Multidisciplinary Care in Heart Failure Strategies from Interventional

Multidisciplinary Care in Heart Failure: Strategies from Interventional and Clinical Cardiology New Treatment Horizons in HFr. EF and HFp. EF

Faculty Ileana L. Piña, MD, MPH, FAHA, FACC • • • Professor of Medicine, Wayne State University Clinical Prof of Medicine, Central Michigan University Director of CVD Research and Academic Affairs Regional and National Director of Heart Failure Detroit Medical Center, Cardiovascular Institute Detroit, MI Navin K. Kapur, MD, FAHA, FACC, FSCAI • Associate Professor, Dept of Medicine/Division of Cardiology • Executive Director, The Cardio. Vascular Center for Research and Innovation (CVCRI) • Director, Acute Circulatory Support Program • Director, Interventional Research Laboratories • Investigator, Molecular Cardiology Research Institute • Tufts Medical Center • Boston, MA Tariq Ahmad, MD, MPH, FACC • Assistant Professor of Medicine (Cardiology) • Advanced Heart Failure and Transplant Cardiologist • Investigator, Center for Outcomes Research and Evaluation • Yale University School of Medicine • Yale New Haven Health System • New Haven, CT

Activity Description Target Audience • This activity is intended for interventional cardiologists, primary care physicians, nurses and others with an interest in the care of heart failure. Activity Purpose • Heart failure (HF) remains a complex and costly disease to diagnose, treat and manage. Healthcare providers need guidance and implementing appropriate systems and processes to reduce HF hospitalizations/re-hospitalizations. Targeted therapy for HF often requires patient-level personalization, especially for HF subtypes such as HF with preserved ejection fraction (HFp. EF). This activity will serve to educate cardiology clinicians on the latest evidence-based clinical and interventional strategies for managing HF in both the acute setting and for longer-term management. Support • Supported by an educational grant from Novartis Pharmaceuticals Corporation. Sponsorship • Sponsored by the Academy for Continued Healthcare Learning (ACHL).

Learning Objectives Upon completion of this activity, participants will be able to: • Discuss strategies to optimize medical therapy in patients with heart failure • Interpret data from recent clinical trials and post-marketing studies with sacubitril/valsartan and ivabradine • Identify diverse HF patients who may benefit from the use of newer medical therapies • Employ multidisciplinary approaches to improve collaboration, transitions of care, and patient outcomes

Accreditation & Credit Designation • The Academy for Continued Healthcare Learning is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. • The Academy for Continued Healthcare Learning designates this live activity for a maximum of 1. 00 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Faculty Disclosures § The Academy for Continued Healthcare Learning (ACHL) requires that the faculty participating in a CME activity disclose all affiliations or other financial relationships (1) with the manufacturers of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation and (2) with any commercial supporters of the activity. All conflicts of interest have been resolved prior to this CME activity. § The following financial relationships have been provided: Ileana L. Piña, MD, MPH, FAHA, FACC • Advisory Board: Relypsa, Inc. § Tariq Ahmad, MD, MPH, FACC • Consulting Agreements: Amgen Inc. , Cytokinetics, Inc. § Navin K. Kapur, MD, FAHA, FACC, FSCAI • Grants/Research Support: Abiomed, Abbott, Boston Scientific, Maquet , MD Start, Medtronic • Consultant/Advisory Board: Abiomed, Abbott, Boston Scientific, Maquet , MD Start, Medtronic • Honorarium/Speakers Bureau: Abiomed, Abbott, Boston Scientific, Maquet , MD Start, Medtronic § Discussion of Off-Label, Investigational, or Experimental Drug/Device Use: IABP, Impella, ECMO § ACHL staff members and others involved with the planning, development, and review of the content for this activity have no relevant affiliations or financial relationships to disclose.

