WCN Congress Amsterdam Novermber 28-29,2019 Clinical update Heart Failure: Trials changing patient´s lives? Univ.-Prof. Dr. Burkert Pieske Department of Internal Medicine and Cardiology Charité University Medicine, Campus Virchow-Klinikum and Department of Internal Medicine and Cardiology, German Heart Center Berlin, Germany burkert.pieske@charite.de https://kardio-cvk.charite.de www.dhzb.de
Disclosures • Speaker fees, Advisory Board or Steering Committee honoraria from Bayer Healthcare, Novartis, MSD, AstraZeneca, BMS, Stealth Peptides, Daiichi-Sankyo, Servier, MedScape
Heart Failure Clinical Trials update 2019 • Heart Failure Definitions • Heart Failure with reduced LVEF • Heart Failure with mid-range and preserved LVEF
Heart Failure is a prevalent and deadly disease 2017 Heart failure outcomes as poor as for Actual 1 year Mortality in Europe many cancer types (ESC Heart Failure Registry) • 4 AP Maggioni Heart Fail Clin . 2015 Oct;11(4):625-35 Mamas MA et al. , Eur J Heart Fail. 2017 Sep;19(9):1095-1104
ESC 2016: New Heart Failure classification ESC 2016: „ Signs and symptoms of HF are often non-specific and do not discriminate well between HF and other clinical conditions “ Ponikowski et al., Eur Heart J. 2016 Jul 14;37(27):2129-200.
Event rates in HFmrEF and HFpEF Event rates (per 100 pat.years) PARAGON HF: (HFpEF): 14.6 PARAGON HF (HFmrEF range): 16.4 PARADIGM HF (HFrEF): 19.2 Courtesy Scott Solomon
Heart Failure Clinical Trials update 2019 • Heart Failure Definitions • Heart Failure with reduced LVEF • Heart Failure with mid-range and preserved LVEF
ESC HF Guideline 2016: HFrEF
ESC 2014: PARADIGM – NEP inhibition in systolic heart failure
PARADIGM-HF: CV Death or Heart Failure Hospitalization 40 1117 Enalapril Kaplan-Meier Estimate of 32 (n=4,212) Cumulative Rates (%) 914 24 LCZ696 (n=4,187) 16 HR = 0.80 (0.73 – 0.87) 8 P = 0.0000004 Number needed to treat = 21 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236 HR=hazard ratio McMurray JJV et al., N Engl J Med 2014;371:993 – 1004
In-hospital initiation of Sacubitril/Valsartan in comparison with Enalapril After initial stabilization from ADHF (24 hours – 10 days after presentation) Elevated natriuretic peptides ( ≥1600 pg/mL or 400 pg/mL, NTproBNP or BNP) 8 week multicenter randomized double blind Velazquez EJ et al., NEJM 2019; 380:539-548
Early in hospital ARNI after recompensation Velazquez EJ et al., NEJM 2019; 380:539-548
Clinical outcomes with early ARNI initiation Post-hoc adjudication of events Morrow DA et al. , Circulation. 2019 May 7;139(19):2285-2288
Clinical outcomes with early ARNI initiation Severe Composite Endpoints CV death of HF rehospitalisation HF rehospitalisation Includes LVAD, listing for transplant Morrow DA et al., Circulation. 2019 May 7;139(19):2285-2288
Early initiation of Sacubitril/Valsartan: TRANSITION Wachter R et al., Eur J Heart Fail. 2019 Aug;21(8):998-1007
Transition: 50% in hospital, 50% W1 after discharge Wachter R et al. , Eur J Heart Fail. 2019 Aug;21(8):998-1007
Tolerability of early Sac/Val initiation: Doses @ W10 Wachter R et al., Eur J Heart Fail. 2019 Aug;21(8):998-1007
McMurray JJV et al., N Engl J Med. 2019 Sep 19 [Epub ahead of print]
Assessing Dapagliflozin in Patients with Chronic HFrEF With or Without T2D1-4 4744 patients Dapagliflozin 10 mg • ≥18 years of age + standard of care Double-blind • With or without T2D • Diagnosis of symptomatic HFrEF 1:1 (NYHA class II-IV) for ≥ 2 months • LVEF ≤40% within last 12 months • Placebo Elevated NT-proBNP • eGFR ≥30 ml/min/1.73 m 2 + standard of care • Stable SoC HFrEF treatment Visit 1 (enrollment) Visit 2 (randomization) Visit 3 Visit 5 Visit 4 Visit 6, etc. Day -14 Day 0 Day 14 Day 60 Day 120 Every 120 days Target primary endpoint events: 844 1 Median follow-up: 18.2 months 2 Completion: July 2019 3 Primary Endpoint Secondary Endpoints • Time to first occurrence of either of the components of the composite: CV • Time to first occurrence of any of the death or hHF components of the composite: CV • Total number of (first and recurrent) hHF and CV death • Change from baseline measured at 8 months in the total symptom score of the death or hHF or an urgent HF visit KCCQ • Time to first occurrence of any of the components of the composite: ≥50% sustained decline in eGFR or reaching ESRD or renal death • Time to death from any cause
