Download Stage C – More on β

Chronic Heart Failure Part II
Stage C - Treatment - 42
• The measures listed as Class I recommendations for patients in stages A and B are also appropriate for
patients in stage C. These include ACEI/ARB and β-blockers
• Additional drug entities have been proven to improve survival and/or reduce hospitalizations and
symptoms.
★ They include: Aldosterone antagonists, Hydralazine/ISDN, and ACEI / ARB combination
• Must also consider symptom management with: Diuretics, and Digoxin
Stage C – More on ACEIs and ARBs - 43
• Additional agents have been studied specifically in patients with symptomatic HF
• Ace inhibitors causing more hyperkalemia over ARBs has not been shown clinically
• The elderly population of patients could consider Lisinopril 20 mg daily as a target dose.
• Patients with good renal function or continued high blood pressure my have a Target Dose of 40 mg,
BUT above this could cause adverse effects. Remember Target (optimal) Dose!
ACEI / ARB
Starting dose
Target dose
Lisinopril (ATLAS trial)
2.5 mg (elderly) 5 mg daily
35 mg daily (difficult to achieve)
Candesartan
8 mg daily
32 mg daily
★ Class IA - ACEIs are recommended for all patients with current or prior symptoms of HF and reduced
LVEF, unless contraindicated
★ Class IA - ARBs are recommended in patients with current or prior symptoms of HF and reduced LVEF
who are ACEI intolerant
Stage C - CHARM Trials - 44
• Three component trials comparing Candesartan to placebo (CHARM – alternative, added, and
Preserved)
• CHARM Alternative:
• LVEF ≤ 40%, ACEI intolerant, n = 2028 – This study included Candesartan versus Placebo
• Primary outcome: CV death or HF hospitalization
★ Results: Candesartan reduced the primary outcome by an absolute rate of 7% and RRR 23% making
this a reasonable option in patients with HFrEF IF they have an ACEI allergy
Stage C - HEALL trial - 46
• This new study compared Losartan 50 mg (which is NOT non-inferior to captopril) versus Losartan 150
mg. Patients who were ACEI intolerant were started on losartan 25 mg and titrated to either Losartan 50
mg versus Losartan 150 mg
• Losartan 150 mg daily reduced the primary outcome with a RRR of 10%
• Individual components separately showed no difference in all cause death between low-dose versus
high-dose, High-dose Losartan main effect was in reduction in hospitalization for HR
★ Heart failure experts typically will not use Losartan as an ARB alternative, but will go with candesartan
or valsartan based on evidence currently available.
Stage C – ARB plus ACEI - 47
• Class IIB - The addition of an ARB may be considered in persistently symptomatic patients with
reduced LVEF who are already being treated with conventional therapy.
• Concerns regarding dual RAAS inhibition include: ↑ SIDE EFFECTS!
• Hypotension, renal dysfunction (50% increase), hyperkalemia (3x increase)
• Place in therapy NYHA
1
★ On standard therapy with NYHA Class II or III and EF ≤ 40% it is then reasonable to add
candesartan 32 mg BID or valsartan 160 BID on top of standard therapy
Stage C – CHARM-added - 48
• Purpose to evaluate whether adding the ARB candesartan to ACEI therapy could improve clinical
outcome. Patients had LVEF ≤ 40%, ACEI treated, n=2548
• Results included a 15% relative risk reduction (RRR) in the primary outcome
• However, there was not a significant reduction in cardiovascular mortality in this study
★ The main effect was the reduction in hospitalizations for HF
Stage C – Val-HeFT - 49
• This study used valsartan in patients with symptomatic heart failure beyond standard therapy
• The study showed no reduction of all cause mortality
• There was also observed a significant reduction in hospitalizations for HF
★ There are complications with using an ACEI / ABR together AND there is a benefit in the terms of
reduction in hospitalizations for HF, BUT not in of decreasing mortality.
