Hyponatremia as a Cardiovascular Biomarker

Transcription

1 Hyponatremia as a Cardiovascular Biomarker 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 B3 Hyponatremia and HF Incidence Clinical significance Results of available trials Management

4 Prevalence of Hyponatremia in HF w Hyponatremia (serum sodium < 135 meq/l) is common in patients hospitalized with HF 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)

5 Development of Hyponatremia During HF Hospitalization in the EVEREST Trial Baseline Normonatremic (n=1785) Baseline Hyponatremic (n=232) % Normal Serum Sodium % % 0 Baseline Day 1 Day 7/Discharge 11% of EVEREST placebo patients were hyponatremic at baseline, and by Day 7/Discharge 17% of patients were hyponatremic

6 Hyponatremia in ADHF Mechanisms

7 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.

8 Neuroendocrine Activity and HF Francis G et al Circulation 1990;82;1724 B8

9 Mechanisms of Hyponatremia in HF wincreased non-osmotic release of AVP (Low CO, decreased RBF, Low BP mediated stimulation of baroreceptors). wpotent thirst stimulation mediated by low CO and Angiotensin II. wdiuretics (Thiazides, Spironolactone, Loop diuretics)

10 Hyponatremia in ADHF Prognostic Significance

11 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:

12 Relation between hyponatremia and mortality

13 Hyponatremia and mortality in HF Rusinaru D et al Eur J HF 2012;14:1139

14 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 Hyponatremia was present in 10.2% of patients.

15 J Cardiac Fail 2012;18:74 By multivariable analysis hyponatremia was significant for all cause mortality (HR 1.42) and CV death/rehospitalization (HR 1.45)

16 What therapeutic Options are Available for the Treatment of our Case? B16 1. Fluid restriction. 2. IV loop Diuretics. 3. Non-loop diuretics. 4. Vaptans. 5. Hypertonic saline

17 Current Treatment Practice and Outcomes Hyponatremia Registry Kidney Intern 2015;88:167 B patients with Na 130 meq/l in 225 centers

18 Current treatment practice and outcomes. Report of the hyponatremia registry Kidney Int 2015;88:167 wna increase during the first day : w no treatment 1 meq/l. w Fluid restriction 2 meq/l w isotonic saline 3 meq/l. w Hypertonic saline 5 meq/l. w Tolvaptan 4 meq/l. At discharge, serum Na was < 135 meq/l in 78% of patients and < 130 meq/l 49%.

19 Water Restriction I IIa IIb III Fluid restriction (1.5 to 2 L/d) is reasonable in stage D, especially in patients with hyponatremia, to reduce congestive symptoms.

20 What therapeutic Options are Available for the Treatment of our Case? B20 1. Fluid restriction. 2. IV loop Diuretics. 3. Non-loop diuretics. 4. Vaptans. 5. Hypertonic saline

21 HYPONATREMIA and diuretic resistance w Retrospective cohort study in 499 hospitalized AHF patients treated with intravenous loop diuretics for 48 hours Nadir Sodium, meq/l < 130 P-value Initial dose, mg/d 65±43 75±84 71± Mean hourly UO, ml/h 79±37 85±43 80± *p< ±450* 84± ±165 OR <130 vs vs 135 Diuretic resistance 2.62 (1.16,5.88) 0.91 (0.43,1.93) Ng T, Cao D, Elkayam U et al. J Am Coll Cardiol 2012;59(13 suppl A):A

22 Hyponatremia and acute worsening of renal function Nadir Sodium, meq/l < 130 P-value GFR peak, ml/min/m 2-13±14* -20±20* -29±30* <0.001 BUN peak, mg/dl 7±8* 11±14* 16±16* <0.001 OR (95% CI) vs (1.41,3.42) 4.42 (2.45,7.97) Ng T, Cao D, Elkayam U et al. J Am Coll Cardiol 2012;59(13 suppl A):A