Primary Endpoint: CV Death or hHF or an Urgent HF Visit 36 32 28 Placebo 26% RRR Cumulative Percentage (%) 24 HR 0.74 (0.65, 0.85) DAPA p=0.00001 20 NNT = 21 16 12 8 4 0 0 3 6 9 12 15 18 21 24 No. at Risk Months from Randomization 2373 2305 2221 2147 2002 1560 1146 612 210 DAPA 2371 2258 2163 2075 1917 1478 1096 593 210 Placebo McMurray J et al., NEJM 2019; Sep., e-pub ahead of print
Primary Endpoint: Prespecified Subgroups Characteristics HR (95% CI) HR (95% CI) Characteristics HR (95% CI) HR (95% CI) Type 2 diabetes at baseline a NYHA Class Yes 0.75 (0.63, 0.90) II 0.63 (0.52, 0.75) No 0.73 (0.60, 0.88) III or IV 0.90 (0.74, 1.09) Baseline eGFR (mL/min/1.73 m 2 ) LVEF (%) <60 0.72 (0.59, 0.86) ≤Median 0.70 (0.59, 0.84) ≥60 0.76 (0.63, 0.92) >Median 0.81 (0.65, 0.99) MRA at baseline NT-proBNP (pg/mL) Yes 0.74 (0.63, 0.87) ≤Median 0.63 (0.49, 0.80) No 0.74 (0.57, 0.95) >Median 0.79 (0.68, 0.92) Atrial Fibrilation or Flutter at Enrollment ECG Yes 0.82 (0.63, 1.06) No 0.72 (0.61, 0.84) 0.50 0.80 1.00 1.25 2.00 0.50 0.80 1.00 1.25 2.00 DAPA Better Placebo Better DAPA Better Placebo Better McMurray J et al., NEJM 2019; Sep., e-pub ahead of print
Total Mortality 24 20 Placebo 17% RRR Cumulative Percentage (%) 16 HR 0.83 (0.71, 0.97) DAPA p=0.022* 12 8 4 0 0 3 6 9 12 15 18 21 24 No. at Risk Months from Randomization DAPA 2373 2342 2296 2251 2130 1666 1243 672 233 Placebo 2371 2330 2279 2231 2092 1638 1221 665 235 McMurray J et al., NEJM 2019; Sep., e-pub ahead of print
2019 ESC Guidelines on diabetes Recommendations for the treatment of patients with diabetes to reduce heart failure risk Recommendations Class Level SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) are associated with a lower risk of HF I A hospitalization in patients with DM, and are recommended. Metformin should be considered for DM treatment in patients with HF, if the eGFR is stable and >30 IIa C mL/min/1.73 m 2 . GLP1-RAs (lixisenatide, liraglutide, semaglutide, exenatide, and dulaglutide) have a neutral effect on the risk of IIb A HF hospitalization, and may be considered for DM treatment in patients with HF. The DPP4 inhibitors sitagliptin and linagliptin have a neutral effect on the risk of HF hospitalization, and may IIb B be considered for DM treatment in patients with HF. Insulin may be considered in patients with advanced systolic HFrEF. IIb C Thiazolidinediones (pioglitazone and rosiglitazone) are associated with an increased risk of incident HF in III A patients with DM, and are not recommended for DM treatment in patients at risk of HF (or with previous HF). The DPP4 inhibitor saxagliptin is associated with an increased risk of HF hospitalization, and is not III B recommended for DM treatment in patients at risk of HF (or with previous HF).
Heart Failure Clinical Trials update 2019 • Heart Failure Definitions • Heart Failure with reduced LVEF • Heart Failure with mid-range and preserved LVEF
HF- PEFF Algorithm
HF- PEFF Algorithm – Step 2 (E)
HF- PEFF Algorithm – Step 2 (E) Major: 2 points; Minor: 1 point Exclusion : ≤1 point; Diagnostic: >4 points; Grey zone: 2-4 points
HF- PEFF Algorithm – Step 3 (F1)
HFpEF: Central hemodynamics with exercise Controls vs. HFPEF patients, invasive hemodynamics & exercise Borlaug et al.; Eur Heart J 2011; 32: 670-679
Exercise stress echocardiography (50W) Echocardiography at Rest and during Exercise Patient R.W., 76 y: HF, NYHA class III Functional parameters during Exercise Functional parameters at Rest: E/e ´ mean 20.4 – TR 3.3 m/s E/e ´ mean 13.2, TR 2.6 m/s
HF- PEFF Algorithm – Step 4 (F2)
Recommendations for treatment of patients with HFmrEF Ponikowski et al., Eur Heart J. 2016 Jul 14;37(27):2129-200.
Pitt et al., N Engl J Med. 2014 Apr 10;370(15):1383-92
TOPCAT components of primary endpoint HF hospitalisations CV Death Pitt et al. 2014
Aldosterone antagonists in HFmrEF/HFpEF? AHA/ACC: Class IIb recommendation (Level of Evidence: B-R) Aldosterone antagonists in HF patients with EF ≥45%, elevated NP or HF admission within 1 year, Estimated glomerular filtration rate >30 and creatinine <2.5 mg/dl, potassium <5.0 mEq /L), Might be considered to decrease hospitalizations. Yancy CW, Jessup M, Bozkurt B, et al., Focused Update of the AHA/ACC HF Guidlines 2017
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