State of the Art Treatment - Hyponatremia, Heart Rate, et al

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1 State of the Art Treatment - Hyponatremia, Heart Rate, et al Uri Elkayam, MD Professor of Medicine University of Southern California Keck School of Medicine elkayam@usc.edu

2 Disclosure Research grant from Otsuka for the study: Tolvaptan in the treatment of volume overload in hyponatremic patients with heart failure (AQUA-AHF).

3 Prevalence of Hyponatremia in HF 50 w Hyponatremia (serum sodium < 135 meq/l) is common in patients hospitalized with HF 40 Patients (%) OPTIME ACTIV OPTIMIZE-HF ESCAPE EVEREST OPTIME-CHF-Klein L; Circulation. 2005; 111: ACTIV-Gheorghiade M, JAMA. 2004; 291 OPTIMIZE-HF- Gheorghiade M, Euro Heart J. 2007; 28: ESCAPE-Gheorghiade M, Arch Intern Med. 2007; 167 (18): EVEREST-Konstam M, JAMA. March 2007, 297 (12)

4 Arginine Vasopressin (AVP, ADH) Stimulation and Effects 1. Osmolality 2. Angiotensin II/NE 3. Arterial pressure/ cardiac volume + 1. Osmolality 2. Natriuretic peptides 3. Arterial pressure/ cardiac volume V1b-Ant pituitary Pancreas, Adrenal medula V 1a Receptor (VSMC, cardiomyocytes) AVP V 2 Receptors (collecting ducts) Vasoconstriction Myocardial stimulation Renal H 2 O reabsorption Verbalis JG. Cleve Clin J Med. 2006;73(suppl 3):S24-S33; Lee CR, et al. Am Heart J. 2003;146:9-18.

5 Hyponatremia Is Associated With Rehospitalization in HF Patients* % Na <135 meq/l Na 135 meq/l P<.0001 for all % Length of Stay, d In-Hospital Mortality, % *OPTIMIZE-HF registry data; N=48,612. Postdischarge Mortality, % Death or Rehospitalization Since Discharge, % Reprinted with permission from Gheorghiade M, et al. Eur Heart J. 2007;28:

6 PROGNOSTIC VALUE OF HYPONATREMIA VS. BNP PARK ET AL, JACC 2014;63:A786

7 J Cardiac Fail 2012;18:74 1 Duke data base :1,045 patients with heart failure due to systolic dysfunction, undergoing cardiac catheterization between 2000 and 2008

8 Hyponatremia and Long Term Outcome in HF The Duke Data Base Betari L et al J Cardiac Fail 2012;18:74 10%

9 Hyponatremia and Long Term Outcome in HF The Duke Data Base Betari L et al J Cardiac Fail 2012;18:74 Betari L et al J Cardiac Failure 2012:18:74

10 Relation of Serum Na Level to Long- Term Outcome After 1 st Hospitalization for HFPEF Rusinaru D et al Am J Cardiol 2009;103:405 Corrected vs. Persistent Hyponatremia

11 Hyponatremia in ADHF Treatment

12 Treatments for Hyponatremia In Patients With HF Improving hemodynamics. ACE inhibitors. Fluid restriction (poorly tolerated, only 1-2 meq/l per day). Diuresis (Hypertonic saline). Vasopressin receptor antagonists..

13 Nonpeptide AVP Receptor Antagonists Tolvaptan Lixivaptan Satavaptan Conivaptan Receptor V 2 V 2 V 2 V 1a /V 2 Route of administration Oral Oral Oral IV Urine volume Urine osmolality Na + excretion/ 24 h for low dose for high dose Company Otsuka CardioKine sanofiaventis Astellas Reprinted with permission from Verbalis JG, et al. Am J Med. 2007;120:S1-S21.

14 Change in Serum [Na + ] After 4 Days of Continuous IV Infusion of Conivaptan Placebo IV Conivaptan 40 mg/day IV Conivaptan 80 mg/day (n=29) (n=29) (n=26) 12 * LS Mean ± SE Change From Baseline [Na + ], meq/l * * * * * * Reprinted with permission from Zeltzer D, et al. Am J Nephrol. 2007;27: No Myelinolysis Time, day *P<.001, P=.034 vs placebo.

