This review summarizes the pharmacologic options for managing systolic heart failure, focusing on modulating pathways through the renin-angiotensin-aldosterone system. Angiotensin converting enzyme (ACE) inhibitors are recommended for all patients with reduced ejection fraction as clinical trials showed they reduce mortality and attenuate ventricular remodeling. Angiotensin receptor blockers (ARBs) are an alternative for those intolerant of ACE inhibitors. Mineralocorticoid receptor antagonists further block the renin-angiotensin-aldosterone system and clinical trials demonstrated reduced mortality when added to standard therapy.

1. Canadian Journal of Cardiology (2015)
Review
Pharmacologic Options for the
Management of Systolic
Heart Failure: Examining
Underlying Mechanisms
G.B. John Mancini, MD, Jonathan G. Howlett, MD, Jeffrey Borer, MD,
Peter P. Liu, MD, Mandeep R. Mehra, MD, Marc Pfeffer, MD, Karl
Swedberg, MD, and Jean-Claude Tardif, MD
Juan J. Araya C.
Interno Medicina Interna – Universidad de Antofagasta
Módulo Cardiología

2.  “The primary goal of this review is to provide a
mechanistic explanation of the complementary role of
therapeutic interventions in modulating pathways leading
to progressive systolic heart failure. A secondary goal is
to summarize the key findings of the pivotal clinical trials
that have demonstrated the efficacy of these agents in
this population.”

3. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Recommendations for use:
– for all HF patients with a left ventricular (LV) ejection
fraction (LVEF) < 40%
– in all patients after an acute myocardial infarction (MI) after
the patient has been stabilized should be continued
indefinitely if LVEF is < 40% or if there is ongoing HF

4. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Evidence-based agents and doses:

5. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Clinical trial evidence:
 CONSENSUS, 1987 enalapril 2.5-40 mg daily vs
placebo was evaluated among 253 patients with severe
HF 
Effects of enalapril on mortality in severe congestive heart failure. Results of the
Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The
CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.
27% relative risk reduction in overall mortality for the
active treatment arm (P< 0.003).

6. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Clinical trial evidence:
 SOLVD trial 2569 patients with class 2-3 HF were
randomized to enalapril 2.5-20 mg per day or placebo 
Konstam MA, Rousseau MF, Kronenberg MW, et al. Effects of the angiotensin converting
enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in
patients with heart failure. SOLVD Investigators. Circulation 1992;86:431-8.
At 41 months, there was a relative risk reduction of 16%
in mortality in favour of enalapril, associated with a
significant reduction in end-diastolic LV volume index at
4 months.

7. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Clinical trial evidence:
– Survival and Ventricular Enlargement (SAVE; captopril)
– Acute Infarction Ramipril Efficacy (AIRE)
– Trandolapril Cardiac Evaluation (TRACE)
Flather MD, Yusuf S, Kober L, et al. Long-term ACE inhibitor therapy in patients with heart
failure or left ventricular dysfunction: a systematic overview of data from individual patients.
ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575-81.
26% relative risk reduction in all-cause mortality
for ACE inhibition vs placebo

8. ACE Inhibitors: The Gold Standard
Modulator of the Renin-Angiotensin-
Aldosterone System
 Mechanistic rationale:
– 1) inhibition of the conversion of angiotensin I to
angiotensin II
– 2) inhibition of the breakdown of inflammatory
mediators like bradykinin.

9.  modulation of myocyte
 responses to the intracardiac renin-angiotensin system
 attenuation of ventricular remodelling and improvement in
ventricular function
 reduction in sympathetic activity
 positive effects on endothelial function
 cytokine levels,
 plasma fibrinolytic activity
 lung function
 exercise capacity
 arterial compliance

10. The one consistent finding in studies of ACE
inhibitors for HFrEF is attenuation of remodelling,
with an approximate 10% reduction in LV volumes.
Udelson JE, Konstam MA. Relation between left ventricular remodeling
and clinical outcomes in heart failure patients with left ventricular systolic
dysfunction. J Card Fail 2002;8(6 suppl):S465-71.

