Transcript Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan (EVEREST)

Efficacy of Vasopressin antagonism
in hEart failuRE: outcome Study with
Tolvaptan (EVEREST)
Marvin A. Konstam, MD; Mihai Gheorghiade, MD; John C. Burnett, Jr.,
MD; Liliana Grinfeld, MD; Aldo P. Maggioni, MD; Karl Swedberg, MD;
James E. Udelson, MD; Faiez Zannad, MD; Thomas Cook, PhD; John
Ouyang, PhD; Christopher Zimmer, MD; Cesare Orlandi, MD; for the
EVEREST Investigators & Committee Members
Presenter Disclosure Information
Efficacy of Vasopressin antagonism in hEart failuRE:
outcome Study with Tolvaptan (EVEREST)
The following relationships exist related to this presentation:
M.A. Konstam:
M. Gheorghiade:
J.C. Burnett, Jr.:
L. Grinfeld:
A.P. Maggioni:
K. Swedberg:
J.E. Udelson:
F. Zannad:
T. Cook:
J. Ouyang:
C. Zimmer:
C. Orlandi:
2
Otsuka: grants/contracts, consultant, honoraria
Otsuka: grants/contracts, consultant, honoraria
Otsuka: consultant, honoraria
Otsuka: grants/contracts, honoraria
Otsuka: grants/contracts, honoraria
Otsuka: grants/contracts, honoraria
Otsuka: grants/contracts, consultant, honoraria
Otsuka: grants/contracts, honoraria
Otsuka: grants/contracts, honoraria
Otsuka: employee
Otsuka: employee
Otsuka: employee
EVEREST Committees
Executive Steering Committee
Clinical Events Committee
• Marvin A. Konstam, MD Chair (Boston, USA)
• Alan Miller, MD Co-Chair (Jacksonville, USA)
• John C. Burnett, MD Co-Chair (Rochester, USA)
• Christopher O’Connor, MD Co-Chair
(Durham, USA)
• Mihai Gheorghiade, MD Co-Chair (Chicago, USA)
• Liliana Grinfeld, MD (Buenos Aires, Argentina)
• Maria Cecilia Bahit, MD (Buenos Aires,
Argentina)
• Aldo P. Maggioni, MD (Florence, Italy)
• Peter Carson, MD (Washington DC, USA)
• Cesare Orlandi, MD (Rockville, USA)
• Paul Hauptman, MD (St Louis, USA)
• Karl Swedberg, MD (Göteborg, Sweden)
• Marco Metra, MD (Brescia, Italy)
• Faiez Zannad, MD (Nancy, France)
• Markus Haass, MD (Mannheim, Germany)
• Ron Oren, MD (Iowa City, USA)
Independent Data Monitoring Committee
• Richard Patten, MD (Boston, USA)
• Sidney Goldstein, MD -Chair (Detroit, USA)
• Ileana Piña, MD (Cleveland, USA)
• Henry Dargie, MD (Glasgow, UK)
• Sherryn Roth, MD (Toronto, Canada)
• David DeMets, PhD (Madison, USA)
• Jonathan Sackner-Bernstein, MD (New
York, USA)
• Kenneth Dickstein, MD (Stavanger, Norway)
• Barry Greenberg, MD (San Diego, USA)
• Jorge Lerman, MD (Buenos Aires, Argentina)
• Barry Massie, MD (San Francisco, USA)
• Bertram Pitt, MD (Ann Arbor, USA)
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Participating Investigators
ARGENTINA: O. Allall, M. Amuchastegui,
J. J. Blugermann, R. Colque, L. Guzmán, M. A. Riccitelli,
M. Sultan, J. Tronge, A. E. Ballestrini,
S. M. Chekherdemian, L. Girotti, O. Grosso, M. Halac,
S. Llois, D. Nul, E.R. Perna, S. M. Salzberg, N. Vulcano
BELGIUM: J. Salembier, F. Charlier, G. De Keulenaer,
L. Gabriel, B. Marchandise
BULGARIA: S. Dimitrova, H. Benov, A. Mihov, D. Raev, V.
