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Faiez Zannad, MD, PhD

Short-term effects of Tolvaptan in acute decompensated heart failure. Understanding the results of EVEREST. Faiez Zannad, MD, PhD

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Faiez Zannad, MD, PhD

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  1. Short-term effects of Tolvaptan in acute decompensated heart failure. Understanding the results of EVEREST. Faiez Zannad, MD, PhD Karl Swedberg2, Mihai Gheorghiade3, John C Burnett4, Liliana Grinfeld5, Aldo P Maggioni6, James E Udelson7, Thomas Cook8, John Ouyang9, Christopher Zimmer9, Cesare Orlandi9 and Marvin A Konstam. 1 Inserm and CHU, Nancy, France ; 2Sahlgrenska University Hospital, Gothenburg, Sweden; 3Northwestern U Feinberg School of Medicine, Chicago, IL; 4Mayo Clinic, Rochester, MN; 5Hospital Italiano, Buenos Aires, Argentina; 6Associazione Nazionale Medici Cardioligi Ospedalieri Research Center, Florence, Italy; 7Tufts-NEMC, Boston, MA; 8University of Wisconsin, Madison, WI and 9Otsuka Maryland Research Institute, Rockville, MD.

  2. Approved Agents for AHFS

  3. More than 50% of Patients Have Little or No Weight Loss During Hospitalization • Current treatment options • Loop diuretics • IV inotropes • Nitrates • Nesiritide 35 33% 30 24% 25 20 Patients (%) 15 13% 15% 10 7% 6% 5 3% 2% 0 (<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7): 21.

  4. Median Plasma AVP (pg/mL) in SOLVD Trial1 4 3 2 1 Tolvaptan 0 Control Prevention Treatment (1.4-2.3) (1.7-3.0) (2.3-4.4) Arginine Vasopressin Francis et al. Circulation 1990;82:1724-1729.

  5. EVEREST Participating Sites EUROPE Belgium (4) Bulgaria (5) Czech Republic (13) France (8) Germany (18) Italy (13) Lithuania (5) Netherlands (10) Norway (4) Poland (14) Romania (12) Spain (7) Sweden (8) Switzerland (1) United Kingdom (4) Russia (25) Canada (16) United States (157) Brazil (17) Argentina (18) 359 enrolling sites in 20 countries Sponsor: OTSUKA

  6. EVEREST investigated the effect of tolvaptan, for relieving congestion in patients hospitalized with acute decompensated heart failure with systolic dysfunction. We report short-term effects of Tolvaptan on body weight with relation to changes in individual signs and symptoms related to congestion.

  7. 4133 pts enrolled from October 7, 2003 and February 3, 2006 n=2048 n=2085 Short-Term Clinical Status Trial Design 7 days or discharge Sites assigned to Trial A or B Oral Tolvaptan 30 mg QD Trial A Placebo QD Long-term outcomes trial Long-term outcomes trial Randomization Oral Tolvaptan 30 mg QD Trial B Placebo QD Visits daily in-hospital through day 7 or discharge Primary Endpoint: Composite of change in body weight and improvement in patient-assessed global status (VAS)

  8. Key Entry Criteria Inclusions • Hospitalization for HF <48hrs • LVEF ≤40% • Fluid overload; ≥2 of the following: • Jugular venous distention • Pitting edema (>1+) • Dyspnea Exclusions • Recent or planned revascularization or device implant • STEMI during hospitalization • Systolic BP <90 mm Hg • Creat >3.5 mg%; K >5.5 mEq/L; Hgb <9 g%

  9. Trial Population

  10. Baseline Characteristics

  11. Rank sum analysis: Clinical Status Trials: Primary Composite Endpoint Change from baseline at day 7 or hospital discharge Patient global assessment (VAS) Body weight & TRIAL A Benefit with Tolvaptan P=0.0004 TRIAL B Benefit with Tolvaptan P<0.0001

  12. Patient global assessment (VAS) Body weight & Change from baseline at day 7 or hospital discharge • Patient’s self-assessed global clinical status visual analog scale • Score 0 for “worst state you can imagine” • Score 100 for “best state you can imagine”.