Stage C – More on β-blockers
• Additional agents have been studied specifically in patients with symptomatic HF
• Class IA - Use of 1 of the 3 beta blockers proven to reduce mortality ( e.g., bisoprolol, carvedilol, and
sustained release metoprolol succinate) is recommended for all stable patients with current or prior
symptoms of HF and reduced LVEF, unless contraindicated
• Other β-blockers recently studied not included in 2009 Guidelines are Nebivolol (SENIORS) and
Bucindolol (BEST) – Bucindolol is not available, but Nebivolol is only available for hypertension
Pharmacological Properties of β-blockers Utilized in Heart Failure - 51
• Metoprolol succinate is beta-1 selective up to a certain point; studies have suggested that doses above
100 mg is as nonselective as carvedilol (worsen asthma, and lung disease)
• Bisoprolol is beta-1 selective and better at lowering heart rate at equipotent doses compared to other beta
blockers
• Bucindolol is nonselective (not available)
• Carvedilol nonselective with alpha-1 blockage and suggested ancillary properties being an antioxidant as
well. However, this is yet to be proven
• Nebivolol is the most selective for the beta-1 receptors, and will potentiate nitric oxide (no FDA
approval for HF)
Primary Outcome in β-blocker Trials - 52
• Nebivolol in the SENIORS trial only showed a reduction in the primary outcome (CV death or HF
hospitalization) of only about 15%. However, other beta blockers Bisoprolol (CIBIS II), Metoprolol
succinate (MERIT-HF), Carvedilol
(COPERNICUS) showed a more substantial effect.
β-blockers and COPD - 53
• Observational studies have shown COPD is not a
contraindication for β-blocker use regardless of
severity
Effect of HF-Approved β-Blockers on Lung Function 54
• Another interesting study published in JACC 2010
was conducted to see if there was differences in lung function according to beta blocker. This is a
crossover study including carvedilol, bisoprolol, and metoprolol.
2
★ The study found that no patient decompensated into a COPD exacerbation, and it is safe to say that any
of these beta blockers can be used in patients with COPD. If the patient has severe COPD it may be
safer to focus on a beta-1 selective beta blocker
Target Doses for β-blockers - 56
Agent
Starting Dose
Target Dose <
85 kg
Target Dose >
85 kg
Bisoprolol
1.25 mg daily (1.25 mg not available in US)
5 mg daily
10 mg daily
Carvedilol
3.125 mg bid
25 mg bid
50 mg bid
Metoprolol XL
25 mg daily (NYHA Class II)
12.5 mg daily (NYHA Class III and IV)
200 mg daily
200 mg daily
Nebivolol
1.25 mg daily ( not FDA approved for HF)
10 mg daily
10 mg daily
Which medication do we start 1st ACEI or β-blocker? - 57
• Most patients admitted to the hospital for heart failure are discharged on both of these medications
• Most heart failure clinicians would use the Ace inhibitor first because this was the first medication
approved with mortality benefits, and then add beta blocker.
CIBIS III Trial - 58
• This trial was conducted with over 1000 patients with the typical primary outcome
• One group was started on the beta blocker (Bisoprolol 10 mg daily) another group started on an Ace
inhibitor (Enalapril 10 mg BID)
• Patients were then titrated to maximum tolerated doses over 6 months and the opposite drug was added
★ Results showed there was no difference in mortality or re-hospitalization
★ However, worsening CHF requiring hospitalization did show a nonsignificant increase when starting
with beta blocker. This seems reasonable, because you may decompensated patient. Up titration is based
on vital signs (e.g.↑ HR get β-Blocker to target dose 1st, etc.)
Stage C – Aldosterone Antagonists - 59
• Class IA - Addition of an aldosterone antagonist is recommended in selected patients with moderately
severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal
function and normal potassium concentration. SCr should be 2.5 mg/dL or less in men or 2.0 mg/dL or
less in women and potassium should be less than 5.0 mEq/l. Under circumstances where monitoring for
hyperkalemia or renal dysfunction is not anticipated to be feasible, the risks may outweigh the benefits.
