Treating HF Patients with ARNI s Why, When and How?

Treating HF Patients with ARNI s Why, When and How? 19 th Annual San Diego Heart Failure Symposium for Primary Care Physicians January 11-12, 2019 La Jolla, CA Barry Greenberg M.D. Distinguished Professor of Medicine Director, Advanced Heart Failure Treatement Program University of California, San Diego La Jolla, CA

2013 ACC/AHA Guideline Recommendations for Treating Chronic HFrEF Patients HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta Blocker For all volume overload, NYHA class II-IV patients For persistently symptomatic African Americans, NYHA class III-IV For NYHA class II-IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist Yancy, et al. Circulation 2013;128:e240 319

Widespread Neurohormonal Activation Occurs in Heart Failure Patients Prostaglandin In addition to the RAAS and SNS, counter-regulatory neurohormonal systems are also activated These systems modulate adverse effects of the RAAS and SNS Many compensatory peptide mediators are degraded by neprilysin Bradykinin Adrenomedullin NPs (Natriuretic peptides) ANP BNP CNP Urodilatin Dendroaspis ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NP, natriuretic peptide; NPS, natriuretic peptide system. Mann DL et al. Braunwald s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015.

Blocking Neprilysin Increases Levels of Counter-Regulatory Peptides Source: Courtesy of Akshay S. Desai, MD, MPH.

PARADIGM-HF: Primary Endpoint of CV Death or HF Hospitalization Cumulative Probability 1.0 0.6 0.5 0.4 0.3 0.2 0.1 Number needed to treat = 21 HR 0.80 (95% CI, 0.73 0.87), p<0.001 Enalapril 1117 events (26.5%) Sac/Val 914 events (21.8%) 20% Number at Risk Sac/Val Enalapril 0 0 180 360 540 720 900 1080 Days since Randomization 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 1260 249 236 Sac/Val = Sacubitril/Valsartan; HR = hazard ratio. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its Components Sac/Val (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) p- Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 (0.73 0.87) <0.001 All-cause mortality 711 (17.0%) 835 19.8% 0.84 (0.76 0.93) <0.001 Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 (0.71 0.89) <0.001 Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 (0.71 0.89) <0.001 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

Combined Angiotensin Neprilysin Inhibition Doubles Effect on CV Death of Current RAAS Inhibitors 0 Angiotensin Receptor Blocker 1 ACE Inhibitor 2 Angiotensin Neprilysin Inhibitor 3 Decrease in Mortality (%) 10 20 30 15% 18% 20% 1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Effect of Combined Neurohormonal Agents on Survival in HF Heather Burnett et al. Circ Heart Fail. 2017;10:e003529

Use of ARNIs in Patients with HFrEF Results of the CHAMP-HF Registry Despite only ~1 having contra-indications to their use, ARNI s are prescribed to only 12.8% of eligible patients. Most patients(56%) prescribed ARNI s are getting only the lowest dose.

Questions About Using Sacubitril- Valsartan in HFrEF Patients How do I start and increase dose? Can you use in ACEI/ARB naïve patients? Are side effects prohibitive? How to manage hypotension if it occurs? Does the drug still improve outcomes at a lower dose? Do the elderly benefit from this therapy? Should I consider in patients who are stable and doing well (e.g. NYHAClass II and not recently hospitalized)? Is starting the drug during a HF hospitalization safe and effective?

Sacubitril / Valsartan Dose Selection and Titration Equivalent of >10mg Enalapril: Lisinopril >10mg Ramipril >5mg Equivalent of 10mg Enalapril: Lisinopril 10mg Ramipril 5mg STOP ACEi for 36 hours before starting Valsartan/Sacubitril to prevent angioedema Start Valsartan/Sacubitril 49/51mg bid, increase to 97/103mg bid in 2-4 weeks Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid Equivalent of > 160mg Valsartan: Losartan > 50mg Olmesartan > 10mg Equivalent of 160mg Valsartan: Losartan 50mg Olmesartan 10mg Start Valsartan/Sacubitril 49/51mg bid, increase to 97/103mg bid in 2-4 weeks Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid Not currently taking ACEi s or ARB s Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid

PARADIGM-HF: Adverse Events Prospectively identified adverse events Sac/Val (n=4187) Enalapril (n=4212) p- Value Symptomatic hypotension 14.0% 9.2% <0.001 Serum potassium > 6.0 mmol/l 4.3% 5.6% 0.007 Serum creatinine 2.5 mg/dl 3.3% 4.5% 0.007 Cough 11.3% 14.3% <0.001 Discontinuation for adverse event 10.7% 12.3% 0.03 Discontinuation for hypotension 0.9% 0.7% 0.38 Discontinuation for hyperkalemia 0.3% 0.4% 0.56 Discontinuation for renal impairment 0.7% 1.4% 0.002 Angioedema (adjudicated) Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52 Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31 Airway compromise 0 0 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Managing Hypotension Use with caution in patients with low pressure and those who are salt/water depleted. If hypotension occurs consider reducing dose of: - diuretic - anti-hypertensive medications (e.g. amlodipine) - sacubitril-valsartan Overall, likelihood of discontinuation is low

Does Reduced Dose Offer Similar Benefits? Eur J Heart Fail. 2016 Oct; 18(10): 1228 1234.