Disclaimer • The content for this activity was developed independently of the commercial supporter. All materials are included with permission. The opinions expressed are those of the faculty and are not to be construed as those of the publisher or grantor. • This educational activity was planned and produced in accordance with the ACCME Accreditation Criteria, Policies, and Standards for Commercial Support. Recommendations involving clinical medicine in a continuing medical education (CME) activity must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients. All scientific research referred to, reported, or used in CME in support or justification of a patient care recommendation must conform to the generally accepted standards of experimental design, data collection, and analysis. • This CME activity might describe the off-label, investigational, or experimental use of medications and/or devices that may exceed their FDA-approved labeling. Physicians should consult the current manufacturers’ prescribing information for these products. ACHL requires the speaker to disclose that a product is not labeled for the use under discussion.

Method of Participation • To receive credit, participants are required to participate in the live activity and complete the evaluation and submit on-site. A certificate will be emailed to participants within 6 weeks. There is no fee to participate in the activity or for the generation of the certificate. • Inquiries may be directed to Melissa Stradal at mstradal@achlcme. org

Ileana L. Piña, MD, MPH, FAHA, FACC and Panel Case 1: Refractory Outpatient HFr. EF

Case 1: Refractory Outpatient HFr. EF Patient Video

Case 1: Refractory Outpatient HFr. EF • 69 yo African-American female visits PCP for early-stage HFr. EF-related decompensation. • Previously treated with ACE inhibitor (ineffective; negative side effects) • Gradual onset of HF symptoms have occurred over past 6 -12 months • • • Worsening edema in both feet/legs Persistent cough/wheezing Palpitations Unable to climb stairs/do light housework when required without fatigue Presented to PCP after increasingly bothersome symptoms • Previously warned by PCP about possible kidney problems; no dialysis • BP 149/92, HR 95, BMI 32, NAD, JVP 14 cm, S 3 gallop, prominent P 2 • Lungs clear, palpable edema in both legs. • EKG SR w/ narrow QRS, NT-pro. BNP 11292 pg/ml , Na 122, BUN 53 • Cr 2. 4.

Case 1: Refractory Outpatient HFr. EF Q: What treatment should we offer IN the hospital, with the goal of preventing rehospitalizations? (Patient was previously prescribed ACE inhibitor, with negative effects) A. Sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) B. Enalapril (target dose, 10 mg twice daily) C. Spironolactone (eg, aldactone in IV loop) D. Other DISCUSSION

Impact of Medical Therapy in Heart Failure w/ Reduced Ejection Fraction Therapy RR Red Mortality (%) NNT (36 mo) RR Red Hosp (%) ACEI or ARB 17 26 31 Beta Blocker 34 9 41 Aldo antagonist 30 6 35 Hydralazine/Isordil** 43 7 33 **Tested in African-American patients in A-He. FT: African-American Heart Failure Trial. Taylor AL et al. N Engl J Med. 2004; 351: 2049 -2057. Yancy CW et al. 2013 ACC AHA HF Guidelines

Angiotensin Receptor – Neprilysin Inhibitor Vardney O et al. JACC Heart Fail. 2014 Dec; 2(6): 663 -70.

Angiotensin Receptor Neprilysin Inhibitor/ARNI 2016 ACC HF/HFr. EF guidelines – Recommendation Class I • “In pts w/ chronic HFr. EF NYHA II or III who tolerate an ACEi or ARB, replacement by an ARNI (eg, sacubritil/valsartan) is recommended to further reduce morbidity and mortality. ” • Inhibition of RAS w/ ACEi, or ARBs, or ARNI in conjunction with evidence-based BBs and MRA in selected pts is recommended for pts w/ chronic HFr. EF to reduce morbidity and mortality. • (…but not w/ ACEi, w/in 36 h of ACEi or angioedema)

Other ARNI Benefits § 21% in worsening HF death, 80% in SCD • Eur Heart J 2015; 36: 1990 -1997 § Reduction HF hospitalizations apparent in first 30 d • Circulation 2015; 131: 54 -61 § Absolute benefit across spectrum of patient risk • JACC 2015; 66: 2059 -2071 § Benefit consistent regardless of background Rx • Circ. HF 2016; 9: e 003212

• PIONEER-HF: Compared efficacy of salcubritil-valsartan therapy versus enalapril in hospitalized HFr. EF patients with acute decompensation • Target dose: 97 mg sacubritil with 103 mg valsartan, 2 X daily, OR • Target dose: 10 mg enalapril, 2 X daily CONCLUSION: Hospitalized HFr. EF pts in acute decompensation led to greater reduction in the NT-pro. BNP concentration than enalapril therapy Velazquez EJ et al. New Eng J Med. 2019 Feb 7; 380(6): 539 -48.

