Heart failure in Women

Transcription

1 Heart failure in Women The Melbourne Women s and Children s Update 2018 Dr Hendrik Zimmet MBBS FRACP FCSANZ Heart Failure Cardiologist Associate Clinical Dean, Monash University Central Clinical School Epworth Clinical Senior Lecturer, University of Melbourne Disclosures Speaking Honoraria - Bristol-Myers Squibb - Menarini - Novartis - Pfizer - Vifor - ZOLL Sponsorship - AstraZeneca - Merck Sharp & Dohme - Menarini - Servier Site Principal Investigator - AMGEN Advisory Board Membership - Otsuka 2 SUMMARY Terminology Heart Failure in Women ARNIs (ie. Entresto) SGLT2 Inhibitors Heart Failure in Pregnancy TERMINOLOGY 3 Heart Failure - a very frightening term What does your patient think when they hear this? mortally challenged kidney failure = dialysis liver failure = transplant heart failure =?? Heart Failure - a very frightening term Rephrasing and explaining The term "heart failure" is misleading It does NOT mean the heart has "failed" or stopped working. It simply means that your heart does not work as well as it should. Heart Dysfunction 5 6 1

2 Heart Failure is a SYNDROME not a single disease DEFINITIONS combination of typical symptoms and signs due to a number of different underlying heart disorders 8 Causes of Heart Failure CAUSES OF HF Ischaemic Heart Disease Hypertension Valvular Heart Disease Cardiomyopathy Acute (typically myocarditis) Dilated Hypertrophic Restrictive High-output Cardiac Failure Tachycardia-induced Thyroid, other Pericardial 10 CATEGORIZATION HFREF VS HFPEF 2

3 Ventricular Function In Heart Failure Systolic HF (aka HFREF) Systolic (HFREF - HF with reduced EF) vs Diastolic - HF with preserved ejection fraction (HFPEF) Heart failure with reduced left ventricular ejection fraction (ie. LVEF <50%) decreased ability of the heart to contract Diastolic HF (aka HFPEF) Definition of HFrEF and HFpEF Patients with symptoms & signs of heart failure and preserved LVEF (ie. LVEF >50%) Definite HFrEF (LVEF <40%) Uncertain (40% LVEF <50%) Definite HFpEF (LVEF 50%) Also known as HFPEF(heart failure with preserved ejection fraction) decreased ability of the heart to fill, typically due to impaired myocardial relaxation 50% 14% 36% 0% 20% 40% 60% 80% 100% Proportion of patients 15 HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LVEF: left ventricular ejection fraction Steinberg et al. Circulation 2012;126:65 75 HEART FAILURE IN WOMEN EPIDEMIOLOGY 3

4 As there are no national data for heart failure in Australia, the Australian Institute of Health and Welfare has used overseas findings to estimate incidence in Australia BEACH. Management of heart failure in general practice patients Australian Bureau of Statistics Population Projections, Australia, 2012 to Available at ww.abs.gov.au/ausstats/abs@.nsf/latestproducts/3222.0main Features32012 (base) to 2101?opendocument&tabname=Summary&prodno=3222.0&issue=2012%20(base)%20to%202101&num=&view=. Accessed September Australian Bureau of Statistics, Causes of Death, Australia, 2013 Available at A ccessed July Australian Institute of Health and Welfare Cardiovascular disease: Australian facts Cardiovascular disease series. Cat. no. CVD 53. Canberra: AIHW. 5. National Heart Foundation of Australia. A systematic approach to chronic heart failure care: a consensus statement. Melbourne: National Heart Foundation of Australia, Available at Accessed June National Heart Foundation of Australia. Australian Heart Disease Statistics Available at Accessed June HF in Women - Epidemiology I More likely to be diagnosed at an older age More likely to be hypertensive and have preserved systolic function Less coronary artery disease Prior MI associated with a higher risk of developing HF 19 HF in Women - Epidemiology II Have better survival after onset of HF, with a mortality risk approximately 15-20% less than men Tend to be more symptomatic at presentation Have higher HF hospitalization rate than men 20 CVD in women with Diabetes Mellitus (DM) CVD presents later in life in women however, this agerelated difference is attenuated in women with DM 1 DM increases the risk of cardiovascular disease 3-4x in women compared with 2-3x in men 1 DM may reduce gender-related differences in prevalence of CVD by fading the vascular protective effects afforded by oestrogen in females 2 Relationship between changes of balance of oestrogen receptors (ERα and ERβ) with dichotomous effects by estrogen 2 1. Norhammar A, Schenck-Gustafsson K. Type 2 diabetes and cardiovascular disease in women. Diabetologia Sep 4;56(1): Dantas APV, Fortes ZB, de Carvalho MHC. Vascular Disease in Diabetic Women: 21 Why Do They Miss the Female Protection? Experimental Diabetes Research. 2012;2012(11):1 10. Heart failure affects a large number of Australians each year, placing a significant burden on the healthcare system 1-5 >400,000 Australians (1.7%) had heart failure in ,2 50,983 hospitalisations With primary diagnosis of heart failure in Australia in ,244 deaths were listed as caused by heart failure in Australia in ~30,000 Australians are newly diagnosed >$1 billion per annum in costs to the Australian economy 5 with chronic heart failure every year days average length of stay 4 Mortality in Heart failure HF is associated with significant mortality The Vulnerable Period 30% of patients discharged following a HF hospitalization are readmitted with the first 30 days Vulnerable period = 1st 30 days post discharge Strategies - Early review post-discharge (within 2 weeks) - Cardiac Rehab (ideally HF specific)

