Hyponatremia & Preventing Thromboembolic Complications Peter P. - PowerPoint PPT Presentation

Advanced Heart Failure: Hyponatremia & Preventing Thromboembolic Complications Peter P. Liu, MD Professor of Medicine and Physiology Peter Munk Cardiac Centre University Health Network Toronto, Ontario ACC Rockies Conference, 2012

Case Discussion • 76 yr retired gentleman with previous MI and systolic HF, now admitted in failure • After one dose of furosemide, you found that his [Cr] has risen (140->250), [Na] fallen (136->131) • What would you do now for the patient? – 1. Withhold diuretics – 2. Give hypertonic saline intravenously – 3. Furosemide infusion – 4. Restrict fluid intake – 5. Consider vasopressin antagonist

Outcomes After Acutely Decompensated Heart Failure Hospitalization  Mortality  11.6% at 30 days 1  33.1% at 12 months 1  Hospital readmissions  20% at 30 days  50% at 6 months 1. Jong P et al. Arch Intern Med. 2002;162:1689 – 1694.

In-hospital Mortality Risk Groups According to the ADHERE Risk Stratification • BUN > 42  3.34 (3.08 – 3.62) • SBP ≤ 115  3.09 (2.85 – 3.35) • DBP ≤ 55  2.87 (2.62 – 3.14) • Serum [Na + ] < 134  2.26 (2.08 – 2.47) • SCr > 3.2  1.99 (1.78 – 2.24) • Age > 78 years  1.88 (1.74 – 2.04) • Dyspnea at Rest  1.57 (1.45 – 1.70) • HR > 84  1.20 (1.11 – 1.30) Abraham WT et al. J Am Coll Cardiol. 2005;46(1):57-64.

Prevalence of Hyponatremia in ADHF OPTIMIZE-HF Registry N=48,612 pts. Gheorghiade M et al. Eur Heart J. 2007;28(8):980-988.

[Na] & Mortality in HF Cohort Bettaro L, et al., J Cardiac Fail 2012; 18:74-81 Duke HF Database

Relationship Between Serum [Na + ] and In-hospital Mortality in OPTIMIZE-HF 0.08 0.07 In- Hospital Mortality Rate 0.06 0.05 0.04 0.03 0.02 0.01 0 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 n= 227 254 349 451 547 752 949 1263 1619 2216 2725 3510 4502 4824 4944 4888 4160 3313 2315 1500 929 471 260 Admission Serum [Na + ] (mmol/L) Mean admission serum [Na + ] in the total cohort was 138 ± 5 mmol/L, and 19.7% of patients had values <135 mmol/L. Gheorghiade M et al. Eur Heart J. 2007;28(8):980-988.

Treatment Algorithm for Acute HF 8 Leadership. Knowledge. Community. Erratum. Can J Cardiol 2006;22(3):271.

List of Acute HF Trials that Reduced Mortality or Hospitalization • • •

NHLBI DOSE Study Design Acute Heart Failure (1 symptom AND 1 sign) <24 hours after admission 2x2 factorial randomization Low Dose (1 x oral) Low Dose (1 x oral) High Dose (2.5 x oral) High Dose (2.5 x oral) Q12 IV bolus Continuous infusion Q12 IV bolus Continuous infusion 48 hours 1) Change to oral diuretics 2) continue current strategy 3) 50% increase in dose 72 hours Co-primary endpoints 60 days Clinical endpoints

Death, Rehospitalization, or ED Visit HR for Continuous vs. Q12 = 1.19 HR for High vs. Low = 0.83 95% CI 0.86, 1.66, p = 0.30 95% CI 0.60, 1.16, p = 0.28 0.6 0.6 Proportion with Death, Rehosp, or ED visit Proportion with Death, Rehosp, or ED Visit 0.5 High Low Continuous Q12 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Days Days

DOSE Trial Summary • There was no evidence of benefit for continuous infusion compared to Q12 hour bolus on any secondary endpoint • Despite transient changes in renal function, there was no evidence for higher risk of clinical events at 60 days associated with the high intensification strategy • High intensification (2.5 x oral dose) was associated with trends towards greater improvement in multiple domains: – Symptom relief (global assessment and dyspnea) – Weight loss and net volume loss – Proportion free from signs of congestion – Reduction in NT-proBNP

Ultra- Filtration: External Fluid Removal

UNLOAD Trial n = 200 with ADHF IV Diuretics Ultrafiltration for 48 hours Costanzo MR. J Am Coll Cardiol . 2007;49:675-83

Ultrafiltration Improved Weight Loss But Not Symptoms End points Ultrafiltration Diuresis p n 83 84 48 hours • Weight loss, primary end point 5.0 3.1 0.001 (mean kg) • Dyspnea score, primary end 6.4 6.1 0.35 point (mean) • Net fluid loss (mean L) 4.6 3.3 0.001 • K<3.5 mEq/L (%) 1 12 0.018 • Need for vasoactive drugs (%) 3 13 0.015 Costanzo MR. J Am Coll Cardiol . 2007;49:675-83

Role of Ultrafiltration • Patient with acute decompensated heart failure and significant volume overload • Unresponsive to IV diuretics • Adequate blood pressure and perfusion • Reasonable renal function • Can tolerate full anticoagulation • Local nephrology expertise and support

Cost-Effectiveness of UF Bradley S, et al. Circ CV Qual Outcomes 2009; 2:566-73

Neurohormonal Pathophysiology of HF Schrier RW, Abraham WT. N Engl J Med . 1999;341(8):577-585.

