Strategies to Optimize Heart Failure Treatment: New Insights and Challenges Harleen Singh, Pharm.D.,BCPS-AQ Cardiology, BCACP Clinical Associate Professor OSU/OHSU College of Pharmacy Objectives • Examine evidence-based guidelines for the management of heart failure with reduced ejection fraction, including the role of newer agents • Recognize the challenges associated with up-titration of HF medications • Design individualized therapy to optimize treatment • Describe the key self-care interventions in the management of HF GDTM in the Outpatient Setting J Am Coll Cardiol 2018;72:351–66) GDTM in HFrEF J Am Coll Cardiol 2018;72:351–66)
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Strategies to Optimize Heart Failure Treatment: New Insights and Challenges
Harleen Singh, Pharm.D.,BCPS-AQ Cardiology, BCACP Clinical Associate Professor
OSU/OHSU College of Pharmacy
Objectives • Examine evidence-based guidelines for the management
of heart failure with reduced ejection fraction, including the role of newer agents
• Recognize the challenges associated with up-titration of HF medications
• Design individualized therapy to optimize treatment
• Describe the key self-care interventions in the management of HF
GDTM in the Outpatient Setting
J Am Coll Cardiol 2018;72:351–66)
GDTM in HFrEF
J Am Coll Cardiol 2018;72:351–66)
Classification of Heart FailureClassification EF (%) Description
Heart failure with reduced ejection fraction (HFrEF)
≤40 • Systolic HF• Randomized clinical trials have mainly enrolled
patients with HFrEF, and it is only in these patients that efficacious therapies have been demonstrated to date
Heart failure with preserved ejection fraction (HFpEF)
≥50 • Diastolic HF• Diagnosis of HFpEF is challenging because it is
largely one of excluding other potential noncardiaccauses of symptoms suggestive of HF
• To date, efficacious therapies have not been identified
HFpEF, borderline 41‐49 • These patients’ characteristics, treatment patterns, and outcomes appear similar to those with HFpEF
HFpEF, improved >40 • Patients with improved or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF
• Further research is needed to better characterize these patients
For patients with persistent volume overload, NYHA class II-IV
Titrate
Diuretics
Diuretics: Place in TherapyHFrEF Stage C
Treatment
ACEI/ARBs and beta blockers with diuretic as
needed
Yancy et al. JACC VOL. 71:2 ,2018
Pharmacologic Properties of Loops
Property Furosemide Torsemide Bumetanide
Relative potency 1x 2x 40x
Bioavailability (%) 10‐100 80‐100 80‐100
Oral/IV dosing 2:1 1:1 1:1
Time to onset (min) 60 60 30‐60
Oral peak serum concentration (h) 1 1 1‐2
Absorption affected by food Yes No Yes
Average half‐life (h) 2 3.5 1‐1.5
Duration of effect (h) 6‐8 6‐16 4‐6
Decreased kaliuresis No Yes No
Am Heart J 2015;169:323-33
Diuretics: Initiation and Titration
Select initial loop diuretic dose based on:• Diuretic naïve • Renal function
• Titrate doses to response over days to weeks• May reduce diuretic doses in the setting of
titrating ACEI, ARBs, or ARNI• Monitor: blood pressure, electrolytes, and renal
function both after initiation and titration
Patients who have received doses of furosemide equivalent to 120 mg twice daily consider:
• Changing to a different loop diuretic• Adding a thiazide-like diuretic• Monitor blood pressure, electrolytes, and
renal function both after initiation and titration
Diuretics
Yancy et al. JACC VOL. 71:2 ,2018
Dose-Response Relationship
Normal
Heart Failure
Decreased max response
Elevated diuretic threshold (resistance)
Ceiling Dose
J Card Fail. 2014;20(8):611-22
“Steep” part of dose-response
curve
Patients with heart failure require a higher serum diuretic concentration to elicit the same diuretic response (diuretic resistance) and have diminished responses to ceiling doses of loop diuretics.