Secondary Efficacy and Safety Outcomes* CAVEATS for these data: • Enalapril dose tested=10 mg BID: • VS. therapeutic equivalent of 160 mg BID valsartan (97 mg/103 mg sacubritilvalsartan) • Higher clinical enalapril dose= currently in use which was NOT tested; • Majority of HFr. EF patients are not up-titrated to maximum therapeutic dose. Sacubitril-Valsartan (N=440) Enalapril (N=441) Worsening renal function∔ 60 (13. 6) 65 (14. 7) 0. 93 (0. 67 to 1. 28) Hyperkalemia 51 (11. 6) 41 (9. 3) 1. 25 (0. 84 to 1. 84) Symptomatic hypotension 66 (15. 0) 56 (12. 7) 1. 18 (0. 85 to 1. 64) 1 (0, 2) 6 (1. 4) Outcome Key safety outcomes – no. (%) Angioedema Sacubitril-Valsartan vs. Enalapril Relative risk (95% CI) Secondary biomarker outcomes – % (95% CI)� 0. 17 (0. 02 to 1. 38) Ratio of change (95% Cl) Change in high-sensitivity treponin T concentration -36. 6 (-40. 8 to -32. 0) -25. 2 (-30. 2 to -19. 9) 0. 85 (0. 77 to 0. 94) Change in B-type natriuretic peptide concentration -28. 7 (-35. 5 to -21. 3) -33. 1 (-39. 5 to -25. 9) 1. 07 (0. 92 to 1. 23) 35. 2 (28. 8 to 42. 0) -8. 3 (-3. 6 to -12. 7) Change in ratio of B-type natriuretic peptide to NT-pro. BNP Exploratory clinical outcomes – no. (%) Composite of clinical events 1. 48 (1. 38 to 1. 58) Hazard ratio (95% Cl)§ 249 (56. 6) 264 (59. 9) 0. 93 (0. 78 to 1. 10) Death 10 (2. 3) 15 (3. 4) 0. 66 (0. 30 to 1. 48) Rehospitalization for heart failure 35 (8. 0) 61 (13. 8) 0. 56 (0. 37 to 0. 84) Implantation of left ventricular assist device 1 (0. 2) 0. 99 (0. 06 to 15. 97) 0 0 NA 2 (0. 5) 1. 00 (0. 14 to 7. 07) Use of additional drug for heart failure 78 (17. 7) 84 (19. 0) 0. 92 (0. 67 to 1. 25) Increase in dose of diuretics of >50% 218 (49. 5) 222 (50. 3) 0. 98 (0. 81 to 1. 18) Composite of serious clinical events �� 41 (9. 3) 74 (16. 8) 0. 54 (0. 37 to 0. 79) Inclusion on list for heart transplantation Unplanned outpatient visit leading to use of intravenous diuretics * NA denotes not available. ∔ Worsening renal function was defined by an increase in the serum creatinine concentration of 0. 5 mg per deciliter or more (≥ 44 µmol per liter) and a decrease in the estimated glomerular filtration rate of 25% or more. � Shown are data on the time-averaged proportional change, from the baseline value to the geometric mean of values obtained at weeks 4 & 8. § Hazard ratios and associated 95% confidence intervals were calculated with a Cox Proportional-hazards model. Confidence intervals have not been adjusted for multiple comparisons, and therefore, inferences drawn from these intervals may not be reproducible. �� The outcome of a composite of serious clinical events was added to the list of exploratory clinical outcomes in May 2018, before the database was locked and unblinding occurred. This end point included death, rehospitalization for heart failure, implantation of left ventricular device, and inclusion on the list of patients eligible for heart transplantation. Velazquez EJ et al. New Eng J Med. 2019 Feb 7; 380(6): 539 -48.

