Advances in Heart Failure Jonathan D Davis, MD, MPHS Director, - PowerPoint PPT Presentation

Advances in Heart Failure Jonathan D Davis, MD, MPHS Director, Heart Failure Program Assistant Clinical Professor | Division of Cardiology Zuckerberg San Francisco General Hospital Department of Medicine | University of California, San Francisco jonathan.davis@ucsf.edu | @JonathanDavisHF June 15, 2020 Zuckerberg San Francisco General

Disclosures  I have no relevant financial relationships with any companies related to the content of this course. Zuckerberg San Francisco General Advances in Heart Failure 2

Overview  Heart Failure Survival and Outcomes  Heart Failure with Preserved EF (HFpEF, EF >50%)  Heart Failure with Reduced EF (HFrEF, EF <40%) - Medical Therapies - Devices  Key Take Home: New Standard of Care for HFrEF Zuckerberg San Francisco General Advances in Heart Failure 3

Heart Failure Epidemiology Zuckerberg San Francisco General

Poor Survival Regardless of EF HFrEF HFmrEF HFpEF Park JJ, et al. JACC. 2018;71(18):1947-57) Vasan RS, et al. JACC Cardiovasc Imaging. 2017 Zuckerberg San Francisco General Advances in Heart Failure 5

Mortality Increases with Each Hospitalization 30-day all-cause mortality after 1 st admission: 10-12%  1-year all-cause mortality after 1 st admission: 22-34%  Setoguchi S et al. Am Heart J. 2007;154:260-266. Loehr LR, et al. Am J Cardiol. 2008;010:1016-1022 Zuckerberg San Francisco General Advances in Heart Failure 6

Heart Failure with Preserved Ejection Fraction Zuckerberg San Francisco General

Medications with a Class I Recommendation for HFpEF Zuckerberg San Francisco General Advances in Heart Failure 8

October 24, 2019 PARAGON-HF  Primary outcome: 13% relative risk reduction (RR, 0.87; 95% CI, 0.75 - 1.01; P = 0.06)  For sacubitril/valsartan as compared to valsartan: - No difference in death from cardiovascular causes (HR 0.95; 95% CI, 0.79 to 1.16) - Suggestion of reduction in total HF hospitalizations (rate ratio, 0.85; 95% CI, 0.72 to 1.00) - NYHA Class Improved (odds ratio, 1.45; 95% CI, 1.13 to 1.86) Solomon, SD, et al. NEJM. 9/1/19. Zuckerberg San Francisco General Advances in Heart Failure 9

Pooling Sacubitril/Valsartan Data  Pre-specified pooled analysis of 13,195 patients from PARADIGM- HF (EF ≤40%) & PARAGON - HF (EF ≥45%)  Overall, sacubitril/valsartan was superior for: 1 st CV death or HF hospitalization (HR 0.84, 95% CI 0.78, 0.90) - - Cardiovascular death (HR 0.84, 95% CI 0.76, 0.92) - Heart failure hospitalization (HR 0.84, 95% CI 0.77, 0.91) - All-cause mortality (HR 0.88, 95% CI 0.81, 0.96) Solomon, SD, et al. Circulation. 11/17/19. Zuckerberg San Francisco General Advances in Heart Failure 10

Continuous Treatment Effects of ARNI vs. Active Comparator by Sex Solomon SS, et al. Circulation. 2020;141:352–361 Zuckerberg San Francisco General Advances in Heart Failure 11

Rhythm Control Versus Rate Control in Patients With Atrial Fibrillation and HFpEF  15,682 fee ‐ for ‐ service Medicare patients. 1857 were treated w/ rhythm control & 13,825 w/ rate control  Lower 1 ‐ year all ‐ cause death in rhythm control group (after risk adjustment; adjusted HR, 0.86; 95% CI, 0.75–0.98; P=0.02) Zuckerberg San Francisco General Kelly JP, et al. JAHA. Vol 8, Issue 24. 17 Dec 2019 Advances in Heart Failure 12

Heart Failure with Reduced Ejection Fraction Zuckerberg San Francisco General

Guideline-Directed Medical Therapy  Current State, Class I Recommendations: - RAAS inhibition (Class I) - Beta blocker (Class I) - Mineralocorticoid Receptor Antagonist (Class I) - Hydralazine/isosorbide dinitrate (Class I)  BUT: Utilization is Suboptimal Zuckerberg San Francisco General Advances in Heart Failure 14

New GDMT: Quad Therapy  Angiotensin receptor neprilysin inhibitor (ARNI)  Beta blocker  Mineralocorticoid (aldosterone) antagonist  SGLT2-Inhibitor  Hydralazine/isosorbide dinitrate  New: Vericiguat and Omecamtiv Mecarbil Zuckerberg San Francisco General Advances in Heart Failure 15

Suboptimal GDMT Use – CHAMP 26% 33% 66% ONLY 22.1% were simultaneously prescribed some dose of ACEI/ARB/ARNI, beta-blocker, and MRA therapy Greene SJ, et al. JACC. 2018 Jul, 72 (4) 351-366. Zuckerberg San Francisco General Advances in Heart Failure 16