Effects of Sacubitril-Valsartan According to Age in PARADIGM-HF Jhund PS et al. Eu Heart J2015 Oct 7; 36(38): 2576 2584

Will Stable Patients Benefit? PARADIGM-HF: Prespecified Subgroup Analyses McMurray JJ et al. N Engl J Med 2014

PARADIGM-HF: Adverse Events Prospectively identified adverse events Sac/Val (n=4187) Enalapril (n=4212) p- Value Symptomatic hypotension 14.0% 9.2% <0.001 Serum potassium > 6.0 mmol/l 4.3% 5.6% 0.007 Serum creatinine 2.5 mg/dl 3.3% 4.5% 0.007 Cough 11.3% 14.3% <0.001 Discontinuation for adverse event 10.7% 12.3% 0.03 Discontinuation for hypotension 0.9% 0.7% 0.38 Discontinuation for hyperkalemia 0.3% 0.4% 0.56 Discontinuation for renal impairment 0.7% 1.4% 0.002 Angioedema (adjudicated) Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52 Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31 Airway compromise 0 0 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PIONEER-HF Study Design Hospitalized with Acute Decompensated HF with Reduced EF Stabilized Sacubitril/valsartan 97/103 mg twice daily* vs Enalapril 10 mg twice daily* In-hospital initiation Study Drug for 8 weeks Evaluate biomarker surrogates of efficacy Evaluate safety and tolerability Explore clinical outcomes *Target Dose HF, Heart Failure. EF, Ejection Fraction Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Key Entry Criteria Hospitalized for Acute Decompensated Heart Failure (ADHF) LVEF 40% within the last 6 months NT-proBNP 1600pg/mL or BNP 400 pg/ml* Stabilized while hospitalized PIONEER-HF SBP 100 mmhg in prior 6h; no symptomatic hypotension No increase in IV diuretics in prior 6h No IV vasodilators in prior 6h No IV inotropes in prior 24h Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Study Endpoints* Primary endpoint: Time-averaged proportional change in NT-proBNP from baseline at 4 and 8 weeks Safety Worsening renal function Hyperkalemia Symptomatic hypotension Angioedema Exploratory Clinical Outcomes PIONEER-HF Serious Clinical Composite: Death, Hospitalization for HF, LVAD or listing for cardiac transplant Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Baseline Characteristics PIONEER-HF Sacubitril/Valsartan (n=440) Enalapril (n=441) Age (years) 61 (50.5, 71) 63 (54, 72) Women (%) 25.7 30.2 Black (%) 35.9 35.8 Prior HF diagnosis (%) 67.7 63.0 LVEF (median (25 th, 75 th )) 0.24 (0.18, 0.30) 0.25 (0.20, 0.30) Systolic pressure (mm Hg) 118 (110, 133) 118 (109, 132) NT-proBNP (pg/ml) 2883 (1610, 5403) 2536 (1363, 4917) ACEi/ARB therapy (%) 47.3 48.5 Beta-adrenergic blockers (%) 59.6 59.6 Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

PIONEER-HF Primary Endpoint Percent Change from Baseline 10 0-10 - 20-30 - 40-50 - 60-70 Time-average proportional change of NT-proBNP from baseline* Enalapril Sacubitril/Valsartan Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week since Randomization Ratio of Change 0.71 (95% CI 0.63, 0.81) P<0.001 Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Serious Clinical Composite Endpoint KM estimate of Event Rate (%) 20 10 PIONEER-HF Composite of Death, HF re-hospitalization, LVAD, Listing for Transplant HR = 0.54; 95% CI 0.37-0.79 P = 0.001 NNT= 13 Enalapril N=441 Sacubitril/Valsartan N=440 0 0 7 14 24 28 35 42 49 56 Days since Randomization Serious Clinical Composite endpoints were driven by a reduction in death and HF re-hospitalizations Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

PIONEER-HF Additional Clinical Endpoints Sacubitril/ Valsartan (n=440) Enalapril (n=441) HR P-value Serious Composite, % 9.3 16.8 0.54 0.001 Death, % 2.3 3.4 0.66 0.311 Re-hospitalization for HF, % 8.0 13.8 0.56 0.005 Requirement of LVAD, % 0.2 0.2 0.99 0.999 Cardiac Transplant, % 0 0 - - Serious Clinical Composite endpoints were driven by a reduction in death and HF re-hospitalizations

PIONEER-HF Safety Safety Events (%) Sacubitril/ Valsartan (n=440) (%) Enalapril (n=441) (%) RR (95% CI) Worsening renal function a 13.6 14.7 0.93 (0.67-1.28) Hyperkalemia 11.6 9.3 1.25 (0.84-1.84) Symptomatic hypotension 15.0 12.7 1.18 (0.85-1.64) Angioedema events b 0.2% 1.4% 0.17 (0.02-1.38) Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Treating HF Patients with ARNIs ARNIs significantly improve outcomes in HFrEF patients compared to ACEI/ARB therapy. Sacubitril-valsartan has an acceptable side effect profile. However, utilization is sub-optimal. Sacubitril-valsartan is effective in stable outpatients and offers substantial benefits in patients who experience HF hospitalization.