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Pharmacotherapy in Chronical Systolic Heart Failure
1. Pharmacotherapy
In
Chronicsystolic HeartFailure
Prof. U. C. SAMAL
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex- Prof. Cardiology & Ex-HOD Medicine
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
National Convener , Heart Failure Sub Specialty -CSI
Permanent & Chief Trustee, ICC-Heart Failure Foundation
2. Objectives in the management of heart failure
The goals of treatment in patients with established HF are to
relieve symptoms and signs (e.g. oedema), prevent hospital
admission, and improve survival.
Although the focus of clinical trials was previously mortality, it
is now recognized that preventing HF hospitalization is
important for patients and healthcare systems.
2
3. Treatment options for patients with chronic symptomatic
systolic heart failure (NYHA functional class II–IV).
The Task Force for the
Diagnosis and Treatment
of Acute and Chronic
Heart Failure 2012 of the
European Society of
Cardiology. Developed in
collaboration with the
Heart Failure Association
(HFA) of the ESC
Authors/Task Force Members:
John J.V. McMurray (Chairperson) (UK)*, Stamatis
Adamopoulos (Greece), Stefan D. Anker (Germany),
Angelo Auricchio (Switzerland), Michael Bo¨hm
(Germany), Kenneth Dickstein (Norway),Volkmar
Falk (Switzerland),Gerasimos Filippatos (Greece),
Caˆndida Fonseca (Portugal), Miguel Angel Gomez-
Sanchez (Spain),TinyJaarsma (Sweden), Lars
Køber (Denmark), GregoryY.H. Lip (UK), Aldo Pietro
Maggioni (Italy), Alexander Parkhomenko
(Ukraine), Burkert M. Pieske (Austria), Bogdan A.
Popescu (Romania), Per K. Rønnevik (Norway),
Frans H. Rutten (The Netherlands),Juerg Schwitter
(Switzerland), Petar Seferovic (Serbia), Janina
Stepinska (Poland),PedroT.Trindade (Switzerland),
Adriaan A.Voors (The Netherlands), Faiez Zannad
(France), Andreas Zeiher (Germany).
3ESC Guidelines: European Heart Journal (2012) 33, 1787–1847
4. AHA-ACC stages of heart failure.
Modified from Hunt SA, Abraham WT, Chin MH, et al: 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the
American College of Cardiology Foundation/American Heart Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.
Circulation 119:e391–e479, 2009; and Yancy CW, Jessup M, Bozkurt B, et al: 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology
Foundation/American Heart Association task force on practice guidelines. Circulation 128:e240–327, 2013.
4
5. AHA-ACC stages of heart failure.
Modified from Hunt SA, Abraham WT, Chin MH, et al: 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the
American College of Cardiology Foundation/American Heart Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.
Circulation 119:e391–e479, 2009; and Yancy CW, Jessup M, Bozkurt B, et al: 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology
Foundation/American Heart Association task force on practice guidelines. Circulation 128:e240–327, 2013.
5
6. Recommendations for pharmacological therapy for
management of stage C HFrEF
6
Yancy CW, Jessup M, Bozkurt B, et al. 2013.
J Am Coll Cardiol 2013; 62:e147.
7. Pharmacological treatments indicated in potentially all patients with
symptomatic (NYHA functional class II–IV) systolic heart failure
Recommendations Class Level
An ACE inhibitor is recommended, in addition to a beta-blocker, for
all patients with an EF ≤40% to reduce the risk of HF hospitalization
and the risk of premature death.
I A
A beta-blocker is recommended, in addition to an ACE inhibitor (or
ARB if ACE inhibitor not tolerated), for all patients with an EF ≤40%
to reduce the risk of HF hospitalization and the risk of premature
death.
I A
An MRA is recommended for all patients with persisting
symptoms (NYHA class II–IV) and an EF ≤35%, despite treatment
with anACE inhibitor (or anARB if anACE inhibitor is not tolerated)
and a beta-blocker, to reduce the risk of HF hospitalization and the
risk of premature death.