Stage C – RALES study - 60
• Aldosterone antagonist were proven to have a benefit in patients with reduced EF in this study that was
published in 1999.
• At this time standard therapy for HF was diuretic, digoxin, and Ace inhibitor.
★ This study randomized patients to Spironolactone versus placebo, and results showed a 30% reduction in
mortality with the use of Spironolactone.
Stage C – EMPHASIS
• This was a post-MI trial where patients were started on Eplerenone 25 mg daily, and results showed a
15% reduction in the primary outcome of mortality in this study.The starting dose of the Eplerenone was
50 mg daily, but the 25 mg dose showed equal efficacy to the 50 mg dose.
3
Stage C – EMPHASIS-HF - 61
• This is a newer study which expanded the indication for Eplerenone. The inclusion criteria included:
• Age > 55 – EF ≤ 30% or ≤ 35% & QRS > 130 ms (denotes remodeling of the heart) – NYHA class
II – Max tolerable doses of β-blocker & ACEI or ARB – Serum K+ ≤ 5.0 mmol/L – eGFR ≥ 30
mL/min/1.73 m2 – Recent (< 6 months) CV hospitalization or elevated natriuretic peptide (BNP)
• This trial dosed the drug based on eGFR and if the patient had a eGFR > 50ml/min the received
Eplerenone 25 mg daily with the target dose of 50 mg. If the patient’s eGFR was between 30-49 ml/min
they received Eplerenone 25 mg every other day versus placebo with the primary outcome of CV death
or HF hospitalization
★ This trial was stopped early because of the BENEFIT of the medication.there was a 34% RRR in the
primary outcome (reduction – hospitalization for HF, mortality, and hospitalizations for any reason)
★ It would be more efficacious to add an aldosterone antagonist as opposed to an ARB to standard therapy
in Sage C patients
• Be cautious with the adverse event of hyperkalemia when using an aldosterone antagonist.
• Make sure patient is dosed appropriately, eliminate potassium supplements, and control patients
diabetes the risk of hyperkalemia are LOW.
There
was also no difference in gynecomastia compared to placebo when using Eplerenone (which does
•
not affect progesterone receptors like Spironolactone)
How to Use an Aldosterone Antagonist - 65
• Who would be the Appropriate patient?
• EF ≤ 35%, NYHA II-IV, & optimal dose of β-blocker and ACEI or ARB
• Check renal function and electrolytes at baseline which is similar to an ACEI.
• Consider contraindications
• Serum K+ > 5.0 mmol/l, SCr > 2.5 mg/dl (CrCl < 30 ml/min), concomitant K-sparing diuretic or
KCl supplement, or ACEI + ARB combination
• Know common initiation and titration doses
Aldosterone Antagonist Starting dose and Target dose
Aldosterone Antagonist
•
•
•
Starting dose
Target dose
Spironolactone
12.5 - 25 mg daily
50 mg daily
Eplerenone
25 mg daily
50 mg daily
Recheck renal function and electrolytes in 1 week and 1 month after starting and dose titration
Consider dose increase in 4-8 weeks
Recheck renal function and electrolytes in 2, 3, 6 months and q6months thereafter
Common Problems with AAs - 66
• Breast tenderness and/or enlargement
• Switch to equipotent dose of Eplerenone
- Spironolactone 50 mg → Eplerenone 100 mg, Spironolactone 25 mg → Eplerenone 50 mg
• Worsening renal function
• May half or discontinue based on increase in SCr or decrease in CrCl
• Hyperkalemia
• If > 5.5 mmol/l, half dose or take every other day
• If > 6.0 mmol/l, discontinue, and may restart at a lower dose if the patient was on an offending
agent. Would not restart if the patient is prone to hyperkalemia
Stage C – ACEI plus ARB versus ACEI or ARB plus AA - 67
• ARB added to standard background HF therapy reduces HF hospitalizations, but no mortality benefit.