Mechanisms of loop diuretic resistance
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.215
Metolazone
Pharmacokinetics Metolazone Hydrochlorothiazide
Bioavailability 90‐95% 65‐75%
Onset of action ~60 min 2 hours
Elimination half‐life 6‐20 hours 6‐15 hours
Duration of action >24 hours 6‐12 hours
• Metolazone is most commonly prescribed for combination therapy in the U.S.
• Retains efficacy in advanced renal failure• However, other thiazides at equipotent doses are likely
to have the same synergistic effects
J Am Coll Cardiol. 2010;56(19):1527-34
Timing of CDT Doses• Pre-dosing of oral metolazone 30-60 min prior to
furosemide is common practice– Increased regimen complexity– Inconvenient
• No published clinical studies compared pre-dosing to simultaneous dosing
• Onset of metolazone is unlikely to be clinically significant with chronic treatment once steady-state is achieved
• TD (with longer duration of action) maintains diuresis after short acting LD has worn out
J Am Coll Cardiol. 2010;56(19):1527-34
TX
VAD
CRT
ICD
Beta blocker ACEI/ARB MRA
Ivabradine
ARNI
Digoxin
H-ISDN
HFrEF: The Building Blocks of Therapy
GDMT RR Reduction in Mortality
NNT for Mortality Reduction
(Standardized to 36 months)
RR Reduction in HF
Hospitalizations
ACEI or ARB 17% 26 31%
Beta blocker 34% 9 41%
Aldosterone antagonist
30% 6 35%
Hydralazine/nitrate 43% 7 33%
ARNI 20% 21* 21%
*Standardized to 27 months, active comparator (enalapril) vs placebo
Magnitude of Benefits Demonstrated in RCTs
JACC 2013;62:e147-239
HFrEF – ACEIACEI DosesGeneric Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials
Captopril Capoten 6.25mg TID 50mg TID 122.7 mg/day
*No difference between mortality between high and low dose groups, but 12% lower risk of death or hospitalization in high dose group vs. low dose group.
JACC 2013;62:e147-239
HFrEF – ARB
ARB DosesGeneric Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials
Barriers to titration • Symptomatic hypotension/bradycardia
• Overdiuresis• Other medications • Autonomic dysfunction
• Transient worsening of HF symptoms• Dyspnea, fatigue, or dizziness
Monitoring • Fatigue, dyspnea, dizziness, HR
Yancy et al. JACC VOL. 71:2 ,2018
B‐Blocker Dose‐response outcomes
J Am Coll Cardiol 2017;69:2542–50)
Clinical ScenariosScenario I:Which beta blocker to initiate?
Scenario 2:Able to tolerate target doses of one and less than target doses of the other therapeutic agent?
Consider metoprolol succinate for patients who are hypotensive on carvedilol, cannot tolerate much lower blood pressures, or patients with atrial fibrillation, COPD/asthma
Optimal SNS modulation with target doses of beta blocker appears to have the best effect on HFrEF outcomes (cardiovascular mortality, pump failure mortality,and sudden cardiac death).
Early Versus Late Stages of Chronic Heart Failure
Br J Cardiol 2005;12:448–454.
• 20 % relative risk reduction in the primary outcome
• 4.7% absolute risk reduction in the primary outcome
• NNT: 21 over 27 months
N Engl J Med. 2014;371:993-1004
primary endpoint : death from cardiovascular causes and hospitalization for heart failure
ACEI/ARB Naive 24/26 mg bid 97/103 mg bid Dose is doubled every 2 to 4 weeks
Previously on ACEI/ARB
Total daily dose <10 mg Total daily dose >10 mg
Total daily dose <160 mg£ Total daily dose >160 mg
24/26 mg bid49/51 mg bid
24/26 mg bid49/51 mg bid
97/103 mg bid Allow 36 hour washout between ACEIand ARNIDose is doubled every 2 to 4 weeks
Severe Renal Impairment (eGFR<30 ml/min)
24/26 mg bid 97/103 mg bid Dose is doubled every 2 to 4 weeks. No dose adjustment needed for mild‐moderate renal impairement.