I A
7ESC Guidelines: European Heart Journal (2012) 33, 1787–1847
8. Other treatments with less-certain benefits in patients with
symptomatic (NYHA class II–IV) systolic heart failure
8
Recommendations Class Level
ARB
Recommended to reduce the risk of HF hospitalization and the risk of premature death in patients with an EF ≤40% and unable to tolerate an ACE inhibitor because
of cough (patients should also receive a beta-blocker and an MRA).
I A
Recommended to reduce the risk of HF hospitalization in patients with an EF ≤40% and persisting symptoms (NYHA class II–IV) despite treatment with an ACE
inhibitor and a beta-blocker who are unable to tolerate an MRA.
I A
IVABRADINE
Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting
symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that),ACE inhibitor (or ARB), and
an MRA (or ARB).
IIa B
May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to tolerate a beta-
blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB).
IIb C
DIGOXIN
May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤45% who are unable to tolerate a beta-blocker (ivabradine is an
alternative in patients with a heart rate ≥70 b.p.m.). Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB).
IIb B
May be considered to reduce the risk of HF hospitalization in patients with an EF ≤45% and persisting symptoms (NYHA class II–IV) despite treatment with a beta-
blocker,ACE inhibitor (or ARB), and an MRA (or ARB).
IIb B
H-ISDN
May be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature death in patients
with an EF ≤45% and dilated LV (or EF ≤35%). Patients should also receive a beta-blocker and an MRA.
IIb
B
May be considered to reduce the risk of HF hospitalization and risk of premature death in patients in patients with an EF ≤45% and dilated LV (or EF ≤35%) and
persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker,ACE inhibitor (or ARB), and an MRA (or ARB).
IIb B
An n-3 PUFAf preparation may be considered to reduce the risk of death and the risk of cardiovascular hospitalization in patients treated with an ACE inhibitor (or
ARB), beta-blocker, and an MRA (or ARB).
IIb
B
ESC Guidelines: European Heart Journal (2012) 33, 1787–1847
9. 9
ACE/ARBs
Routinely combining an ACE inhibitor, an ARB, and an aldosterone antagonist.
III:
Harm
C
Aldosterone Receptor Antagonists
Inappropriate use of aldosterone receptor antagonists is potentially harmful because of life-threatening
hyperkalemia or renal insufficiency when serum creatinine is more than 2.5 mg/dL in men or more than 2.0 mg/dL
in women (or estimated glomerular filtration rate <30 mL/min/1.73 m2), and/or potassium more than 5.0 mEq/L.
III:
Harm
B
Anticoagulation
Anticoagulation is not recommended in patients with chronic HFrEF without AF, a prior thromboembolic event, or
a cardioembolic source.
III: No
Benefit
B
Statins
Statins are not beneficial as adjunctive therapy when prescribed solely for HF.
III: No
Benefit
A
Drugs of unproven value orThat may cause harm
Nutritional supplements as treatment for HF are not recommended in patients with current or prior symptoms of
HFrEF.
III: No
Benefit
B
Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HFrEF are
potentially harmful and should be avoided or withdrawn whenever possible (e.g., most antiarrhythmic drugs,
most calcium channel blocking drugs (except amlodipine), NSAIDs, or thiazolidinediones).
III:
Harm B
Calcium Channel Blockers
Calcium channel blocking drugs are not recommended as routine therapy for patients with HFrEF.
III: No
Benefit
A
Recommendations Class Level
22. ACC/AHA Updated Guidelines,2013 :
Treatment of Symptomatic Left Ventricular Systolic Dysfunction Stage C)
INDICATION COR LOE
Pharmacologic Interventions
Measures listed as class I recommendations for patients in stages A and B are recommended where appropriate.
I A, B, C
GDMT should be the mainstay of pharmacologic therapy for HFrEF. A
Diuretics
Diuretics are recommended in patients with HFrEF who have evidence of fluid retention, unless
contraindicated, to improve symptoms.
I C
ACE/ARBs
ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated,
to reduce morbidity and mortality.
I A
ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACE inhibitor intolerant,
unless contraindicated, to reduce morbidity and mortality.
A
ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as first-line therapy for
patients with HFrEF, especially for patients already taking ARBs for other indications, unless contraindicated.
IIa A
Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being
treated with an ACE inhibitor and a β-blocker in whom an aldosterone antagonist is not indicated or tolerated.
IIb A
Routinely combining an ACE inhibitor, an ARB, and an aldosterone antagonist.