5 Many patients are discharged with unresolved congestion, which is associated with poor long-term outcomes Recurrent Hospital Admission - Causes OFTEN DUE TO INEFFECTIVE FLUID REMOVAL Lack of patient understanding of importance of daily weighs and when to seek help Lack of patient understanding of fluid restriction, and how to follow it Incomplete medication list, and lack of understanding of importance of medications Heart failure imposes a significant economic burden on the healthcare system PATHOPHYSIOLOGY 27 HF in Women - Pathophysiology Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy Growing body of evidence to suggest female myocardium has distinct adaptive mechanisms more robust than males Differences in Myocardial calcium handling due to oestrogens NO synthesis Reduction of matrix turnover by oestrogens Down-regulation of the RAAS by endogenous oestrogens Shah RU, Klein L, Lloyd-Jones DM. Heart failure in women: epidemiology, biology and treatment. Womens Health (Lond) Sep;5(5): Natriuretic peptide system 1 NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone HFrEF SYMPTOMS Fibrosis & PROGRESSION Hypertrophy The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β-blockers indicate that the SNS also plays a key role 1 ACEI: angiotensin-converting-enzyme inhibitor; Ang: angiotensin; ARB: angiotensin receptor blocker; AT 1R: angiotensin II type 1 receptor; MRA: mineralocorticoid receptor antagonist; NPs: natriuretic peptides; NPRs: natriuretic peptide receptors; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system 1. McMurray et al. Eur Heart J 2012;33: ; Figure References: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012;365 71; Schrier & Abraham. N Engl J Med 2009;341: Sympathetic nervous system Epinephrine Norepinephrine α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Renin-angiotensinaldosterone-system Ang II AT 1R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis 5

6 Key Symptoms CLINICAL PRESENTATION Shortness of Breath NYHA Class ORTHOPNOEA Paroxysmal nocturnal dyspnoea (PND) Oedema Peripheral oedema (Ascites) 32 Quantifying Oedema DONT JUST CHECK THE ANKLES!! Follow the oedema up the legs and ascertain how high it goes. Good places to look - lateral and posterior lower leg - lateral and medial thigh - lower abdominal wall - sacral region Approximating amount of fluid - Feet ~500ml each - Lower leg ~ 1L each - Thighs ~2-3L each Oedema extending above the knees typically responds poorly to oral Frusemide Once Oedema extends above the level of the knees, there is usually a significant amount of gut / splanchnic oedema This gut oedema results in reduced absorption of oral Frusemide Other medications appear to NOT be significantly affected Patients with this degree of oedema / fluid overload typically require intravenous Frusemide to achieve effective diuresis INVESTIGATIONS Investigations Echo, echo, echo... ABSOLUTE KEY INVESTIGATION IN ANY PATIENT WITH SUSPECTED HEART FAILURE Cardiac size & structure Systolic & diastolic function Left side vs right side Pulmonary pressures Valves Pericardium 36 6

