Saturday, March 24 - Interrupting the Revolving Door of Chronic Heart Failure
1. Interrupting the Revolving Door
of Chronic Heart Failure
Marcus C. Ravnan, Pharm.D., FCSHP, FASHP
Professor, Department of Pharmacy Practice
Assistant Dean, Office of Pre-Pharmacy & Pre-Health Affairs
University of the Pacific
Thomas J. Long School of Pharmacy and Health Sciences
2. Disclosure of Interest
In preparing this presentation, I disclose that there are
no potentially biasing relationships of a professional or
personal nature that exist related to the content or
direction of this educational presentation. I have no
relevant financial interests or other relationships with
the manufacturer(s) of commercial products and/or
provider(s) of commercial services discussed in this
educational presentation.
3. Program Objectives:
- Describe the heart failure landscape, including prevalence,
incidence, re-admission and mortality rates.
- Evaluate the safety, efficacy, and mechanism of action of
pharmacologic agents, both old and new and their
impact on heart failure outcomes.
- Assess evidence supporting the use and application of novel
therapies in todays clinical practice.
- Outline the pharmacists role in transitions of care that
support improving patient outcomes
4. • 2011 to 2014 - 6.5 million Americans carried a HF diagnosis
• It is projected that by 2030 – over 8 million Americans will
carry the diagnosis
• The care environment is currently seeing 960,000 new HF
cases annually
• Lifetime risk 20-45% age 45-95 years
• Age is associated with the greatest disease-related incidence
• 9.2 per 1000 age 65-74
• 22.3 per 1000 age 75-84
• 43.0 per 1000 age >85
• Heart Disease and Stroke Statistics – 2017 Update. Circulation. 2017;135:e146-603.
• Forecasting the impact of heart failure in the United States: a policy statement from the
American Heart Association. Circ Heart Fail. 2013;6:606–619.
The current disease landscape
5. • Current projections reveal survival after onset has
improved slightly attributed to evidence-based
therapeutic management
• Mortality remains high ~50% within 5 years of diagnosis
• Hospitalization remains high
• Within 1-year of diagnosis, 83% of patients expected to be hospitalized at
least once, 43% at least 4 times
• Case fatality rate within 30 days of hospital admission is 10.4%
• Heart Disease and Stroke Statistics – 2017 Update. Circulation. 2017;135:e146-603.
• Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure
epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med. 2015;175:996–1004.
• Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure
hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. JAMA.
2011;306:1669–1678.
6. Why are HF Patients Hospitalized?
• Pneumonia/Respiratory Related
• Arrhythmia
• Worsening renal function
• Edema/Weight gain
• Dyspnea
• Medication related issue
• Hypertension
Precipitating Clinical Factors, Heart Failure Characterization, and Outcomes in Patients Hospitalized With Heart Failure With
Reduced, Borderline, and Preserved Ejection Fraction. Kapoor JR, Kapoor R, Ju C, et al. JACC Heart Fail. 2016;4(6):464-472.
7. Projected Direct Costs of Cardiovascular Disease
Forecasting the future of cardiovascular disease in the United States: a policy
statement from the American Heart Association. Circulation. 2011;123:933–944.
8. Syndrome of Structural and Functional impairment
Abnormal ventricular function
Inadequate tissue perfusion
Intravascular & Interstitial volume overload
What is Heart Failure?
9. The sequelae
Renal Hemodynamics
Vascular Hemodynamics
Compensatory Systems
Myocardial Dynamics
Inflammation and Immune Activation
Tissue Metabolism, Energy Utilization & Delivery
10. The complexity of the sequelae
Katz M. Pathophysiology of heart failure: identifying targets for pharmacotherapy
Med Clin North Am. 2003 Mar;87(2):303-16.
11. Simplified View
•Briasoulis, A., Androulakis, E., Christophides, T. et al. Heart Fail Rev (2016) 21: 169.
•Robert J. Mentz, Christopher M. O'Connor. Nature Reviews Cardiology volume 13,pages 28–35 (2016).
