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Primary Care Update January 26 & 27, 2017 New Approaches for Systolic Heart Failure Thomas Cimato, MD, PhD, FACC, FAHA Associate Professor Division of Cardiovascular Medicine Educational Goals: • Review the definition, diagnostic criteria and medical therapy for congestive heart failure • Understand why sacubatril-valsartan is superior to ACE inhibitor therapy in chronic systolic heart failure • Understand the benefits and adverse reactions of sacubatril-valsartan therapy in patients with systolic heart failure Question 1: Sacubatril-valsartan is recommended in patients with NYHA Class II-III systolic congestive heart failure who can tolerate an ACE inhibitor or ARB with prior hospitalization in the past 12 months? A. True B. False Question 2: Therapy with sacubatril-valsartan reduces hospitalization for congestive heart failure? A. True B. False Question 3: Which of the following statements regarding use of sacubatril-valsartan treatment are true? A. It can cause angioedema B. It cannot be given with an ACEi or ARB C. It cannot be used in patients with systolic blood pressure < 100 mm Hg D. It cannot be used in patients with eGFR < 30 E. All of the above Congestive Heart FailureDefinition • A disorder of EITHER cardiac filling (diastole) or contraction (systole) resulting in symptoms of shortness of breath • How do we know that the shortness of breath is due to heart failure and not another cause? What are the criteria for the diagnosis of heart failure? Congestive Heart Failure-Definition Yturralde and Gaasch (2005) Prog Cardiovasc Dis 47(5): 314-9 e l red BNP Levels in Diagnosis REVIEW of Heart Failure B-type natriuretic peptide (ng/L) 1400 1200 1000 800 600 400 200 0 No congestive heart failure (n=770) Dyspnoea due to non-cardiac causes in patients with a history of left-ventricular dysfunction (n=72) Dyspnoea due to congestive heart failure (n=744) Figure 2: BNP concentrations in patients presenting with dyspnoea and enrolled in the BNP multinational study Guideline Directed Therapy for Congestive Heart Failure Guideline-Directed Medical Therapy – “GDMT” I IIa IIb III Adapted from Yancy et al, Circulation 2013 Intensive Review of Cardiology COMBINED NEPRILYSIN AND RAS INHIBITION FOR TREATMENT OF HEART FAILURE JCHF. 2014;2(6):663-670. doi:10.1016/j.jchf.2014.09.001 Sacubatril-Valsartan Inhibits Degradation of BNP • SOLVDwasthe OnlytrialinHF Toshowasignificant reductioninmortality WithanACEinhibitor Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure n e w e ng l a n d j o u r na John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., The Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees* A BS T R AC T hospitalizationforCHF From the British Heart Foundation (BHF) Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.); the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College London, London (K.S.); and the Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston (M.R.Z.). Address reprint requests to Dr. Packer at the Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, or at [email protected]; or to Dr. McMurray at the BHF Cardiovascular Research Centre, University Pl., University of Glasgow, Glasgow, Scotland G12 8QQ, United Kingdom, or at john [email protected]. * A complete list of the investigators in the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting– Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) is provided in the Supplementary Appendix, available at NEJM.org. Drs. McMurray and Packer contributed equally to this article. This article was published on August 30, 2014, and updated on September 11, 2014, at NEJM.org. Methods Cumulative Probability 1.0 receptor–neprilysin inhibitor LCZ696 with enalapril We compared the angiotensin Hazard 0.80 (95% in patients who had heart failure with a reduced ejection fraction. ratio, In previous studies, enalapril improved survival in such patients. P<0.001 0.6 In this double-blind trial, we randomly assigned 8442 patients with class II, III, or 0.5 fraction of 40% or less to receive either LCZ696 (at IV heart failure and an ejection a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. 