Yordanova
BRAZIL: D. P. Rossi, J. C. Rocha, S. Rassi, L. Maia,
J. F. Kerr Saraiva, G. Greque, E. R. Fernandes Manenti,
O. Dutra, C. Blacher, D. Albuquerque, N. Clausell,
G. Soares Feitosa, P. Pimentel Filho, A. C. Pereira Barreto,
G. Reis, M. Sanali Moura de Oliveira Paiva,
L. Soares da Costa
CANADA: A. Bakbak, A. Ducharme, J.E. Goode,
F. Halperin, F. Halperin, T. Huynh, S. Kouz, S. LePage, A.
Morris, S. Roth, B. Sussex, Y.K. Chan, D. Delgado,
W. P. Klinke, P. Ma, G. Moe, T. Rebane
CZECH REPUBLIC: B. Cernosek, J. Drazka, L. Golan,
J. Jandik, J. Janousek, I. Oral, J. Vitovec, P. Vojtisek,
D. Alan, L. Hoskova, E. Mandysova, F. Padour, D.Tichy
FRANCE: P. Gibelin, T. Laperche, J.-N. Trochu, Z. Chati,
M. Ferriere, M. Galinier, M. Martelet, F. Zannad
GERMANY: T. Dengler, R. Erbel, S. Felix, R. Hambrecht,
D. Horstkotte, S. Möbius-Winkler, J. Müller-Ehmsen,
H. Ochs, R. Schwinger, U. Sechtem, H. Vogelsberg,
W. von Scheidt, T. Wichter, M. Buerke, H. Darius, H.-R.
Figulla, S. Fredersdorf, G. Hasenfuß, G. Hauf, S. Holmer,
J. Kolditz, H. Neuser
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ITALY: A. Caporotondi, F. Cobelli, C. Marabotti, M. Porcu,
S. Ricci, P. Terrosu, P. Agostoni, V. Cirrincione, F. Cosmi,
P. Giannuzzi, F. Masini, M. Metra, C. Opasich, L. Tavazzi,
R. Tramarin
LITHUANIA: A. Kavoliuniene, S. Norkiene, B.
Petrauskiene, I. Skripkauskiene, R. Mazutavicius
NORWAY: V. Bonarjee, T. Omland, C. Ostvold, A. Semb
NETHERLANDS: G. Bertels, E. Buys, F. den Hartog, R.
Groutars, D. Hertzberger, P. Kalmthout, P. Leemans, P.
de Milliano, R. Veldcamp, A.Willems, D. Lok, P. van der
Burgh, J. Wesdorp
POLAND: E. Fiutowska, J. Grzybowski, J. Kopaczewiski,
W. Pluta, P. Ruszkowski, R. Sciborski, K. Jaworska, M.
Krzciuk, J. Maciejewicz, A. Malinski,
M. Ogorek, G. Opolski, F. Prochaczek, W. Sinkiewicz
ROMANIA: M. Cinteza, S. Dragulescu,
C. Fierbinteanu Braticevici, C. Ginghina, D. Ionescu, M.
Radoi, G. Tatu-Chitouiu, R. Capalneanu, M. Datcu, C.