12. Types of Heart Failure
• Systolic (or squeezing) heart failure
– Decreased pumping function of the heart, which results in fluid back up in
the lungs and heart failure
• Diastolic (or relaxation) heart failure
– Involves a thickened and stiff heart muscle
– As a result, the heart does not fill with blood properly
– This results in fluid backup in the lungs and heart failure
17. Compensatory Mechanisms:
Renin-Angiotensin-Aldosterone System
Renin + Angiotensinogen
Angiotensin I
Angiotensin II
Peripheral
Vasoconstriction
Afterload
Cardiac Output
Heart Failure
Cardiac Workload
Preload
Plasma Volume
Salt & Water Retention
Edema
Aldosterone Secretion
ACE
Kaliuresis
Beta
Stimulation
• CO
• Na+
Fibrosis
18. Guideline Approach
Stages and Treatment of HF
STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE B
Structural heart disease
but without signs or
symptoms of HF
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Prevent hospitalization
· Prevent mortality
Strategies
· Identification of comorbidities
Treatment
· Diuresis to relieve symptoms
of congestion
· Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
· Revascularization or valvular
surgery as appropriate
STAGE C
Structural heart disease
with prior or current
symptoms of HF
THERAPY
Goals
· Control symptoms
· Patient education
· Prevent hospitalization
· Prevent mortality
Drugs for routine use
· Diuretics for fluid retention
· ACEI or ARB
· Beta blockers
· Aldosterone antagonists
Drugs for use in selected patients
· Hydralazine/isosorbide dinitrate
· ACEI and ARB
· Digoxin
In selected patients
· CRT
· ICD
· Revascularization or valvular
surgery as appropriate
STAGE D
Refractory HF
THERAPY
Goals
· Prevent HF symptoms
· Prevent further cardiac
remodeling
Drugs
· ACEI or ARB as
appropriate
· Beta blockers as
appropriate
In selected patients
· ICD
· Revascularization or
valvular surgery as
appropriate
e.g., Patients with:
· Known structural heart disease and
· HF signs and symptoms
HFpEF HFrEF
THERAPY
Goals
· Heart healthy lifestyle
· Prevent vascular,
coronary disease
· Prevent LV structural
abnormalities
Drugs
· ACEI or ARB in
appropriate patients for
vascular disease or DM
· Statins as appropriate
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Reduce hospital
readmissions
· Establish patient’s end-
of-life goals
Options
· Advanced care
measures
· Heart transplant
· Chronic inotropes
· Temporary or permanent
MCS
· Experimental surgery or
drugs
· Palliative care and
hospice
· ICD deactivation
Refractory
symptoms of HF
at rest, despite
GDMT
At Risk for Heart Failure Heart Failure
e.g., Patients with:
· Marked HF symptoms at
rest
· Recurrent hospitalizations
despite GDMT
e.g., Patients with:
· Previous MI
· LV remodeling including
LVH and low EF
· Asymptomatic valvular
disease
e.g., Patients with:
· HTN
· Atherosclerotic disease
· DM
· Obesity
· Metabolic syndrome
or
Patients
· Using cardiotoxins
· With family history of
cardiomyopathy
Development of
symptoms of HF
Structural heart
disease
Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013
19. ACE Inhibitors
• Improve survival in patients with all severities of heart failure.
• Considered the mainstay of therapy
• Begin therapy low and titrate up as possible:
• Enalapril – 2.5 mg po BID
• Captopril – 6.25 mg poTID
• Lisinopril – 5 mg po QDaily
• Tolerability can be an issue
SOLVD NEJM 1991;325:293-302.
SOLVD Investigators NEJM 1992;327:685-691
V-HeFT II NEJM 1991;325:303-310
CONSENSUS NEJM 1987;316:1429-1435
HOPE NEJM 2000;342:145-153
SAVE NEJM 1992;327:669-677
20. Drug
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses
Achieved in Clinical
Trials
ACE Inhibitors
Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d
Enalapril 2.5 mg twice
10 to 20 mg
twice
16.6 mg/d
Fosinopril 5 to 10 mg once 40 mg once ---------
Lisinopril 2.5 to 5 mg once
20 to 40 mg
once
32.5 to 35.0 mg/d
Perindopril 2 mg once 8 to 16 mg once ---------
Quinapril 5 mg twice 20 mg twice ---------
Ramipril
1.25 to 2.5 mg
once
10 mg once ---------
Trandolapril 1 mg once 4 mg once ---------
2013 ACCF/AHA Guideline for the Management of Heart Failure
Which ACE I; How Much?
22. ARB therapy
• Considered by some the starting point or equivalent
• Somewhat better tolerated as compared to ACE-I therapy
• Can have cross-intolerance issues
ELITE II (Lancet 2000;355:1582-1587)
RESOLVD (Circulation 1999;100:1056-1064)
ValHeFT (NEJM 2001;345:1667-1675)
CHARM - Overall (Lancet 2003;362:759-766)
23. ACC/AHA Guidelines 2013
Drug
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses
Achieved in Clinical
Trials
ARBs
Candesartan 4-8 mg qd 32 mg qd 24mg/d
Losartan 25-50 mg qd 50 to 100 mg qd 129 mg/d
Valsartan 20-40 mg BID 160 mg bid 254 mg/d
Which ARB; How Much?
