4 - Therapeutics Of Chronic Hf Sp2019 Instructor (1).pptx
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Therapeutics of Chronic Heart Failure W. CHENG YUET, PHARM.D., BCACP ASSISTANT PROFESSOR OF PHARMACOTHERAPY UNT SYSTEM COLLEGE OF PHARMACY [email protected]
2
Learning Objectives 1.
Justify the role of therapies used in chronic HF management, including pharmacologic effects, place in therapy, and impact on outcomes.
2.
Recall initial and target dosing of heart failure medications based on most recently revised guidelines by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and literature supporting these recommendations.
3.
Discuss causes and management of diuretic resistance.
4.
Discuss the efficacy, safety, and patient education relevant to each therapy used in management of HF.
5.
Identify and discuss medications not recommended in heart failure patients.
6.
Provide evidence-based, patient-centered recommendations to optimize efficacy and tolerability of treatment regimens in patients with HF.
Review of Pathophysiology: Types of HF HFpEF – HF with Preserved Ejection Fraction • Referred as diastolic HF • Condition in which myocardial relaxation and filling are impaired and incomplete and/or increased diastolic stiffness • Characterized by signs and symptoms of HF with preserved LVEF defined as 50% or greater HFrEF – HF with Reduced Ejection Fraction • Referred as systolic HF • Ventricle too weak to pump sufficient blood for adequate perfusion • Characterized by signs and symptoms of HF and reduced LVEF defined as 40% or less KNOW DEFINITIONS OF HFpEF and HFrEF (e.g., EF cutoffs)
3
4
Review of Pathophysiology: Clinical Presentation
Fatigue Activity limitation Chest congestion
Edema or ankle swelling Shortness of breath
5
Review of Pathophysiology: Classification of HF (1 of 2) ACCF/AHA used to evaluate HF progression
NYHA used to classify symptoms according to clinician’s assessment
ACCF/AHA Classification
NYHA Functional Class
Stage A
B
Description At high risk for heart failure but without structural heart disease or symptoms of HF Structural heart disease but without symptoms of HF
Class
Description
No comparable functional class I
No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
ACCF/AHA Classification Stage
Description Structural heart disease with prior or current symptoms of HF
NYHA Functional Class Class
Description
I
No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.
III
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.
C
IV
D
Refractory HF requiring specialized interventions
IV
Unable to carry out any physical activity without symptoms of HF, or symptoms of HF at rest. Unable to carry out any physical activity without symptoms of HF, or symptoms of HF at rest.
6
CLASSIFICATION OF HF (2 OF 2)
7
Desired Outcomes
Improve patient’s quality of life (reduce morbidity) Relieve or reduce symptoms
Prevent or minimize hospitalizations for exacerbations of HF
Slow progression of disease
Prolong survival (reduce mortality)
8
Guidelines
2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Management of Heart Failure 2017 Focused Update
Numerous large, randomized, double-blinded, multi-center trials guide treatment options in HFrEF (refer to handout)
No randomized trials conducted in HFpEF
9
Overview of Available Agents Drug Class
Who Receives It?
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression ACEi or ARB
All patients with reduced EF unless contraindication
Beta-blockers
All patients with reduced EF unless contraindication
Aldosterone antagonists
Patients with reduced EF who are symptomatic and meet other criteria
Hydralazine/nitrate
Black patients with reduced EF who are symptomatic despite optimized doses of lifesaving agents
Ivabradine
Patients with reduced EF who are symptomatic on maximum tolerated beta-blocker dose
Sacubitril/valsartan (ARNI)
Patients with reduced EF who are symptomatic and can tolerate ACEi or ARB
Digoxin
Patients with low EF who continue to require hospitalization despite taking optimized doses of life-saving agents Agents that improve symptoms only
Diuretics
Patients with congestive symptoms
Same Drugs, Different Disease State!
For each medication class, please know: Why the drug has a role in HF therapy Pharmacologic effects
Who the drug should be given to
What is the impact of this drug on outcomes Which agents to use (not all agents are equal) How the drug should be used and monitored
Initial and target doses; how to titrate
10
11
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression
ANGIOTENSIN CONVERTING ENZYME INHIBITOR (ACEI) ANGIOTENSIN RECEPTOR BLOCKER (ARB) BETA-ADRENERGIC ANTAGONIST (BETA-BLOCKER)
ALDOSTERONE ANTAGONISTS HYDRALAZINE AND NITRATE COMBO IVABRADINE ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)
DIGOXIN
12
ACE Inhibitors
Pharmacologic effect
Lowers BP which decreases afterload
Decreases production of angiotensin II
Who? All stable patients with HFrEF unless contraindicated (Class I, LOE A)
Impact on outcomes
Slows HF progression
Reduces ventricular remodeling
Improves survival
Lowers aldosterone levels which decreases preload
Reduces rate of hospitalizations
Slows HF progression
Reduces rate of reinfarction
Increases bradykinin (vasodilator) which decreases afterload but causes ADE
13
ACE Inhibitors - Class Effect
Need to know initial and target doses Agent
Initial Dose
Target Dose
Captopril (Captoten)
6.25 mg TID
50 mg TID
Enalapril (Vasotec)
2.5 mg BID
At least 10 mg BID; preferred 20 mg BID
Lisinopril (Prinivil, Zestril)
2.5 mg or 5 mg daily
20 mg to 40 mg daily
Ramipril (Altace)
1.25 mg daily
10 mg daily
Titration strategy: Start low! Consider increasing dose every 2 weeks until target or max tolerated dose is reached Intensification usually takes 2-4 months with appropriate follow-up Agents are often under-used and under-dosed
14
ACE Inhibitors
Adverse Effects
Contraindications
Angioedema (potentially fatal)
Serum creatinine > 3.0 mg/dL
Hyperkalemia
History of angioedema or hyperkalemia
Cough
Bilateral renal stenosis
Renal dysfunction
Severe aortic stenosis
Hypotension (dizziness, syncope, lightheadedness)
Pregnancy
Rash
Taste disturbance
Labile BP and hypotension (increases risk of cardiogenic shock
ACE Inhibitors
15
Monitoring
Safety
Baseline: BUN, SCr, potassium, and BP
Follow-up within 1-2 weeks from initiation or dose adjustment: BUN, SCr, potassium, and BP
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
ACE Inhibitors
16
Summary
Very beneficial treatment for all HF patients unless contraindicated!
Decreases afterload and preload; reverses remodeling – good for the heart!
Outcomes – good for the institution and patient!
Extensively studied in patients with reduced EF
Start low and titrate slow to reach target or max tolerated dose
Important to monitor safety (e.g., symptoms, labs) especially during titration
17
ARBs
Pharmacologic effects
Who?
Lowers BP which decreases afterload
Blocks effects of angiotensin II on angiotensin receptor subtype 1 (AR1)
Patients with HFrEF who are unable to tolerate ACEi (Class I, LOE A)
Reasonable alternative to ACEi as first-line therapy in HFrEF in patients already taking ARBs for other indications (Class IIa, LOE A)
Useful due to ACE escape! ACE inhibitors incompletely block the formation of angiotensin II
Attenuates deleterious effects of angiotensin II on ventricular remodeling
Less accumulation of bradykinin which lowers risk of ADE
Similar clinical benefits and potentially fewer ADE compared to ACEi
Impact on outcomes
Improves survival
Reduces hospitalization
Slows HF progression
18
ARBs – Not a Class Effect! Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Valsartan (Diovan)
40 mg BID
160 mg BID
Candesartan (Atacand)
4 or 8 mg daily
32 mg daily
Losartan (Cozaar)
25 mg daily
50 mg to 150 mg daily
Titration strategy: Start low! Consider increasing dose every 2 weeks until target or max tolerated dose Intensification usually takes 2-4 months with appropriate follow-up
19
ARBs
Adverse effects
Similar to ACEi but have have different frequency
Lower incidence of cough
Monitoring
Baseline: BUN, SCr, potassium, and BP
Follow-up within 1-2 weeks from initiation or dose adjustment: BUN, SCr, potassium, and BP
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
ARBs
20
Summary
Similar clinical benefits as ACEi – good for the heart, patient, and institution!
Use in patients who cannot tolerate ACEi
Titrate to target dose or max tolerated dose – Know selected agents since there is not a class effect
Adverse effects similar to ACEi but with different frequencies
Important to monitor safety (e.g., symptoms, labs) especially during titration
21
Beta-Blockers
Pharmacologic effects
Who? All stable patients with HFrEF unless contraindicated (Class I, LOE A)
Impact on outcomes
Slows heart rate and lowers BP
Decreases work load on heart
Increases ventricular filling which improves CO
Short term (e.g., during titration): decreases force of contraction of the heart
Long term (e.g., after 3 months): improves ventricular contractility
Anti-arrhythmic properties
Blocks effects of NE
Improves survival
Reduces hospitalization
Slows HF progression
Beta-Blockers – Not a Class Effect!