7 BNP (Brain Natriuretic Peptide) Utility of Cardiac MR in Cardiomyopathy Produced by Ventricular Muscle under stretch / strain SUPPLEMENTS CLINICAL JUDGEMENT When cause of dyspnoea uncertain 3 different assays: BNP, probnp, NT-proBNP - reference ranges NOT comparable - only NT-proBNP can be used to track progress in patients on ARNIs (Entresto) NOT Medicare Rebatable Highly accurate EF assessment Detection of myocardial oedema and inflammation (eg. myocarditis) Patterns of fibrosis characteristic appearances for ischaemia, DCM, HCM and other aetiologies arrhythmic risk TREATMENT Tiers of Heart Failure Therapy TREATMENT OF UNDERLYING CAUSE Non-pharmacological Fluid intake Salt intake Pharmacological Tablets (Inotropes) Devices ICDs Cardiac resynchronization (CRT) / Biventricular pacing Cardiac Rehabilitation & MULTI-DISCIPLINARY CARE Transplantation (& Mechanical Circulatory Support) 40 HF in Women - Therapy Women comprise <20% of patient in most major HF Clinical Trials to date β-blockers have the most data to support their use in women Older women with heart failure are less likely to receive guideline recommended treatments Women are 3 times less likely than men to receive an ICD NON-PHARMACOLOGICAL Surgical therapies for advanced HF, such as high risk CABG, mitral valve repair, left ventricular assist device implantation and cardiac transplantation, are far less likely to be used in women 41 7

8 Optimal Fluid Balance Management KEY PRINCIPLE 1L of fluid = 1kg of weight PILLARS OF MANAGEMENT Daily weighs Fluid Restriction (1.5L/day) NOT always required ONLY required in patients with problems of fluid overload OPTIMIZATION Patient diary Medical review if weight increase >1kg/day for 2 days >2.5kg over 1 week PHARMACOLOGICAL Fluid Restriction patient education handout Track / Record Fluid Intake for 1 week until routine established 43 HFrEF survival rates have improved over time with the introduction of new therapies TREAT CONGESTION!! Euvolaemia is everything! 45 The Addition of I for Ivabradine (aka Coralan) ARNI: angiotensin receptor neprilysin inhibitor Sinus Node Inhibitor - reduces heart rate (HR) Place in therapy - patients intolerant of beta-blockers - patients on max tolerated beta-blocker with HR > 70 bpm SHIFT trial - LVEF <35% - HR > 70 bpm

9 O HO HN O OH O O N N N N O OH NH 50 LCZ696 simultaneously inhibits neprilysin (via LBQ657) and blocks AT 1 receptors (via valsartan) ANP, BNP, CNP, other vasoactive peptides* LCZ696 RAAS Angiotensinogen (liver secretion) Sacubitril (AHU377; pro-drug) Inactive fragments Enhancing LBQ657 (NEP inhibitor) Valsartan Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Ang: angiotensin; ANP: atrial natriuretic peptide; AT 1: angiotensin II type 1; BNP: B-type natriuretic peptide; CNP: C-type natriuretic peptide; NEP: neprilysin; RAAS: reninangiotensin-aldosterone system Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier & Abraham. N Engl J Med 2009;341:577 85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9; Feng et al. Tetrahedron Letters 2012;53:275 6 Ang I Ang II AT 1 receptor Inhibiting Vasoconstriction Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy Sodium and water retention PARADIGM-HF Trial Summary of Results Baseline demographics were similar between treatment groups 1 ENTRESTO Enalapril (n=4187) (n=4212) Age, mean 63.8± ±11.3 Female, % (n) 21.0 (879) 22.6 (953) Heart rate, beats/min 72±12 73±12 SBP, mmhg 122±15 121±15 LVEF, % 29.6± ±6.3 Ischaemic cardiomyopathy, % (n) 59.9 (2506) 60.1 (2530) I 4.3 (180) 5.0 (209) II 71.6 (2998) 69.3 (2921) NYHA class, % (n)* III 23.1 (969) 24.9 (1049) IV 0.8 (33) 0.6 (27) Missing data 0.2 (7) 0.1 (6) White 66.0 (2763) 66.0 (2781) Black 5.1 (213) 5.1 (215) Race, % (n) Asian 18.1 (759) 17.8 (750) Other 10.8 (452) 11.1 (466) 51 Adapted from McMurray JJ et al. (2014). 1 *The data for NYHA class reflect the status of patients at the time of randomisation. Patients were required to have at least NYHA Class II symptoms at screening. Race or ethnic group was reported by the investigators. LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; SBP: systolic blood pressure. 1. McMurray JJ et al. N Engl J Med 2014;371(11): Therapeutic Algorithm for patient with symptomatic HFREF Diastolic Heart Failure (HFPEF) Management?? Consider reducing HR to <70 bpm >50%) β-blocker 9