0.4 The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results 0.3 C Hospitalization HearttheFailure LCZ696 was superior to enalaprilfor in reducing risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov num1.0 ber, NCT01035255.) Hazard ratio, 0.79 (95% 1.0 CI, 0.73–0.87) Enalapril 0.2according to prespecified rules, after a median followThe trial was stopped early, up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the0.1 time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard 0.0 ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 0 180 360 540 720 900 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), Days since respectively, died from cardiovascular causes (hazard ratio, 0.80; Randomization 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospiNo.foratheart Risk talization failure by 21% (P<0.001) and decreased the symptoms and physicalLCZ696 limitations of heart4187 failure (P 3922 = 0.001). The LCZ696 group 3663 3018had higher 2257 pro-1544 portions of patients with hypotension and nonserious angioedema but lower pro-1488 Enalapril 4212 3883 3579 2922 2123 portions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions B Death from Card LCZ696 1080 896 853 Cumulative Probability A Primary End Point DeathCVcausesor Background CI, 0.71–0.89) 0.5 0.4 0.3 0.2 0.1 0.0 1260 249 236 0.6 0 No. at Risk LCZ696 Enalapril 4187 4212 D Death from Any 1.0 Neprilysin Inhibition — A Novel Therapy for Heart Failure editorials Mariell Jessup, M.D. U. S. -T AH D LV SO EF M T AD IT -C RT SH EM IF PH T AS PA I RA S-H F D IG M -H F Ca rv ed ilo lG ro up No. Needed to Treat to Reduce Death from Any Cause other noteworthy, successful trials The Food In PARADIGM-HF (Prospective Comparison of 250 (FDA) last 1)3-5Drug ? TheAdministration with heart failure (Tableand approved 220 [Angiotensin Receptor–Neprilysin Inhibitor] included patients witha new New oral Yorkdrug (hydralazine–isosor- ARNI dinitrate) patients with heart failure and with ACEI [Angiotensin-Converting–Enzyme Ination class II,bide III, or IV heartfor failure 200 a reduced fraction in 2005 — and this hibitor] to Determine Impact on Global Morejection fraction of lessejection than 40% changed to drug 35% was or recommended less by an only for150self-identified tality and Morbidity in Heart Failure Trial), black patients who continued to have symptoms McMurray et al. report that LCZ696, as comto the protocol) and who were redespite evidence-based treatment.1 The aldoste- pared with a target-dose enalapril-based regibest available medical therapy. The 100 rone antagonist eplerenone was approved for the men, significantly reduced the rates of death o participated in PARADIGM-HF treatment of heart failure in 2003. (In 2012, the from any72 cause and from cardiovascular causes to those in other studies involving European Medicines Agency approved for worsening 50 ivabradine, and the rates34of hospitalizations 35 h mild to moderately severe heart 26 which has not received FDA approval.) 23 a heart failure in patients with a reduced ejection 22 Now, novel drug, LCZ696, a dual inhibitor of angioten- fraction. In addition, patients’ quality of life, as 0 LCZ696 succeed in improving outsin II receptor and neprilysin, may prove to be the measured on the Kansas City Cardiomyopathy onvincingly in this representative first disruptive agent to the heart-failure treat- Questionnaire, was significantly improved.2 of patients? Drugs that inhibitwhich the has remained essentially Who were the patients in this remarkable ment algorithm, tensin–aldosterone system (RAAS) trial, and how do they compare with the patients unchanged for a decade. oundational to cardiovascular drug almost three decades. RAAS inhibiable 1. Mean Baseline Characteristics of Patients with Heart Failure and a Reduced Ejection Fraction in Five Trials.