Diastolic Heart Failure

Dr. Alexander Lyon Senior Lecturer and Consultant Cardiologist

Royal Brompton Hospital and Imperial College, London

Clinical Lead for Cardio-Oncology

Heart Failure Association of ESC Board Member

a.lyon@rbht.nhs.uk

Advanced Medicine 2017

Heart Failure with Preserved Ejection Fraction

Dr. Alexander Lyon Senior Lecturer and Consultant Cardiologist

Royal Brompton Hospital and Imperial College, London

Clinical Lead for Cardio-Oncology

Heart Failure Association of ESC Board Member

a.lyon@rbht.nhs.uk

Advanced Medicine 2017

Overview

• What is ventricular diastole?

• What is Heart Failure with Preserved Ejection Fraction (HFpEF)?

• Mechanisms

• Treatment options

• Management plan

What is ventricular diastole?

• Ventricular filling

• AV closure - Isovolumic relaxation

• MV opening – Early filling – active

relaxation – E wave

– Late filling – passive (ventricle), active atria – A wave

• Isovolumic contraction

• Ends with AV opening

DIASTOLE DIASTOLE

Normal Diastolic Ventricular Filling

E A E A E A

Typical Modern Echo report

Diastolic Function / Dysfunction

Diagnostic algorithm for a diagnosis of heart failure

Piotr Ponikowski et al. Eur Heart J 2016;37:2129-2200

Left Ventricular Ejection Fraction

Ejection Fraction LVEF = LVEDV-LVESV

LVEDV

EuroHeart Failure Survey

Healthy Subjects

Classification of Heart Failure based upon Left Ventricular Ejection Fraction

Structural cardiac remodelling • Left atrial dilatation and/or • Left ventricular hypertrophy Functional diastolic dysfunction • Elevated E/E’

Normal vs HFpEF

HFpEF Pathophysiology Cardiac Non Cardiac

Borlaug, Nature Reviews Cardiology, 2013 Sharma K. Circ Res 2014

Hierarchy of mechanisms of diastolic dysfunction

David A. Kass et al. Circulation Research. 2004;94:1533-1542

What is HFpEF?

Patel HC et al Eur J Heart Fail. 2014 Jul;16(7):767-71.

1. 22% of HHF have an EF>50%

2. 0.6% of HHF cohort suitable for RDT-HFpEF

What is HFpEF?

Patel HC et al Eur J Heart Fail. 2014 Jul;16(7):767-71.

One syndrome, multiple causes and phenotypes

• Elderly – ageing • COPD • Chronic renal failure • Diabetes • Obesity • Obstructive Sleep Apnoea • Previous cancer therapy

– Chemotherapy – doxorubicin, epirubicin – Radiotherapy – left breast DXT

• Post myocardial infarction • Post AVR for severe aortic stenosis • Cardiac amyloidosis • Hypertrophic Cardiomyopathy • Reverse remodelled HFrEF

How to treat HFpEF?

Phase III studies HFpEF All NEGATIVE:

Also:

SWEDIC (carvedilol)

J-DHF (carvedilol)

ELANDD (nebevilol)

ALDO DHF (spironolactone)

Hong Kong DHF

irbesartan/ramipirl

RAAM (eplerenone)

RELAX (sildenafil)

Why? 1. Suboptimal trial design:

- Targeting wrong patients (some were HF-REF or did not have HF) - Patients already on RAAS drugs prior to randomisation - Intolerance of study drug/optimal dose not achieved - Underpowered

2. Inadequate attenuation of the intended pathway

Open label phase 2 trial to assess safety and efficacy of RSD in symptomatic stable ambulatory patients with HFpEF

Randomised 2:1 RSD vs control (no sham)

POBA design

Do we have any options?

• 3,445 participants randomised to spironolactone (target dose 30mg OD) vs placebo

• HFpEF – EF>45%, either HHF or elevated BNP (>100pg/ml or NT-proBNP >360) • 1o endpoint composite

– CV mortality, aborted cardiac arrest or HF hospitalisation

• No difference in 1o endpoint • Reduction in HF hospitalisations (12 vs 14% p=0.04) • Pts enrolled with high BNP – significant benefit • HOWEVER

– All cause hospitalisations no difference – Geographical variation

• 2/3 US patients – enrolled with BNP – benefit • 1/3 Russia/Georgia – enrolled with HHF – no benefit

– ~33% off study drug at end of trial

Pitt et al NEJM 2014

Who develops HFpEF?

Kaplan–Meier Estimates of the Rate of End Points, According to Study Group. BP Control with Indapamide +/- Perindopril prevents HF in the Elderly

Beckett NS et al. NEJM 2008;358:1887-1898.

The all-cause mortality treatment effect of

ACE inhibitor and ARB hypertension trials.

van Vark L C et al. Eur Heart J 2012;33:2088-2097

Zinman B et al. N Engl J Med 2015;373:2117-2128

Empagliflozin reduced new onset heart failure and CV mortality in Type 2 Diabetes

New guideline recommendations to prevent heart failure

Piotr Ponikowski et al. Eur Heart J 2016;37:2129-2200

Practical Guide to Symptomatic Patients with HFpEF

• Diuretics for oedema or hypertension – Indapamide if elderly >80 years – HYVET trial – Thiazide if younger – Spironolactone* TOPCAT trial BNP subgroup

• ACE inhibitors for hypertension – irrespective of age – HYVET trial

• ARBs acceptable if intolerant of ACE I – losartan effect from LIFE trial

• Empagliflozin for type 2 diabetics with CV risk factors • Exclude

– Ischaemia – Chronotropic incompetence

• Avoid rate controlling medication

– Exaggerated HR or BP response

• ?Target Co-morbidities • Research trials – HFpEF service at Royal Brompton Hospital

HFpEF – not so easy….

29 April – 2 May 2017 PARIS, France

Abstract submission deadline: 13 January

4 days of scientific exchange

6 100+ healthcare professionals

2 000+ abstracts and cases submitted

110+ scientific sessions

300+ expert faculty members

100+ countries represented

45+ industry sessions/workshops

Topics include:

• How to deliver a Cardio-Oncology service

• Training in Cardio-Oncology

• eHealth and Cardio-Oncology

• How do I measure the quality of my service?

• Role of primary care in cancer survivors

• Immunotherapy and emerging cardiotoxicity

• Personalised medicine & genetics

• EP session –who should have ablation, ICDs, CRT?

• Anticoagulation and antithrombotic (AF, ACS)

• Radiation-induced cardiotoxicity

• Managing cardiac issues during BMSC transplants

• Cardiac tumours, carcinoid valvular disease, amyloid

• Hormone therapy and CV risk

September 20-21, 2017