22
Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Carvedilol • Immediate Release (Coreg) • Controlled Release (Coreg CR)
3.125 mg BID 10 mg daily
25 mg BID if < 85 kg; 50 mg BID if > 85 kg 80 mg daily
Metoprolol succinate (Toprol XL)*
12.5 mg daily
200 mg daily
Bisoprolol (off-label use)
1.25 mg daily
10 mg daily
*Metoprolol tartrate (Lopressor) has not been shown to be beneficial in HF therapy Both carvedilol formulations should be taken with food Metoprolol succinate tablets are scored and can be cut (not crushed or chewed)
Beta-Blockers
23
Initiation and Titration
Initiation
Do NOT start in patients who are hospitalized in ICU or recently required IV inotropic support
Only in stable patients who have no or minimal evidence of fluid overload
Beta-blockers should still be given even if symptoms are mild or well-controlled with ACEi +/- diuretic
ACEi dose does not have to be optimized prior to starting a beta-blocker – Addition of beta-blocker is likely to be of greater benefit than increasing ACEi alone
Dose Titration
Start low and titrate slowly to target dose – Beta-blockers are harder to tolerate due to effects on HR, BP, and symptoms such as fatigue
Consider increasing dose every 2 weeks if no evidence of clinically significant worsening HF and if vitals are stable
Intensification may be delayed if HF symptoms worsen
24
Beta-Blockers
Adverse effects
Symptoms may worsen initially – should be mild to continue beta-blockers
Fatigue
Depression
Drug interactions
Additive effects with other drugs that reduce HR (e.g., digoxin, verapamil) Additive effects with other drugs that reduce BP
Contraindications and precautions
Decompensated heart failure
Can worsen heart failure if not started and titrated appropriately
Slows HR and decreases force of contraction
Bradycardia (HR < 60 bpm)
Hypotension (e.g., SBP < 80 mm Hg)
Sick sinus syndrome
2nd or 3rd degree AV block
Pulmonary disease (beta-blocker selectivity)
Hemodynamic instability
Fluid overloaded
Beta-Blockers Monitoring
Safety
Monitor for ADE within 1-2 weeks of initiation and dose adjustments and then periodically once stabilized on a dose
BP, HR, and signs of congestion
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
25
Beta-Blockers
26
Summary
Very beneficial treatment for all HF patients unless contraindicated!
Decreases afterload, reverse remodeling – good for the heart!
Outcomes – good for patient and institution!
Initiate in stable patients (do not use in acute decompensated heart failure) regardless of whether ACEi therapy is optimized
Starting low with slow titration is especially important for this medication class
Important to monitor safety (e.g., BP, HR) and tolerance with initiation and titration
Patient education is key to adherence and long term benefits of therapy
27
Aldosterone Antagonist a.k.a. Mineralocorticoid Receptor Antagonist (MRA)
Pharmacologic effects
Mildly lowers BP
Inhibits cardiac extracellular matrix and collagen deposition
Attenuates cardiac fibrosis and ventricular remodeling
Who? Refer to next slide
Impact on outcomes
Improves survival
Slows HF progression
No direct effect on heart rate or contractility
Improves symptoms
Weak diuretic at low doses
Reduces hospitalizations
Potassium-sparing which contributes to mortality benefit
28
Aldosterone Antagonist Who should be taking this?
Population 1
Patients with NYHA class II-IV HF with LVEF ≤ 35% unless contraindicated (Class I, LOE A)
Patients with NYHA class II HF should have history of cardiovascular hospitalization or elevated plasma natriuretic peptide levels
On standard therapy (e.g., ACEi, beta-blocker) which do not have to be optimized before MRA initiation
Scr should be ≤ 2.5 mg/dL in men or ≤ 2.0 mg/dL in women (or estimated GFR > 30 mL/min/1.722)
Potassium should be < 5.0 mEq/L
Population 2
Following an acute MI in patients who have LVEF ≤ 40% who develop symptoms of HF or who have a history of diabetes unless contraindicated
Consider use of eplerenone
Do NOT use in patients using ACEi and ARB concurrently (Class III, LOE C)
29
Aldosterone Antagonist Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Spironolactone (Aldactone)*
12.5 mg to 25 mg daily
50 mg daily if no ADE with progression of HF
Eplerenone (Inspra)
25 mg daily
50 mg daily
*Renal dose adjustments exist since decreased clearance will result in hyperkalemia Titration strategies: Consider increasing dose at least every 2 weeks until target or max tolerated dose is reached
30
Aldosterone Antagonist
Adverse effects
Gynecomastia – higher incidence with spironolactone
Hyperkalemia
Hyponatremia
Contraindications
Spironolactone
Anuria
CrCl < 10 mL/min
Hyperkalemia
Potassium supplements and potassium-sparing diuretics
Monitoring
Baseline: BUN, SCr, potassium
Above labs 2-3 days after initiation and then 7 days after initiation or titration
Check monthly for 3 months and then every 3 months afterward
Eplerenone
CrCl < 30 mL/min for all patients
CrCl < 50 mL/min in patients with elevated SCr > 1.8 mg/dL in women or > 2.0 mg/dL in men
T2DM with microalbuminuria
Aldosterone Antagonist
31
Summary
Beneficial medication for certain patients!
Slows progression of HF (inhibition of cardiac fibrosis) – good for the heart!
Outcomes – good for patient and institution!
Understand the place in therapy compared to ACEi and beta-blockers
Know which patients to avoid in (think contraindications/precautions)
Important to monitor renal function and potassium levels soon after initiation or dose modification – They will RAPIDLY CHANGE potassium levels
Hydralazine and ISDN Combination
Pharmacologic effects
Nitrate is venodilator that reduces preload
Hydralazine is an arterial dilator that reduces afterload
Impact on outcomes (black patients)
Reduces mortality
Reduces hospitalizations
Improves quality of life
Potentially slows HF progression
32
Who? Combination of hydralazine and isosorbide dinitrate (ISDN) recommended for black patients with HFrEF who remain symptomatic despite optimization of ACEi and beta-blockers (Class I, LOE A)
Who else? Patients with prior or current symptoms of HFrEF who cannot be given ACEi or ARB (Class IIa, LOE B)
33
Hydralazine and ISDN Combination Know the Initial and Target Doses Agents
Fixed Dose Combination • Hydralazine 37.5 mg and ISDN 20 mg (BiDil) Individual Medications • Hydralazine • ISDN
Initial Dose 1 tablet TID
Target Dose 2 tablets TID
25 mg to 50 mg TID 300 mg daily in divided doses 20 mg to 30 mg TID or four times daily 120 mg daily in divided doses
Titration Strategies: Select initial doses either as fixed dose combination or individual medications Consider increasing hydralazine and/or ISDN every 2 weeks until target or max tolerated dose is reached
34
Hydralazine and ISDN Combination
Nitrate-free interval
Repeated administration of nitrates results in smooth muscle relaxation in blood vessels, tolerances, and unwanted ADE
Tolerance develops quickly but wears off after a brief nitrate-free interval E.g., Minimum 12-hour nitrate-free interval in a 24-hour period
Adverse effects
Hypotension
Headache
Monitoring
Tolerability
Baseline: BP and HR
Follow-up: BP and HR after initiation and during titration
Hydralazine and ISDN Combination Summary
Beneficial in a subset of patients!
Decreases preload and afterload – good for the heart!
Outcomes – good for black patients (some benefits in non-black populations) and the institution!
Who should receive?
Black patients with symptomatic HFrEF despite optimal standard therapy
Patients with HFrEF who are intolerant to ACEi or ARB
Medication adherence
Pill burden
Nitrate-free interval
Tolerability of adverse effects
35
36
Self-Assessment Question We have now discussed well-established therapies that are proven to slow progression of heart failure and improve survival. Which of the following agents are recommended in ALL stable heart failure patients? I. ACE inhibitor A.
I only
B.
II only
C.
I and II only
D.
I, II, and III only
E.