III:
Harm
C
β-Blockers
Use of one of the three β-blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained-release
metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless
contraindicated, to reduce morbidity and mortality.
I A
23. 23
INDICATION COR LOE
Aldosterone Receptor Antagonists
Aldosterone receptor antagonists (or mineralocorticoid receptor antagonists) are recommended in patients with
NYHA class II-IV and who have LVEF ≤ 35%, unless contraindicated, to reduce morbidity and mortality.
I A
Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in
patients who have LVEF ≤ 40% who develop symptoms of HF or who have a history of diabetes mellitus, unless
contraindicated.
I B
Inappropriate use of aldosterone receptor antagonists is potentially harmful because of life-threatening
hyperkalemia or renal insufficiency when serum creatinine is more than 2.5 mg/dL in men or more than 2.0 mg/dL
in women (or estimated glomerular filtration rate <30 mL/min/1.73 m2), and/or potassium more than 5.0 mEq/L.
III:
Harm
B
Hydralazine and Isosorbide Dinitrate
The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for
patients self-described as African Americans with NYHA class III–IV HFrEF receiving optimal therapy with ACE
inhibitors and β-blockers, unless contraindicated.
I A
A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients
with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug
intolerance, hypotension, or renal insufficiency, unless contraindicated.
IIa B
Digoxin
Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF. IIa B
24. 24
INDICATION COR LOE
Anticoagulation
Patients with chronic HF with permanent/persistent/paroxysmal AF and an additional risk factor for cardioembolic
stroke (history of hypertension, diabetes mellitus, previous stroke or transient ischemic attack, or ≥75 years of
age) should receive chronic anticoagulant therapy.
I A
The selection of an anticoagulant agent (warfarin, dabigatran, apixaban, or rivaroxaban) for
permanent/persistent/paroxysmal AF should be individualized on the basis of risk factors, cost, tolerability,
patient preference, potential for drug interactions, and other clinical characteristics, including time in the
international normalized ratio therapeutic range if the patient has been taking warfarin.
I C
Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/persistent/paroxysmal AF
but are without an additional risk factor for cardioembolic stroke.
IIa B
Anticoagulation is not recommended in patients with chronic HFrEF without AF, a prior thromboembolic event, or
a cardioembolic source.
III: No
Benefit
B
Statins
Statins are not beneficial as adjunctive therapy when prescribed solely for HF.
III: No
Benefit
A
Omega-3 Fatty Acids
Omega-3 polyunsaturated fatty acid (PUFA) supplementation is reasonable to use as adjunctive therapy in
patients with NYHA class II-IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and
cardiovascular hospitalizations.
IIa B
25. 25
INDICATION COR LOE
Drugs of unproven value orThat may cause harm
Nutritional supplements as treatment for HF are not recommended in patients with current or prior symptoms of
HFrEF.
III: No
Benefit
B
Hormonal therapies other than to correct deficiencies are not recommended for patients with current or prior
symptoms of HFrEF.
C
Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HFrEF are
potentially harmful and should be avoided or withdrawn whenever possible (e.g., most antiarrhythmic drugs,
most calcium channel blocking drugs (except amlodipine), NSAIDs, or thiazolidinediones).
III:
Harm B
Long-term use of infused positive inotropic drugs is potentially harmful for patients with HFrEF, except as
palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (see
recommendations for stage D).
C
Calcium Channel Blockers
Calcium channel blocking drugs are not recommended as routine therapy for patients with HFrEF.
III: No
Benefit
A
26. 26
INDICATION COR LOE
Nonpharmacologic Interventions
Fluid restriction (1.5 to 2 L/day) is reasonable in stage D, especially in patients with hyponatremia.
III: No
Benefit
B
Inotropic Support
Until definitive therapy (e.g., coronary revascularization, MCS, heart transplantation) or resolution of the acute
precipitating problem, patients with cardiogenic shock should receive temporary intravenous inotropic support to
maintain systemic perfusion and preserve end-organ performance.
I C
Continuous intravenous inotropic support is reasonable as “bridge therapy” in patients with stage D refractory to
GDMT and device therapy who are eligible for and awaiting MCS or cardiac transplantation.