10 PRESCRIBING ENTRESTO Prescribing Entresto Use of Entresto is very similar to ACEI & ARBs Side effect profile of Entresto. is very similar to ACEI & ARBs 2 Major Exceptions must have 36 hour washout period between ACEI Entresto has an additional diuretic effect which varies between patients PARADIGM-HF: Select inclusion and exclusion criteria 1 Inclusion At least 18 years of age NYHA Class II IV EF 35%* BNP 150 pg/ml or NT-proBNP 600 pg/ml OR BNP 100 pg/ml or NT-proBNP 400 pg/ml (if hospitalised for HF in previous 12 months) Exclusion Symptomatic hypotension SBP <100 mmhg at screening or <95 mmhg at randomisation egfr <30 ml/min per 1.73 m 2 or a decrease of >35% between screening and randomisation Serum K + >5.2 mmol/l at screening or >5.4 mmol/l at randomisation History of angioedema or unacceptable side effects during treatment with ACEIs or ARBs 57 *40% before protocol amendment. 25% before protocol amendment. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin-receptor blocker; BNP: B-type natriuretic peptide; EF: ejection fraction; egfr: estimated glomerular filtration rate; HF: heart failure; NT-proBNP: N-terminal probnp; NYHA: New York Heart Association; SBP: systolic blood pressure. 1. McMurray JJ et al. N Engl J Med 2014;371(11): Switching to ENTRESTO : Patients previously on an ACEI Switching to ENTRESTO : Patients previously on an ARB ACEI equivalent dose Choose initial dose of ENTRESTO based on current treatment and titrate to the target dose 1 ARB equivalent dose Choose initial dose of ENTRESTO based on current treatment and titrate to the target dose 1 Patients receiving a total daily dose of >10 mg of enalapril or therapeutically equivalent doses of another ACEI; for example 1,2 Perindopril erbumine >4 mg Ramipril >5 mg Patients receiving a total daily dose of 10 mg of enalapril or therapeutically equivalent doses of another ACEI; for example 1,2 Perindopril erbumine 4 mg Ramipril <5 mg Stop ACEI 36 hours before starting ENTRESTO Stop ACEI 36 hours before starting ENTRESTO Start ENTRESTO at the recommended dose of 49/51 mg twice daily 1 Start ENTRESTO at Double the dose after the recommended 2 to 4 weeks to 49/51 dose of 24/26 mg mg twice daily, as twice daily tolerated by the patient Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient Patients receiving a total daily dose of >160 mg of valsartan or therapeutically equivalent doses of another ARB; for example 2 Irbesartan >150 mg Candesartan >16 mg Patients receiving a total daily dose of 160 mg of valsartan or therapeutically equivalent doses of another ARB; for example 2 Irbesartan 150 mg Candesartan 16 mg Start ENTRESTO at the recommended dose of 49/51 mg twice daily 1 Start ENTRESTO at Double the dose after the recommended 2 to 4 weeks to 49/51 dose of 24/26 mg mg twice daily, as twice daily tolerated by the patient Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient ACEI: angiotensin-converting enzyme inhibitor. 1. ENTRESTO Product Information. TGA-approved Product Information. Novartis Pharmaceuticals Australia Pty Limited. 2. Data on file. CSR CLCZ696B2228. Novartis Pharmaceuticals Corp; East Hanover, NJ. November Important safety information ENTRESTO is contraindicated with concomitant use of an ACEI and in patients with a history of angioedema related to previous ACEI therapy. 1 ARB: angiotensin-receptor blocker. 1. ENTRESTO Product Information. TGA-approved Product Information. Novartis Pharmaceuticals Australia Pty Limited. 2. Data on file. CSR CLCZ696B2228. Novartis Pharmaceuticals Corp; East Hanover, NJ. November Important safety information ENTRESTO is contraindicated in patients with a history of angioedema related to previous ARB therapy. Avoid use of ENTRESTO with an ARB