Hepatic Impairment (Child‐Pugh B classification)
24/26 mg bid 97/103 mg bid Dose is doubled every 2 to 4 weeks. Use in severe hepatic impairment not recommended
Lisinopril £Valsartan
Common Clinical Scenarios
Scenario 1: When to initiate ARNI?
Scenario 2: Initiation of an ARNI de novo without prior exposure to ACEI or ARB
Scenario 3: Is use of aldosterone antagonist mandatory prior to using ARNI?
In persistently symptomatic patients who tolerate an ACEI or ARB, switching to an ARNI
“Accept the uncertainty about effectiveness and safety as well as potentially greater out-of-pocket costs, de novo initiation of ARNI with close follow-up and serial assessments(blood pressure, electrolytes, and renal function) might be considered”
Not mandatory prior to changing a patient to ARNI.
HFrEF – Aldosterone Antagonists
Aldosterone Antagonist DosesGeneric Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials
Appropriate follow-up laboratory testing across all time periods occurred in 25.2% of patients with inpatient initiation compared with 2.8% of patients begun as an outpatient. Patients with chronic kidney disease had higher rates of both hyperkalemia and acute kidney failure in the early (1.3% and 2.7%, respectively) and extended (5.6% and 9.8%, respectively) post-initiation periods compared with those without chronic kidney disease.
Circ Cardiovasc Qual Outcomes. 2017;10:e002946
Spironolactone causes hyperkalemia in a dose-dependent fashion
Optimal dosing of MRA in HF is limited by hyperkalemia
The RALES Investigators. Am J Cardiol 1996, 78(8):902-7
Aldosterone Antagonists
Eplerenone Spironolactone
eGFR(ml/min/1.73m2)
≥50 30 to 49 ≥50 30 to 49
Initial dose (only if K+ ≤ 5mEq/L)
25 mg once daily
25 mg once every other day
12.5 to 25 mg once daily
12.5 mg once daily or every other day
Maintenance dose (after 4 wk for K+ ≤ 5mEq/L)
50 mg once daily
25 mg once daily
25 mg once or twice daily
12.5 to 25 mg once daily
JACC 2013;62:e147-239
Clinical Scenarios
• Scenario 1: When to initiate aldosterone antagonists?
• Scenario 2: Is it mandatory to be on target or max tolerated doses of beta blockers and ACEI/ARB prior to initiating aldosterone antagonists?
In patients who are already receiving beta blockers and ACEI/ARB/ARNI who do not have contraindications.
In practice we would like to optimize beta blockers and ACEI/ARBs first. However, in patients with persistent hypokalemia, earlier addition of an aldosterone antagonists may be considered.
ACEI/ARBs and beta blockers with diuretic as needed
Hydralazine/ Isosorbide
dinitrate
HFrEF Stage C Treatment
Yancy et al. JACC VOL. 71:2 ,2018
Hydralazine/ Isosorbide
dinitrate
Select an initial dose either as individual medications or
fixed–dose combination
Consider increasing dose every 2 weeks
Monitor BP
Hydralazine/Isosorbide Dinitrate:Initiation and Titration
Yancy et al. JACC VOL. 71:2 ,2018
African AmericansEstablish GDMT with ACEI/ARB, beta blocker, and an aldosterone antagonist, then switch to ARNI (akin to patients studied in PARADIGM); if stable, follow with HYD/ISDN if patient has persistent class III to IV symptoms with careful blood pressure monitoring.
Establish GDMT with ACEI/ARB, beta blocker, and an aldosterone antagonist and then proceed with HYD/ISDN if persistent class III to IV symptoms (akin to patients studied in A-HeFT) if stable, follow with ARNI substitution for ACEI/ARB with careful blood pressure monitoring.