IIa B
Short-term, continuous intravenous inotropic support may be reasonable in those hospitalized patients
presenting with documented severe systolic dysfunction who present with low blood pressure and significantly
depressed cardiac output to maintain systemic perfusion and preserve end-organ performance.
IIb B
Long-term, continuous intravenous inotropic support may be considered as palliative therapy for symptom
control in select patients with stage D despite optimal GDMT and device therapy who are not eligible for either
MCS or cardiac transplantation.
B
Long-term use of either continuous or intermittent intravenous parenteral positive inotropic agents, in the
absence of specific indications or for reasons other than palliative care, is potentially harmful in the patient with
HF.
III: Harm B
ACC/AHA Guidelines for Treatment of Patients with End-
Stage Heart Failure (Stage D
27. 27
INDICATION COR LOE
Mechanical Circulatory Support (MCS)
MCS is beneficial in carefully selected patients with stage D HFrEF in whom definitive management (e.g., cardiac
transplantation) or cardiac recovery is anticipated or planned.
IIa B
Nondurable MCS, including the use of percutaneous and extracorporeal ventricular assist devices (VADs), is
reasonable as a “bridge to recovery” or “bridge to decision” for carefully selected patients with HFrEF with acute,
profound hemodynamic compromise.
I B
Durable MCS is reasonable to prolong survival for carefully selected patients with stage D HFrEF. IIa B
CardiacTransplantation
Evaluation for cardiac transplantation is indicated for carefully selected patients with stage D HF despite GDMT,
device, and surgical management.
I C
28. Pharmacokinetics of the Loop Diuretics
28
From Felker GM, Mentz RJ: Diuretics and ultrafiltration in
acute decompensated heart failure. J Am Coll Cardiol
59:2145–2153, 2012.
Practical Issues in the Use of Diuretics in Heart Failure
Patients with evidence of volume overload or a history of fluid
retention should be treated with a diuretic to relieve their symptoms.
In patients who have moderate to severe HF symptoms and/or renal
insufficiency, a loop diuretic is generally required. Diuretics should
generally be titrated as needed to relieve signs and symptoms of fluid
overload. One commonly used method for finding the appropriate
dose is to double the dose until the desired effect is achieved or the
maximal dose of diuretic is reached. Patients with chronic heart failure
can be instructed on parameters for self-adjustment of diuretics based
on daily weights and symptoms .Although furosemide is the most
commonly used loop diuretic, bumetanide or torsemide may be
preferable in selected patients because of their increased
bioavailability . Changing to torsemide in particular may induce
diuresis in patients seemingly refractory to oral furosemide. With the
exception of torsemide, the commonly used loop diuretics are short
acting (<3 hours). For this reason, loop diuretics usually are more
effective when given at least twice daily to minimize periods where
the concentration in the tubular fluid declines below a therapeutic
level, which may produce postdiuretic sodium retention or “rebound.”
Infrequent dosing may therefore lead to sodium retention that
exceeds natriuresis, especially if dietary sodium intake is not
restricted.
29. Classes of diuretics and their mechanisms of actions. MRA,
Mineralocorticoid receptor antagonist.
29
Modified fromWile D: Diuretics: a review. Ann Clin
Biochem 49:419–431, 2012.
30. Dose response curves of loop diuretics in chronic heart
failure (CHF) and chronic renal failure (CRF) patients
compared with normal controls.
30
Reproduced from Ellison DH: Diuretic therapy and
resistance in congestive heart failure. Cardiology
96:132–143, 2001.
In heart failure patients, higher doses are
required to achieve a given diuretic effect and
the maximal effect is blunted.
32. Outcomes with ACE inhibitors compared with
placebo in a pooled analysis
32
From Garg R,YusufS: Overview of
randomized trials of angiotensin-
converting enzyme inhibitors on mortality
and morbidity in patients with heart
failure. Collaborative Group on ACE
InhibitorTrials.JAMA 273:1450–1456,
1995.
33. Outcomes with ARBs compared with the placebo in heart
failure.
