NPO presentor presentation

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


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

10 Principles for Successful Treatment of HF

Yancy et al. JACC VOL. 71,NO.2,2018

Key:

Class I recommendation

Class II recommendation

HFrEF Stage C Treatment

ACEI/ARBAND

Beta blocker with diuretic as

needed

For patients with persistent volume

overload, NYHA class II-IV

For persistently symptomatic

African Americans,

NYHA class III-IV

For patients stable on

ACEI/ARB, NYHA class II-III

For patients with eGFR ≥ 30

mL/min/1.72 m2, K+ <5.0 mEq/dLNYHA class II-IV

For patients with resting HR ≥ 70,

on maximally tolerated beta

blocker dose in sinus rhythm,

NYHA class II-III

Titrate Add Switch Add Add

DiureticsHydralazine+ Isosorbide

dinitrateARNI IvabradineAldosterone

Antagonist

Yancy et al. JACC VOL. 71:2 ,2018

Diuretics

Nat Rev Cardiol. 2015;12(3):184-92.

~25%

~5%

Loops:• Furosemide• Torsemide• Bumetanide

Thiazides:• Hydrochlorothizide• Chlorthalidone• Chlorthiazide• Metolazone

Aldosterone Antagonists:• Spironolactone• Eplerenone

Other K-Sparing:• Amiloride• Triamterene

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


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


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

Enalapril Vasotec 2.5mg BID 20mg BID 16.6 mg/day

Fosinopril Monopril 5‐10mg daily 80mg daily N/A

Lisinopril Zestril/Prinivil

2.5‐5mg daily 20mg daily *4.5 mg/day (low dose ATLAS)33.2 mg/day (high dose ATLAS)

Quinapril Accupril 5mg BID 80mg daily N/A

Ramipril Altace 1.25‐2.5mg daily 10mg daily N/A

Trandolapril Mavik 1mg daily 4mg daily N/A

*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

Candesartan Atacand 4‐8 mg daily 32 mg daily 24 mg/day

Losartan* Cozaar 12.5‐25 mg daily 150 mg daily 129 mg/day

Valsartan Diovan 40 mg BID 160 mg BID 254 mg/day

*Not FDA approved for HF

JACC 2013;62:e147-239

ACEI/ARB: Initiation and Titration

ACEI/ARB

Select an initial dose of ACEI/ARB

Consider increasing dose every 2 weeks

Monitor BP, renal function and potassium

Barriers to titration • Worsening renal function• Hyperkalemia• Bilateral renal artery stenosis• Symptomatic Hypotension

• Overdiuresis• Other medications

Monitoring• SCr and K assessed within 1-2 weeks of

initiation or dose increase


What we know about RAASi dose response?

Trial Drug Groups N Age, years

Male, %

Follow-up,

months

ATLAS1 Lisinopril LD = 2.5-5.0 mgdaily

HD = 32.5-35 mg daily

1,596/ 1,568

64 79 46

HEAAL2 Losartan LD = 50 mg daily, HD = 150 mg

daily

1,919/ 1,927

66 71 56

1. Packer M, et al. Circulation 1999;100:2312-23182. Konstam MA, et al. Lancet 2009;374:1840-1848

Circulation. 1999;100:2312-2318 Lancet 2009; 374: 1840–48

ACEI/ARB with Renal Impairment

Generally considered safe when:• SCr <3.0 mg/dL• Renal impairment (eGFR 30-60 mL/min/1.73m2)

Should we stop ACEI/ARB in CKD stage 4 and 5?

Hyperkalemia: Is It Real? Pseudohyperkalemia

• Delayed processing– Central vs. local labs– Traumatic draw

• Presence/absence of hyperglycemia

Target Serum Potassium Ranges in HF

• Heart Failure– 4.0-5.0 mEq/L1,2

– 4.5-5.5 mEq/L3

• Expert opinion

• Hyperkalemia– 5.0 vs. 5.5 vs. 6.0 mEq/L

1. Circulation. 2004,110(5):588-636.2. Arch Intern Med. 2000;160(16):2429-2436.3. J Am Coll Cardiol. 2004;43(2):155-161.

2

3

4

5

6

7

Serum Potassiu

m (m

Eq/L)

Hyperkalemia

Hypokalemia

Normal

Mortality by Prior RAAS Inhibitor Dose

9.8

13.7

5.0 4.1

20.3

27.7

10.18.2

22.4

30.1

13.111.0

0

5

10

15

20

25

30

35

CKD Stage 3‐4n = 43,288

Heart Failuren = 20,529

Diabetesn = 79,087

Totaln = 201,655

Percent o

f Patients

Maximum Dose Sub‐Maximum Dose Discontinued

Am J Manag Care. 2015;21:S212-S220.