Plasma Vasopressin According to HF Severity 40 Vasopressin (pmol/L) ** 26.9 30 * 20 13.4 10 5.5 4.9 1.7 0 Aged- NYHA NYHA NYHA NYHA Matched Class I Class II Class III Class IV Control (n=10) (n=10) (n=19) (n=23) (n=20) * P <.05 vs control; ** P <.001 vs control. Data from 72 subjects with CHF admitted to Omiya Medical Center in Japan. Nakamura T et al. Int J Cardiol . 2006;106(2):191-195.

Copeptin & Survival in HF Pts (BACH) Maisel A, Anker S, et al., Circ Heart Fail 2011; 4:613-20

Action of Vasopressin

EVEREST Outcomes Trial Design Randomisation Treatment Period Safety (Median 9.9 months) Follow-up ≤48 hours 60 days 14 days Tolvaptan 30 mg QD + Hospitalisation Standard Therapy for Worsening HF (n=2072) Placebo QD+ TLV (n=2072) Standard Therapy Placebo (n=2061) (n=2061) 1065 Deaths Dual Primary Endpoints: Short-Term Endpoints: • All-cause mortality • Composite of change in weight and VAS between baseline and • CV death or HF hospitalisation Day 7 or discharge Konstam MA et al. JAMA . 2007;297(12):1319-1331.

Distribution of Baseline Serum [Na + ] in the EVEREST Trial Hyponatremia 250 Tolvaptan 30 mg Placebo n=475 200 (11.5%) No. of Subjects 150 Severe Mild n=92 n=383 (2.2%) (9.3%) 100 50 0 115 120 125 130 135 140 145 150 155 160 Baseline Serum [Na + ] Level (mmol/L) Data on file: Protocol 156-03-236.

Neutral Effect on Outcomes – All Patients All-Cause Mortality CV Mortality or HF Hospitalisation 1.0 HR 0.98; 95%CI (0.87 – 1.11) 1.0 HR 1.04; 95%CI (0.95 – 1.14) Meets criteria for 0.9 0.9 Proportion Without Event non-inferiority 0.8 0.8 Proportion Alive 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 Tolvaptan 30 mg Tolvaptan 30 mg 0.3 0.2 Placebo Placebo 0.2 0.1 0.1 Peto-Peto Wilcoxon Test: P =.68 Peto-Peto Wilcoxon Test: P =.55 0.0 0.0 2072 1812 1446 1112 859 589 404 239 97 TLV 2072 1562 1146 834 607 396 271 149 58 TLV PLC 2061 1781 1440 1109 840 580 400 233 95 2061 1532 1137 819 597 385 255 143 55 PLC 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months in Study Months in Study Konstam MA et al. JAMA . 2007;297(12):1319-1331.

CV Mortality/Morbidity in Pts with Hyponatremia (Sodium < 130 mmol/L) Subjects with Baseline Sodium Subjects with Baseline Sodium ≥130 mmol/L (ITT Population) <130 mmol/L (ITT Population) 1.0 Proportion Remaining in Study Tolvaptan Tolvaptan 0.9 Placebo Placebo 0.8 0.7 P <.05 0.6 0.5 0.4 0.3 0.2 Hazard Ratio: 1.065 Hazard Ratio: 0.603 0.1 95% CI Limits: 0.973, 1.165 95% CI Limits: 0.372, 0.979 0.0 PLC 2007 1748 1415 1090 824 569 394 228 92 PLC 54 19 13 9 8 4 2 2 2 TLV 2034 1784 1424 1095 844 580 398 235 95 TLV 38 23 14 12 10 7 5 3 1 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months in Study Months in Study Overall CV Mortality/Morbidity (ITT) HR 1.04; 95% CI (.95‒1.14). Data on file: Protocol 156-02-236.

Change in Serum [Na + ] Concentrations – Hyponatremic Subgroup 145 Mean ( ± SE) Serum [Na + ] Concentration (mmol/L) 140 * * * * * * * * * 135 130 Tolvaptan 30 mg (n=235) Placebo (n=226) 125 BSL Day 1 Day 7 1 4 8 16 24 32 40 48 56 Inpatient Outpatient Week * P <.05 Data on file: Protocol 156-03-236.

Dyspnea Improvement With Tolvaptan ∆ 6.4% ∆ 13.5% 80 Tolvaptan P <.0001 Placebo P =.028 60 Percent Improved 40 20 0 Overall HF HF/Hyponatremia (n=3664) (n=409) Konstam MA et al. JAMA . 2007;297(12):1319-1331. Data on file: Protocol 156-03-236.

Body Weight Reduction – Hyponatremic Subgroup Day 1 Day 7/Discharge 0 Change From Baseline in Body Weight (kg) ‒1 Tolvaptan Placebo ‒2 ∆ 0.7 kg ‒3 ‒4 ∆ 0.8 kg P <.001 P <.05 (n=460) (n=463) OC Analysis Konstam MA et al. JAMA . 2007;297(12):1319-1331. Data on file: Protocol 156-03-236.

Adjusted Mean Lengths of Stay in Pts with Normal Sodium & Hyponatremia Cyr PL, Hauptman PJ, et al., Am J Health System Pharm 2011; 68:328-33

Effect of Tolvaptan Rx on Mean Lengths of Stay in Pts with Hyponatremia EVEREST Trial of Tolvaptan vs Placebo in ADHF Cyr PL, Hauptman PJ, et al., Am J Health System Pharm 2011; 68:328-33