33
A, Reproduced from Maggioni
AP, Anand I, Gottlieb SO, et al:
Effects of valsartan on
morbidity and mortality in
patients with heart failure not
receiving angiotensin-
converting enzyme inhibitors.J
Am CollCardiol 40:1414–1421,
2002;
B, Reproduced from Granger
CB, McMurray JJ,YusufS, et al:
Effects of candesartan in
patients with chronic heart
failure and reduced left-
ventricular systolic function
intolerant to angiotensin-
converting-enzyme inhibitors:
the CHARM-Alternative trial.
Lancet 362:772–776, 2003.
A, Kaplan-Meier curves for mortality in the valsartan (dotted line) and placebo (solid line) groups (n = 185 and
181, respectively) without angiotensin-converting enzyme (ACE) inhibitor background therapy (P = 0.017 by
log-rank test) in theValsartan Heart FailureTrial (Val-HeFT). B, Kaplan-Meier cumulative event curves for the
primary outcome (all-cause mortality, cardiovascular death, or hospitalization) in the Candesartan Heart
Failure:Assessment of Reduction in Mortality and Morbidity trial (CHARM-Alternative) in ACE-intolerant
patients.
34. Practical Tips
34
ACE Inhibitors
Starting and target doses for commonly used ACE inhibitors and ARBs are shown in Table. Because fluid
retention can attenuate the effects of ACE inhibitors, it is preferable to optimize the dose of diuretic first
before starting the ACE inhibitor. However, it may be necessary to reduce the dose of diuretic during the
initiation of an ACE inhibitor to prevent symptomatic hypotension.ACE inhibitors should be initiated in
low doses, followed by increments in dose if lower doses have been well tolerated.Titration is generally
achieved by doubling doses every 3 to 5 days.The dose of ACEI should be increased until the doses used
are similar to those that have been shown to be effective in clinical trials or to the maximally tolerated
dose. Higher doses are more effective than lower doses in preventing hospitalization based on the ATLAS
trial. For stable patients, it is acceptable to add therapy with β-blocking agents before full target doses of
ACE inhibitors are reached. Blood pressure (including postural changes), renal function, and potassium
should be evaluated within 1 to 2 weeks after initiation of ACE inhibitors, especially in patients with
preexisting azotemia, hypotension, hyponatremia, diabetes mellitus, or in those taking potassium
supplements. Abrupt withdrawal of treatment with an ACE inhibitor may lead to clinical deterioration and
should therefore be avoided in the absence of life-threatening complications (e.g., angioedema,
hyperkalemia).
35. 35
ARBs
MultipleARBs that are approved for the treatment of hypertension are now available to
clinicians.Three of these, losartan, valsartan, and candesartan, have been extensively
evaluated in the setting of HF. ARBs should be initiated with the starting doses shown in
Table, which can be uptitrated every 3 to 5 days by doubling the dose of ARB.As with ACE
inhibitors, blood pressure, renal function, and potassium should be reassessed within 1 to
2 weeks after initiation and followed closely after changes in dose.
37. β-blockers
Analogous to the use of ACE inhibitors, β-blockers should be initiated in low doses , followed by gradual
increments in the dose if lower doses have been well tolerated. The dose of β-blocker should be increased until
the doses used are similar to those that have been reported to be effective in clinical trials . Furthermore, in
patients taking a low dose of an ACE inhibitor, the addition of a β-blocker appears to produce a greater
improvement in symptoms and reduction in the risk of death than an increase in the dose of the ACE inhibitor,
although this question has never been specifically subjected to randomized trials. However, unlike ACE inhibitors,
which may be uptitrated relatively rapidly, the dose titration of β-blockers should proceed no sooner than 2-week
intervals, because the initiation and/or increased dosing of these agents may lead to worsening fluid retention
because of the abrupt withdrawal of adrenergic support to the heart and the circulation. Therefore, it is important
to optimize the dose of diuretic before starting therapy with β-blockers. If worsening fluid retention does occur, it
is likely to occur within 3 to 5 days of initiating therapy and will be manifest as an increase in body weight and/or
symptoms of worsening HF. The increased fluid retention can usually be managed by increasing the dose of
diuretics. Patients need not be taking high doses of ACE inhibitors before being considered for treatment with a
β-blocker, because most patients enrolled in the β-blocker trials were not taking high doses of ACE inhibitors.