4
• Increased rates of complications: hyperkalemia, hypotension, worsening renal function
★ Aldosterone antagonists confer both morbidity and mortality benefits
• Fewer complications than ACEI plus ARB with exception of hyperkalemia
• ACEI plus ARB combination has limited value
• EF 40% with NYHA class II-III symptoms, no ACS
• EF 35%, narrow QRS, class II-III symptoms, no ACS
Stage C – Hydralazine/ISDN - 68
• Class IA - The combination of hydralazine and nitrates (HYD/ISDN) is recommended to improve
outcomes for patients self-described as African-Americans, with moderate / severe symptoms on
optimal therapy with ACEIs, β-blockers, and diuretics.
• Class IIA - The addition of HYD/ISDN is reasonable for patients with reduced LVEF who are already
taking an ACEI and beta blocker for symptomatic HF and who have persistent symptoms.
• Class IIB – A combination of HYD/ISDN might be reasonable in patients with current or prior
symptoms of HF and reduced LVEF who cannot be given an ACEI or ARB because of drug intolerance,
hypotension, or renal insufficiency.
V-HeFT I - Survival - 69
• The study compared HYD/ISDN, prazosin versus placebo. It is known from a previous study that alpha
blockers worsen heart failure. Initially in this trial there was an improvement with HYD/ISDN however
at the end the Kaplan-Meier curve started to cross over due to patient dropout. (old early 90s study)
★ It would be reasonable to use the fixed dose concentration of HYD/ISDN or each of them separately for
afterload reduction in patients who cannot take an Ace inhibitor or ARB
V-HeFT II - Survival - 70
• This study compared the afterload reducing agent Enalapril versus HYD/ISDN with mortality benefit
and also reduction in hospitalizations.
★ Enalapril was superior to the fixed dose combination of HYD/ISDN
A-HeFT – Mortality or 1st HF hospitalization - 71
• This study showed that African Americans benefited more from the combination of HYD/ISDN then
any of the other ethnicities. This study was designed with patients that were on standard therapy for
heart failure were randomized to either fix dose HYD/ISDN versus placebo
★ The study was stopped early because of the HUGE benefit of survival in the African-American
population.
A-HeFT – Blood Pressure Differences - 72
• African-American patients most likely have heart failure due to uncontrolled hypertension.
• African-American patients can tolerate max doses of heart failure medications better than other
ethnicities.
• Clinicians are concerned with BiDil (HYD/ISND) because of blood pressure lowering
★ However, compared to placebo there was only about a 4 mmHg decrease in blood pressure using BiDil®
• The average dose in the study was 1.5 tablets TID – this relates to the physics of heart failure when
afterload is reduced cardiac output will increase, BUT blood pressure will not reduce in a HF patient like
it would in someone without heart failure.
A-HeFT – Adverse Effects - 73
• Adverse effects were common with BiDil® in this study. The starting dose was 1 tablet TID with a
target dose of 2 tablets TID.
• One tablet is 37.5 mg of HYD / 20 mg of ISDN
• Adverse reactions seen were severe headaches, dizziness not associated with low BP, etc.
• To make the medication more tolerable start with 1/2 tablet TID, and then titrated to target dose of 2
tablets TID
5
•
Clinically not many patients can tolerate this Target Dose of 2 tablets TID because of dizziness making
the usual dose of 1 to 1 & 1/2 tablets TID
How to Use Hydralazine/ISDN - 74
• Used in addition to standard therapy, especially in AA patients or patients who cannot tolerate
ACEI/ARBs. Consider contraindications which include Symptomatic hypotension and systemic lupus
erythematosus (SLE) which would occur quickly on initiation (joint pain, or muscle pain)
• A standard question that comes up in practice in patients on standard therapy. Do we add an aldosterone
antagonist or BiDil® in an African-American patient?