* Figure 1. Numbers of Patients with Heart Failure te vasoconstriction, myocyte hyperWho Would Need to Be Treated Reduce Any-Cause SystolictoBlood myocardial fibrosis, Left an Ventricular effect that ial Age Ejection Fraction NYHA Class in Seven HeartClinical Rate Trials. Pressure Treatment Mortality ed into clinically meaningful imSOLVD-T denotes Studies of Left Ventricular Dysfunction– ACE MineraloICD with in functional status and survival. study are BetaTreatment.9 The data for the MADIT-CRTInhibitor corticoid or without peptides, which include atrial natrior ARB of Blocker Antagonist CRT from the initial report, with an average follow-up de, B-type natriuretic peptide, and % of2.5 years. yr % patients beats/min mm Hg % of patients re secreted by the heart, vasculature, HEFT 57 24 95 in class III NA 126 87 74 38 18 central nervous system in response ADIT-CRT 65 24 85 in class II NA 122 97 93 31 100 cardiac-wall stress and other stimHIFT 60 29 49 in class II; 79 121 91 89 60 5 during the run-in phase because of an adverse tic peptides have potent natriuretic 50 in class III Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure Milton Packer, CumulativeHospitalizations MD*; John J.V. McMurray, MD*; Akshay S. Desai, MD, MPH; Cumulative Number of Hospitalizations for Heart Failure per 100 Patients Jianjian Gong, PhD; Martin P. Lefkowitz, MD; Adel R. Rizkala, PharmD; Jean L. Rouleau, MD; Victor C. Shi, MD; Scott D. Solomon, MD; Karl Swedberg, MD, PhD; Michael Zile, MD; 60MD, PhD; Juan Luis Arango, MD; J. Malcolm Arnold, MD; Jan Bĕlohlávek, MD, PhD; Karl Andersen, Michael Böhm, MD; Sergey Boytsov, MD; Lesley J. Burgess, MBBCh, PhD; Walter Cabrera, MD; Rate ratio 0.77 (0.67-0.89) Carlos Calvo, MD; Chen-Huan Chen, MD; Andrej Dukat, MD; Yan Carlos Duarte, MD; P < 0.001 Andrejs Erglis, MD, PhD; Michael Fu, MD; Efrain Gomez, MD; Angel Gonzàlez-Medina, MD; Albert A. Hagège, MD, PhD; Jun Huang, MD; Tzvetana Katova, PhD; Songsak Kiatchoosakun, MD; Kee-Sik Kim, MD, PhD; Ömer Kozan, Prof Dr; Edmundo Bayram Llamas, MD; Felipe Martinez, MD; Bela Merkely, MD; Iván Mendoza, MD; Arend Mosterd, MD, PhD; Marta Negrusz-Kawecka, MD, PhD; Keijo40 Peuhkurinen, MD; Felix J.A. Ramires, MD, PhD; Jens Refsgaard, MD, PhD; Enalapril Arvo Rosenthal, MD, PhD; Michele Senni, MD; Antonio S. Sibulo Jr, MD; José Silva-Cardoso, MD, PhD; Iain B. Squire, MD; Randall C. Starling, MD, MPH; (n=4212) John R. Teerlink, MD; Johan Vanhaecke, MD, PhD; Dragos Vinereanu, MD, PhD; Raymond Ching-Chiew Wong, MBBS; on behalf of the PARADIGM-HF Investigators and Coordinators† LCZ696 20 (n=4187) Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received October 11, 2014; accepted October 20, 2014. From the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX (M.P.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK (J.J.V.M.); Brigham and Women’s Hospital, Cardiovascular Medicine, MA (A.S.D., S.D.S.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Université de Montréal, Institut de Cardiologie, Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, Gothenburg, Sweden (K.S.); The Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.Z.); School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (K.A.); Unidad de Cirugía Cardiovascular de Guatemala, Guatemala City, Guatemala (J.L.A); Western University, Department of Medicine and Physiology, Ontario, Canada (J.M.A.); 2nd Department of Medicine, Cardiovascular Medicine, General University Hospital and 1st Medical School, Charles University in Prague, Prague, Czech Republic (J.B.); Department of Cardiology, University of the Saarland, Homburg/Saar, Germany (M.B.); National Research Center for Preventive Medicine, Moscow, Russia (S.B.); TREAD Research, Cardiology Unit, Department of Internal Medicine, Stellenbosch University and Tygerberg Hospital, Parow, South Africa (L.J.B.); Clinica Vesalio, Lima, Peru (W.C.); Unidad de Hipertensión Arterial y Riesgo Vascular, Hospital Clínico Universitario, Santiago de Compostela, A Coruña, Spain (C.C.); Department of Medicine, National Yang-Ming University, Taiwan, Republic of China (C.