Clinical update Heart Failure: Trials changing patients lives? - - PowerPoint PPT Presentation

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

Clinical update Heart Failure: Trials changing patient´s lives?

WCN Congress Amsterdam Novermber 28-29,2019

Disclosures

• Speaker fees, Advisory Board or Steering Committee honoraria

from Bayer Healthcare, Novartis, MSD, AstraZeneca, BMS, Stealth Peptides, Daiichi-Sankyo, Servier, MedScape

• Heart Failure Definitions
• Heart Failure with reduced LVEF
• Heart Failure with mid-range and preserved LVEF

Heart Failure Clinical Trials update 2019

Heart Failure is a prevalent and deadly disease

• AP Maggioni Heart Fail Clin. 2015 Oct;11(4):625-35

4

Actual 1 year Mortality in Europe (ESC Heart Failure Registry) 2017 Heart failure outcomes as poor as for many cancer types

Mamas MA et al., Eur J Heart Fail. 2017 Sep;19(9):1095-1104

ESC 2016: New Heart Failure classification

Ponikowski et al., Eur Heart J. 2016 Jul 14;37(27):2129-200.

ESC 2016: „Signs and symptoms of HF are often non-specific and do not discriminate well between HF and other clinical conditions“

Event rates (per 100 pat.years) PARAGON HF: (HFpEF): 14.6 PARAGON HF (HFmrEF range): 16.4 PARADIGM HF (HFrEF): 19.2

Event rates in HFmrEF and HFpEF

Courtesy Scott Solomon

• Heart Failure Definitions
• Heart Failure with reduced LVEF
• Heart Failure with mid-range and preserved LVEF

Heart Failure Clinical Trials update 2019

ESC HF Guideline 2016: HFrEF

ESC 2014: PARADIGM – NEP inhibition in systolic heart failure

16 32 40 24 8

Enalapril

(n=4,212)

LCZ696

(n=4,187)

HR = 0.80 (0.73–0.87) P = 0.0000004 Number needed to treat = 21 360 720 1080 180 540 900 1260

Kaplan-Meier Estimate of Cumulative Rates (%) Days After Randomization

4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk

1117 914

PARADIGM-HF: CV Death or Heart Failure Hospitalization

McMurray JJV et al., N Engl J Med 2014;371:993–1004 HR=hazard ratio

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

Morrow DA et al., Circulation. 2019 May 7;139(19):2285-2288

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

Wachter R et al., Eur J Heart Fail. 2019 Aug;21(8):998-1007

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

McMurray JJV et al., N Engl J Med. 2019 Sep 19 [Epub ahead

• f print]

Assessing Dapagliflozin in Patients with Chronic HFrEF With or Without T2D1-4

Target primary endpoint events: 8441 Median follow-up: 18.2 months2 Completion: July 20193

Placebo + standard of care Dapagliflozin 10 mg + standard of care

1:1 Double-blind

4744 patients

• ≥18 years of age
• With or without T2D
• Diagnosis of symptomatic HFrEF

(NYHA class II-IV) for ≥ 2 months

• LVEF ≤40% within last 12 months
• Elevated NT-proBNP
• eGFR ≥30 ml/min/1.73 m2
• Stable SoC HFrEF treatment

Visit 1 (enrollment) Day -14 Visit 2 (randomization) Day 0 Visit 6, etc. Every 120 days Visit 5 Day 120 Visit 3 Day 14 Visit 4 Day 60

Secondary Endpoints

• Time to first occurrence of either of the components of the composite: CV

death or hHF

• Total number of (first and recurrent) hHF and CV death
• Change from baseline measured at 8 months in the total symptom score of the

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

• Time to first occurrence of any of the

components of the composite: CV death or hHF or an urgent HF visit

Primary Endpoint: CV Death or hHF or an Urgent HF Visit

210 593 1096 1478 1917 2075 2163 2258 2371 Placebo 210 612 1146 1560 2002 2147 2221 2305 2373 DAPA 32 28 24 20 16 12 8 4 24 21 15 18 12 9 6 3