• Evidence would suggest adding an Aldosterone Antagonist first. If the patient has a low potassium
definitely go with the aldosterone antagonist. If blood pressure is high may consider BiDil®
• Know starting and target dosing
• Starting dose HYD / ISDN 37.5 / 20 mg TID with Target dose 75 / 40 mg TID
• Consider dose-titration in 2-4 weeks
• Potential adverse effects
• Symptomatic hypotension
• Drug induced SLE (lupus) if this occurs STOP the drug and call health care provider
• Arthralgia, myalgia, rash, fever, pericarditis, pleuritis
Stage C - Symptomatic Management - 75
★ Maximize standard HF therapies to improve survival
• β-blockers, RAAS inhibitors, HYD/ISDN
• Diuretics
• Thiazide-type diuretics, Higher doses of HCTZ and chlorthalidone,
• Metolazone
• Loop diuretics
• Furosemide, Bumetanide, Torsemide, Ethacrynic acid
• Digoxin
Stage C - Diuretics - 76
Class IA - Diuretics and salt restriction are indicated in patients with current or prior symptoms of HF and
reduced LVEF who have evidence of fluid retention.
• It is considered unethical to withhold a diuretic in a patient who had symptomatic heart failure. An
observational study showed that lower doses of a diuretic are associated with improved survival, and a
higher dose with lower survival. This probably represented the underlying severity of HF and not the
dose of the diuretic.
Nephron – Diuretic Site of Action - 77
• Carbonic anhydrase inhibitors work at the proximal tubules, but these drugs are not used in HF
• Loop diuretics are effective in the ascending loop of Henle
• Thiazide diuretics work at the distal tubule
• Aldosterone antagonists work in the collecting duct
How to Use Diuretics - 78
• Check baseline renal function and electrolytes
• Assess fluid status of patient
• Start with lowest dose possible
• Goal – maintain dry weight with lowest possible dose
• In HF loop diuretic are USED whereas thiazide
diuretics are NOT
6
Diuretic
Starting dose (mg)
Usual daily dose (mg)
Duration (hr)
Furosemide
20-40
40-240
6-8
Bumetanide
0.5-1
1-5
4-6
Torsemide
5-10
10-20
12-16
HCTZ
25
25-100
6-12
Indapamide
2.5
2.5-5
Chlorthalidone
12.5
25
24-72
Metolazone
2.5
2.5-10
12.24
★ This chart also shows the ratio of doses (e.g. Furosemide 40 mg = Bumetanide 1 mg)
• Counsel patient on prn dosing based on home weight trends
• Check renal function and electrolytes and regular intervals based upon dose adjustments
Managing Diuretic Resistance - 79
Causes of diuretic resistance
• Noncompliance – eat < 2 g of sodium, lesson 1.5 L of fluids
• Drug interactions –patients should not use NSAIDs
• Suboptimal dose
• Absorption variability
• Oral furosemide has a bioavailability of between 10–70% – gut edema could reduce bioavailability
from 70% down to 10% – patients with volume excess can be switched to equipotent Bumetanide or
Torsemide which has a constant 90% absorption
• Metolazone given 30 minutes - 1 hour before loop diuretic causes sequential nephron blockade, and
monitor for hyponatremia which is common with this medication.
• Distal hypertrophy
• Managing diuretic resistance
• Change dosing strategy, Switch diuretic, Sequential nephron blockade with metolazone
Do Some Patients Need Diuretics? - 80
• Adjusted Survival Plots Grouped by BUN and High or Low Loop Diuretic Use
• The theory is some patients are chronically congested on the right side of the heart and renal function
may worsen over time because of passive congestion and high intrathoracic pressures causing the patient
to require a diuretic to keep things flowing.
• This study observed patients with a low BUN and a high loop diuretic dose. With a low BUN means that
the neurohormones were not activated and in this trial these patients had a higher survival rate
• Patients with a high BUN and a high loop diuretic dose did worse in terms of survival
• Conclusions: The risk associated with High-dose loop diuretic use is strongly dependent on BUN
concentrations with reduced survival in patients with an elevated BUN level and improved survival in
patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop
diuretic associated mortality.