24. Beta Blocker therapy
• Certain Beta blockers (carvedilol, metoprolol, bisoprolol) can improve overall
and event free survival in NYHA class II to III HF, probably in class IV.
• Require some “selling” as effects are noticed by patients
• Slow, careful titration
• Contraindicated:
• Heart rate <60 bpm
• Symptomatic bradycardia
• Signs of peripheral hypoperfusion
• COPD, asthma
• PR interval > 0.24 sec, 2nd or 3rd degree block
CIBIS II (Lancet 1999;353:9-13)
MERIT-HF (Lancet 1999;353:2001-2007)
US Carvedilol Heart Failure Trial (NEJM 1996;334:1349-1355)
CAPRICORN (Lancet 2001;357:1385-1390)
COMET (Lancet 2003;362:7-13)
25. Drug
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses Achieved
in Clinical Trials
Beta Blockers
Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg/d
Carvedilol 3.125 mg bid 50 mg bid 37 mg/d
Carvedilol CR 10 mg qd 80 mg qd ---------
Metoprolol
succinate extended
release (metoprolol
CR/XL)
12.5 - 25 mg
qd
200 mg qd 159 mg/d
2013 ACCF/AHA Guideline for the Management of Heart Failure
Which Beta Blocker; How Much?
26. Hydralazine ISDN
V-HeFT I (NEJM 1986;314:1547-1552)
V-HeFT II (NEJM 1991;325:303-310)
A-HeFT (NEJM 2004;351:2049-2057)
27. Dose and Administration
V-HeFT I (NEJM 1986;314:1547-1552)
V-HeFT II (NEJM 1991;325:303-310)
A-HeFT (NEJM 2004;351:2049-2057)
BiDil
Remember: This is on top of effective ACE/Beta-Blocker therapy
28. Diuretics
•Loop diuretics
• Furosemide, Bumetanide, Torsemide
• For Fluid control, and to help relieve symptoms in all stages
• Tolerance – may be aided with addition of metolazone
• Compensatory Reset
•Potassium-sparing diuretics
• Spironolactone, Eplerenone
• Help enhance diuresis
• Maintain potassium
• Shown to improve survival in CHF
30. Drug
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses
Achieved in
Clinical Trials
Aldosterone Antagonists
Spironolactone 12.5 to 25 mg qd 25 mg qd 26 mg/d
Eplerenone 25 mg qd 50 mg qd 42.6 mg/d
• Eplerenone is a more specific aldosterone receptor antagonist; it can be
used if spironolactone causes gynecomastia or breast pain.
• It causes the same effects on potassium and renal function as
spironolactone.
Aldosterone Antagonists
31. Medical Therapy for Stage C HFrEF:
Magnitude of Benefit in RCTs
RR
↓ Mortality
NNT to ↓ mortality
(standardized 36
months)
RR
↓ HF Hospital.
ACE I / ARB 17% 26 31%
Beta-Blockers 34% 9 41%
Aldosterone
Antagonists 30% 6 35%
Nitrates/Hydralazine 43% 7 33%
32. Neprilysin as a Therapeutic Target
Inactive
fragments
Neprilysin
Natriuretic peptides
Adrenomedullin
Bradykinin
Substance P
(angiotensin II)
• Neprilysin breaks down endogenous
vasoactive peptides, including the natriuretic
peptides
• Inhibition of neprilysin potentiates the action
of those peptides
• Because angiotensin II is also a substrate
for neprilysin, neprilysin inhibitors must be
co-administered with a RAAS blocker
• The combination of a neprilysin inhibitor and
an ACEI is associated with unacceptably high
rates of angioedema
Corti R et al. Circulation. 2001;104:1856-1862.