  13. Additional weight loss 0.6 kg 0.9 kg No difference in GCS improvement Composite Components(Day 7 or Discharge) Change in Body Weight Change in Global Clinical Status Tolvaptan Placebo P=0.51 P=0.52 20 15 1 P<0.0001 P<0.0001 mm 10 0 n=1007 n=1008 n=1031 n=997 5 -1 n=903 n=910 n=931 n=900 kg 0 -2 Trial A Trial B -3 -4 -5 Trial A Trial B

  14. Correlation Between Body Weight and Patient-Assessed Dyspnea subjective ease of breathing relative to pretreatment 7-point scale Worse No change Min Better Mod Better Mark Better Improvement in Dyspnea at Day 1

  15. Physician-Assessed Signs and Symptoms (Not pre-specified endpoints) • Rales • 4-point scale (no rales, bases, bases to 50% way up, or bases to 50% way up); • Pedal edema (Pre-specified) • 5-point scale (absent, trace, slight, moderate, or marked); • Jugular venous distention • 4-point scale (6 cm, 6-9 cm, 10-15 cm, or15 cm) • Dyspnea, orthopnea, and fatigue • 4-point scales (none, seldom, frequent, or continuous).

  16. * * * Orthopnea Physician-assessed Signs and Symptoms (% Patients with Improvement) Tolvaptan Placebo * * * * Dyspnea * P<0.05 * * * * * * Fatigue Edema

  17. 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5 -5.0 Change in Physician-Assessed Signs and Symptoms and Change in Weight at Discharge from Hospital 0.0 0,0 Dyspnea Rales -0.5 -0,5 -1.0 -1,0 -1.5 -1,5 -2.0 -2,0 -2.5 -2,5 -3.0 -3,0 -3,5 -3.5 -4,0 -4.0 -4,5 -4.5 0.0 Edema JVD -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5 Improvement Improvement

  18. Tolvaptan Placebo Change in Serum Na+ (mEq/L)(baseline <134 mEq/L) 12 159 153 159 148 10 8 6 4 2 0 –2 Day 7 or Discharge Day 1

  19. Furosemide Use • mean reduction from baseline dosage at discharge • Tolvaptan group –55.8 mg/d • Placebo group –42.9 mg/d • P=.002.

  20. Long term : Primary End Points All-Cause Mortality CV Mortality or HF Hospitalization HR 0.98; 95%CI (.87-1.11) HR 1.04; 95%CI (.95-1.14) 1.0 1.0 Meets criteria for non-inferiority 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Proportion Without Event Proportion Alive 0.5 0.5 0.4 1-year rate: > 50% 1 year mortality 25.0% 0.4 0.3 0.3 0.2 Median follow-up: 9.9 mos 0.2 TLV 30 mg TLV 30 mg 0.1 0.1 PLACEBO PLACEBO Peto-Peto Wilcoxon Test: P=0.68 Peto-Peto Wilcoxon Test: P=0.55 0.0 0.0 2072 1812 1446 1112 859 589 404 239 97 TLV TLV 2072 1562 1146 834 607 396 271 149 58 PLC 2061 1781 1440 1109 840 580 400 233 95 PLC 2061 1532 1137 819 597 385 255 143 55 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months In Study Months In Study

  21. Safety:Adverse Events

  22. SafetyNo change • Heart rate • Blood pressure • Renal function • Electrolytes other than Serum Na+

  23. Conclusions • In well-treated patients hospitalized with HF, oral tolvaptan, 30 mg daily, facilitates management of volume overload with • Early and sustained weight reduction • Improvement in dyspnea and edema • Normalization of serum sodium • Remarkable safety profile • preservation of renal function • No change in Heart rate, blood pressure, electrolytes • Long-term treatment had no effect on long-term mortality or HF morbidity. Tolvaptan is a potentially useful agent for treating patients with an exacerbation of heart failure.

  24. AHFS clinical trial endpoint A Clinician’s View: Short Term: Patient global self-assessment with Visual Analog Scale does not detect significant changes in clinically relevant changes in signs and symptoms related to congestion and body weight changes. Long Term: AHFS M&M event rate is extremely high in “optimally” treated patients. Long term outcome results are critical in AHFS

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