Canadian Journal of Cardiology (2015)

ReviewPharmacologic Options for the

Management of SystolicHeart 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

“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.”

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

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

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).

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.

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

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.

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

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 remodelingand clinical outcomes in heart failure patients with left ventricular systolicdysfunction. J Card Fail 2002;8(6 suppl):S465-71.

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:

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.

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

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

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

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.

Recommendations

for combination ACE/ARB therapy

are variable

ARBs: An Alternative to ACE Inhibitors

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

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

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

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

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.

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).

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%.

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

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:

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.

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).

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.

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.

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

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.

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.

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

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).

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

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)

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.

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.

HRindependent 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