I, II, III, and IV
II. Beta-blocker
III. MRA
IV. Hydralazine/ISDN
37
Ivabradine
Pharmacologic effects
Reduces heart rate at rest and during exercise in patients in sinus rhythm
Maintains myocardial contractility and atrioventricular conduction
Who? Stable, symptomatic HF with all of the below (Class IIa, LOE B-R):
EF ≤ 35%
In sinus rhythm with resting heart rate ≥ 70 bpm
Either on max tolerated dose of betablocker or have a contraindication to beta-blocker use
On standard therapy (e.g., beta-blocker, ACEi or ARB, MRA)
Persistent symptoms (NYHA class II-IV)
Impact on outcomes
Reduces hospitalizations
Ivabradine
38
Dosing and Administration
Brand name only (Corlanor); take with meals
Initial dose: 5 mg BID in patients < 75 years old
Reduced initial dose of 2.5 mg BID in patients ≥ 75 years old, who has history of conduction defects, or who may experience hemodynamic compromise due to bradycardia
Max dose: 7.5 mg BID
Titration strategies:
After 2 weeks, adjust dose to achieve resting HR between 50 bpm and 60 bpm
Thereafter, adjust dose as needed based on resting HR and tolerability
Discontinue or decrease dose if HR < 50 bpm or s/sx of bradycardia
39
Ivabradine
Adverse effects
Contraindications
Bradycardia
Acute decompensated heart failure
Hypertension
Severe liver impairment
Atrial fibrillation
BP < 90/50 mm Hg
Luminous visual phenomena
Resting HR < 60 bpm
HR solely maintained by pacemaker
Sick sinus syndrome
Pregnancy
Fetal harm may occur
Sinoatrial block
Effective contraception is recommended in women of reproductive potential
Third degree AV block
Strong inhibitors of CYP3A4
40
Ivabradine SHIFT Trial •
Patients randomized to ivabradine titrated to 7.5 mg BID or placebo
•
Reduced hospital admissions for worsening HF in ivabradine group
•
Did not reduce CV death in ivabradine group
•
More bradycardia vs placebo
•
Average 15 bpm reduction in HR in addition to optimal therapy
Ivabradine Summary
Beneficial in a certain subset of HFrEF patients
Reduces hospitalization but NOT mortality
Relatively new agent that lacks long-term safety and efficacy data
Caution due to a number of contraindications and potentially severe ADE
Dose is adjusted based on HR – Main monitoring parameter
41
42
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
Pharmacologic effects
Vasodilation
Decreases sympathetic tone
Decreases aldosterone levels
Decreases fibrosis
Decreases hypertrophy
Decreases blood pressure
Natriuresis and diuresis
Who? Patients with symptomatic HFrEF who tolerate an ACEi or ARB
Replacement by an ARNI is recommended to further reduce morbidity and mortality (Class I, LOE B-R)
Impact on outcomes
Reduces hospitalizations
Reduces cardiovascular death
Equivalent to ≤ 10 mg BID of enalapril or ≤ 160 mg daily of valsartan
43
ARNI Dosing and Administration • Sacubitril/valsartan (Entresto) is only available as branded fixed dose combination tablet • Also initiate at lower dose in patients with severe renal impairment • Should not be administered with ACEi or within 36 hours of last ACEi dose • Assess tolerability in 2-4 weeks after initiation; If possible, then increase stepwise increase dose to target • Monitoring • BUN, SCr, electrolytes, and BP at baseline, after initiation, and during titration
44
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
Adverse effects
Contraindications
Hypotension
Hypersensitivity
Hyperkalemia
Cough
History of angioedema related to previous ACEi or ARB therapy
Renal impairment
Concomitant use with ACEi
Angioedema
Concomitant use with aliskiren (Tekturna) in patients with diabetes
Special populations
Drug interactions
Lactation: discontinue drug or breastfeeding
Do not use with ACEi, ARB, or aliskiren
Do not use in severe hepatic impairment
Potassium-sparing diuretics – elevated potassium
Lithium – increased risk of lithium toxicity
NSAIDs – increased risk of renal impairment
45
ARNI PARADIGM-HF Trial •
Designed to replace ACEi and ARB as cornerstone of HF therapy
•
Patients randomized to enalapril 10 mg BID or sacubitril/valsartan 200 mg BID
•
Reduction in composite of death from CV causes or a first hospitalization for worsening HF
•
Less cough and lesser incidence of increased SCr > 2.5 mg/dL
•
Study prematurely stopped due to lower CV mortality seen in intervention arm by prespecified interim analysis
46
Angiotensin Receptor-Neprilysin Inhibitor (ANRI)
Outcomes – good for both patients and the institution!
Based on new clinical trial data, the ACCF/AHA guidelines support replacing ACEi or ARB therapy with ARNI to further reduce morbidity and mortality
Used in conjunction with beta-blockers and aldosterone antagonists in selected patients
This has not translated to clinical practice due to the cost/availability of Entresto
Unique instructions for selecting the initial dose and titrating
47
Digoxin
Pharmacologic effects
Slows heart rate which increases AV nodal refractoriness (this is good for atrial fibrillation) Increases ventricular force of contraction (this is good for HF)
Who? Patients with HFrEF who have symptoms despite optimized standard therapy (Class I, LOE B) Primarily in systolic HF Concomitant atrial fibrillation
Impact on outcomes Improves symptoms and exercise tolerance Reduces hospitalizations Does NOT improve survival
48
Digoxin Dosing and Administration
Most patients will need 0.125 mg to 0.25 mg daily
Lower initial dose (0.125 mg daily or every other day) for certain patient populations
Elderly patients (> 70 years)
Patients with renal dysfunction
Low lean body mass
Patients with interacting drugs (e.g., amiodarone)
Loading doses of digoxin generally not needed in chronic HF
Narrow therapeutic range
Monitor blood levels (goal 0.5 to 0.9 ng/mL)
Levels may be different for various disease states
Not necessary to monitor routinely unless suspecting toxicity, worsening renal function, drug interactions, or other conditions that may affect levels
Toxicity (see next slide on Adverse Effects)
Hypokalemia, hypomagnesemia, hypercalcemia
49
Digoxin Adverse Effects Non-Cardiac • Anorexia, nausea, vomiting, abdominal pain • Visual disturbances • Halos, photophobia, problems with color perception (yellow-green, redgreen), scotomata • Fatigue, weakness, dizziness, headache, neuralgia, confusion, delirium, psychosis
Cardiac • Ventricular arrhythmias • Premature ventricular depolarizations, bigeminy, trigeminy, ventricular tachycardia, ventricular fibrillation • Atrioventricular (A-V) block • First degree, second degree, third degree block • Atrial arrhythmias • Sinus bradycardia • Potassium abnormalities
50
Digoxin Drug Interactions
Pharmacokinetic
Digoxin is a substrate of p-glycoprotein (P-gp)
Inhibitors of P-gp include amiodarone, diltizem, verapamil
Pharmacodynamic
Drugs affecting HR: verapamil, diltiazem, betablockers, amiodarone
Drugs affecting potassium levels: diuretics, ACEi, aldosterone antagonists
Miscellaneous
Antacids decrease digoxin absorption
Licorice interferes with digoxin assay
Monitoring
Baseline and 1-2 weeks of initiation: HR, symptoms, BUN, SCr, potassium
Within 2 weeks of initiation and dose adjustments and at least annually: digoxin blood levels
Digoxin Summary
Beneficial for subset of patients!
Improves contractility, rhythm – good for the heart!
Outcomes – good for patient and institution! (does not improve survival)
Who should receive digoxin?
Optimized on ACE-I/ARB, beta blockers, and aldosterone antagonists + symptomatic
Atrial fibrillation with HFrEF
Systolic heart failure
Know appropriate initial doses and how/when to monitor digoxin levels
Safety! – drug interactions, adverse effects including toxicity
51
52
Agents that improve symptoms only
DIURETICS
53
Diuretics
Pharmacologic effects
Decreases volume overload which decreases preload
Mildly lowers blood pressure
May mildly increase heart rate
No direct effect on ventricular contractility
Who? Patients with HFrEF who have evidence of fluid retention unless contraindicated (Class I, LOE C)
Impact on outcomes
Improves symptoms
Improve exercise tolerance
Improve quality of life
NOT shown to improve survival
Diuretics – Loop Diuretics are Preferred
54
Know the Initial and Maximum Doses Agents
Initial Dose
Maximum Dose
Furosemide (Lasix)
20 mg to 40 mg daily
600 mg daily in divided doses
Bumetanide (Bumex)
0.5 mg to 1 mg daily or BID
10 mg daily in divided doses
Torsemide (Demadex)
10 mg to 20 mg daily
200 mg daily
Metolazone (Zaroxolyn)
2.5 mg taken 30 minutes before loop diuretic
10 mg (rare)
Titration strategies: Initiate at lowest effective dose Increase dose until urine output increases and weight decreases (-0.5 kg to 1 kg daily) May require BID dosing to maintain active diuresis and sustain weight loss Reduce dose if patient is not volume overloaded or if they are dry
55
Diuretics
Do NOT use as monotherapy!
Bioavailability differs among agents
Monitoring
Furosemide IV to PO conversion – 1:2 (e.g., 20 mg IV = 40 mg PO) Torsemide and bumetanide IV to PO conversion – 1:1 (e.g., 20 mg IV = 20 mg PO) Furosemide 40 mg PO = Bumetanide 1 mg = Torsemide 10 - 20 mg
Onset 15-60 minutes; peak effect within 3090 minutes
Baseline, 1-2 weeks following change in therapy, and periodically thereafter: BUN, SCr, electrolytes, and BP
Goal potassium > 4.0 mEq/L
Fluid status
Daily morning weights with minimum to no clothing
Contact health care provider if weight gain of 1 lb/day for several consecutive days OR 3-5 lbs/week
56
Diuretic Resistance
Causes
Advanced heart failure
Renal dysfunction
NSAIDs, thiazolidinediones (TZDs)
Hyponatremia
Hypotension
Lifestyle (e.g., fast food)
Metolazone to the rescue!