PIONEER-HF: incidence of increase in serum creatinine of ≥ 0. 5 mg/d. L from baseline Velazquez EJ et al. New Eng J Med. 2019 Feb 7; 380(6): 539 -48.

Case 1 HFr. EF: What about longer-term risks/complications? OPEN PANEL DISCUSSION

Ivabradine Inhibition of Hyperpolarization-activated Cyclic Nucleotide–gated (HCN) Channels Psotka MA, Teerlink JR. Circulation. 2016 May 24; 133(21): 2066 -75.

Ivabradine 2016 ACC HF/HFr. EF guidelines – Class IIa • Ivabradine can be beneficial to reduce HF hospitalization for pts w/ NYHA II-III stable chronic HFr. EF who are receiving guideline-directed evidence-based medical therapy, including a BB at maximum tolerated dose, and who are in SR with a HR of 70 bpm or greater at rest.

Patient with symptomatic HFr. EFb Class IIa (Up-titrate to maximum tolerated evidence-based doses) IF LVEF ≤ 35% despite OMT or A history symptomatic VT/VF, implant ICD Diuretics to relieve symptoms and signs of congestion Therapy with ACE-I and beta-blocker No Still symptomatic and LVEF ≤ 35% Yes Add MR antagonist (up-titrate to maximum tolerated evidence-based dose) Yes No Still symptomatic and LVEF ≤ 35% Yes Able to tolerate ACEI (or ARB) Sinus rhythm, QRS duration ≥ 130 msec Sinus rhythm HR ≥ 70 bmp ARNI to replace ACE-1 Evaluate need for CRT Ivabradine These above treatments may be combined if indicated Resistant symptoms Yes Consider digoxin or H-ISDN Or LVAD, or heart transplantation No No further action required consider reducing diuretic dose

Navin K. Kapur, MD, FAHA, FACC, FSCAI and Panel Case 2: Ventricle Stabilization in AMI Patient/HF Prevention

Case 2: Ventricle Stabilization in AMI Patient/HF Prevention Patient Video

Case 2: Ventricle Stabilization in AMI Patient/HF Prevention § 44 yo white male, obese (BMI=32), works highstress job as prison guard in maximum-security facility § Presents to ED with a 2 day history of chest and jaw pain that resolved. Patient now complains of nausea and dyspnea. § VS: BP 130/95; HR 100; RR 23 O 2 Sat 99% • JVP 12, S 3 heart sound; • lungs w/ basilar rales • No peripheral edema; benign abdomen • LHC shown (right) • LVEF 25% by cath and echo, LV normal size, no MR, septal akinesis; LA= normal size

Case 2: Ventricle Stabilization in AMI Patient/HF Prevention § Interventional Decision Making: • LVEF 25% • 90% tubular mid-LAD lesion + 50% LADD 1 ostial stenosis § Should we use Acute MCS? • RHC: RA 12; PA 38/16; PCWP 16; PA Sat 67% • CI 2. 7 L/min/m 2; Cardiac Power Output : 0. 75 • PA Pulsatility Index : 1. 83 § No we do not need acute MCS at this time. § Consider acute MCS if: • CPO < 0. 5 or hypotensive requiring pressors • If using support for AMI/Shock, deploy either pre. PCI or before leaving the cath lab

Case 2: Ventricle Stabilization in AMI Patient/HF Prevention 28

Heart Attacks Lead to Heart Failure Top 10 Causes of Death Worldwide Exponential Growth in Heart Failure (WHO Data) CABG Terzic et al. Trends in CV Med. 2016 Jul 1; 26(5): 395 -404. World Health Organization 2012.