Sacubitril/Valsartan (LCZ696):
Angiotensin Receptor–Neprilysin Inhibitor (ARNI)
34. Angiotensin–Neprilysin Inhibition versus
Enalapril in Heart Failure
John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H.,
Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean
L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl
Swedberg, M.D., Ph.D., Michael R. Zile, M.D., for the PARADIGM-HF
Investigators and Committees
NEJM
Volume 371(11):993-1004
September 11, 2014
35. 1. McMurray JJ et al. N Engl J Med. 2014;371:993-1004
PARADIGM-HF: CV Death or HF
Hospitalization (Primary Endpoint)
36. Sacubitril/Valsartan (ARNI)
• Administered in conjunction with other heart
failure therapies, in place of an ACE inhibitor
or other ARB
• If switching from an ACE inhibitor a washout
period of 36 hours is required
• The starting dose of is 49/51 mg
(sacubitril/valsartan) twice-daily doubled
after 2 to 4 weeks to the target maintenance
dose of 97/103 mg (sacubitril/valsartan)
twice-daily
37. Sacubitril/Valsartan
• Angioedema risk is low but higher in black patients
• Hypotension (18%), hyperkalemia (12%), renal impairment (5%)
were the most common side effects observed in the Paradigm
study
• Interactions similar to ACE inhibitors
– NSAIDS
– Lithium
– Potassium and diuretics
• Some concerns Alzheimer's potential
• Consider spacing from other vasoactive agents, metoprolol better
tolerated vs. carvedilol?
38. Medical Therapy for Stage C HFrEF:
Magnitude of Benefit in RCTs
↓ Mortality NNT to ↓ mortality
(standardized 36
months)
↓ HF Hospital.
ACE I / ARB 17% 26 31%
Beta-Blockers 34% 9 41%
Aldosterone
Antagonists 30% 6 35%
Nitrates/Hydralazine 43% 7 33%
ARNI +15% 21 21%
39. Results of random effect network meta-analysis for all-cause
mortality: hazard ratios for intervention versus placebo for all-
cause mortality and 95% credible intervals.
Heather Burnett et al. Circ Heart Fail. 2017;10:e003529
41. Ivabradine
• The funny current drives the rate of diastolic
depolarization ultimately the automaticity of
the sinus node
• As the funny current controls the rate of the
sinus node activity, it determines the heart
rate
• Ivabradine selectively blocks the HCN
channels activity reducing persistent elevated
heart rate seen in many HF patients
42. 0
10
20
30
40
50
60
0 1 2 3
incidenceofprimarycompostieendpoint(%)
Time (years)
Ivabradine, Less severe
Ivabradine, Severe
Placebo, Less severe
Placebo, Severe
Efficacy of ivabradine in patients
according to heart failure severity
www.shift-study.com
Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503
43. Efficacy of ivabradine in patients with
heart failure
www.shift-study.com
Lancet Volume 376, No. 9744, p875–885, 11 September 2010
Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503
44. Efficacy of ivabradine in patients with
heart failure
www.shift-study.com
Lancet Volume 376, No. 9744, p875–885, 11 September 2010
Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503
• SHIFT showed
• Heart-rate reduction improves clinical outcomes and plays an
important role in the pathophysiology of this disorder
• Raised heart rate (≥70 bpm) is known to be a risk factor in patients
with stable coronary artery disease and left ventricular dysfunction
• Ivabradine decreased incidence of hospitalization and incidence of
heart failure related death
• SHIFT supports lowering HR to 60 for optimal outcome
• Criticism – optimized beta-blocker use at baseline in the study
population
45. Efficacy of ivabradine in patients with
heart failure
• Indication HFREF with HR>60 after maximization of
beta-blocker therapy or in patients with beta-blocker
intolerance
• Not used in patients with baseline HR <60, those with
heart blocks, patients with pacemaker, BP <90/60,
ADHF, advanced liver disease
• Main Efficacy measure HR between 50-60
48. Treatment of heart failure
Tool for the Provider
NYHA I
NYHA II
NYHA III
NYHA IV
Ischemic etiology Nonischemic etiology
ACEI/ARB + BB + ASA ACEI/ARB
ACEI/ARB + BB + ASA
+ spironolacton + diuretics
ACEI/ARB + BB
+ diuretics
Affects morbidity/ mortality
Affects “only“ symptoms of HF
ARNI/ACEI/ARB + BB + spironolactone
+ Ivabradine
+ diuretics + digoxin
Advanced
Interventional
ARNI/ACEI/ARB + BB +
spironolactone + Ivabradine
+ diuretics + digoxin
Program
Teaching Tool
50. Depression & Anxiety in Patients with HF
• Moderate-to-Severe depression and anxiety increases
mortality in HF
• Patients are twice as likely to be seen in the ER if
Depression/Anxiety are present
• Knowing the patient is key to discovering changes in
behavior & attitude
• Caregiver reporting must be welcome and should be
sought
55. Within 7-10 days of discharge
• Assess Laboratory Findings and Address Issues
• Cover Medications with the Patient & Caregiver Frequently
• Talk About Smoking Cessation
• Discuss Vaccination Importance and Record Maintenance
• Talk About Diet
• Talk About Exercise Goals
• Discuss the importance of recording weight
• Consider Provider Directed Diuretic Protocol