Inhibits sodium reabsorption at cortical diluting segment of nephron when sodium absorption blocked at ascending loop of Henle
Creates synergistic diuresis – can be profound (must monitor closely)
Preferred to thiazide diuretics – longer duration, does not reduce GFR
**Not typically used daily due to major electrolyte deficiencies**
Diuretics
57
Summary
Beneficial in volume overloaded patients!
Improves symptoms but not survival
Do not use as monotherapy for HF treatment
Bioavailability differs among agents
Diuretic resistance
Identify causes of diuretic resistance
Metolazone not typically used daily (major electrolyte deficiencies – potentially dangerous to patient!)
Patient education (e.g., monitoring fluid status)
58
Self-Assessment Question A patient with NYHA class III heart failure (EF ~37%) presents with symptoms of fluid overload. She complains of increased swelling causing pain with walking. The patient denies missed doses of metoprolol succinate, lisinopril, furosemide, and glimepiride. Additionally, she has been taking 10-12 tablets daily of Aleve for headache. Vitals: BP 142/92, HR 67.
Which of the following is likely contributing to her symptoms? A.
Hypotension
B.
Glimepiride
C.
Nonadherence
D.
NSAIDs
59
Self-Assessment Question Which of the following agents reduce hospitalizations for patients with heart failure? I. Digoxin
II. Diuretics
I only B. II only C. I and II only D. I, II, and IV only E. I, III, and IV only A.
III. Ivabradine
IV. Sacubitril/valsartan
60
Summary of Available Agents Drug Class
Who Receives It?
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression ACEi or ARB
All patients with reduced EF unless contraindication
Beta-blockers
All patients with reduced EF unless contraindication
Aldosterone antagonists
Patients with reduced EF who are symptomatic and meet other criteria
Hydralazine/nitrate
Black patients with reduced EF who are symptomatic despite optimized doses of lifesaving agents
Ivabradine
Patients with reduced EF who are symptomatic on maximum tolerated beta-blocker dose
Sacubitril/valsartan (ARNI)
Patients with reduced EF who are symptomatic and can tolerate ACEi or ARB
Digoxin
Patients with low EF who continue to require hospitalization despite taking optimized doses of life-saving agents Agents that improve symptoms only
Diuretics
Patients with congestive symptoms
Deleterious Medications in HF
NSAID and COX-2 Inhibitor – fluid retention
Metformin – lactic acidosis
TZD – fluid retention
Non-DHP CCB – weakens ventricular contraction (negative inotrope)
TNFα antagonist (e.g., anti-rheumatic “mabs”) – increase mortality and hospitalizations
Serotonin agonist (e.g., “triptans”) – increases afterload
61
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Non-Pharmacological Management
Dietary Modification
Risk Factor Reduction
Sodium restriction: 2 g/day
Smoking cessation
Fluid restriction: 2 L/day (from all sources)
Manage hyperlipidemia, hypertension, and endocrine conditions (e.g., diabetes, thyroid)
Immunizations
Physical activity as tolerated
Weight reduction if overweight
Not necessary in all patients
63
Treatment Algorithms for HFrEF: Stages A-C* Remember that heart failure is a combination of STRUCTURAL DISEASE and SYMPTOMS
*Stage D = will be taught in acute decompensated heart failure
64
Treatment Algorithm: Stages A and B • Stage A: Patient is AT RISK for heart failure (no structural disease or symptoms) • Stage B: Patient has structural disease but does not have symptoms
65
Treatment Algorithm: Stage C • Stage C: Patient has both structural disease and symptoms (most patients are in this stage)
66
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Evidence-Based Pharmacotherapy for HFpEF Recommendations
Recommendation Grade
Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines
B
Diuretics should be used for relief of symptoms due to volume overload
C
Use of beta-blocking agents, ACEi, and ARBs for hypertension in HFpEF
C
ARBs might be considered to decrease hospitalizations in HFpEF
C
Nutritional supplementation is not recommended in HFpEF
C
Strength of recommendations: A, randomized controlled clinical trials; B, cohort and case control studies based on observations from observational studies or registries, post hoc, subgroup, and metaanalysis; C, expert opinion, epidemiologic findings from observational studies, and safety findings from large-scale use.
68
Self-Assessment Question PB is a 68 yo white male with HTN and heart failure (EF 25%). He is newly diagnosed and taking furosemide 20 mg BID. He presents to the clinic with 2 kg weight gain and increasing SOB within the last week, including SOB with minimal exertion. Labs are within normal limits. BP 130/70, HR 78 What is the most accurate staging for his heart failure? A. B. C. D.
ACCF/AHA Stage B, NYHA Class I ACCF/AHA Stage C, NYHA Class II ACCF/AHA Stage C, NYHA Class III ACCF/AHA Stage D, NYHA Class IV
69
Self-Assessment Question PB is a 68 yo white male with HTN and heart failure (EF 25%). He is newly diagnosed and taking furosemide 20 mg BID. He presents to the clinic with 2 kg weight gain and increasing SOB within the last week, including SOB with minimal exertion. Labs are within normal limits. BP 130/70, HR 78 In addition to increasing his furosemide dose, which of the following should be initiated at today’s visit? A. Digoxin 0.125 mg daily B. Lisinopril 5 mg daily C. Metoprolol succinate 12.5 mg daily D. Spironolactone 25 mg daily
70
Self-Assessment Question JK is a 45 yo black male with ACCF/AHA Stage C, NYHA Class II heart failure (EF 25%). He takes lisinopril 10 mg daily and furosemide 20 mg BID. Physical exam is unchanged from baseline. BP 156/89, HR 68. Which of the following is the best intervention to make today? Increase lisinopril to 40 mg daily B. Initiate BiDil 1 tablet TID C. Initiate metoprolol succinate 12.5 mg daily D. Initiate spironolactone 12.5 mg daily A.
71
Self-Assessment Question TJ is a 56 yo white male with atrial fibrillation and ACCF/AHA Stage C, NYHA Class III heart failure (EF 30%). He takes ramipril 10 mg daily, metoprolol succinate 200 mg daily, and furosemide 20 mg daily. He remains symptomatic despite the above treatment. Labs and vitals are within normal limits. Which of the following is the best therapy to initiate today? A.
Candesartan 32 mg daily
B.
Digoxin 0.125 mg daily
C.
BiDil 1 tablet TID
D.
Spironolactone 25 mg daily
72
Self-Assessment Question PJ is a 55 yo black female with ACCF/AHA Stage C, NYHA Class III heart failure (EF 20%), HTN, and CKD Stage IV. She takes lisinopril 40 mg daily, carvedilol 50 mg BID, amlodipine 10 mg daily, and furosemide 40 mg daily. Physical exam is unchanged from baseline. BP 132/75, HR 62. This patient would greatly benefit from which of the following therapies? A.
Increasing furosemide dose
B.
Initiating eplerenone
C.
Initiating hydralazine/ISDN
D.
Initiating ivabradine
3 to 6 months later on optimal therapy… Therapy is stabilized. What to do next?
73
Assess response to therapy and cardiac remodeling
Repeat lab tests including BNP/NT-proBNP and BMP
Repeat echocardiogram
Repeat EKG
FYI - Consider referral to electrophysiology for cardiac resynchronization therapy (CRT) or implantable cardioverter (ICD)
74
Key Points for Chronic HF Therapy
Chronic HF treatment should include appropriate doses of ACEi and beta-blocker unless the patient has contraindications
Symptomatic fluid overload is treated with loop diuretics (do not give loop diuretics as monotherapy)
Patients with symptomatic HF (NYHA class II-IV) on standard therapy should be given an aldosterone antagonist unless the patient has contraindications (CrCl < 30 mL/min, K > 5.0 mEq/L)
Digoxin should be reserved for patients with systolic HF on optimized standard therapy who remain symptomatic unless the patient has contraindications
75
Key Points for Chronic HF Therapy
Black patients should be on appropriately titrated ACEi and beta-blocker +/- aldosterone antagonist
Once on stable doses, black patients should be started on hydralazine and ISDN combination
Emerging therapies include ivabradine and sacubitril/valsartan Closely monitor all medications for safety and effectiveness (before and during treatment)
Laboratory monitoring
Blood pressure
Heart rate
Volume overload symptoms
Medication reconciliation - look for dangerous medications (e.g., NSAIDs, COX-2 inhibitors, TZD) Counsel patients on non-pharmacologic management of HF
76
Tips for Exam Preparation
Systematic approach to patient cases What is the patient’s staging (ACCF/AHA) and presentation (NYHA)? Are they on appropriate medications? If not, are there any contraindications or precautions to starting therapy?
If you want to start a medication Is this appropriate for this patient? Do they need to be at max doses and/or on standard therapy before starting this
medication? What do we need to monitor for safety and efficacy of drug therapy?