• No. at Risk

Months from Randomization Cumulative Percentage (%) 36

HR 0.74 (0.65, 0.85) p=0.00001 NNT = 21 DAPA Placebo 26% RRR

McMurray J et al., NEJM 2019; Sep., e-pub ahead of print

Primary Endpoint: Prespecified Subgroups

0.80 0.50 1.00 1.25 2.00 Placebo Better DAPA Better Characteristics HR (95% CI) HR (95% CI) NYHA Class II 0.63 (0.52, 0.75) III or IV 0.90 (0.74, 1.09) LVEF (%) ≤Median 0.70 (0.59, 0.84) >Median 0.81 (0.65, 0.99) NT-proBNP (pg/mL) ≤Median 0.63 (0.49, 0.80) >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) 0.80 0.50 1.00 1.25 2.00 Placebo Better DAPA Better Characteristics HR (95% CI) HR (95% CI) Type 2 diabetes at baselinea Yes 0.75 (0.63, 0.90) No 0.73 (0.60, 0.88) Baseline eGFR (mL/min/1.73 m2) <60 0.72 (0.59, 0.86) ≥60 0.76 (0.63, 0.92) MRA at baseline Yes 0.74 (0.63, 0.87) No 0.74 (0.57, 0.95)

McMurray J et al., NEJM 2019; Sep., e-pub ahead of print

Total Mortality

McMurray J et al., NEJM 2019; Sep., e-pub ahead of print

24 20 16 12 8 4 24 21 15 18 12 9 6 3 Cumulative Percentage (%)

DAPA Placebo

235 665 1221 1638 2092 2231 2279 2330 2371 Placebo 233 672 1243 1666 2130 2251 2296 2342 2373 DAPA

• No. at Risk

Months from Randomization

HR 0.83 (0.71, 0.97) p=0.022*

17% RRR

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 hospitalization in patients with DM, and are recommended. I A Metformin should be considered for DM treatment in patients with HF, if the eGFR is stable and >30 mL/min/1.73 m2. IIa C GLP1-RAs (lixisenatide, liraglutide, semaglutide, exenatide, and dulaglutide) have a neutral effect on the risk of HF hospitalization, and may be considered for DM treatment in patients with HF. IIb A The DPP4 inhibitors sitagliptin and linagliptin have a neutral effect on the risk of HF hospitalization, and may be considered for DM treatment in patients with HF. IIb B 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 patients with DM, and are not recommended for DM treatment in patients at risk of HF (or with previous HF). III A The DPP4 inhibitor saxagliptin is associated with an increased risk of HF hospitalization, and is not recommended for DM treatment in patients at risk of HF (or with previous HF). III B

• Heart Failure Definitions
• Heart Failure with reduced LVEF
• Heart Failure with mid-range and preserved LVEF

Heart Failure Clinical Trials update 2019

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

Borlaug et al.; Eur Heart J 2011; 32: 670-679

Controls vs. HFPEF patients, invasive hemodynamics & exercise

Exercise stress echocardiography (50W)

Echocardiography at Rest and during Exercise

Functional parameters during Exercise E/e´ mean 20.4 – TR 3.3 m/s Patient R.W., 76 y: HF, NYHA class III Functional parameters at Rest: 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

Pitt et al. 2014

TOPCAT components of primary endpoint

CV Death HF hospitalisations

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

• r 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

SPIRIT HF: Aldosterone antagonists in HFmrEF/HFpEF?

Risk-enriched patient population: up to 2100 patients with symptomatic HF (NYHA Class II–IV) and LVEF 40% + additional evidence for HFmrEF/HFpEF (HHF within last 12 mo, Echo LAE or DD, elevated NPs)

Screening period

Primary outcome: Recurrent Heart Failure Hospitalizations and CV Death (anticipated ~753 primary events)

PARAGON-HF Trial design

Solomon SD et al. JACC-Heart Fail 2017:471-482

Primary Endpoint Composite of total (first and recurrent) HF hospitalizations and CV death Secondary Endpoints:

• Improvement in NYHA functional classification at 8 months
• Changes in KCCQ clinical summary score at 8 months
• Time to first occurrence of worsening renal function
• Time to all-cause mortality

Randomized, double-blind, active comparator trial testing the hypothesis that sacubitril/valsartan, compared with valsartan, would reduce the composite outcome of total HF hospitalizations and CV death