Randomized trial data from the IMPACT HF study show that β-blockers can be safely started before discharge
even in patients hospitalized for HF, provided that the patients are stable and do not require intravenous HF
therapy. Contrary to initial concerns, the aggregate results of clinical trials suggest that β-blocker therapy is well
tolerated by the great majority of HF patients (>85%), including patients with comorbid conditions, such as
diabetes mellitus, chronic obstructive lung disease, and peripheral vascular disease. Nonetheless, there are a
subset of patients (10%-15%) who remain intolerant to β-blockers because of worsening fluid retention or
symptomatic hypotension and a minority who are intolerant because of reactive airway disease.
37
38. All-cause mortality in the Carvedilol or Metoprolol
European Trial (COMET) with carvedilol compared with
immediate-release metoprolol tartrate.
38
Reproduced from Poole-Wilson PA, Swedberg
K, ClelandJG, et al: Comparison of carvedilol
and metoprolol on clinical outcomes in patients
with chronic heart failure in the Carvedilol Or
Metoprolol EuropeanTrial (COMET):
randomised controlled trial. Lancet 362:7–13,
2003.
39. The effect of angiotensin-converting enzyme (ACE)
inhibitors and β-blockers on ventricular remodeling.
39
A and B, Reproduced from
Konstam MA, Kronenberg
MW, Rousseau MF, et al:
Effects of the angiotensin
converting enzyme
inhibitor enalapril on the
long-term progression of
left ventricular dilatation
in patients with
asymptomatic systolic
dysfunction. SOLVD
(Studies of Left Ventricular
Dysfunction) Investigators.
Circulation 88:2277–2283,
1993. C, Reproduced from
Colucci WS, Kolias TJ,
Adams KF, et al:
Metoprolol reverses left
ventricular remodeling in
patients with
asymptomatic systolic
dysfunction: the REversal
of VEntricular Remodeling
with Toprol-XL (REVERT)
trial. Circulation 116:49–
56, 2007. D, Reproduced
from Doughty RN, Whalley
GA, Gamble G, et al: Left
ventricular remodeling
with carvedilol in patients
with congestive heart
failure due to ischemic
heart disease. Australia-
New Zealand Heart Failure
Research Collaborative
Group. J Am Coll Cardiol
29:1060–1066,1997.
A and B, Left ventricular end-diastolic volumes (LVEDV) (mean ± SE) in enalapril and placebo patients within the
prevention trial and the previously reported treatment trial who had measurements made at all five time points.
Measurements are at baseline, 4 months, 1 year, and at study end (mean of 25 months and 33 months for prevention trial
and treatment trial patients, respectively). The final data point on each graph is after withdrawal (wd) of study drug for a
minimum of 5 days. P values shown are for comparison of placebo and enalapril groups by repeated-measures analysis
applied to all time points. Baseline volumes were significantly higher in treatment trial patients (P <0.005). In the
prevention trial and the treatment trial, placebo-treated patients manifested progressive increases in ventricular volumes,
whereas enalapril-treated patients showed an early and sustained reduction in LV volumes. Treatment difference between
the placebo and enalapril groups was significantly greater within the treatment trial than within the prevention trial (P
<0.02 at 1 year). C, Effect of metoprolol succinate on LV volumes. Shown are the least square mean changes (SE) in LVEDVI
(B) compared with baseline for patients receiving metoprolol succinate 200 mg (triangles), 50 mg (squares), or placebo
(diamonds). *P <0.05 versus baseline. D, Changes in left ventricular end-diastolic volume index (LVEDVI) from baseline (BL)
to 6 months (6M) and 12 months (12M). Data are presented as mean value ± SE. P values comparing carvedilol and placebo
are for repeated measures multivariate analysis of variance (MANOVA) over 12 months of treatment.
41. Mineralocorticoid Receptor Antagonists
The administration of an MRA is recommended for patients with NYHA
class II to IV HF who have ejection fraction less than 35% and who are
receiving standard therapy, including diuretics, ACEIs, and β-blockers.
Spironolactone should be initiated at a dose of 12.5 to 25 mg daily, and
uptitrated to 25 to 50 mg daily, whereas eplerenone should be initiated at
doses of 25 mg/day and increased to 50 mg daily. As noted previously,
potassium supplementation is generally stopped after the initiation of
aldosterone antagonists, and patients should be counseled to avoid high
potassium-containing foods. Potassium levels and renal function should
be rechecked within 3 days and again at 1 week after initiation of an
aldosterone antagonist. Subsequent monitoring should be dictated by the
general clinical stability of renal function and fluid status but should occur
at least monthly for the first 6 months.
