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"Old School" But Still Essential Drug Therapies for Heart Failure
Stephanie H. Dunlap, DO
Medical Director, Heart Failure Program
Professor of Medicine
Augusta University Medical Center
Medical College of Georgia
Augusta, GA
Conflicts
None
Objectives
Discuss neurohormonal activation in HFrEF
Provide treatment “pearls” for diuretics,
renin angiotensin aldosterone system
(RAAS) inhibitors and beta blockers
Present an overall treatment algorithm
Neurohormonal Activation in HFrEF
ACEI
ARB
MRA
Endogenous
Vasoactive Peptides(natriuretic peptides, bradykinin
adrenomedullin, substance P)Inactive
Metabolites
Neprilysin
Myocyte injury
Diuretics -Activate the renin-AII system
“Pearls”: Use lowest dose
Bumetanide better absorbed
≤ 3 g Na restriction
Pharmacological Treatment for Stage C HF With Reduced EF
Renin-Angiotensin System Inhibition With ACE-Inhibitor
or ARB or ARNI (ARB + Neprilysin Inhibitor)
I
ACE-I: A
The clinical strategy of inhibition of the
renin-angiotensin system with ACE-Is
(Level of Evidence: A), OR ARBs (Level
of Evidence: A), OR ARNI (Level of
Evidence: B-R) in conjunction with
evidence-based beta blockers, and
aldosterone antagonists in selected
patients, is recommended for patients
with chronic HFrEF to reduce morbidity
and mortality.
NEW: Recent
clinical trial data
prompted
clarification and
important
updates.ARB: A
ARNI:
B-R
COR LOE RecommendationsComment/
Rationale
COR: Class of Recommendation; I Strong
B-R: Moderate-quality evidence from 1 or more RCTs
Meta-analyses of moderate-quality RCT’s
ACEI/ARB Guideline Recs
EF ≤ 40%, symptomatic and asymptomatic (NYHA I-IV)
Aim for target dose in trials
Initial Dose Target Dose (max)
ACEILisinopril 2.5-5 mg once 20 mg (40 mg) once
Ramipril 1.25-2.5 mg once 10 mg once
Enalapril 2.5 mg once 10 mg (20 mg) twice
Captopril 6.25 mg 3 times 50 mg 3 times
Trandolapril 1 mg once 4 mg once
Quinapril 5 mg twice 20 mg twice
Fosinopril 5-10 mg once 40 mg once
Perindopril 2 mg once 8-16 mg once
ARBLosartan 25-50 mg once 50-150 mg once
Valsartan 20-40 mg twice 160 mg twice
Candesartan 4-8 mg once 32 mg once
Know The Meds That You Are Using
Especially be aware of half-life, active drug, or pro-drug that
requires conversion
Losartan: T ½: 2 hrs; metabolite is 6-9 hours
Valsartan T ½: 6-9 hours
Lisinopril T ½ : 12.5 hours
Enalapril T ½: 11.5 hours
Captopril T ½: Probably less than 2-3 hours
Consider administering the total daily dose as a split dose BID
in those patients who are still highly symptomatic
Have patients take diuretic, then lay down for an hour
HIGH* vs. LOW DOSE ACE-I or ARB
HEAAL trial(ACE- intolerant)
ATLAS trial
Drug Lisinopril Losartan
Dose 2.5-5 vs. 32.5-35 50 vs. 150 mg
EF/NYHA ≤ 30%; II-IV ≤ 40%; II-IV
Mortality same same
Death/HF Hosp 15%* 10%*
HF Hosp 24%* 13%*
ACEI/ARB: “Pearls”
Avoid routine use of ACEI + ARB + MRA
due to ↑risk of hyperkalemia, renal insufficiency
If SBP < 100 mmHg, start low
i.e. lisinopril 2.5 mg daily
i.e. losartan 12.5 mg daily
√ Renal function in 1-2 wks
Can start ACEI/ARB in congested pts
Start ACEI/ARB before BB and add BB
quickly i.e lisinopril 5 mg daily then BB
Some is better than none
More is better (↓hospitalization)
Beta Blocker Guideline Recs
EF ≤ 40%, sx and asx (NYHA I-IV)
Add Early
Aim for target dose in trials
Initial Dose Target Dose
Beta Blockers
Bisoprolol
ß-1 selective
1.25 mg once 10 mg once
Carvedilol 3.125-6.25 mg
twice
25-50 mg twice
Metoprolol
succinate
ß-1 selective
12.5-25 mg once 200 mg once
Metoprolol
tartrate(not guideline rec)
12.5-25 mg twice
or three
100 mg twice
Coreg CR(not generic)
10 mg once 80 mg once
BB:Does Dose Matter?
Trial Beta
Blocker
Daily Dose
(mg)
Mortality Hospitalization
MOCHA carvedilol 6.25 twice 12.5 twice 25 twice
MERIT-HF* metoprolol
succinate
100
200 CIBIS* bisoprolol 1.25-3.75
5-7.5 10
BB:Does Dose Matter?
Trial Beta
Blocker
Daily Dose
(mg)
Mortality
MOCHA carvedilol 6.25/12.5/25
twice
MERIT-HF* metoprolol
succinate
100 No effect
200 CIBIS* bisoprolol 1.25-3.75 No effect
5-7.5 10
Carvedilol
Placebo0
1
2
3
4
5
6
7
8
L
VE
F (
EF
un
its)
†
†
†
Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261).