2
Learning Objectives 1.
Justify the role of therapies used in chronic HF management, including pharmacologic effects, place in therapy, and impact on outcomes.
2.
Recall initial and target dosing of heart failure medications based on most recently revised guidelines by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and literature supporting these recommendations.
3.
Discuss causes and management of diuretic resistance.
4.
Discuss the efficacy, safety, and patient education relevant to each therapy used in management of HF.
5.
Identify and discuss medications not recommended in heart failure patients.
6.
Provide evidence-based, patient-centered recommendations to optimize efficacy and tolerability of treatment regimens in patients with HF.
Review of Pathophysiology: Types of HF HFpEF – HF with Preserved Ejection Fraction • Referred as diastolic HF • Condition in which myocardial relaxation and filling are impaired and incomplete and/or increased diastolic stiffness • Characterized by signs and symptoms of HF with preserved LVEF defined as 50% or greater HFrEF – HF with Reduced Ejection Fraction • Referred as systolic HF • Ventricle too weak to pump sufficient blood for adequate perfusion • Characterized by signs and symptoms of HF and reduced LVEF defined as 40% or less KNOW DEFINITIONS OF HFpEF and HFrEF (e.g., EF cutoffs)
3
4
Review of Pathophysiology: Clinical Presentation
Fatigue Activity limitation Chest congestion
Edema or ankle swelling Shortness of breath
5
Review of Pathophysiology: Classification of HF (1 of 2) ACCF/AHA used to evaluate HF progression
NYHA used to classify symptoms according to clinician’s assessment
ACCF/AHA Classification
NYHA Functional Class
Stage A
B
Description At high risk for heart failure but without structural heart disease or symptoms of HF Structural heart disease but without symptoms of HF
Class
Description
No comparable functional class I
No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
ACCF/AHA Classification Stage
Description Structural heart disease with prior or current symptoms of HF
NYHA Functional Class Class
Description
I
No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.
III
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.
C
IV
D
Refractory HF requiring specialized interventions
IV
Unable to carry out any physical activity without symptoms of HF, or symptoms of HF at rest. Unable to carry out any physical activity without symptoms of HF, or symptoms of HF at rest.
6
CLASSIFICATION OF HF (2 OF 2)
7
Desired Outcomes
Improve patient’s quality of life (reduce morbidity) Relieve or reduce symptoms
Prevent or minimize hospitalizations for exacerbations of HF
Slow progression of disease
Prolong survival (reduce mortality)
8
Guidelines
2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Management of Heart Failure 2017 Focused Update
Numerous large, randomized, double-blinded, multi-center trials guide treatment options in HFrEF (refer to handout)
No randomized trials conducted in HFpEF
9
Overview of Available Agents Drug Class
Who Receives It?
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression ACEi or ARB
All patients with reduced EF unless contraindication
Beta-blockers
All patients with reduced EF unless contraindication
Aldosterone antagonists
Patients with reduced EF who are symptomatic and meet other criteria
Hydralazine/nitrate
Black patients with reduced EF who are symptomatic despite optimized doses of lifesaving agents
Ivabradine
Patients with reduced EF who are symptomatic on maximum tolerated beta-blocker dose
Sacubitril/valsartan (ARNI)
Patients with reduced EF who are symptomatic and can tolerate ACEi or ARB
Digoxin
Patients with low EF who continue to require hospitalization despite taking optimized doses of life-saving agents Agents that improve symptoms only
Diuretics
Patients with congestive symptoms
Same Drugs, Different Disease State!
For each medication class, please know: Why the drug has a role in HF therapy Pharmacologic effects
Who the drug should be given to
What is the impact of this drug on outcomes Which agents to use (not all agents are equal) How the drug should be used and monitored
Initial and target doses; how to titrate
10
11
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression
ANGIOTENSIN CONVERTING ENZYME INHIBITOR (ACEI) ANGIOTENSIN RECEPTOR BLOCKER (ARB) BETA-ADRENERGIC ANTAGONIST (BETA-BLOCKER)
ALDOSTERONE ANTAGONISTS HYDRALAZINE AND NITRATE COMBO IVABRADINE ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)
DIGOXIN
12
ACE Inhibitors
Pharmacologic effect
Lowers BP which decreases afterload
Decreases production of angiotensin II
Who? All stable patients with HFrEF unless contraindicated (Class I, LOE A)
Impact on outcomes
Slows HF progression
Reduces ventricular remodeling
Improves survival
Lowers aldosterone levels which decreases preload
Reduces rate of hospitalizations
Slows HF progression
Reduces rate of reinfarction
Increases bradykinin (vasodilator) which decreases afterload but causes ADE
13
ACE Inhibitors - Class Effect
Need to know initial and target doses Agent
Initial Dose
Target Dose
Captopril (Captoten)
6.25 mg TID
50 mg TID
Enalapril (Vasotec)
2.5 mg BID
At least 10 mg BID; preferred 20 mg BID
Lisinopril (Prinivil, Zestril)
2.5 mg or 5 mg daily
20 mg to 40 mg daily
Ramipril (Altace)
1.25 mg daily
10 mg daily
Titration strategy: Start low! Consider increasing dose every 2 weeks until target or max tolerated dose is reached Intensification usually takes 2-4 months with appropriate follow-up Agents are often under-used and under-dosed
14
ACE Inhibitors
Adverse Effects
Contraindications
Angioedema (potentially fatal)
Serum creatinine > 3.0 mg/dL
Hyperkalemia
History of angioedema or hyperkalemia
Cough
Bilateral renal stenosis
Renal dysfunction
Severe aortic stenosis
Hypotension (dizziness, syncope, lightheadedness)
Pregnancy
Rash
Taste disturbance
Labile BP and hypotension (increases risk of cardiogenic shock
ACE Inhibitors
15
Monitoring
Safety
Baseline: BUN, SCr, potassium, and BP
Follow-up within 1-2 weeks from initiation or dose adjustment: BUN, SCr, potassium, and BP
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
ACE Inhibitors
16
Summary
Very beneficial treatment for all HF patients unless contraindicated!
Decreases afterload and preload; reverses remodeling – good for the heart!
Outcomes – good for the institution and patient!
Extensively studied in patients with reduced EF
Start low and titrate slow to reach target or max tolerated dose
Important to monitor safety (e.g., symptoms, labs) especially during titration
17
ARBs
Pharmacologic effects
Who?
Lowers BP which decreases afterload
Blocks effects of angiotensin II on angiotensin receptor subtype 1 (AR1)
Patients with HFrEF who are unable to tolerate ACEi (Class I, LOE A)
Reasonable alternative to ACEi as first-line therapy in HFrEF in patients already taking ARBs for other indications (Class IIa, LOE A)
Useful due to ACE escape! ACE inhibitors incompletely block the formation of angiotensin II
Attenuates deleterious effects of angiotensin II on ventricular remodeling
Less accumulation of bradykinin which lowers risk of ADE
Similar clinical benefits and potentially fewer ADE compared to ACEi
Impact on outcomes
Improves survival
Reduces hospitalization
Slows HF progression
18
ARBs – Not a Class Effect! Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Valsartan (Diovan)
40 mg BID
160 mg BID
Candesartan (Atacand)
4 or 8 mg daily
32 mg daily
Losartan (Cozaar)
25 mg daily
50 mg to 150 mg daily
Titration strategy: Start low! Consider increasing dose every 2 weeks until target or max tolerated dose Intensification usually takes 2-4 months with appropriate follow-up
19
ARBs
Adverse effects
Similar to ACEi but have have different frequency
Lower incidence of cough
Monitoring
Baseline: BUN, SCr, potassium, and BP
Follow-up within 1-2 weeks from initiation or dose adjustment: BUN, SCr, potassium, and BP
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
ARBs
20
Summary
Similar clinical benefits as ACEi – good for the heart, patient, and institution!
Use in patients who cannot tolerate ACEi
Titrate to target dose or max tolerated dose – Know selected agents since there is not a class effect
Adverse effects similar to ACEi but with different frequencies
Important to monitor safety (e.g., symptoms, labs) especially during titration
21
Beta-Blockers
Pharmacologic effects
Who? All stable patients with HFrEF unless contraindicated (Class I, LOE A)
Impact on outcomes
Slows heart rate and lowers BP
Decreases work load on heart
Increases ventricular filling which improves CO
Short term (e.g., during titration): decreases force of contraction of the heart
Long term (e.g., after 3 months): improves ventricular contractility
Anti-arrhythmic properties
Blocks effects of NE
Improves survival
Reduces hospitalization
Slows HF progression
Beta-Blockers – Not a Class Effect!