The Size of Your Heart Attack Matters Median Infarct Size Despite 1 o PCI: 17. 9% of Total LV Mass >2600 patients treated with Door to Balloon Strategy identified that for every 5% increase in myocardial infarct size 1 -year all-cause mortality increases by 19% and HF hospitalization by 20%. Stone GW, Selker HP, Udelson JE et al. JACC 2016 Apr 12; 67(14): 1674 -83.

Heart Attacks Lead to Heart Failure 39% 76% 10% Ezekowitz JA et al. JACC. 2009 Jan 6; 53(1): 13 -20.

GDMT to Reduce HF after AMI SAVE AIRE TRACE Index MI EPHESUS ALBATROS S Early introduction of OPTIMAAL VALIANT aldosterone antagonist. Benefit is time dependent, should be started within 7 days of index MI. Early Initiation of ACEI within first 24 hours. Forty percent of survival benefit from ACEI is conferred in the first day. 0 Hours Immediate perfusion for ST-segment elevation. Early revascularization for cardiogenic shock. Bahit MC et al. JACC HF. 2018; 6(3): 179 -86 24 Hours Discharge Avoid beta-blockers for first 24 hours for ongoing heart failure. Re-evaluate eligibility for beta-blocker therapy throughout hospitalization. CAPRICORN COMMIT-CCS-2 It is critical to titrate doses of medications (including ACE inhibitors and beta-blockers) to optimal levels in the postdischarge time period. Post-Discharge Follow up

Late-Term Cardiac Remodeling after Acute MI C rho=0. 48 P=0. 002 Konstam MA, Kramer DG et al. JACC: CI. 2011 Jan 1; 4(1): 98 -108. ; Kramer DG, Udelson JE et al. JACC. 2010 Jul 27; 56(5): 392 -406.

Case 2: Ventricle Stabilization in AMI Patient/HF Prevention • Pt started on IV furosemide, enalapril 5 mg bid uptitrated to 10 mg bid, toprol XL 25 mg increased to 50, and spironolactone 25 mg over the next 72 hours. • Diuresed 2 liters over 38 hours. JVP dropped to 10. Pt ambulating on day 2 • BP 110/80, HR 75 at discharge • Discharged and seen 7 -10 days in the outpatient clinic. • Enalapril increased to 15 mg bid, Toprol to 100. • Continued uptitration to 20 mg bid or enalapril, metoprolol to 150 spironolactone • Hx of hypertension not adherent to meds • 3 months later, EF improved to 40%. Off diuretics. • Pro. BNP=956

Tariq Ahmad, MD, MPH, FACC and Panel Case 3: Hospitalized Patient with HFp. EF

Case 3: Hospitalized Patient with HFp. EF Patient Video

Case 3: Hospitalized Patient with HFp. EF • • • 56 yo Hispanic female, hospitalized with acute decompensated HF; obese (BMI=35) Gradual onset of symptoms (2 -3 weeks, possibly longer) Dyspnea, leg swelling Presented to ED after sudden dyspnea/collapse at work (Factory worker, stands for long periods) BP 180/98, HR 90, on exam has elevated neck veins; bilateral crackles Cr=1. 7, Ejection fraction 62 • • • Comorbidities: History of COPD Former smoker (Quit 2 years ago) Persistent hypertension >4+ years, nonadherent to BP meds “because they make me feel dizzy/funny” No known family history of HFp. EF/other congenital disease Eats high-sodium traditional Mexican-American diet, including many “grab and go” meals from food trucks/stands near factory where she works; likely has undiagnosed ischemic hard disease due to lifestyle/obesity

Case 3: 56 yo Hispanic female, hospitalized with acute decompensated HF • How would/should we treat this patient? GENERAL PANEL DISCUSSION

HFp. EF • Clearly multifactorial • Strongly associated with aging • Fibrosis and stiffening of the ventricle seem to play a part • Changes in renal function and volume avidity play a part • Impaired contractile reserve seems to play a part • Molecular mechanisms are largely unknown, although recent data suggest the sarcomeric protein titin is important • Improved patient phenotyping is critical to moving the field forward

HFp. EF: Prevalence Increasing GWTG-HF: N=110, 621 patients hospitalized with HF P<0. 0001 for trend of increased HFp. EF prevalence Proportion of hospitalized heart failure patients (%) 60 50 ~50% EF > 50% 40 ~35% EF < 40% 30 20 ~15% EF 40 -50% 10 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Oktay AA, Rich JD, Shah SJ. Curr Heart Fail Rep. 2013 Dec; 10(4): 401 -10.