*Multicenter Oral Carvedilol Heart Failure Assessment.
Adapted from Bristow et al. Circulation. 1996;94:2807-2816.†P.05 vs placebo
MOCHA: Carvedilol Dose-Response Trial
25 mg bid6.25 mg bid 12.5 mg bid
Beta Blockers: “Pearls”
Do not use in patients with active bronchospasm
Euvolemic
Caution: SBP<80, HR<55
Start low, ↑2-4 wks
Some is better than none
More is better (↑EF)
Most need a diuretic
Do not abruptly stop
unless shock
Reactive airway dz:
use ß-1 selective
Bisoprolol best tolerated
LVEF
Eichhorn, E. J. et al. Circulation 1996;94:2285-2296
Mineralocorticoid Receptor Antagonists (MRA)
Guideline Recommendations
EF ≤ 35%
NYHA class II-IV
If class II:
- hx CV hosp or
- ↑BNP
AMI + EF ≤ 40% or DM
GFR > 30 and K < 5
MRA“Pearls”
↑K is common: 24-36%
Dose adjust for GFR
Monitor K/Cr: 2-3 days, 1 wk, 1 mo, q 3 mo
If K > 5, ↓dose; dc ≥ 5.5
Assess: K supplements, diet, salt substitutes,
NSAIDs
Avoid routine use ACE-I + ARB + MRA
Hydralazine + Nitrate
Guideline Recs: EF ≤ 40%
African Americans
NYHA class III-IV
ACE-I/ARB intolerant
↓43% mortality
N= 1050, NYHA III/IV
LVEF≤35% / ≤45% + LVEDd>6.5
ACE-I/ARB 69/17%
BB 74%
AA 39%
African American Heart Failure Trial
Taylor AL et al. N Engl J Med 2004;351:2049-57
“Pearls”
Start one at low dose
Add next
Uptitrate to target
Hydralazine 25-50 mg 3-4/d 300 mg total/d
Hydralazine with ACEI/ARB 25-75 mg 3/d 225 mg total/d
Isosorbide 20-30 mg 3-4/d 160 mg total/d
Isosorbide with ACEI/ARB 10-40 mg 3/d 120 mg total/d
Time to all-cause death
n-3 polyunsaturated fatty acids (1 g daily)
Absolute RR = 1.8%
NNT = 56
Adjusted HR (0.91 (0.83 – 0.99), p = 0.041
Also ↓ death or CV hospitalization
↓ 1st hosp for ventricular arrhythmias
n-3 PUFA
Placebo
Lancet 2008
GISSI-HFOmega-3 fatty acids
N=7,975
NYHA II-IV
50% CAD
LVEF ≤ 40% or
> 40% + hosp (9%)
Mean EF 33%
FU: 3.9 yrs
ACE-I/ARB 94%
BB 65%
AA 39%
Statin open 23%
Digoxin
Guideline Rec: Hospitalization
Improves hemodynamics, sx, exercise tolerance
No reduction in total mortality
“Pearls”
-More is NOT better
-Low dose i.e, 0.125 mg/d
Level 0.5-0.9 ng/ml
-Consider in NYHA IV
esp with ↓BP
-Does not control exercise
HR in Afib
Mortality
Adams et al. J Am Coll Cardiol 2005;46:497-504
Hypertension
COR LOE RecommendationsComment/
Rationale
Treating Hypertension in Stage C HFrEF
I C-EO
Patients with HFrEF and
hypertension should be prescribed
GDMT titrated to attain
SBP < 130 mm Hg.
NEW:
Recommendation has
been adapted from
recent clinical trial data
but not specifically
tested per se in a
randomized trial of
patients with HF.
COR: Class of Recommendation; I Strong
C-EO: Consensus of expert opinion based on clinical experience
Diuretic +
ACEI/ARB≤3 g sodium/d
Hypervolemia
Titrate ACEI/ARB + ß-Blocker ± diuretic
If CAD: ASA, statin
Consider revascularizationEuvolemia
MRAeGFR >30, K<5
Hydralazine+nitrate
ARNI replaces
ACEI/ARB
ASSESS VOLUME DEFINE ETIOLOGY
Chronic stable NYHA II-III
African American
EF ≤ 40%, NYHA III-IV
EF ≤ 35% NYHA III-IVNYHA II if CV hosp/↑BNP AMI, EF ≤ 40% or DM
Device Therapy REASSESS EF
If EF ≤ 35%
after 3-6 mos
OMTAdvanced Therapies Hospice
Additional RxIvabradineEF ≤ 35%, HR ≥70
+NYHA II-III, +max dose ß-B
or ß-B intolerantDigoxinPUFAExercise/Rehab
If HTN:
SBP < 130
Bensimhon H, Sueta C Netter’s Cardiology 2018 in press
Sueta et al. AJC 2015; 116:413–419
Medication Adherence after Hospitalization
In Heart Failure Patients: ARIC study
N = 402 HF pts; 75 yrs, 70% F, 41% AA
Medicare Part D claims
Adherence = ≥ 80% Proportion ambulatory
days covered (PADC)
Better adherence if a claim within 30 days
Significant decline 2-4 mos post dc
ACEI/ARB
BB Diuretic
Patient education
Includes info on new drugs
PDF available for free
https://news.unchealthcare.org/som-vital-signs/attachments/2016/living-with-
heart-failure-patient-booklet