22
Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Carvedilol • Immediate Release (Coreg) • Controlled Release (Coreg CR)
3.125 mg BID 10 mg daily
25 mg BID if < 85 kg; 50 mg BID if > 85 kg 80 mg daily
Metoprolol succinate (Toprol XL)*
12.5 mg daily
200 mg daily
Bisoprolol (off-label use)
1.25 mg daily
10 mg daily
*Metoprolol tartrate (Lopressor) has not been shown to be beneficial in HF therapy Both carvedilol formulations should be taken with food Metoprolol succinate tablets are scored and can be cut (not crushed or chewed)
Beta-Blockers
23
Initiation and Titration
Initiation
Do NOT start in patients who are hospitalized in ICU or recently required IV inotropic support
Only in stable patients who have no or minimal evidence of fluid overload
Beta-blockers should still be given even if symptoms are mild or well-controlled with ACEi +/- diuretic
ACEi dose does not have to be optimized prior to starting a beta-blocker – Addition of beta-blocker is likely to be of greater benefit than increasing ACEi alone
Dose Titration
Start low and titrate slowly to target dose – Beta-blockers are harder to tolerate due to effects on HR, BP, and symptoms such as fatigue
Consider increasing dose every 2 weeks if no evidence of clinically significant worsening HF and if vitals are stable
Intensification may be delayed if HF symptoms worsen
24
Beta-Blockers
Adverse effects
Symptoms may worsen initially – should be mild to continue beta-blockers
Fatigue
Depression
Drug interactions
Additive effects with other drugs that reduce HR (e.g., digoxin, verapamil) Additive effects with other drugs that reduce BP
Contraindications and precautions
Decompensated heart failure
Can worsen heart failure if not started and titrated appropriately
Slows HR and decreases force of contraction
Bradycardia (HR < 60 bpm)
Hypotension (e.g., SBP < 80 mm Hg)
Sick sinus syndrome
2nd or 3rd degree AV block
Pulmonary disease (beta-blocker selectivity)
Hemodynamic instability
Fluid overloaded
Beta-Blockers Monitoring
Safety
Monitor for ADE within 1-2 weeks of initiation and dose adjustments and then periodically once stabilized on a dose
BP, HR, and signs of congestion
Efficacy
Symptoms
Imaging: usually after ~3 months of optimal therapy or stabilization to assess evidence of reverse remodeling
25
Beta-Blockers
26
Summary
Very beneficial treatment for all HF patients unless contraindicated!
Decreases afterload, reverse remodeling – good for the heart!
Outcomes – good for patient and institution!
Initiate in stable patients (do not use in acute decompensated heart failure) regardless of whether ACEi therapy is optimized
Starting low with slow titration is especially important for this medication class
Important to monitor safety (e.g., BP, HR) and tolerance with initiation and titration
Patient education is key to adherence and long term benefits of therapy
27
Aldosterone Antagonist a.k.a. Mineralocorticoid Receptor Antagonist (MRA)
Pharmacologic effects
Mildly lowers BP
Inhibits cardiac extracellular matrix and collagen deposition
Attenuates cardiac fibrosis and ventricular remodeling
Who? Refer to next slide
Impact on outcomes
Improves survival
Slows HF progression
No direct effect on heart rate or contractility
Improves symptoms
Weak diuretic at low doses
Reduces hospitalizations
Potassium-sparing which contributes to mortality benefit
28
Aldosterone Antagonist Who should be taking this?
Population 1
Patients with NYHA class II-IV HF with LVEF ≤ 35% unless contraindicated (Class I, LOE A)
Patients with NYHA class II HF should have history of cardiovascular hospitalization or elevated plasma natriuretic peptide levels
On standard therapy (e.g., ACEi, beta-blocker) which do not have to be optimized before MRA initiation
Scr should be ≤ 2.5 mg/dL in men or ≤ 2.0 mg/dL in women (or estimated GFR > 30 mL/min/1.722)
Potassium should be < 5.0 mEq/L
Population 2
Following an acute MI in patients who have LVEF ≤ 40% who develop symptoms of HF or who have a history of diabetes unless contraindicated
Consider use of eplerenone
Do NOT use in patients using ACEi and ARB concurrently (Class III, LOE C)
29
Aldosterone Antagonist Need to Know Initial and Target Doses Agents
Initial Dose
Target Dose
Spironolactone (Aldactone)*
12.5 mg to 25 mg daily
50 mg daily if no ADE with progression of HF
Eplerenone (Inspra)
25 mg daily
50 mg daily
*Renal dose adjustments exist since decreased clearance will result in hyperkalemia Titration strategies: Consider increasing dose at least every 2 weeks until target or max tolerated dose is reached
30
Aldosterone Antagonist
Adverse effects
Gynecomastia – higher incidence with spironolactone
Hyperkalemia
Hyponatremia
Contraindications
Spironolactone
Anuria
CrCl < 10 mL/min
Hyperkalemia
Potassium supplements and potassium-sparing diuretics
Monitoring
Baseline: BUN, SCr, potassium
Above labs 2-3 days after initiation and then 7 days after initiation or titration
Check monthly for 3 months and then every 3 months afterward
Eplerenone
CrCl < 30 mL/min for all patients
CrCl < 50 mL/min in patients with elevated SCr > 1.8 mg/dL in women or > 2.0 mg/dL in men
T2DM with microalbuminuria
Aldosterone Antagonist
31
Summary
Beneficial medication for certain patients!
Slows progression of HF (inhibition of cardiac fibrosis) – good for the heart!
Outcomes – good for patient and institution!
Understand the place in therapy compared to ACEi and beta-blockers
Know which patients to avoid in (think contraindications/precautions)
Important to monitor renal function and potassium levels soon after initiation or dose modification – They will RAPIDLY CHANGE potassium levels
Hydralazine and ISDN Combination
Pharmacologic effects
Nitrate is venodilator that reduces preload
Hydralazine is an arterial dilator that reduces afterload
Impact on outcomes (black patients)
Reduces mortality
Reduces hospitalizations
Improves quality of life
Potentially slows HF progression
32
Who? Combination of hydralazine and isosorbide dinitrate (ISDN) recommended for black patients with HFrEF who remain symptomatic despite optimization of ACEi and beta-blockers (Class I, LOE A)
Who else? Patients with prior or current symptoms of HFrEF who cannot be given ACEi or ARB (Class IIa, LOE B)
33
Hydralazine and ISDN Combination Know the Initial and Target Doses Agents
Fixed Dose Combination • Hydralazine 37.5 mg and ISDN 20 mg (BiDil) Individual Medications • Hydralazine • ISDN
Initial Dose 1 tablet TID
Target Dose 2 tablets TID
25 mg to 50 mg TID 300 mg daily in divided doses 20 mg to 30 mg TID or four times daily 120 mg daily in divided doses
Titration Strategies: Select initial doses either as fixed dose combination or individual medications Consider increasing hydralazine and/or ISDN every 2 weeks until target or max tolerated dose is reached
34
Hydralazine and ISDN Combination
Nitrate-free interval
Repeated administration of nitrates results in smooth muscle relaxation in blood vessels, tolerances, and unwanted ADE
Tolerance develops quickly but wears off after a brief nitrate-free interval E.g., Minimum 12-hour nitrate-free interval in a 24-hour period
Adverse effects
Hypotension
Headache
Monitoring
Tolerability
Baseline: BP and HR
Follow-up: BP and HR after initiation and during titration
Hydralazine and ISDN Combination Summary
Beneficial in a subset of patients!
Decreases preload and afterload – good for the heart!
Outcomes – good for black patients (some benefits in non-black populations) and the institution!
Who should receive?
Black patients with symptomatic HFrEF despite optimal standard therapy
Patients with HFrEF who are intolerant to ACEi or ARB
Medication adherence
Pill burden
Nitrate-free interval
Tolerability of adverse effects
35
36
Self-Assessment Question We have now discussed well-established therapies that are proven to slow progression of heart failure and improve survival. Which of the following agents are recommended in ALL stable heart failure patients? I. ACE inhibitor A.
I only
B.
II only
C.
I and II only
D.
I, II, and III only
E.