Stage C - Digoxin - 81
• Class IIA - Digitalis can be beneficial in patients with current or prior symptoms of HF and reduced
LVEF to decrease hospitalizations for HF
•
•
The classic mechanism of action for digoxin is likely not the mechanism for use in heart failure
For heart failure digoxin inhibits neurohormonal activity much like a beta blocker
7
★ Digoxin is typically added to therapy in addition to standard therapy if the patient is symptomatic, but
euvolemic
DIG Trial - 82
• The evidence comes from the DIG trial. In this trial digoxin was compared to placebo which showed no
difference in mortality from any cause, BUT death or hospitalization from worsening HF digoxin was
very effective.
★ Adding Digoxin there is a significant reduction in hospitalization for HF
DIG Trial Outcome by Serum Concentration - 83
• In the DIG trial it was subdivided in serum drug concentration of Digoxin with the different arms
including:
• Placebo – 0.5-0.8 ng/mL – 0.9-1.1 ng/mL – >1.2 ng/mL
• Digoxin levels above 1.2 ng/mL was associated with a positive inotropic effect which gave patients
worsening survival
★ Patients with a serum Digoxin level between 0.5-0.8 ng/mL had the best survival this serum
concentration is targeted for symptomatic management of HF and potentially improving mortality
benefit.
How to Use Digoxin - 84
• Appropriate patient
• EF ≤ 40%, NYHA II-IV, & optimal dose of β-blocker, ACEi/ARB, diuretic
• Utilized to control rate in addition to optimized β-blocker
• Check renal function and electrolytes at baseline
• Consider contraindications
• Second or third-degree heart block or sick sinus syndrome (w/o pacemaker),sinus bradycardia (< 50
bpm), hypo or hyperkalemia or hypo- hyper-magnesemia
Be
aware
of drug interactions
•
• Amiodarone, antibiotics, diltiazem, verapamil
• Know common initiation and titration doses
• 0.125 mg or 0.25 mg daily
• May use 0.125 mg every-other-day in renal impairment, elderly, low lean body mass
• Recheck renal function, electrolytes, and serum digoxin concentration within 1 month
• Potential adverse effects
• Cardiac arrhythmias, GI symptoms, Neurological
Devices – Biventricular Pacemaker - 85
Cardiac resynchronization therapy (CRT)
Criteria include:
• EF ≤ 35%, NSR, NYHA III-IV, QRS ≥ 120 ms
• +/– Implantable cardioverter-defibrillator (ICD)
Stage D – Refractory HF - 86
• Refractory HF – marked symptoms at rest despite maximized medical therapy
• Utilize measures in Stages A-C
• Emphasize fluid restriction and proper utilization of diuretics
• Treatment options
• Transplant, Continuous infusion of inotropes, Mechanical support (LVAD), Palliative care, Hospice
Heart Failure with Preserved Ejection Fraction - 87
• Minimal data to support use of any particular medication or regimen
• Associated with faster onset of severe symptoms
8
•
Three aspects of care to remember include:
• Caused by diastolic dysfunction
• Control heart rate, Control blood pressure,
Utilize diuretics to maintain euvolemia
Lifestyle Modifications and Education - 88
• Diet
• Na+
- 2-3 grams (mild)
- Less than 2000 mg
(moderate to severe)
• Fluid
• Less than 2 L
• Weight
• Reduction if obese
• Supplementation if
uncontrolled weight loss
(cachexia)
• MVI if on a diuretic
• Monitoring
• Daily morning weight
• Daily BP
- Prior to and 2-3 h after
medications
• Daily signs or symptoms
• Of HF
- DOE, fatigue
• Medication AE
• Dizziness
Take home message…
• Heart failure is an epidemic
• Best treatment is prevention through treatment of risk factors
• RAAS inhibitors and β-blockers remain cornerstone of therapy
• Combination RAAS blockade, aldosterone antagonists, HYD/ISDN are often utilized for survival
benefits, reduce HF hospitalizations, and/or improve symptoms
• Diuretics and digoxin are for symptomatic improvement only and too much drug is associated with
worse outcomes
• Don’t forget about lifestyle modification and monitoring
9