Epidemiology and Pharmacological Management of Heart Failure

Dr A Al-Mohammad, MD(Damascus), MD(Aberdeen), FRCP(Edinburgh), FRCP(London),

FESC, FHFA Consultant Cardiologist and Hon. Senior Clinical Lecturer

Sheffield Teaching Hospitals NHS Foundation Trust 03/05/2018

Conflicts of interest

• Consultant Cardiologist to Sheffield Teaching Hospitals

• Past Clinical Adviser: NICE-CG 108 CHF 2010

• Past member of the: NICE-CG 187 AHF 2014

• Past Expert Co-optee: NICE-NG 31 CoDA 2015

• Past Expert Co-optee: NICE-NG 45 Pre-Op tests 2016

• PI for PARAGON, Galactic HF, Ironman trials

• Member of the GC NICE CHF guidelines committee 2015-2018

• Expert Adviser to the Centre for Clinical Guidelines at NICE 2017-2020

• Editorial board member World Journal of Cardiology and Heliyon

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

Epidemiology of HF… History

• HF Framingham study 1971:

- prevalence of HF of 0.8% (50 and 59 y), 9.1% (>80 y)

- incidence of HF of 0.2% (54 y) - 0.4% (85 y)

• North-west London: 30 204 case records:

- prevalence of HF of 3.8/100 cases in the general population

Incidence and prevalence of HF in the UK

Incidence

63,000 new cases

PA

29,000 Females 34,000 Males

Prevalence

878,000

Total cases

405,000 Females 473,000 Males

Left ventricular ejection fraction (LVEF)

• In the acute and short term, the lower the LVEF, the worse is the prognosis

• There is however evidence to suggest that in the long term it does not matter what the LVEF, even in older people as the mortality rates appear to be identical whether the HF is associated with preserved or reduced LVEF

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

Raised hormones in HF

• In the SOLVD sub-study, patients with HF have significantly elevated levels of Arginine-Vasopressin, Noradrenaline and Renin compared with normal people

RAA

• Renin cleaves angiotensinogen producing angiotensin I

• Angiotensin converting enzyme (ACE) converts angiotensin I to II (AT II).

• AT II affects receptor I that leads to vasoconstriction, cell growth, water and salt retention and sympathetic activation; while AT II receptor II activation results in vasodilatation and is anti-proliferation

• AT II stimulates the secretion of Aldosterone

Sympathetic system

• In the short term secretion of noradrenaline could support myocardial function

• In the medium and long terms, the constant stimulation by Noradrenaline results in deleterious effects on the myocardium including pro-inflammatory changes that actually damage the myocardium

Aldosterone

• Retains salt and water

• Causes inflammation and scarring of the myocardium

• It is stimulated by ATII, corticotrophin, serum potassium, endothelin, vasopressin, catecholamines

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

Pharmacological interventions

• Diuretics

• ACEI

• β Blockers

• MRA (mineralocorticoid receptor antagonists)

• Hydralazine + nitrates

• ARB

• Digoxin

• Ivabradine

• Sacubitril-Valsartan

ACEI

• Improve the symptoms of HF

• Reduce hospitalisation risk

• Improve the survival rate

Beta-Blockers and HF

Several studies using cardio-selective (Bisoprolol, Nebivolol and metoprolol) and non-cardioselective (Carvedilol) beta-blockers have confirmed the effectiveness of these BB in reducing HF:

1. Mortality,

2. Hospitalisation,

3. Sudden Cardiac Death.

The trials recruited almost exclusively patients with HFREF.

The effect of reducing mortality is limited to those in SR 2014

Mineralocorticoids

• Aldosterone and eplerenone reduce the morbidity and mortality of HFREF

• While on ACEI and MRA, the patients’ renal function should be closely monitored

ARB

• They reduce the hospitalisation rate and the combined hospitalisation and mortality rates of HFREF

• They do not reduce mortality as an end point

• They are therefore not an equivalent to ACEI

Lesser response to ACEI therapy in black as compared with white patients with LV dysfunction Lancet 2001;344:1351-7

• Pooling of data from the SOLVD prevention and treatment trials.

• 1196 white pts, and 800 black pts.

• Enalapril therapy is associated with a significant reduction in the risk of hospitalisation for HF among white pts with LV dysfunction, but not among similar black pts.

Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure NEJM

2001;344:1358-65

• US Carvedilol Heart Failure Trials Program: 217 black pts and 877 non-black pts.

• NYHA II-IV, LVEF < 0.35.

• Carvedilol lowered the risk of death or hospitalisation from any cause.

• Carvedilol reduced the risk of worsening HF.

• Carvedilol improved functional class + LVEF.

• These effects were observed in all races with no significant difference in the magnitudes of these effects.

Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. (AHeFT TRIAL)

AL Taylor et al. N Engl J Med 2004;351: 2049-57

• 1050 black pts NYHA III/IV HF with dilated ventricles

• randomised to fixed dose of ISDN + hydralazine vs. placebo in addition to standard therapy for HF.

• Terminated early due to higher mortality in the placebo (10.2% vs. 6.2%, P=0.02).

• 43% reduction in death from any cause

• 33% relative reduction in first HF hospitalization

• Addition of a fixed dose of ISDN + hydralazine to standard therapy for HF including neurohormonal blockers increases survival among black pts with advanced HF.