OR
JACC 2013;62:e147-239
Ivabradine Doses for HFrEF
Population Initial Dose Max dose
Max tolerated beta‐blocker dose with persistent resting HR ≥ 70
5 mg BIDTitrate to HR 50‐60
bpmMax dose 7.5mg BIDHistory of conduction defects 2.5 mg BID
Age ≥ 75 years 2.5 mg BID
J Am Coll Cardiol. 2018;71(2):201‐230.
For patients with resting HR>70 bpm, on maximally tolerated beta blocker in sinus rhythm, NYHA
Class II-III
Add
Ivabradine
Ivabradine: Place in Therapy
HFrEF Stage C Treatment
ACEI/ARBs and beta blockers with diuretic as
needed
Yancy et al. JACC VOL. 71:2 ,2018
Ivabradine Monitoring
• Resting heart rate decreases persistently below 50 bpm or if symptoms of bradycardia occur
• If a patient develops persistent/continuous atrial fibrillation (AF) during therapy
• Luminous phenomena (phosphenes – visual color spots)
Wait! What About Digoxin?
• Reduced number of hospitalizations• Improvements in
– Symptoms– Exercise tolerance– Quality of life
• Typical dose: 0.125 mg daily
Target Cp: 0.5-0.9 ng/mL
NO SURVIVAL BENEFIT!
Self-Care in Cardiovascular Disease
J Am Heart Assoc.2017;6:e006997
Patient Case 1: Initiation of therapy
KS is a 67-year-old white man with a remote hx of heart failure. Recent ECHO on 3/5/2018 showed an ejection fraction of 25%. Today he reports trace edema and dyspnea with less than normal activity.
2. Assess patient’s current therapy for heart failure
KS’s physician plans to discontinue amlodipine and chlorthalidone. She also asks for a recommendation on starting GDMT. What would you recommend?
HFrEF Stage C NYHA Class III
ACSAP 2018
Patient Case 1A. Initiate lisinopril 5mg daily
B. Initiate lisinopril 20mg daily
C. Initiate carvedilol 3.125mg BID
D. Initiate lisinopril 5mg daily and carvedilol 3.125mg twice daily
ACSAP 2018
Patient Case 1 (cont.)
At his 6-month visit, KS is taking lisinopril 20mg daily and carvedilol 25mg twice daily. He is also taking furosemide 20mg three times weekly as needed based on daily weight.
KS is clinically stable, but states that he “gets winded a little easier than he used to be with normal activities.” What would you recommend adding to K.S’s HF regimen?
ACSAP 2018
Patient Case 1 (cont.)A. Spironolactone 12.5mg daily
B. Sacubitril/valsartan 24mg/26mg BID
C. Valsartan 40mg BID
D. Digoxin 0.125mg daily
ACSAP 2018
Patient Case 2: ExacerbationKJ is a 60 year old woman with HFrEF who is referred to the HF clinic for evaluation. Her EF is 30% and prior work-up was negative for coronary disease.
Current HF medications – Sacubitril/valsartan 49/51 mg BID– Metoprolol succinate 100mg daily (increased 2 weeks ago from 50mg
KJ currently complains of worsening fatigue, dyspnea, and weight gain (5lbs)BP: 100/60 mm Hg HR: 95 BPM1+ pitting edema to her shin + JVDlungs are clearSCr 1.2 mg/dL (stable)K is 5.1 mEq/L
Which one of the following, in addition to increasing furosemide to 40mg BID, is best to recommend for KJ?
Patient Case 2A. Decrease metoprolol to 50mg daily
B. No other changes to current therapy
C. Increase sacubitril/valsartan to 97/103 mg BID
D. Increase metoprolol to 150 mg daily
ACSAP 2018
Patient Case 3: ARNI
PK is a 55-year-old white woman with HFrEF, stage C, NYHA class III with a history of angioedema with lisinopril.