11. ARBs: An Alternative to ACE
Inhibitors
 Recommendations for use:
– in patients who cannot tolerate an ACE inhibitor; and as
adjunctive therapy to ACE inhibitors when B-blockers are
either contraindicated or not tolerated
 Evidence-based agents and doses:

12. ARBs: An Alternative to ACE
Inhibitors
 Clinical trial evidence:
 Valsartan in Acute Myocardial Infarction (VALIANT)
 14,703 patients with MI complicated by LV systolic dysfunction,HF,
or both
valsartan 160 mg twice daily, captopril 50 mg 3 times daily, or the
combination of valsartan 80 mg twice daily and captopril 50 mg 3 times
daily
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated
by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.
There was no significant difference found between any of the
treatment arms with respect to all-cause mortality, nor any
significant difference for fatal and nonfatal vascular events.

13.  Candesartan in Heart Failure Assessment of Reduction
in Mortality and Morbidity (CHARM)
– included 3 separate trials, each evaluating
candesartan (target dose 32 mg once daily) vs
placebo in different HF populations with the same
primary combined end point of cardiovascular death
or hospital admission for worsening HF.
ARBs: An Alternative to ACE
Inhibitors

14.  CHARM-Alternative study
– 2028 patients with NYHA class II-IV HF and LVEF <
40%, who were not receiving ACE inhibitors, were
randomized to candesartan vs placebo
– candesartan was associated with a 23% relative risk
reduction of the primary combined end point.
ARBs: An Alternative to ACE
Inhibitors

15.  The CHARM-Added study
–  candesartan 32 mg vs placebo in combination with ACE
inhibitors in patients with NYHA class II-IV HF and LVEF < 40%.
–  candesartan was associated with a 15% relative risk reduction
in the combined primary end point of death or hospitalization (P
<0.01).
 Cause a Lack of confirmatory mortality reduction with combination
therapy…
…Despite a cautious recommendation in recent Canadian
Cardiovascular Society guidelines in selected patients with stable
HF and LVEF <40%,7 use in the community is very uncommon in
Canada.
high rate of drug discontinuation
(> 25%)
ARBs: An Alternative to ACE
Inhibitors

16.  Valsartan Heart Failure Trial (Val-HEFT) trial,41
hospitalization was reduced by 20% compared with
solitary ACE treatment, without any mortality signal.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker
valsartan in chronic heart failure. N Engl J Med 2001;345: 1667-75.
 Cochrane meta-analysis
– combination ACE and ARB therapy did not show a
reduction in mortality but did report an increase in drug
withdrawal because of side effects and complications,
chiefly, renal dysfunction and hyperkalemia
Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor
blockers for heart failure. Cochrane Database Syst Rev 2012;4: Cd003040.
ARBs: An Alternative to ACE
Inhibitors

17.  The third CHARM study, in patients with HF with
preserved ejection fraction
–  no statistically significant difference between
candesartan and placebo for the primary end point.
– HF hospitalizations were decreased.
ARBs: An Alternative to ACE
Inhibitors

18.  Mechanistic rationale:
 inhibit angiotensin II effects by blocking the angiotensin I
receptor.
– more complete blockade of the negative effects of
angiotensin II than with ACE inhibition, (angiotensin II
continues to be generated through non-ACE pathways)
 full angiotensin I receptor blockade leads to increased
circulating angiotensin II, which might then affect
angiotensin II receptors
ARBs: An Alternative to ACE
Inhibitors

19. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Recommendations for use:
– treatment for patients older than 55 years with mild to
moderate HF with LVEF 30%.
– Recent (within 6 months) hospitalization for cardiovascular
disease, or with increased levels of brain natriuretic
peptide (BNP) or N-terminal pro-BNP.
– Patients after MI with LVEF < 40% and HF or patients with
LVEF 30% and diabetes.
– LVEF < 30% and severe symptomatic HF (NYHA IIIB-IV)
despite

20. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Evidence-based agents and doses:

21. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Clinical trial evidence:
 1. The RALES study  1663 patients with severe HF
(current NYHA class IV) or class III with a history of class
IV within the previous 6 months and LVEF 35%,
randomized to spironolactone 12.5-75 mg once daily or
placebo. All patients were also receiving an ACE inhibitor
and a loop diuretic.
– relative risk reduction for all-cause mortality, 30%
– also associated with symptomatic improvement.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341: 709-17.

22. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Clinical trial evidence:
 2. The EPHESUS study included 6632 HF patients with
acute MI and LVEF 40%.46 Subjects were randomized to
eplerenone (titrated to 50 mg once daily) or placebo.
– 15% relative risk reduction in all-cause mortality (P ¼
0.008).

23. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Clinical trial evidence:
 3. EMPHASIS-HF included 2737 patients with NYHA
class II HF and LVEF 35%.
– eplerenone (up to 50 mg daily) or placebo and followed
for a median of 21 months.
– relative risk reduction of 37%. For all-cause mortality
alone, the relative risk reduction was 24%.

24. MRAs (aldosterone antagonsits):
Another Key Contributor to RAAS
Blockade
 Mechanistic rationale:
– inhibit the effects of aldosterone
– why MRAs work in HF is still to be fully elucidated.
– improve vascular endothelial function
– reduce myocardial fibrosis
– increase levels of serum potassium
– attenuation of remodelling with low LVEF

25. B-Blockers: HR Control and Beyond
 Recommendations for use:
 all HF patients with LVEF 40%
(true contraindication symptomatic hypotension
despite adjustment of other therapies, severe reactive
airway disease, symptomatic bradycardia, or significant
atrioventricular block without a permanent pacemaker
 Evidence-based agents and doses:

26. B-Blockers: HR Control and Beyond
 Clinical trial evidence:
 1.US Carvedilol HF Program (USCP)
– patients with chronic HF (LVEF 35%) to carvedilol or
placebo. 95 %percent were receiving an ACE inhibitor.
–  all-cause mortality was reduced by 65% (P < 0.001).
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and
mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study
Group. N Engl J Med 1996;334: 1349-55.

27. B-Blockers: HR Control and Beyond
 2. Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)
– patients with NYHA class III or IV HF and LVEF 35% to
bisoprolol titrated to 10 mg per day or placebo. (96%)
patients were receiving an ACE inhibitor at baseline
– relative risk reduction for all-cause mortality was 34%
(hazard ratio 0.66; 95% CI, 0.54-0.81).

28. B-Blockers: HR Control and Beyond
 3. Metoprolol CR/XL Randomized Intervention Trial in
Chronic HF (MERIT-HF)
– CR/XL metoprolol up to 200 mg daily was compared
with placebo among 3991 patients with NYHA class II-IV
HF and LVEF 40% (90% were receiving an ACE inhibitor at
baseline)
–  total mortality or hospitalizations because of worsening
HF, was reduced by 31% with metoprolol.

29. B-Blockers: HR Control and Beyond
 4. Carvedilol Prospective Randomized Cumulative
Survival trial (COPERNICUS)
– carvedilol vs placebo and added to standard therapies in
patients with severe HF (symptoms at rest or on minimal
exertion and ejection fraction < 25%)
– relative risk reductions of 27% for death or
cardiovascular hospitalization and 31% for the combined
risk of death or hospitalization for worsening HF.

30. B-Blockers: HR Control and Beyond
 Mechanistic rationale:
– blockade of adrenergic receptors
– HR reduction
– enhancement of cardiac myocyte function and survival
– increase LVEF
– modulate LV remodelling
– reduce myocardial oxygen consumption and blood pressure
inhibition of myocardial ischemia
– Increased availability of energy for myocyte maintenance and repair
– prevention of arrhythmogenesis
– inhibition of renin secretion

31. B-Blockers: HR Control and Beyond
 Mechanistic rationale:
 HR reduction benefits in HF morbidity and mortality
– every HR reduction of 5 beats per minute (bpm) was
associated with an 18% reduction in mortality risk.
– change in HR and favourable changes in LV volume
McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-
blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med
2009;150:784-94.