Shift study

• Ivabradine blocks the If current of the SA node

• Its addition to therapy in patients with HFREF whose HF>70-75 bpm, has resulted in 18% reduction in morbidity and mortality.

• The patient has to be in sinus rhythm

• It is given at 2.5 mg bd, increased to 5 and then 7.5 mg bd

• It does not affect BP

SACUBITRIL-VALSARTAN

• A neprilysin inhibitor and angiotensin receptor blocker is superior to ACEI in the treatment of HFREF (PARADIGM trial NEJM 2014)

When to give a patient Sacubitril-Valsartan?

• HFREF

• LVEF<35%

• Continues to be symptomatic on optimised therapy with ACEI+BB+MRA

• Had been treated with ACEI and is thus tolerant of it

Iron and HF

• Iron deficiency affects up to 50% of patients with HFrEF, irrespective of anaemia

• i.v. Iron treatment in HFrEF improves the 6MWT and QoL (Anker et al. Eur J Heart Fail; doi:10.1002/ejhf.823)

• Meta-analysis suggested reduction in HF hospitalisation

• Oral iron does not improve Peak VO2, 6MWT, KCCQ score or NTproBNP (IRONOUT-HF trial. Lewis et al. JAMA 2017;317:1958-1966)

Efficacy of β blockers in patients with HF plus AF: an individual-patient data meta-analysis. Kotecha et al. Lancet 2014;384:2235-43

• ? the efficacy of β blockers in patients with concomitant AF is uncertain.

• 10 RCT β blockers versus placebo in HF. • The primary outcome was all-cause mortality. • 18,254 patients: 13,946 (76%) had SR and 3066 (17%) had AF. • Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were

16% in patients with SR and 21% in patients with AF. • β-blocker therapy led to a significant reduction in all-cause

mortality in patients with SR (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with AF (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002).

• β blockers should not be regarded as standard therapy to improve prognosis in patients with concomitant HF and AF

HR, Heart Rhythm, and Prognostic Benefits of BB in HF: Individual Patient-Data Meta-Analysis. Kotecha et al. JACC 2017 (doi:

10.1016/j.jacc.2017.04.001) 2

• 11RCT’s. All cause mortality reduction in HFrEF • A higher HR at baseline was associated with greater all-cause mortality in pts with

SR (n=14,166; adjusted HR 1.11 per 10 bpm; 95% CI 1.07-1.15, p<0.0001), but not in AF (n=3,034; HR 1.03 per 10 bpm; 0.97-1.08, p=0.38).

• BB reduced VR by 12 bpm in both sinus rhythm and AF. • Mortality was lower for patients in SR randomised to BB (HR 0.73 vs placebo, 95%

CI 0.67-0.79; p<0.001), regardless of baseline HR (interaction p=0.35). • BB had no effect on mortality in patients with AF (HR 0.96, 95% CI 0.81-1.12;

p=0.58) at • any HR (interaction p=0.48). • A lower achieved resting HR, irrespective of treatment, was associated with better

prognosis only for patients in SR (HR 1.16 per 10 bpm increase, 95% CI 1.11-1.22; p<0.0001).

• Regardless of pre-treatment HR, BB reduce mortality in patients with HFrEF in SR • Achieving a lower heart rate is associated with better prognosis, but only for

those in SR

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

HFEF Therapy

• Diuretics

• ACEI (PEP-CHF)

• ARB (CHARM-PRSERVED, I-PRESERVE)

• Beta Blockers (SENIORS 1/3)

• AA/MRA (TOPCAT: reduction of HF hospitalisation by small dose spironolactone)

• Ivabradine (Edify)

• All the trials in italics failed!

Plan

• Epidemiology

• Neuro-endocrine Hypothesis

• HFREF

• HFPEF

• Future Developments?

BETA BLOCKERS

• In an individual patient-level meta-analysis of multiple RCT on BB in HF:

1. BB are not effective in AF and HF

2. BB reduce all cause and CV mortality in patients with SR and either HFrEF or HFmrEF

3. BB are not effective in SR and HFpEF

AHF

AHF and trials…

• Several interventions proved to be a failure!

• TRUE-AHF: ularitide. Failed

• RELAX-AHF2: serelaxin. Failed

• BLAST-AHF: failed using a biased ligand of ATII receptor 1.

• ATHENA-HF: 100 mg spironolactone failed to improve NP or clinical measures

• Possible role for early iv furosemide in an observational study

Anniversaries

• 2017 is 30 years since the first ACEI trial for HFrEF

• 2016 is 30 years since the first ever RCT in HFrEF that showed the first ever positive result in mortality reduction

• 2017 is 50 years since the first heart transplant in the treatment of HFrEF

Final thoughts, individualised therapy

• ACEI+BB in all HFREF • Add MRA if still symptomatic • HR is >75bpm, in SR: add ivabradine • Still symptomatic, LVEF<35%, SBP>100 mmHg, stop ACEI

and add Sacubitril-Valsartan • LVEF<35%, and QRS>130 msec: CRT(P/D) • Black patients with HFREF consider Hydralazine + Nitrate • Digoxin • BB in HFREF+AF • HFPEF: Diuretics + correct (hypertension/ischaemia) &

consider spironolactone

DR A AL-MOHAMMAD Thank you