Hyperkalemia

• Discontinue potassium supplements • Evaluate concomitant use of potassium-

sparing diuretics • Dietary restrictions (salt substitutes)• Temporary discontinuation of either ACEI or

ARB therapy

Hypotension

• Asymptomatic Hypotension – No action is required for asymptomatic hypotension provided

there is no evidence of renal hypoperfusion

• Symptomatic Hypotension – Flexible diuretic dosing or dose reduction – Consider advising patient to take once-daily doses of ACEI in

divided doses – Consider discontinuing or reducing the dose of other

concomitant medications that may affect blood pressure (e.g., calcium antagonists, nitrates)

– Initiate -blockers before ACEI

HFrEF – Beta Blockers

Beta Blocker DosesGeneric Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials

Bisoprolol Zebeta 1.25 mg daily 10 mg daily 8.6 mg/day

Carvedilol Coreg 3.125 mg BID 25 mg BID*50 mg BID

37 mg/day

Metoprololsuccinate

Toprol XL 12.5‐25 mg daily 200 mg daily 159 mg/day

*If patient is >85 kg

JACC 2013;62:e147-239

Beta-Blockers: Initiation and Titration

Beta blockers

Select an initial dose of beta blockers


Monitor BP, HR and signs of congestion

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


B‐Blocker Dose‐response outcomes


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

Sacubitril/ValsartanAngiotensin Receptor-Neprilysin Inhibitor (ARNI)

For patients stable on ACEI/ARB, NYHA class II-

III

Switch

ARNI

Sacubitril/Valsartan: Place in Therapy


ACEI/ARBs and beta blockers with diuretic as needed

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)


Prior to initiation:• 36 hours wash out period with

ACEI• Adequate blood pressure• eGFR ≥ 30 ml/min/1.73m2

Starting dose based on prior dose of ACEI/ARB:• 24/26 mg or 49/51 mg twice daily• Target dose: 97/103 mg twice daily

• In 2-4 weeks, assess tolerability• Increase dose to target• Monitor: blood pressure,

electrolytes, and renal function both after initiation and during titration

ARNI

Sacubitril/Valsartan: Initiation and Titration


Barriers to titration•Symptomatic hypotension•Electrolyte/renal instability, or angioedema•Cost

Monitoring•Hypotension•Hyperkalemia•Cough•Renal function•Monitor NT-proBNP, not BNP

LCZ696(n=4187)

Enalapril(n=4212)

PValue

Prospectively identified adverse eventsSymptomatic hypotension 588 388 < 0.001Serum potassium > 6.0 mmol/l 181 236 0.007Serum creatinine ≥ 2.5 mg/dl 139 188 0.007Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02Discontinuation for hypotension 36 29 NSDiscontinuation for hyperkalemia 11 15 NSDiscontinuation for renal impairment 29 59 0.001

Angioedema (adjudicated)Medications, no hospitalization 16 9 NSHospitalized; no airway compromise 3 1 NSAirway compromise 0 0 ----

Adverse Events

N Engl J Med. 2014;371:993-1004

Sacubitril/Valsartan DosingStarting dose Maintenance Dose Comments

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

Eplerenone Inspra 25 mg daily 50 mg daily 42.6 mg/day

Spironolactone Aldactone 12.5‐25 mg daily 25 mg daily 26 mg/day

JACC 2013;62:e147-239

NYHA class II-IV• eGFR ≥ 30

• Men: SCr ≤ 2.5 mg/dL• Women: SCr ≤ 2.0

mg/dL• K < 5.0 mEq/dL

Add

Aldosterone Antagonist






Select initial dose

• Titrate doses every 2 weeks until maximum tolerated or target dose is achieved

• Monitoring: electrolytes (especially potassium) and renal function in 2-3 days and 7 days after initiation/titration

• Then, check monthly for 3 months and every 3 months afterwards

Aldosterone Antagonist: Initiation and Titration

Barriers to titration • Symptomatic hypotension• Worsening renal function• Hyperkalemia

Monitoring:• Hypotension• Hyperkalemia• Renal function• Gynecomastia (spironolactone)


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.

Hydralazine/Isosorbide Dinitrate

Dose Hydralazine Isosorbide DinitrateInitial dose 25‐50 mg

3‐4 times daily20‐30mg

3 times dailyMax dose 100 mg

3‐4 times daily40mg

3 times daily

JACC 2013;62:e147-239

Hydralazine/Isosorbide Dinitrate:Place in Therapy

For persistently symptomatic AA, NYHA class II-IV

ADD


Hydralazine/ Isosorbide

dinitrate



Hydralazine/ Isosorbide

dinitrate

Select an initial dose either as individual medications or

fixed–dose combination


Monitor BP

Hydralazine/Isosorbide Dinitrate:Initiation and Titration


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


ACEI/ARBs and beta blockers with diuretic as

needed


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.

Today’s vitals + labs:BP 132/77 mm HgHR 80 bpmSCr 0.9 mg/dLBUN 19 mg/dLK 3.8 mEq/LOther labs wnlCurrent

Medications:Aspirin 81mgAtorvastatin 40mgAmlodipine 5mg dailyChlorthalidone 12.5 mg daily

Questions for Discussion:1. How would you

stage/classify patient’s heart failure?

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.

Today’s vitals + labs:BP 119/70 mm HgHR 70 bpmSCr 1.0 mg/dLBUN 14 mg/dLK 4.0 mEq/L

Current Medications:Aspirin 81mgAtorvastatin 40mgLisinopril 20mg dailyCarvedilol 25mg BIDFurosemide 20mg TIW PRN

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

daily)– Spironolactone 12.5 mg daily– Furosemide 40 mg daily

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.

Today’s vitals + labs:BP 120/70 mm HgHR 75 bpmSCr 1.2 mg/dLK 5.0 mEq/L

Current Medications:Carvedilol 25mg BIDFurosemide 40mg BIDSpironolacone 12.5mg dailyLosartan 100mg daily

Which of the following is best to recommend for this patient?

Patient Case 3A. Start sacubitril/valsartan 49/51 mg BID 36 hours after the last

dose of losartan

B. Start sacubitril/valsartan 97/103 mg at the next dosing interval

C. Do not start sacubitril/valsartan because of K 5.0 mEq/L

D. Do not start sacubitril/valsartan because of hx of angioedema with ACE‐i

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NPO presentor presentation