Cumulative Heart Failure Hospitalizations in Patients With Preserved Ejection Fraction With Treatment Patients Shown in Red and Control Patients in Blue 70 60 Control Group – Preserved EF Treatment Group – Preserved EF 50 40 30 20 10 0 0 180 360 540 720 900 Days After Implant B 250 Cumulative Heart Failure Hospitalizations A 225 Control Group – Reduced EF Treatment Group – Reduced EF 200 175 150 125 100 75 50 25 0 0 180 360 540 720 900 Days After Implant Copyright © American Heart Association, Inc. All rights reserved. Philip B. Adamson et al. Circ Heart Fail. 2014; 7: 935 -944.

Epidemiology of HFp. EF Reduced Ejection Fraction (N=2429) Preserved Ejection Fraction (N=2167) P Value Adjusted P Value 71. 7 ± 12. 1 74. 4 ± 14. 4 <0. 001 NA 65. 4 44. 3 <0. 001 28. 6 ± 7. 0 29. 7± 7. 8 0. 002 0. 17 35. 5 41. 4 0. 007 0. 002 Serum creatinine on admission (mg/dl) 1. 6± 1. 0 1. 6± 1. 1 0. 30 Hemoglobin on admission (g/dl) 12. 5± 2. 0 11. 8± 2. 1 <0. 001 Hypertension (% of patients) 48. 0 62. 7 <0. 001 Coronary artery disease (% of patients) 63. 7 52. 9 <0. 001 Atrial fibrillation (% of patients) 28. 5 41. 3 <0. 001 Diabetes (% of patients) 34. 3 33. 1 0. 42 0. 61 Substantial valve disease (% of patients) 6. 5 2. 6 <0. 001 0. 05 29± 10 61± 7 <0. 001 NA Characteristic Age (yr) Male sex (% of patients) Body-mass index Obesity (% of patients) Ejection fraction (%) Owan et al. NEJM. 2006; 355: 251 -9.

Comparison of PARAGON-HF and Prior HFp. EF Trials CHARM-P (n=3, 023) PEP-CHF (n=850) I-PRESERVE (n=4, 128) TOPCAT (n=3, 445) PARAGON-HF (n=4, 800) Treatment arms Candesartan vs. Placebo Perindopril vs. placebo Irbesartan vs. placebo Spironolactone vs. placebo Sacubitril/valsartan vs. valsartan Key inclusion criteria NYHA functional class II to IV, Prior CVH Clinical diagnosis of DHF with signs/symptoms of HF, ≥ 2 of the following: LAE/LVH/impaired LV filling/AF NYHA functional class II-IV + any corroborating evidence (e. g. HF sign), LVH or LAE considered optional corroborating evidence, HFH required unless in NYHA functional class III-IV Yes, ≥ HF symptom + ≥ 1 HF sign, Elevated NP, or HFH Yes, NYHA functional class II-IV, Elevated NT-pro. BNP, Mildly elevated NT-pro. BNP if prior HFH, structural heart disease (LAE or LVH) First of either CVD or HFH First of either-all-cause death of HFH First of either all-cause death or CVH First of either CVD, HFH, or RSD CVD and total HFH (first and recurrent) Endpoint CHARM-P = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-Preserved; CVD= cardiovascular disease, CVH = cardiovascular hospitalization. DHF = diastolic heart failure; HFH = heart failure hospitalization; HFp. EF = heart failure with preserved ejection fraction; I-PRESERVE = Irbesartan in heart failure with Preserved Ejection Fraction; LAE = left atrial enlargement; LV = left ventricular; NP = natriuretic peptide; PARAGON-HF = Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction; PEP-CHF = Perindopril in Elderly People With Chronic Heart Failure; RSD = resuscitated sudden death; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure With Aldosterone Antagonist; other abbreviations as in Table 1 Solomon SD et al. ACC poster session, November 2018.