11 Optimal Dosing / Uptitration Clinical trial evidence is generally for highest / maximum tolerated dose. UPTITRATE AS TOLERATED Which medication first? - relieve symptoms - combination better than single agent - trials suggest outcomes equal whether ACEI/ARB or beta-blocker first Dealing with Side Effects Most common - Reduced BP, elevated K, increased Cr/Ur - Reduced HR (only with beta-blockers & Ivabradine) SEE IF ANOTHER NON-HF MEDICATION CAN BE REDUCED OR CEASED - eg. Slow K, Amlodipine, (even diuretic in patient on Entresto) If no other option then consider - reducing another HF medication - that particular HF medication - ceasing that particular HF medication if absolutely necessary Mechanism of action SGLT2 INHIBITORS 64 Clinical Trial Outcomes Empagliflozin demonstrated an unprecedented 38% reduction in CV mortality in patients with diabetes Highly significant reductions in HF hospitalizations and end-stage kidney disease 1% reduction in HbA1c levels, with favorable reductions in both BP ( 3 6 mmhg) and body weight ( 2 4 kg/m2). EMPA-REG OUTCOME : summary Empagliflozin in addition to standard of care reduced CV risk and improved overall survival in adults with T2D at high CV risk 14% 3P-MACE 38% CV death 32% All-cause mortality 35% Heart failure hospitalisations The overall safety profile of empagliflozin was consistent with previous clinical trials and current label information Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Nov 26;373(22): P-MACE, 3-point major adverse cardiovascular events Empagliflozin is not indicated for CV risk reduction. CV, cardiovascular; T2D, type 2 diabetes Zinman B et al. N Engl J Med 2015;doi: /NEJMoa ; Zinman B. EASD 2015; Oral presentation 66 11

12 Additional Observed Effects Induces plasma volume contraction without activation of the sympathetic nervous system Might improve efficiency of myocardial energetics Decreased vascular stiffness and improved endothelial function HF IN PREGNANCY In future, might even be considered in HF or chronic kidney disease patients without diabetes 1. Martens P, Mathieu C, Verbrugge FH. Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond. Current Treatment Options in Cardiovascular Medicine; 2017 Mar 22;: HF and Pregnancy 2 major types HF emerging during pregnancy in women with documented preexistent CV disease Development of HF in the peripartum period in women without previous evidence of heart disease 69 HF during pregnancy in women with preexistent CV disease May be due to pregnancy-related changes in volume status red cell mass peripheral vascular resistance heart rate circulatory hormones prostaglandins procoagulant factors 70 HF during pregnancy in women with preexistent CV disease Risk of HF dependent on type of pre-existing cardiac lesion phase of the pregnancy Serious complication Increased maternal and foetal mortality Peripartum Cardiomyopathy - Definition, Epidemiology, Risk Factors HF with LV dysfunction occurring in the last months of pregnancy or the first several months postpartum Risk factors - preeclampsia - African ancestry Aetiology remains unknown with multiple hypotheses proposed

13 Peripartum Cardiomyopathy - Treatment and Outcomes Bromocriptine may offer a specific treatment though this will requires further study No evidence-based differences in the management with the exception of - anticoagulation, as pregnancy is associated with hypercoagulability - prohibition of the use of ACE inhibitors KEY POINTS Recovery of LV function quite variable Risk of recurrence with subsequent pregnancies high and woman should be advised of this 73 When To Refer to a Cardiologist? ALWAYS AT DIAGNOSIS WHENEVER THERE IS A SIGNIFICANT CHANGE IN SYMPTOMS OR STATUS IDEALLY - A TEAM EFFORT & APPROACH - Regular GP reviews - Periodic Cardiologist review Key Points HF is a syndrome with multiple underlying causes There are significant differences in HF between men and women Entresto is a new and power addition to current HF theapy HOWEVER it should be used after standard therapies have been trialled and fully uptitrated SGLT2 Inhibitors produce unprecedented reduction in Cardiac and HF events in diabetics AND may ultimately be used to treat HF in their own right SUMMARY Terminology Heart Failure in Women ARNIs (ie. Entresto) SGLT2 Inhibitors Heart Failure in Pregnancy Resources UpToDate Heart Failure Guidelines National Heart Foundation of Australia Cardiac Society of Australia & New Zealand (CSANZ) American Heart Association (AHA) European Society of Cardiology (ESC) iphone & Android AHA & ESC Guidelines