15 CV Mortality or HF Hospitalization Proportion Without Event Peto-Peto Wilcoxon Test: P=0.55 HR 1.04; 95%CI ( ) TLV 30 mg PLACEBO TLV PLC Months In Study

16 Adjudicated CV Mortality/Morbidity EVEREST Trial: Patients with HF and Hyponatremia Subjects with Baseline Sodium 130 meq/l (ITT Population) Tolvaptan Placebo Subjects with Baseline Sodium <130 meq/l (ITT Population) Proportion Remaining in Study Hazard Ratio: % CI Limits: 0.973,1.165) PLC TLV PLC TLV (p<0.05) Hazard Ratio: % CI Limits: 0.372, Months in Study Months in Study Overall CV Mortality/Morbidity (ITT) HR 1.04; 95%CI ( ) ATA on File: Protocols and

17 Efficacy and Safety of Tolvaptan in Patients Hospitalized With AHF The TACTICS-HF Study 257 patients with AHF within 24 hours presentation regardless of EF randomized either to tolvaptan 30 mg or placebo given at 0, 24 and 48 hours

18 Efficacy and Safety of Tolvaptan in Patients Hospitalized With AHF The TACTICS-HF Study 257 patients with AHF within 24 hours presentation regardless of EF randomized either to tolvaptan 30 mg or placebo given at 0, 24 and 48 hours

19 Short Term Effects of tolvaptan in Patients with AHF and Volume Overload- SECRET of CHF Study 250 patients with AHF Mean EF 34% 32% > 45% Randomized within 36 h sfter hospitalization to Tolvaptan30 mg/d or placebo for 7 days Konstam MA et al JACC 2017;69:

20 Short Term Effects of tolvaptan in Patients with AHF and Volume Overload- SECRET of CHF Study Konstam MA et al JACC 2017;69:

21 Short Term Effects of tolvaptan in Patients with AHF and Volume Overload- SECRET of CHF Study Konstam MA et al JACC 2017;69:

22 EVEREST: Furosemide Use Change4in4furosemide4use4(mg/day) Discharge Week41 Week !10!20!30!40 P=0.028!50!60 P=0.019 P=0.002 Follow!up Visit4* Placebo Tolvaptan *7 days post-treatment discontinuation

23 Tolvaptan in Acute Heart Failure- Time to Move On There is a disconnect between weight/fluid loss and dyspnea. It may be time to abandon the dyspnea endpoint in acute heart failure trials. Starling & Young JACC 2017:69;1407-8

24 2013 Guidelines For The Management of Heart Failure

25 Common. Hyponatremia and ADHF Summary Very strong biomarker for prognosis. Vasopressin receptor antagonists are the most effective treatment for correction of hyponatremia and volume overload. The drugs however, have not been shown to improve symptoms or prognosis in patients with both acute and chronic HF

26 HR at Discharge and Mortality / hospitalizations Lasky WK et al J Am Heart Assoc 2015;4;e ,217 medicare patients in Get with the guidelines HF

27 Relation Between Magnitude of HR Reduction and Change in LVEF in BB Trials. 35 trials ~23,000 patients Flannery et al AJC 2008

28 Relation Between Magnitude of HR Reduction and Mortality in BB Trials

29 HR and Survival in 2039 Patients with HFrEF Cullington D et al JACC 2014;2:213 HR significantly associated with survival. Each increase in resting HR by 10 bpm associated with 13% increase in annual mortality (HR: 1.13, 95% CI: 1.03 to 1.24, p ). Patients with HR > 70 bpm had worse survival compared to a reference group of < 57 bpm. ( HR: 1.47; 95% CI: 1.03 to 2.13, p. 0.04).

30 Meta-Analysis: BB Dose, HR Reduction, and Death in Patients With Heart Failure McAlister FA et al Ann Int Med 2009;150:784 Every 5 beats/min reduction in HR = 18% reduction in the risk for death.

31 Is Target Dose More Important Than Target HR? Porapakkham P et al CV Therapeutics 2010:10;1755 Target dose Carvedilol 50 mg /d, Bisoprolol 10 mg/d, Metoprolol Succinate 190 mg/d Target HR 60 bpm

32 HR or BB Dose? Results From The HF ACTION Trial Fiuzat M et al JACC Heart Failure 2016;4:109

33 Beta Blockers, Heart Rate and Outcome There is a strong relation between HR, BB dose and mortality in HF. The effect of BB on outcome is related to the magnitude of HR reduction.

34 Achieving a Maximally Tolerated b-blocker Dose in Heart Failure Patients Is There Room for Improvement? Bhatt AS et al JACC 2017:69;2542

35 Achieving a Maximally Tolerated BB Dose in HF Patients: Is There Room for Improvement? Bhatt AS et al JACC 2017:69;2542 Administration after a meal Smaller doses TID