32. Importance of HR Regulation in HF
Swedberg K, Komajda M. The beat goes on: on the importance of heart rate in chronic
heart failure. Eur Heart J 2012;33:1044-5.
Increased HR
myocardial
function
mechanical
dyssynchrony
inotropy.

33. Ivabradine: A Novel Intervention for
HR Control
 Recommendations for use:
– ivabradine therapy might be considered in patients who
remain symptomatic with a HR > 70 bpm despite optimal
medical therapy including b-blockers, to reduce
hospitalizations and deaths because of HF
McKelvie RS, Moe GW, Ezekowitz JA, et al. The 2012 Canadian Cardiovascular Society
heart failure management guidelines update: focus on acute and chronic heart failure. Can
J Cardiol 2013;29:168-81.
– European and Australian guidelines have endorsed
ivabradine for HF patients with uncontrolled Heart rates
– Starting dose: 5 mg b.i.d Target dose: 7,5 mg b.i.d

34. Ivabradine: A Novel Intervention for
HR Control
 Clinical trial evidence:
 Systolic Heart Failure Treatment With the If Inhibitor
Ivabradine Trial (SHIFT)
– 6558 patients with symptomatic HF and LVEF 35%, in
sinus rhythm with HR > 70 bpm. Subjects were
randomized to ivabradine or placebo. (With stable background
treatment (91% ACE inhibitors or ARBs and 89% receiving b-blockers))
– cardiovascular death or hospital admission for
worsening HF the relative risk reduction was 18%
(hazard ratio, 0.82; 95% CI, 0.75-0.90).

35. Ivabradine: A Novel Intervention for
HR Control
 Mechanistic rationale:
– Ivabradine selectively decreases HR by inhibiting the
pacemaker current If, slowing diastolic depolarization in
the sinus node.
– ivabradine is more active as the HR increases (when
channels are more often open).
– Reducing HR
– reduced myocyte ischemia
– increased available energy for myocyte maintenance and repair.
– reduced LV end-diastolic pressure
– improved LV relaxation
– increased endothelial nitric oxide synthase expression

37. Combined Angiotensin Receptor and
Neprilysin Inhibition: A Novel Intervention for
Augmenting Adaptive Vasoactive Peptides
 Clinical trial evidence:
 (PARADIGM-HF) study
– Angiotensin Receptor -Neprilysin Inhibition (LCZ696 200
mg twice daily)  a combination of valsartan and sacubitril
– was compared with the ACE inhibitor enalapril 10 mg
b.i.d., in class II-IV HF with an LVEF 40%
– death from cardiovascular causes or hospitalization for
worsening HF, produced a 20% relative risk reduction.
(hazard ratio, 0.80; 95% CI, 0.73-0.87)

38. Combined Angiotensin Receptor and
Neprilysin Inhibition: A Novel Intervention for
Augmenting Adaptive Vasoactive Peptides
 Mechanistic rationale:
– work by enhancing the beneficial physiological response of
natriuretic peptides while inhibiting the deleterious effects
of angiotensin-II mediated RAAS activation.

40. Conclusions
 Most patients with HF will benefit from one or more
blockers of the RAAS (ACE inhibitors, ARBs, and MRAs)
and b-blockers, all of which reduce morbidity and
mortality.
 HRindependent risk factor for HF complications
 Addition to our therapeutic armamentarium of ivabradine
will further reduce risk for those with persistently high
HRs despite b-blocker therapy.
 Combination of angiotensin II-receptor and neprilysin
inhibition provides yet another way to improve the
outcome of patients with systolic HF