Randomization 1:1 ~35 months Valsartan 160 mg BID Sacubitril/valsartan 97/103 mg BID On top of optimal background medications for co- morbidities (excluding ACEi and ARB) Double-blind treatment period up to 2 weeks Sacubitril/valsartan 49/51 mg BID Valsartan 80 mg BID Eligibility Screening 3–8 weeks Active single-blind run-in period Valsartan 40 mg BID

Patient Disposition

Screened 10,359 in 848 sites in 43 countries 5,746 entered the valsartan run-in

Median follow-up = 15 days (IQR 12–22 days)

5,205 entered the sacubitril/valsartan run-in

median follow-up = 19 days (IQR 15–23 days)

Valsartan 160 mg BID N = 2,389 Sacubitril/valsartan 200 mg BID N = 2,407 Final vital status known, n = 2,385 Final vital status unknown, n = 4† Final vital status known n = 2,402 Final vital status unknown n = 5†

Excluded from FAS because of site closure due to GCP violation Sacubitril/valsartan N = 12 Valsartan N = 14

Sacubitril/valsartan run-in failures n = 384 (7.3%) Adverse event n = 262 Subject/guardian decision n = 37 Protocol deviation n = 49 Other n = 36

N = 4,796

Sacubitril/ valsartan Valsartan Disconitued treatment for any reason other than death 25% 27% Percent on target dose among patients on study medication at final visit 82% 85%

Valsartan run-in failures n = 541 (9.4%) Adverse event n = 340 Subject/guardian decision n = 98 Protocol deviation n = 62 Other n = 41

4, 822 Randomized

Median follow-up 35 months

†7 withdrew consent, 2 lost to follow-up.

.

PARAGON-HF primary results

Recurrent event analysis of total HF hospitalizations and CV death*

*Semiparametric LWYY method.

5 10 15 20 25 30 35 40 45 50 55 Mean cumulative events per 100 patients 1 2 3 4 Years

Total HF hospitalizations and CV death Valsartan (n = 2389) 1009 events, 14.6 per 100 pt-years Sacubitril/valsartan (n = 2407) 894 events, 12.8 per 100 pt-years Rate ratio 0.87 (95% CI 0.75, 1.01) p = 0.059

HF hospitalizations and CV death

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 1 2 3 4

Years

5 10 15 20 25 30 35 40 45 50 55 1 2 3 4

Years Mean cumulative events per 100 patients

HF hospitalizations*

Proportion

CV death*

Patients Valsartan 212 (8.9%) Sacubitril/valsartan 204 (8.5%) Hazard ratio 0.95 (95% CI 0.79, 1.16) p = 0.62 Events Valsartan 797 Sacubitril/valsartan 690 Rate ratio 0.85 (95% CI 0.72, 1.00) p = 0.056

*Semiparametric LWYY method

Significant Heterogeneity in Multivariate Analysis by Ejection Fraction and Sex

Primary endpoint

Male 980/2317 1.03 (0.85–1.25) 0.73 (0.59–0.90) Sex Female 923/2479 at or below median (57%) 1048/2495 0.78 (0.64–0.95) 1.00 (0.81–1.23) LVEF above median (57%) 855/2301 Rate ratio (95% CI) 0.4 0.6 0.8 1.0 2.0 P = 0.002 (continuous) P = 0.03 (categorical) P < 0.006 Multivariable interaction p-value

Rate ratio (95% CI)

• No. of events/

patients Subgroup

Only interactions for sex and ejection fraction remained nominally significant

Take Home Messages

HFrEF:

• Class I Recommendation for ARNI. Should be initiated early.
• SGLT2 inhibitor (Dapagliflozin) improves outcome independent of T2DM.
• Future: Standard quadruple therapy: ARNI-BB-MRA-SGLT2-I ?

HFmrEF:

• RAS inhibitors and MRAs with potential benefit on HFH.
• Sacubitril/valsartan effective to reduce HFH (PARAGON HF)

HFpEF:

• ESC Diagnostic Algorithm: Diagnostic workup established
• Sacubitril/Valsartan with potential benefit in mildly reduced LVEF
• SGLT2 trials ongoing

Thank you for your attention!