41
42. Kaplan-Meier cumulative event curves for the primary
composite endpoint of cardiovascular death or hospital
admission for worsening heart failure in the Systolic Heart
failure treatment with the If inhibitor Ivabradine Trial
(SHIFT).
42
Reproduced from Swedberg K, Komajda M, Böhm M, et al:
Ivabradine and outcomes in chronic heart failure (SHIFT): a
randomised placebo-controlled study. Lancet 376:875–885,
2010.
43. Kaplan-Meier estimates of overall survival with
isosorbide dinitrate plus hydralazine compared
with placebo in the African-American Heart
Failure Trial (AHEFT).
43
Reproduced fromTaylor AL, ZiescheS,Yancy C, et al:
Combination of isosorbide dinitrate and hydralazine in
blacks with heart failure. N Engl J Med 351:2049–2057,
2004.
44. Hydralazine and Nitrates
H-ISDN should not be used in patients who have no prior use of ACE inhibitors/ARBs or β-
blockers and should not be substituted for ACE inhibitors/ARBs in patients who are
tolerating therapy without difficulty.Adherence to this combination has generally been
poor because of the number of daily doses and tablets required, and the side effect profile
including headache and dizziness. However, the benefit of these drugs can be substantial in
specific patient populations who have been studied in randomized trials.Therefore, slower
titration of the drugs should be performed to enhance tolerance of the therapy. If the fixed-
dose combination is available, the initial dose should be one tablet containing 37.5 mg of
hydralazine hydrochloride and 20 mg of isosorbide dinitrate three times daily.The dose can
be increased to two tablets three times daily for a total daily dose of 225 mg of hydralazine
hydrochloride and 120 mg of isosorbide dinitrate.When the two drugs are used separately,
both pills should be administered at least three times daily. Initial low doses of the drugs
given separately may be progressively increased to a goal similar to that achieved in the
fixed-dose combination trial.
44
45. Kaplan-Meier curve for the primary composite
endpoint (death from cardiovascular causes or
first hospitalization for heart failure),
according to Study Group.
45
Reproduced with permission from McMurray
JJ, Packer M, Desai AS, et al, for the
PARADIGM-HF Investigators and Committees:
Angiotensin-neprilysin inhibition versus
enalapril in heart failure. N Engl J Med
371:993–1004, 2014.
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Comparison of three methods of assessing cardiovascular
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Editor's Notes
Reductions in mortality and hospital admission rates both reflect the ability of effective treatments to slow or prevent progressive worsening of HF. This is often accompanied by reverse LV remodeling and a reduction in circulating natriuretic peptide concentrations. The relief of symptoms, improvement in quality of life, and increase in functional capacity are also of the utmost importance to patients, but they have not been the primary outcome in most trials. This is in part because they are difficult to measure and partly because some treatments previously shown to improve these outcomes also decreased survival. However, effective pharmacological therapies and CRT improve these outcomes, as well as mortality and hospitalization.
Class I: Procedure/Treatment SHOULD be performed/administered (Benefit >>> Risk)
Class IIa: Additional studies with focused objectives needed. IT IS REASONABLE to perform procedure/administer treatment (Benefit >>> Risk)
Class IIb: Additional studies with broad objectives needed; additional registry data would be helpful. Procedure/administer treatment MAY BE CONSIDERED (Benefit ≥ Risk).
Class III: No Benefit (not helpful and of no proven benefit) or class III Harm (excessive cost without benefit or harmful)
The ACC/AHA guidelines also adopt a convention for rating levels of evidence on which recommendations have been based.
Level A recommendations are derived from data from multiple populations with data from multiple randomized clinical trials and/or meta-analyses;
level B recommendations are derived from data from limited populations with data from a single randomized clinical trial or nonrandomized studies; and
level C recommendations are based on very limited populations or the consensus opinion of experts or case studies. The guidelines emphasize that the strength of evidence does not necessarily reflect the strength of a recommendation.