Angiotensin receptor neprilysin inhibitor Zuckerberg San Francisco General

Sacubitril/Valsartan – PARADIGM-HF McMurray JJV, et al. NEJM 2014; 371:993-1004 Zuckerberg San Francisco General Advances in Heart Failure 18

Comparative Effectiveness of ARNI v ACE/ARB A: Primary outcome of all-cause B: All-cause mortality mortality or hospitalization Tan NY, et al. JACC HF. 2020;8(1)43-54 Zuckerberg San Francisco General Advances in Heart Failure 19

Transitioning to Sacubitril/Valsartan  NYHA II-III, BNP > 150 pg/mL or > 100 pg/mL if HF admission in last 12 months  36-hour washout from ACE but not ARB  Lisinopril ≤ 10 mg/day  24/26 mg BID  Sacubitril has natriuretic effects If hypotensive, orthostatic, new AKI  decrease diuretic - Zuckerberg San Francisco General Advances in Heart Failure 20

SGLT2-Inhibitor Zuckerberg San Francisco General

EMPA-REG November 26, 2015 OUTCOME  7020 patients for median observation time of 3.1 years  Primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke  Inclusion: eGFR ≥ 30 ml per minute per 1.73 m 2 of body-surface area - - A1c 7-10% if had received stable glucose-lowering therapy for at least 12 weeks before randomization EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 22

Zuckerberg San Francisco General Diabetes Medications and Heart Failure 23 EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

Glycemic Control Zuckerberg San Francisco General EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

HHF HHF or MACE HHF HHF or MACE HHF HHF or HHF HHF or MACE MACE CV death CV death CV death CV death HHF: Hospitalization for HF MACE: Major adverse cardiovascular events Kluger AY et al. Cardiovasc Diabetol (2019) 18:99 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 25

DAPA-HF Trial Zuckerberg San Francisco General

September 19, 2019 DAPA-HF  Dapagliflozin 10 mg vs. placebo, 4744 patients  New York Heart Association class II, III, or IV  Ejection fraction of 40% or less  60% of enrolled WITHOUT Diabetes  Primary outcome was a composite of worsening HF (hospitalization or an urgent visit resulting in IV therapy for HF) or CV death Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM. 9/19/19. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 27

Characteristic Dapagliflozin (N = 2373) Placebo (N = 2371) 66.2 ± 11.0 66.5 ± 10.8 Age – years Female – No. (%) 564 (23.8) 545 (23.0) Race – No. (%) White 1662 (70) 1671 (70.5) Black 122 (5.1) 104 (4.4) Asian 552 (23.3) 564 (23.8) NYHA Class – No. (%) II 1606 (67.7) 1597 (67.4) III 747 (31.5) 751 (31.7) IV 20 (0.8) 23 (1.0) Principal Cause of HF – No. (%) Ischemic 1316 (55.5) 1358 (57.3) Nonischemic 857 (36.1) 830 (35.0) DAPA-HF. NEJM. 9/19/19. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 28

Characteristic Dapagliflozin (N = 2373) Placebo (N = 2371) HF Medication – No. (%) ACE Inhibitor 1332 (56.1) 1329 (56.1) ~96% ARB 675 (28.4) 632 (26.7) Sacubitril-valsartan 250 (10.5) 258 (10.9) Beta-blocker 2278 (96.0) 2280 (96.2) MRA 1696 (71.5) 1674 (70.6) Device Therapy – No. (%) ICD 622 (26.2) 620 (26.1) CRT 190 (8.0) 164 (6.9) DAPA-HF. NEJM. 9/19/19. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 29

Zuckerberg San Francisco General Diabetes Medications and Heart Failure 30 DAPA-HF. NEJM. 9/19/19.

Similar Outcomes Regardless of Diabetes Status DAPA-HF. NEJM. 9/19/19. Petrie MC, et al. JAMA. 2020;323(14):1353-1368 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 31

Variable Dapagliflozin Placebo P Value (N=2373) (N=2371) DAPA-HF. NEJM. 9/19/19. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 32

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Comprehensive therapy: ARNI, β blocker, MRA, and SGLT2 inhibitor Conventional therapy: ACE inhibitor or ARB and β blocker Quad Therapy: The New Standard in the Treatment of HFrEF Vaduganathan M, et al. Lancet. 2020 May 21;S0140-6736(20)30748-0 Zuckerberg San Francisco General Advances in Heart Failure 34

New Medications for HFrEF Zuckerberg San Francisco General

Armstrong PW, et al. JACC HF. 2018 Zuckerberg San Francisco General Advances in Heart Failure 36

Armstrong PW, et al. N Engl J Med 2020; 382:1883-1893 Zuckerberg San Francisco General Advances in Heart Failure 37

Omecamtiv Mecarbil (OM) Actin Filament Myosin Head Teerlink JR, et al. JACC HF. 2020 Apr, 8 (4) 329-340. Zuckerberg San Francisco General Advances in Heart Failure 38