions
• Fetal toxicity
• Angioedema
• Hypotension: Avoid in patients with SBP < 100mmHg
• Impaired renal function
• Hyperkalemia
Drug Interactions
• ACE Inhibitor/ARB, aliskiren
• Potassium-sparing diuretics
• NSAIDs/COX-2 Inhibitors
• Lithium
31
Product Information for Entresto. Novartis Pharmaceuticals. 2015.
Sacubitril/Valsartan: Monitoring
Adverse Effects
• Angioedema (Black patients 2%; Others <1%)
• Hypotension (18%); Orthostatic hypotension (2%)
• Impaired renal function (1-16%)
• Hyperkalemia (4-16%)
• Dizziness (6%); Falling (2%)
• ??? Risk of dementia
Monitoring Parameters
• Blood pressure
• Renal function and potassium
32
Product Information for Entresto. Novartis Pharmaceuticals. 2015.
ACC/AHA/HFSA Guideline Recommendation
• “The clinical strategy of inhibition of the
renin-angiotensin system with ACE
inhibitors OR ARBs OR ARNI in
conjunction with evidence-based betablockers, and aldosterone antagonists in
selected patients, is recommended for
patients with chronic HFrEF to reduce
morbidity and mortality.”
33
Circulation 2016. DOI: 10.1161/CIR.0000000000000435
ACC/AHA/HFSA Guideline Recommendation
• “In patients with chronic symptomatic
HFrEF NYHA class II or III who tolerate an
ACE inhibitor or ARB, replacement by an
ARNI is recommended to further reduce
morbidity and mortality.”
• “ARNI should not be administered
concomitantly with ACE inhibitors or within
36 hours of the last dose of an ACE inhibitor.”
• “ARNI should not be administered to patients
with history of angioedema.”
34
Circulation 2016. DOI: 10.1161/CIR.0000000000000435
ESC Guideline Recommendation
• “Sacubitril/Valsartan is recommended as a
replacement for an ACE Inhibitor to further
reduce the risk of HF hospitalization and
death in ambulatory patients with HFrEF
who remain symptomatic despite optimal
treatment with an ACE Inhibitor, a betablocker, and an mineralocorticoid receptor
antagonist.”
35
European Heart Journal 2016. DOI: 10.1093/eurheartj/ehw128
European Heart Journal 2016. DOI: 10.1093/eurheartj/ehw128
Cost Considerations
37
https://hcldr.files.wordpress.com/2015/11/money-in-the-pill-bottle.jpg
Clinical Pearls for Sacubitril/Valsartan in HFrEF
• Reduces cardiovascular death and HF
hospitalization
– Patient selection match trial criteria
– Long-term safety remains unknown
• Clinical experience necessary to determine
optimal role, titration, and tolerability
–
–
–
–
Utilize appropriate starting dose
Added blood pressure lowering effects
Stop ACE Inhibitor, ARB, Renin Inhibitor
36 hour washout required when switching from
ACE Inhibitor
• Patient education important
38
Patient Education Points for Sacubitril/Valsartan
Medication Benefits
• Help patients live longer and stay out of the hospital
Medication Replaces ACE Inhibitor/ARB
• Ensure patient has stopped ACE Inhibitor for 36 hours
prior to starting new medication
• Instruct to stop ARB and start new medication
Administration
• Take in the morning and evening, with or without food
• Do not double doses if forget to take medication
Possible Side Effects
• Low blood pressure and feeling dizzy
• Swelling of face, lips, tongue, throat
39
Patient Case #2
74 year old African American male presents to emergency
department with angioedema. Accompanied by spouse
who lives with patient at home. States returned to
Indianapolis this past week after a recent hospitalization
during winter stay in Florida.
• PMH: HFrEF (ACCF/AHA Stage C, NYHA FC III), CAD
with history of MI 3 years ago, HTN, Osteoarthritis
• Vitals: BP 110/74mmHg, HR 64bpm; Ht 6ft, Wgt 215lb
• Medications: unknown, son sets-up pillbox
• Pertinent labs: sCr 1.2, K 4.5
• Echo: LVH, estimated EF = 30%
40
http://www.emsworld.com/article/12141671/ace-inhibitor-related-angioedema
Medication Review
Pharmacist contacts patient’s son for medication
review by phone. Son states sets-up pillbox for a
month in advance then his mom helps remind dad to
take his medications.
Reported Medications
carvedilol 12.5mg po twice daily
lisinopril 10mg po daily
spironolactone 25mg po daily
atorvastatin 80mg po daily
aspirin 81mg po daily
ibuprofen 200mg po twice daily for knee pain
multivitamin once daily
41
Medication Review continued
Receive discharge summary from recent
hospitalization. Patient’s wife remembers 2 new
medications started in hospital and she added to
pillbox. She tells you one was very expensive but
knew it was important for him to take.
Medications per Discharge Summary
carvedilol 25mg po twice daily
Increase dose
sacubitril/valsartan 49/51mg po twice daily STOP lisinopril
spironolactone 25mg po daily
atorvastatin 80mg po daily
furosemide 40mg po twice daily
Add diuretic
aspirin 81mg po daily
multivitamin once daily
42
http://fishduck.com/2012/12/what-happens-in-vegas-matters-a-lot-to-somepeople/who-what-why-when-where-how-sign-post/
Patient Case #2 Assessment – Medication Mistake
Comprehensive Medication List
carvedilol 12.5mg po twice daily
lisinopril 10mg po daily
sacubitril/valsartan 49/51mg po twice daily
spironolactone 25mg po daily
atorvastatin 80mg po daily
aspirin 81mg po daily
furosemide 40mg po twice daily
ibuprofen 200mg po twice daily for knee pain
multivitamin once daily
44
Patient Case #2 – Medication Mistake
Comprehensive Medication List
carvedilol 12.5mg po twice daily Dosage change 25mg
lisinopril 10mg po daily STOP! 36hr washout inpatient
sacubitril/valsartan 49/51mg po twice daily New!
spironolactone 25mg po daily
atorvastatin 80mg po daily
aspirin 81mg po daily
furosemide 40mg po twice daily New!
ibuprofen 200mg po twice daily for knee pain STOP!
multivitamin once daily
45
Trial Comparison to Reduce All-Cause Mortality
Therapeutic
Class
Medication
Trial Name
Number Needed
to Treat: AllCause Mortality
ACE Inhibitor enalapril
SOLVD-T
(1991)
23
Beta-blocker
carvedilol
U.S. Carvedilol
(1996)
22
Vasodilator
hydralazineisosorbide dinitrate
A-HeFT
(2004)
26
Aldosterone
Antagonist
eplerenone
EMPHASISHF (2011)
34
ARNI
sacubitril/valsartan
PARADIGMHF (2014)
35
46
N Engl J Med. 2014;371:1062-64.
Summary: Role of Heart Failure Medications
REDUCE MORTALITY
•
•
•
•
•
•
ACE Inhibitor
ARB
Beta-blocker
Aldosterone Antagonist
Nitrate/Hydralazine
Sacubitril/Valsartan
NO MORTALITY BENEFIT
• Diuretics
• Digoxin
• Ivabradine
47
Neprilysin Inhibitors –
The Mainstay for Heart Failure?
Alison M. Walton, PharmD, BCPS
Associate Professor of Pharmacy Practice – Butler University
Clinical Pharmacy Specialist, Ambulatory Care – St. Vincent
Indianapolis, IN
Email: [email protected]