A treatment may be controversial despite having been evaluated in controlled clinical trials; conversely, a strong recommendation may be supported only by historical data or by no data at all. New for the current set of guidelines is the introduction of the term guideline-directed medical therapy (GDMT), which represents optimal medical therapy as defined by the ACC/AHA guideline-recommended therapies (primarily class I).
In last 30 years GDMT has resulted in remarkable reduction in mortality in Heart Failure Reduced ejection fraction and did not have to present the graphic to tell you, we have very little to offer patients of heart failure with preserver ejection fraction except diruretics in acute cases and drugs to treat hypertension and treatment of co-morbidities and all the trials in Heart failure with preserved ejection fraction as the Milton Pakers quotes “ it once step forward, two step backward, and exercise in futility”. But as
The story is simple and the concept is fantastic in heart failure there is neuroharmonal activation involving in maladaptive and beneficial neuroharmonal agents. Which is well depicted in this cartoon. The red axis is positive adaptive process mediated by the several vasoactive peptides inclusive of BNP and ANP and CNP but are unsustainable as they are degraded by NEP Neutral Endopeptidase Neprilysin. The grey axis is a maladaptive process principally steered by Angeotensin-II ATP receptor .
Thus, neprilysin inhibition leads to beneficial effects of the vasoactive peptitides very well depicted in the cartoon.
LCZ696 is the combination of Sacubitril and valsarten selective one antagonist of equal proportion approved by FDA and being marketed in the name of “Entresto, Novatitis” in the multiple strength. Average daily cost may be 800 bucks and considered to be a “yellow paint ” / is the panacea in the Heart Failure morbidity and may replace several necessary evils like ACI-I and ARBs.
In 30 years of heart failure research there is unprecedented breakthrough angiotensin Neprilysin inhibition with LCZ696 has brought down further mortality more than 20 percentage over and above what we have achieved so far in Heart Failure with reduced ejection fraction and with ongoing Paramount HF study we are longing to have equal benefit for the patient of HFpEF.
In the real sense Heart Failure Panacea .
The best prove of the concept in terms of the absolute benefit when thousands of patients on ACE-I and ARBs changed over to LCZ696 over the period of median 27 months, the quantum of the benefits is well spelled out in this slide.
Dear friends where are we at present. In the patient HFrEf we climbed the pyramid in this fashion to struggle at the level of MRAs with fear of hyperkalemila and renal injury. But, I hope from emerging evidence LCZ696/ ARNI would take the driver seat the first line treatment in the place of ACE-I and ARBs may be the treatment further built up with the addition of beta blockers and the MRAs. I further apprise you with newer non steroidal MRAs like Finerenone and newer hypokilemic agents like ZS-9 (in acute scenario and Patiromer in chronic scenario with the very well fight out the menace of hyperpotissimia . I am sure the golden days are ahead for our heart failure patients which are considered to be pariahs of nature (dejected child of nature).
Class I: Procedure/Treatment SHOULD be performed/administered (Benefit >>> Risk)
Class IIa: Additional studies with focused objectives needed. IT IS REASONABLE to perform procedure/administer treatment (Benefit >>> Risk)
Class IIb: Additional studies with broad objectives needed; additional registry data would be helpful. Procedure/administer treatment MAY BE CONSIDERED (Benefit ≥ Risk).
Class III: No Benefit (not helpful and of no proven benefit) or class III Harm (excessive cost without benefit or harmful)
The ACC/AHA guidelines also adopt a convention for rating levels of evidence on which recommendations have been based.
Level A recommendations are derived from data from multiple populations with data from multiple randomized clinical trials and/or meta-analyses;
level B recommendations are derived from data from limited populations with data from a single randomized clinical trial or nonrandomized studies; and
level C recommendations are based on very limited populations or the consensus opinion of experts or case studies. The guidelines emphasize that the strength of evidence does not necessarily reflect the strength of a recommendation.
A treatment may be controversial despite having been evaluated in controlled clinical trials; conversely, a strong recommendation may be supported only by historical data or by no data at all. New for the current set of guidelines is the introduction of the term guideline-directed medical therapy (GDMT), which represents optimal medical therapy as defined by the ACC/AHA guideline-recommended therapies (primarily class I).