-H.C.); Second Department of Internal Medicine, Comenius University in Bratislava, Bratislava, Slovakia (A.D.); Luis Vernaza Hospital, Guayaquil, Ecuador (Y.C.D.); Faculty of Medicine, Institute of Cardiology, University of Latvia, Riga, Latvia (A.E.); Department of Medicine, Sahlgrenska University Hospital/Ӧstra Hospital, Göteborg, Sweden (M.F.); Clinica Shaio, Bogota, Colombia (E.G.); Hospiten Risk SantoPatients Domingo,at Universidad Autonoma de Santo Domingo, Santo Domingo, Dominican Republic (A.G.-M.); Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Cardiologie; Paris Descartes University, Sorbonne Paris Cité; INSERM U970, Paris Cardiovascular Research 4054Hospital with LCZ696 4187 3885 3276University, 2472 1001 279Sofia, Bulgaria 12(T.K.); Center; Paris, France (A.A.H.); First Affiliated Nanjing Medical China (J.H.);1710 National Hospital of Cardiology, Enalapril 4212 4049 3857 3228 2408 1724 993 278 University Medicine 17 Cardiology, Medicine, Khon Kaen University, Thailand (S.K.); Daegu Catholic University Hospital, Daegu, Korea (K.-S.K.); Dokuz Eylül 4140 Faculty, İzmir, Turkey (O.K.); Fundación Cardiovascular de Aguascalientes A.C., Hidalgo, Mexico (E.B.L.); Titular de Medicina Interna, Universidad Nacional 4143 de Córdoba, Instituto DAMIC/Fundacion Rusculleda, Cordoba, Argentina (F.M.); Heart and Vascular Center Semmelweis University, Budapest, Hungary (B.M.); Circulation.2015;131:54–61.DOI:10.1161/CIRCULATIONAHA.114.013748 Venezuela Instituto Tropical Medicine Universidad Central Venezuela, Caracas, Venezuela (I.M.); Department of Cardiology, Meander Medical Centre, Amersfoort and WCN Dutch Network for Cardiovascular Research, Utrecht, The Netherlands (A.M.); Department and Clinic of Cardiology, Wroclaw Medical University, Poland (M.N.-K.); Department of Medicine, Kuopio University Hospital, Kuopio, Finland (K.P.); Heart Institute (InCor) – University of São Paulo, Medical School, Brazil (F.J.A.R.); Department of Cardiology, Viborg Hospital, Viborg, Denmark (J.R.); Dr. Arvo Rosenthal LLC, Estonia (A.R.); Azienda Ospedaliera Papa Giovanni XXIII, Cardiologia 1 – Scompenso e Trapianti di Cuore, Bergamo, Italy (M.S.); St. Luke’s Heart Institute, Quezon City, Philippines (A.S.S.); Center for Health Technology and Services Research (CINTESIS), Porto Medical School, University of Porto, Portugal (J.S.-C.); Department of Cardiovascular 30 zation 0 0 180 360 540 720 900 1080 1260 1440 Days After Randomization Figure 2. Cumulative number of hospitalizations for heart failure in the enalapril and LCZ696 groups per 100 patients. Shown is Who should be treated with sacubatril-valsartan? • ARNI therapy (valsartan/sacubitril) is recommended in patients with NYHA Class II or III systolic congestive heart failure who can tolerate an ACE inhibitor or ARB as disease modifying therapy with: • Elevated brain derived natriuretic peptide > 150 pg/mL or NT-pro-BNP > 600 pg/mL • Elevated brain derived natriuretic peptide > 100 pg/mL or NT-pro-BNP > 400 pg/mL WITH a prior hospitalization for congestive heart failure in the past 12 months Who should be treated with sacubatril-valsartan? • ARNI should not be administered with ACE inhibitors or ARBs within 36 hours of the last dosage. • Valsartan/sacubitril is not intended for subjects with low systolic blood pressure < 100 mm Hg, eGFR < 30 mL/min/1.73m2, or potassium > 5.2 mmol/L. • Hypotension and angioedema are potential effects of the drug.