Probability Heart Failure Hospitalizations: TOPCAT study Total HF Hosp Spiro : 394 Placebo: 475 P<0. 01* Placebo 245/1723 (14. 2%) 206/1722 (12. 0%) Spironolactone HR = 0. 83 (0. 69 – 0. 99) p=0. 042 *poisson regression Pfeffer MA et al. Circulation: Heart Failure. 2014 Sep; 7(5): 740 -51.

Deaths, Hospitalization – all causes: TOPCAT study Hospitalization HR = 0. 94 (0. 85 – 1. 04) p=0. 248 Placebo Spironolactone [15. 9%] Death Placebo Spironolactone Pfeffer MA et al. Circulation: Heart Failure. 2014 Sep; 7(5): 740 -51. [14. 6%] HR = 0. 91 (0. 77 – 1. 08) p=0. 294

Other HFp. EF Treatment Trials: A Comparison Borlaug BA, Redfield MM. Circulation. 2011; 123: 2006 -2014.

2017 ACC/AHA Guideline Update: Pharmacological Treatment for Stage C HFp. EF COR LOE Recommendations IIb B-R In appropriately selected patients with HFp. EF (with NEW: Current EF ≥ 45%, elevated BNP levels or HF admission within recommendation reflects 1 year, estimated glomerular filtration rate new RCT data. >30 m. L/min, creatinine <2. 5 mg/d. L, potassium <5. /0 m. Eq/L), aldosterone receptor antagonists (MRAs) might be considered to decrease hospitalizations. IIb B The use of ARBs might be considered to decrease hospitalizations for patients with HFp. EF. Yancy et al. Circulation. 2017; 136: e 137–e 161. Comment/Rationale 2013 recommendation remains current.

Unanswered Questions • HFp. EF (PARAGON-HF) Sequential Single-Blind Run-In Period Eligible patients who meet tolerability criteria at each safety/tolerability check visit are switched to the next study period ~ 2 weeks Screening period 1 -4 weeks § 2 -4 weeks * Valsartan singleblind run-in Randomized Double-Blind Long-Term Follow-Up Period Follow-up visits occurred at 4, 16, 32, and 48 weeks and every 12 weeks thereafter. All patients are followed until target number of primary composite (CV deaths and total HF hospitalizations) occur or 26 months after randomization of the last patient elapse, whichever occurs last Sacubitril/Valsartan at target dose of 97/103 mg bid N~4800 Sacubitril/Valsartan Single-blind run-in Valsartan at a target dose of 160 mg bid Safety/tolerability check and Randomizations (if eligible) § Eligible patients are exposed to valsartan 80 mg bid for 1 to 2 weeks, Patients on low pre-study angiotensin converting enzyme inhibitors or angiotensin receptor blocker doses or those with tolerability concerns are first started on valsartan 40 mg bid 1 to 2 weeks and then up-titrated to valsartan 80 mg bid for 1 to 2 weeks * Patients tolerating valsartan 80 mg bid for 1 to 2 weeks are switched to sacubitril /valsartan 49/51 mg bid for 2 to 4 weeks.

PARAMOUNT Figure 2: NT-pro. BNP at 4. 12, and 36 weeks in the LCZ 696 and valsartan groups Solomon SD et al. Lancet. 2012 Oct 20; 380(9851): 1387 -95.

PARAGON-HF • Phase 3 Trial of sacubitril/valsartan in HFp. EF • Completed enrollment Feb 2017 • 4822 participants in 43 countries • Event-driven trial, estimated end date: Early 2019

Summary • Ivabradine decreases HFH but doesn't appear to impact mortality • Sacubitril/valsartan represents significant advance to pharmacologic treatment of HF • Recommended in 2016 ACC HF guidelines for HFr. EF in select patient populations • Ongoing trials needed in HFp. EF to determine additional therapies

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