I, II, III, and IV
II. Beta-blocker
III. MRA
IV. Hydralazine/ISDN
37
Ivabradine
Pharmacologic effects
Reduces heart rate at rest and during exercise in patients in sinus rhythm
Maintains myocardial contractility and atrioventricular conduction
Who? Stable, symptomatic HF with all of the below (Class IIa, LOE B-R):
EF ≤ 35%
In sinus rhythm with resting heart rate ≥ 70 bpm
Either on max tolerated dose of betablocker or have a contraindication to beta-blocker use
On standard therapy (e.g., beta-blocker, ACEi or ARB, MRA)
Persistent symptoms (NYHA class II-IV)
Impact on outcomes
Reduces hospitalizations
Ivabradine
38
Dosing and Administration
Brand name only (Corlanor); take with meals
Initial dose: 5 mg BID in patients < 75 years old
Reduced initial dose of 2.5 mg BID in patients ≥ 75 years old, who has history of conduction defects, or who may experience hemodynamic compromise due to bradycardia
Max dose: 7.5 mg BID
Titration strategies:
After 2 weeks, adjust dose to achieve resting HR between 50 bpm and 60 bpm
Thereafter, adjust dose as needed based on resting HR and tolerability
Discontinue or decrease dose if HR < 50 bpm or s/sx of bradycardia
39
Ivabradine
Adverse effects
Contraindications
Bradycardia
Acute decompensated heart failure
Hypertension
Severe liver impairment
Atrial fibrillation
BP < 90/50 mm Hg
Luminous visual phenomena
Resting HR < 60 bpm
HR solely maintained by pacemaker
Sick sinus syndrome
Pregnancy
Fetal harm may occur
Sinoatrial block
Effective contraception is recommended in women of reproductive potential
Third degree AV block
Strong inhibitors of CYP3A4
40
Ivabradine SHIFT Trial •
Patients randomized to ivabradine titrated to 7.5 mg BID or placebo
•
Reduced hospital admissions for worsening HF in ivabradine group
•
Did not reduce CV death in ivabradine group
•
More bradycardia vs placebo
•
Average 15 bpm reduction in HR in addition to optimal therapy
Ivabradine Summary
Beneficial in a certain subset of HFrEF patients
Reduces hospitalization but NOT mortality
Relatively new agent that lacks long-term safety and efficacy data
Caution due to a number of contraindications and potentially severe ADE
Dose is adjusted based on HR – Main monitoring parameter
41
42
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
Pharmacologic effects
Vasodilation
Decreases sympathetic tone
Decreases aldosterone levels
Decreases fibrosis
Decreases hypertrophy
Decreases blood pressure
Natriuresis and diuresis
Who? Patients with symptomatic HFrEF who tolerate an ACEi or ARB
Replacement by an ARNI is recommended to further reduce morbidity and mortality (Class I, LOE B-R)
Impact on outcomes
Reduces hospitalizations
Reduces cardiovascular death
Equivalent to ≤ 10 mg BID of enalapril or ≤ 160 mg daily of valsartan
43
ARNI Dosing and Administration • Sacubitril/valsartan (Entresto) is only available as branded fixed dose combination tablet • Also initiate at lower dose in patients with severe renal impairment • Should not be administered with ACEi or within 36 hours of last ACEi dose • Assess tolerability in 2-4 weeks after initiation; If possible, then increase stepwise increase dose to target • Monitoring • BUN, SCr, electrolytes, and BP at baseline, after initiation, and during titration
44
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
Adverse effects
Contraindications
Hypotension
Hypersensitivity
Hyperkalemia
Cough
History of angioedema related to previous ACEi or ARB therapy
Renal impairment
Concomitant use with ACEi
Angioedema
Concomitant use with aliskiren (Tekturna) in patients with diabetes
Special populations
Drug interactions
Lactation: discontinue drug or breastfeeding
Do not use with ACEi, ARB, or aliskiren
Do not use in severe hepatic impairment
Potassium-sparing diuretics – elevated potassium
Lithium – increased risk of lithium toxicity
NSAIDs – increased risk of renal impairment
45
ARNI PARADIGM-HF Trial •
Designed to replace ACEi and ARB as cornerstone of HF therapy
•
Patients randomized to enalapril 10 mg BID or sacubitril/valsartan 200 mg BID
•
Reduction in composite of death from CV causes or a first hospitalization for worsening HF
•
Less cough and lesser incidence of increased SCr > 2.5 mg/dL
•
Study prematurely stopped due to lower CV mortality seen in intervention arm by prespecified interim analysis
46
Angiotensin Receptor-Neprilysin Inhibitor (ANRI)
Outcomes – good for both patients and the institution!
Based on new clinical trial data, the ACCF/AHA guidelines support replacing ACEi or ARB therapy with ARNI to further reduce morbidity and mortality
Used in conjunction with beta-blockers and aldosterone antagonists in selected patients
This has not translated to clinical practice due to the cost/availability of Entresto
Unique instructions for selecting the initial dose and titrating
47
Digoxin
Pharmacologic effects
Slows heart rate which increases AV nodal refractoriness (this is good for atrial fibrillation) Increases ventricular force of contraction (this is good for HF)
Who? Patients with HFrEF who have symptoms despite optimized standard therapy (Class I, LOE B) Primarily in systolic HF Concomitant atrial fibrillation
Impact on outcomes Improves symptoms and exercise tolerance Reduces hospitalizations Does NOT improve survival
48
Digoxin Dosing and Administration
Most patients will need 0.125 mg to 0.25 mg daily
Lower initial dose (0.125 mg daily or every other day) for certain patient populations
Elderly patients (> 70 years)
Patients with renal dysfunction
Low lean body mass
Patients with interacting drugs (e.g., amiodarone)
Loading doses of digoxin generally not needed in chronic HF
Narrow therapeutic range
Monitor blood levels (goal 0.5 to 0.9 ng/mL)
Levels may be different for various disease states
Not necessary to monitor routinely unless suspecting toxicity, worsening renal function, drug interactions, or other conditions that may affect levels
Toxicity (see next slide on Adverse Effects)
Hypokalemia, hypomagnesemia, hypercalcemia
49
Digoxin Adverse Effects Non-Cardiac • Anorexia, nausea, vomiting, abdominal pain • Visual disturbances • Halos, photophobia, problems with color perception (yellow-green, redgreen), scotomata • Fatigue, weakness, dizziness, headache, neuralgia, confusion, delirium, psychosis
Cardiac • Ventricular arrhythmias • Premature ventricular depolarizations, bigeminy, trigeminy, ventricular tachycardia, ventricular fibrillation • Atrioventricular (A-V) block • First degree, second degree, third degree block • Atrial arrhythmias • Sinus bradycardia • Potassium abnormalities
50
Digoxin Drug Interactions
Pharmacokinetic
Digoxin is a substrate of p-glycoprotein (P-gp)
Inhibitors of P-gp include amiodarone, diltizem, verapamil
Pharmacodynamic
Drugs affecting HR: verapamil, diltiazem, betablockers, amiodarone
Drugs affecting potassium levels: diuretics, ACEi, aldosterone antagonists
Miscellaneous
Antacids decrease digoxin absorption
Licorice interferes with digoxin assay
Monitoring
Baseline and 1-2 weeks of initiation: HR, symptoms, BUN, SCr, potassium
Within 2 weeks of initiation and dose adjustments and at least annually: digoxin blood levels
Digoxin Summary
Beneficial for subset of patients!
Improves contractility, rhythm – good for the heart!
Outcomes – good for patient and institution! (does not improve survival)
Who should receive digoxin?
Optimized on ACE-I/ARB, beta blockers, and aldosterone antagonists + symptomatic
Atrial fibrillation with HFrEF
Systolic heart failure
Know appropriate initial doses and how/when to monitor digoxin levels
Safety! – drug interactions, adverse effects including toxicity
51
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Agents that improve symptoms only
DIURETICS
53
Diuretics
Pharmacologic effects
Decreases volume overload which decreases preload
Mildly lowers blood pressure
May mildly increase heart rate
No direct effect on ventricular contractility
Who? Patients with HFrEF who have evidence of fluid retention unless contraindicated (Class I, LOE C)
Impact on outcomes
Improves symptoms
Improve exercise tolerance
Improve quality of life
NOT shown to improve survival
Diuretics – Loop Diuretics are Preferred
54
Know the Initial and Maximum Doses Agents
Initial Dose
Maximum Dose
Furosemide (Lasix)
20 mg to 40 mg daily
600 mg daily in divided doses
Bumetanide (Bumex)
0.5 mg to 1 mg daily or BID
10 mg daily in divided doses
Torsemide (Demadex)
10 mg to 20 mg daily
200 mg daily
Metolazone (Zaroxolyn)
2.5 mg taken 30 minutes before loop diuretic
10 mg (rare)
Titration strategies: Initiate at lowest effective dose Increase dose until urine output increases and weight decreases (-0.5 kg to 1 kg daily) May require BID dosing to maintain active diuresis and sustain weight loss Reduce dose if patient is not volume overloaded or if they are dry
55
Diuretics
Do NOT use as monotherapy!
Bioavailability differs among agents
Monitoring
Furosemide IV to PO conversion – 1:2 (e.g., 20 mg IV = 40 mg PO) Torsemide and bumetanide IV to PO conversion – 1:1 (e.g., 20 mg IV = 20 mg PO) Furosemide 40 mg PO = Bumetanide 1 mg = Torsemide 10 - 20 mg
Onset 15-60 minutes; peak effect within 3090 minutes
Baseline, 1-2 weeks following change in therapy, and periodically thereafter: BUN, SCr, electrolytes, and BP
Goal potassium > 4.0 mEq/L
Fluid status
Daily morning weights with minimum to no clothing
Contact health care provider if weight gain of 1 lb/day for several consecutive days OR 3-5 lbs/week
56
Diuretic Resistance
Causes
Advanced heart failure
Renal dysfunction
NSAIDs, thiazolidinediones (TZDs)
Hyponatremia
Hypotension
Lifestyle (e.g., fast food)
Metolazone to the rescue!
