Heart Failure with preserved ejection fraction (HFpEF) Dr. Pierpaolo Pellicori Hull York Medical School Kingston-upon-Hull United Kingdom Conflict of interest: none
Heart failure is a contemporary problem Incidence:- Many people in this room will develop some form of HF Prevalence (depending on definition):- ~3% of adults have some objective evidence ~25% of patients aged >50 years with T2DM or Hypertension ~50% (or more?) of patients with AF
Chan,Lam. EJHF 2013. Ather, JACC 2012
Typical HFPEF Patient Female, in her 70-80s Clinical history of HTN Breathlessness Peripheral oedema and raised JVP 40% AF on ECG NTproBNP above 1000 ng/l (normal < 125 ng/l) IVC (& intrahepatic veins) distended Anaemia and CKD
How to diagnose HFpEF? 2012 ESC-HF guidelines
Key echo structural alterations: left atrial volume index (LAVI) >34 ml/m2 left ventricular mass index (LVMI) 115 g/m2 for males and 95 g/m2 for females. E/e 13 Mean e septal and lateral wall <9 cm/s
NTproBNP Marker of Congestion Strongest predictor of prognosis in CHARM-Preserved PEP-CHF I-PRESERVE Also increased with common co-morbidities Low egfr Atrial Fibrillation
Cleland et al.
SAVOR - TIMI 53 Risk of HF hosp according to NTproBNP > 50% NTproBNP > 125 ng/l # # 12% had previous HF diagnosis; 3% had previous HF hosp; AF not reported Scirica et al, 10.1161/CIRCULATIONAHA.114.010389
National heart failure audit 2014-15
At echocardiography: LVEF might be normal Advanced echo (GLS): impaired LV longitudinal function Dilated left atrium and inferior vena cava (and raised NTproBNP) are powerful predictors of adverse outcome Pellicori P et al. Int J Cardiovasc Imaging. 2014;30(1):69-79
Cameli et al. Am J Cardiol 2013;111(4):595-601. Pellicori et al - Eur Heart J. 2015;36(12):733-42 Novel modalities Left atrial function?
Pellicori et al Int J Cardiol. 2014 Jan 1;170(3):364-70 Pellicori et al Heart. 2015 Jul;101(14):1149-58. Novel modalities jugular vein ultrasound?
How to treat HFpEF? No treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF. Screen for cardiovascular and non-cardiovascular comorbidities Manage them to improve symptoms/outcome.
Goals of Treatment A real clinical outcome should be something that patients and doctors care about Control of Symptoms Independent Living Reducing Morbidity (Hospitalization) Reducing Mortality Most Important? Least Important?
Randomised Controlled Trials ARB ACE-I CHARM-Preserved PEP-CHF I-PRESERVE Beta-blockers SENIORS DIURETICS Mainly MRAs LCZ696 Other treatments
Heart Failure (64% reduction) Placebo P<0.0001 IndapamideSR ±perindopril Placebo IndapamideSR ±perindopril
PEP-CHF: Primary end-point at one year Proportion having an event (%) 20 15 10 CV Death or HF Hosp P=0.01 at one year Placebo Perindopril 4mg 5 0 HR 0.69; 95% CI 0.47 to 1.01; p=0.055 Relative risk reduction -31% 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (mo) Patients at risk Perindopril 424 408 399 390 Placebo 426 405 387 374 374 356
Cumulative Incidence of Primary Events (%) I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization (Mean follow-up 49.5 months) 40-30 - 20 - HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35 Placebo NT-proBNP 320 (131 946) Placebo Irbesartan 75-300mg/day (mean 275mg/day) 10 - All Secondary Endpoints Neutral! 0 - No. at Risk Irbesartan Placebo 0 6 12 18 24 30 36 42 48 54 60 Months from Randomization 2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497 2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446
I-PRESERVE Trial Effect of Irbesartan by baseline NT-proBNP median HR and 95% CI p-value Primary Endpoint All Patients (n=3480) Patients with NT-proBNP < median p=0.37 p=0.003 Patients with NT-proBNP > median Hospitalization for HF and Pump Failure Deaths p=0.47 All Patients (n=3480) Patients with NT-proBNP < median Patients with NT-proBNP > median p=0.68 p=0.001 p=0.19 Anand, Rector, Cleland et al Circ HF 2011 0.4 0.6 0.8 1.0 1.2 1.4 Hazard ratio
158 patients, post MI, LVEF > 40% At 32-month follow-up Propranolol caused a 35% significant reduction in total mortality However, Propranolol was discontinued because of adverse effects in 14% patients because of worsening CHF and hypotension
97 patients with symptoms and/or signs of HF, LVEF > 45% and DD. Carvedilol did not improve LVDD. There was a trend in worsening symptoms in Carvedilol group. LA size and BNP plasma levels significantly increased in Carvedilol group at 6/12.
245 patients (mean age 72, 58% men), LVEF > 40% were randomised to Carvedilol or placebo and followed up a mean of 3.2 years. Carvedilol did not improve prognosis of HFPEF patients Note: median prescribed dose was 7.5 mg/day.
Double-blind trial - 61 patients with HFPEF. Short term use of Ivabradine (7 days) has been shown to significantly decrease the post exercise LV filling pressures (E/E ), improving exercise capacity (peak Vo2) compared with placebo.
22 pts with HFpEF, randomised, X-over, Ivabradine vs placebo for 2 weeks Ivabradine reduced peak Vo2 (primary outcome) Circulation. 2015;132:1719-1725
150 patients LVEF > 45% The use of diuretic (either loop diuretic or thiazide) quickly improved symptoms and quality of life. Significant biochemical (NTproBNP) and echocardiographic improvement at follow up with combined use of diuretic and ACE-I or ARBs.
422 patients with HFPEF Spironolactone improved echocardiographic findings (E/E ). However, changes in E/e were not associated with any clinical improvement. 6WMT, egfr and Hb levels decreased with Spironolactone!!!! Patients were too healthy (median NTproBNP 158 (IQR: 83-299), 77 % grade I DD).
110 patients (57% women) with HFpEF (median NTproBNP ~ 240 ng/l) X-over: Isosorbide mononitrate (up to 120 mg/day) or placebo Results: nitrates decreased level of activity and did not improve QoL.
216 patients with HF, raised NTproBNP and LVEF > 50% Sildenafil (up to 60 mg tds) or placebo for 24 weeks Median NTproBNP ~ 700 ng/l Sildenafil did not improve exercise capacity or clinical status. Serious adverse events: 16% placebo vs. 22% Sildenafil
52 patients with HFpEF and raised PA pressure (mean PAP > 25 mmhg) Median NTproBNP ~ 1000 ng/l Randomised to sildenafil (up to 60 mg TDS) or placebo for 12 weeks Conclusions: sildenafil did not improve haemodinamics Adverse events: similar between placebo and sildenafil (>hypotension)
149 patients with HFpEF, NTproBNP>400 ng/l LCZ696 (up to 200 mg bd) vs valsartan (160 mg bd) for 36 weeks LCZ 696 was well tolerated. LCZ696 led to lower BP and smaller LA volume when compared to valsartan at 36m.
Conclusions Although we do not have much choice (yet). Try to characterize your patient Treat the underlying pathology (AF, HTN, T2DM, valvular disease, IHD, Anaemia) Consider you can make an incorrect diagnosis (and things worse)