23 COMPARATIVE EFFECT ON URINE OUTPUT Ng T, Elkayam U et al J CV Pharmacol Therap 2012;17:373 N=160 N=42 N=40 Continuous infusion furosemide Furosemide + metolazone Continuous infusion Bumetanide

24 COMPARATIVE EFFECT ON URINE OUTPUT Ng T, Elkayam U et al :J CV Pharmacol Therap 2012;17:373 Coninuous infusion Metolazone Bumetanide P value Incidence of 29% 43% 63% ** hyponatremia Incidence of 27% 46% 29% hypokalemia 24

25 What therapeutic Options are Available for the Treatment of our Case? 1. Fluid restriction. 2. IV loop Diuretics. 3. Non-loop diuretics. 4. Vaptans. 5. Hypertonic saline

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

27 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.

28 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.

29 Arginine Vasopressin Antagonists I IIa IIb III In patients hospitalized with volume overload, including HF, who have persistent severe hyponatremia and are at risk for or having active cognitive symptoms despite water restriction and maximization of GDMT, vasopressin antagonists may be considered in the short term to improve serum sodium concentration in hypervolemic, hyponatremic states with either a V2 receptor selective or a nonselective vasopressin antagonist.

30 Conivaptan in Acute Decompensated HF Goldsmith, Elkayam et al J Cardiac Fail 2008;14:641

31 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

32 Adjudicated CV Mortality/Morbidity EVEREST Trial: Patients with HF and Hyponatremia Subjects with Baseline Sodium Subjects with Baseline Sodium 130 meq/l (ITT Population) <130 meq/l (ITT Population) Tolvaptan Placebo 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

33 EVEREST trial-composite Components (Day 7 or Discharge) Change in Body Weight Change in Global Clinical Status Tolvaptan Placebo 1 Additional weight loss 0.6 kg 0.9 kg P=0.51 P= P< P< mm 10 n=997 n=1007 n=1031 n= kg n=903 n=910 n=931 n= Trial A Trial B -3-4 No difference in GCS improvement -5 Trial A Trial B

34 EVEREST: Furosemide Use Change4in4furosemide4use4(mg/day) 10 0!10!20!30!40!50!60 Discharge Week41 Week48 P=0.028 P=0.019 P=0.002 Follow!up Visit4* Placebo Tolvaptan *7 days post-treatment discontinuation

35 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 * * * * * * Time, day Reprinted with permission from Zeltzer D, et al. Am J Nephrol. 2007;27: No Myelinolysis *P<.001, P=.034 vs placebo.

36 Tolvaptan, a Selective Oral Vasopressin V2- Receptor Antagonist, for Hyponatremia The SALT Trials, NEJM 2006

37 Hyponatremia and HF Summary whyponatremia is common in patients with AHF. wit has a strong impact on LOS, short and long-term mortality and rehospitalizations.

38 Hyponatremia and HF Summary Chronic hyponatremia is associated with increased morbidity and mortality, gait disturbances and altered cognition that predisposes increased risk of falls and fractures.

39 Hyponatremia and HF Summary Vasopressin receptor antagonists have strong aqueretic and hemodynamic effects and lead to a correction of volume overload and hyponatremia without effect on other electrolytes or renal function.

40 Hyponatremia and HF Summary On going studies should provide more information on the role of vasopressin antagonists in patients with the ADHF who have both volume overload and hyponatremia.

41 AQUARESIS UTILITY FOR HYPONATREMIC ACUTE HEART FAILURE (AQUA-AHF) STUDY w50 patients with Acute HF with signs or symptoms of volume overload. wserum sodium 130 meq/l at time of or within first 48 hours of hospitalization. wrandomized within 48 hours of presentation to hospital to Tolvaptan 30 mg/d or placebo.

42 B42 AQUA-AHF STUDY Primary efficacy endpoint: Mean urine output at 24 hours post randomization. Primary safety endpoint: Mean change in serum creatinine at 24 hours post randomization. Other end points: Wight loss, LOS, GFR, Serum sodium, diuretic dose.