Inhibits sodium reabsorption at cortical diluting segment of nephron when sodium absorption blocked at ascending loop of Henle
Creates synergistic diuresis – can be profound (must monitor closely)
Preferred to thiazide diuretics – longer duration, does not reduce GFR
**Not typically used daily due to major electrolyte deficiencies**
Diuretics
57
Summary
Beneficial in volume overloaded patients!
Improves symptoms but not survival
Do not use as monotherapy for HF treatment
Bioavailability differs among agents
Diuretic resistance
Identify causes of diuretic resistance
Metolazone not typically used daily (major electrolyte deficiencies – potentially dangerous to patient!)
Patient education (e.g., monitoring fluid status)
58
Self-Assessment Question A patient with NYHA class III heart failure (EF ~37%) presents with symptoms of fluid overload. She complains of increased swelling causing pain with walking. The patient denies missed doses of metoprolol succinate, lisinopril, furosemide, and glimepiride. Additionally, she has been taking 10-12 tablets daily of Aleve for headache. Vitals: BP 142/92, HR 67.
Which of the following is likely contributing to her symptoms? A.
Hypotension
B.
Glimepiride
C.
Nonadherence
D.
NSAIDs
59
Self-Assessment Question Which of the following agents reduce hospitalizations for patients with heart failure? I. Digoxin
II. Diuretics
I only B. II only C. I and II only D. I, II, and IV only E. I, III, and IV only A.
III. Ivabradine
IV. Sacubitril/valsartan
60
Summary of Available Agents Drug Class
Who Receives It?
Agents that reduce hospitalizations, reduce deaths, or interrupt disease progression ACEi or ARB
All patients with reduced EF unless contraindication
Beta-blockers
All patients with reduced EF unless contraindication
Aldosterone antagonists
Patients with reduced EF who are symptomatic and meet other criteria
Hydralazine/nitrate
Black patients with reduced EF who are symptomatic despite optimized doses of lifesaving agents
Ivabradine
Patients with reduced EF who are symptomatic on maximum tolerated beta-blocker dose
Sacubitril/valsartan (ARNI)
Patients with reduced EF who are symptomatic and can tolerate ACEi or ARB
Digoxin
Patients with low EF who continue to require hospitalization despite taking optimized doses of life-saving agents Agents that improve symptoms only
Diuretics
Patients with congestive symptoms
Deleterious Medications in HF
NSAID and COX-2 Inhibitor – fluid retention
Metformin – lactic acidosis
TZD – fluid retention
Non-DHP CCB – weakens ventricular contraction (negative inotrope)
TNFα antagonist (e.g., anti-rheumatic “mabs”) – increase mortality and hospitalizations
Serotonin agonist (e.g., “triptans”) – increases afterload
61
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Non-Pharmacological Management
Dietary Modification
Risk Factor Reduction
Sodium restriction: 2 g/day
Smoking cessation
Fluid restriction: 2 L/day (from all sources)
Manage hyperlipidemia, hypertension, and endocrine conditions (e.g., diabetes, thyroid)
Immunizations
Physical activity as tolerated
Weight reduction if overweight
Not necessary in all patients
63
Treatment Algorithms for HFrEF: Stages A-C* Remember that heart failure is a combination of STRUCTURAL DISEASE and SYMPTOMS
*Stage D = will be taught in acute decompensated heart failure
64
Treatment Algorithm: Stages A and B • Stage A: Patient is AT RISK for heart failure (no structural disease or symptoms) • Stage B: Patient has structural disease but does not have symptoms
65
Treatment Algorithm: Stage C • Stage C: Patient has both structural disease and symptoms (most patients are in this stage)
66
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Evidence-Based Pharmacotherapy for HFpEF Recommendations
Recommendation Grade
Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines
B
Diuretics should be used for relief of symptoms due to volume overload
C
Use of beta-blocking agents, ACEi, and ARBs for hypertension in HFpEF
C
ARBs might be considered to decrease hospitalizations in HFpEF
C
Nutritional supplementation is not recommended in HFpEF
C
Strength of recommendations: A, randomized controlled clinical trials; B, cohort and case control studies based on observations from observational studies or registries, post hoc, subgroup, and metaanalysis; C, expert opinion, epidemiologic findings from observational studies, and safety findings from large-scale use.
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Self-Assessment Question PB is a 68 yo white male with HTN and heart failure (EF 25%). He is newly diagnosed and taking furosemide 20 mg BID. He presents to the clinic with 2 kg weight gain and increasing SOB within the last week, including SOB with minimal exertion. Labs are within normal limits. BP 130/70, HR 78 What is the most accurate staging for his heart failure? A. B. C. D.
ACCF/AHA Stage B, NYHA Class I ACCF/AHA Stage C, NYHA Class II ACCF/AHA Stage C, NYHA Class III ACCF/AHA Stage D, NYHA Class IV
69
Self-Assessment Question PB is a 68 yo white male with HTN and heart failure (EF 25%). He is newly diagnosed and taking furosemide 20 mg BID. He presents to the clinic with 2 kg weight gain and increasing SOB within the last week, including SOB with minimal exertion. Labs are within normal limits. BP 130/70, HR 78 In addition to increasing his furosemide dose, which of the following should be initiated at today’s visit? A. Digoxin 0.125 mg daily B. Lisinopril 5 mg daily C. Metoprolol succinate 12.5 mg daily D. Spironolactone 25 mg daily
70
Self-Assessment Question JK is a 45 yo black male with ACCF/AHA Stage C, NYHA Class II heart failure (EF 25%). He takes lisinopril 10 mg daily and furosemide 20 mg BID. Physical exam is unchanged from baseline. BP 156/89, HR 68. Which of the following is the best intervention to make today? Increase lisinopril to 40 mg daily B. Initiate BiDil 1 tablet TID C. Initiate metoprolol succinate 12.5 mg daily D. Initiate spironolactone 12.5 mg daily A.
71
Self-Assessment Question TJ is a 56 yo white male with atrial fibrillation and ACCF/AHA Stage C, NYHA Class III heart failure (EF 30%). He takes ramipril 10 mg daily, metoprolol succinate 200 mg daily, and furosemide 20 mg daily. He remains symptomatic despite the above treatment. Labs and vitals are within normal limits. Which of the following is the best therapy to initiate today? A.
Candesartan 32 mg daily
B.
Digoxin 0.125 mg daily
C.
BiDil 1 tablet TID
D.
Spironolactone 25 mg daily
72
Self-Assessment Question PJ is a 55 yo black female with ACCF/AHA Stage C, NYHA Class III heart failure (EF 20%), HTN, and CKD Stage IV. She takes lisinopril 40 mg daily, carvedilol 50 mg BID, amlodipine 10 mg daily, and furosemide 40 mg daily. Physical exam is unchanged from baseline. BP 132/75, HR 62. This patient would greatly benefit from which of the following therapies? A.
Increasing furosemide dose
B.
Initiating eplerenone
C.
Initiating hydralazine/ISDN
D.
Initiating ivabradine
3 to 6 months later on optimal therapy… Therapy is stabilized. What to do next?
73
Assess response to therapy and cardiac remodeling
Repeat lab tests including BNP/NT-proBNP and BMP
Repeat echocardiogram
Repeat EKG
FYI - Consider referral to electrophysiology for cardiac resynchronization therapy (CRT) or implantable cardioverter (ICD)
74
Key Points for Chronic HF Therapy
Chronic HF treatment should include appropriate doses of ACEi and beta-blocker unless the patient has contraindications
Symptomatic fluid overload is treated with loop diuretics (do not give loop diuretics as monotherapy)
Patients with symptomatic HF (NYHA class II-IV) on standard therapy should be given an aldosterone antagonist unless the patient has contraindications (CrCl < 30 mL/min, K > 5.0 mEq/L)
Digoxin should be reserved for patients with systolic HF on optimized standard therapy who remain symptomatic unless the patient has contraindications
75
Key Points for Chronic HF Therapy
Black patients should be on appropriately titrated ACEi and beta-blocker +/- aldosterone antagonist
Once on stable doses, black patients should be started on hydralazine and ISDN combination
Emerging therapies include ivabradine and sacubitril/valsartan Closely monitor all medications for safety and effectiveness (before and during treatment)
Laboratory monitoring
Blood pressure
Heart rate
Volume overload symptoms
Medication reconciliation - look for dangerous medications (e.g., NSAIDs, COX-2 inhibitors, TZD) Counsel patients on non-pharmacologic management of HF
76
Tips for Exam Preparation
Systematic approach to patient cases What is the patient’s staging (ACCF/AHA) and presentation (NYHA)? Are they on appropriate medications? If not, are there any contraindications or precautions to starting therapy?
If you want to start a medication Is this appropriate for this patient? Do they need to be at max doses and/or on standard therapy before starting this
medication? What do we need to monitor for safety and efficacy of drug therapy?
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