Macarie, I. Nanea, D. Nastase-Melicovici
RUSSIAN FEDERATION: M. Ballyuzek, A. Baranov,
N. Gratsiansky, A. Martynov, N. Sanina, S. Shustov,
L. Sorkin, D. Zateyschikov, K. Zrazhevsky, O. Berkovich, I.
Bokarev, M. Moyarkin, S. Chernov, V. Kostenko,
V. Mareev, V. Mkrtchuan, V. Novozhenov, N. Perpech,
B. Sodorenko, V. Simanenkov, M. Sitnikova,
G. Storozhakov, R. Stryuk, B. Tankhileitch,
V. Zadionchenk
Participating Investigators
SPAIN: J. Delgado, J. Mercé, M. Vida, . Arizón, A. Grande,
F. Pèrez-Villa, F. Ridocci
SWEDEN: I. Hagerman, T. Kahan, K. Swedberg,
G. Wikström, R. Willenheimer, U. Dahlström,
B. Johansson, C. Linde
SWITZERLAND: T. Moccetti
UNITED KINGDOM: M. Baig, J. Cleland, N. Brooks,
J. Dhawan, J. John
USA: K. Adams, M. Almaleh, Y. Aude, J. Banas,
D. Banish, A. Bank, A. Barbagelata, J. Bengtson,
R. Benza, A. Boyle, D. Bresnahan, D. Brown, R.
Capodilupo, J. Carley, D. Caskey, D. Chapman, E. Chung,
J. Cieszkowski, J. Corbelli, W. Cotts, D. Cullinane,
E. Eichhorn, U. Elkayam, K. Fath, J. Foley, J. Foster,
R. Frantz, S. Friedman, H. Gogia, M. Goldberg, T. Hack,
D. Hassel, C. Haugh, P. Hauptman, J. Heywood,
D. Hinchman, J. Hodsden, H. Ibrahim, T. Ishimori,
B. Iteld, R. Kachel, D. Kraus, M. Kronenberg, H. Ladley, M.
Leonen, M. Liston, B. Lowes, F. Malik, P. Mather,
J. McCriskin, P. McCullough, F. McGrew, V. S. Monroe,
R. Moskowitz, I. Niazi, J. O'Brien, T. O'Brien,
W. Oellerich, M-T Olivari, A. Passer, A.V. Poelnitz,
C. Porter, H. Ribner, S. Rubin, D. Rubin, R. Santos,
J. Schmedtje, G. Schuyler, E. Schwarz, R. Shor,
R. Siegel, B. Singh, J. Sklar, F. Smart, D. Smith,
P. Stockwell, K. Taylor, R. Vicari, K. Vijay, L. Wagoner, M.
Walsh, W. Wickemeyer, J. Wight, M. Yasin, F. Adulia
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J. Alexander, L. Altschul, R. Alvarez, T. Amidon, Y. Aude,
C. Baier, J. Bergin, R. Bijou, M. Bilsker, T. Bishop, C.
Brian, C. Brown, R. Carhart, T. Carlson, A. Chai, R. Clark,
B. Clemson, F. Cobb, H. Colfer, T. Connelly, E. Colfer, H.
Dasgupta, W. Dec, J. Detwiler, B. DeVries,
M. El-Shahawy, M. El-Zaru, P. Fattal, G. Felker, R. Festin,
G. Fishbein, E. Flores, D. Friedman, D. Goldscher,
S. Goldsmith, M. Goldstein, J. Gordon, A. Gradman,
M. Greenspan, D. Gupta, H. Haught, E. Hope, E. Hsich,
M. Imburgia, B. Jackson, D. Jansen, S. Jauhar,
S. Jerome, D. Joyce, B. Kahn, S. Kapadia,
M. Kesselbrenner, R. Kipperman, M. Koren, S. Krueger,
G. Lasala, J. Lash, J. McBride, E. McMillan, L. McNabb,
M. Miyamoto, K. Morris, P. Narayan,
M. Nathan, M.A. Peberdy, N. Pereira, M. Pirwitz,
R. Prashad, P. Rama, D. Richards, J. Roberts, J. Rose,
E. Roth, D. Rubinstein, R. Ryder, M. Saltzberg,
R. Schneider, R. Sequeira, N. Singh, H. Skopicki,
R. Sotolongo, D. Stapleton, R. Starling, J.T. Suh, N. Vijay,
C. Vogel, R. Weiss, F. Whittier, C. Wilkins
Participating Sites
EUROPE
Canada (16)
United States (157)
Brazil (17)
Argentina (18)
Russia (25)
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)
359 enrolling sites in 20 countries
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7
More than 50% of Patients Have Little or
No Weight Loss During Hospitalization
35
30
24%
Patients (%)
25
Current treatment options
33% • Loop diuretics
• IV inotropes
• Nitrates
• Nesiritide
20
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)
Change in Weight (lbs)
8
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7): 21.
(5 to 10)
(>10)
Arginine Vasopressin
4
Median Plasma AVP (pg/mL)
in SOLVD Trial1
V1a
3
Blood vessels
Myocardium
2
1
V2
Renal tubules
0
Control
(1.4-2.3)
Prevention
(1.7-3.0)
Treatment
(2.3-4.4)
Tolvaptan
9
Francis et al. Circulation 1990;82:1724-1729.
EVEREST: 3 Trials in One
OBJECTIVE:
Evaluate tolvaptan effects on signs/symptoms in-hospital
Separate
Sites
Short-term
Clinical Status
Trial A
Short-term
Clinical Status
Trial B
Long-term Outcome Trial
Long-term drug administration
OBJECTIVE
Evaluate tolvaptan effects on morbidity / mortality
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Key Entry Criteria
Inclusions
• Hospitalization for HF <48hrs
• LVEF ≤40%
• Fluid overload; ≥2 of the following:
– Jugular venous distention
– Pitting edema (>1+)
– Dyspnea
Exclusions
•
•
•
•
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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%
Short-Term Clinical Status Trial Design
Sites assigned
to Trial A or B
4133 pts enrolled
7 days or
discharge
from October 7, 2003 and February 3, 2006
Oral Tolvaptan 30 mg QD
Trial A
n=2048
Placebo QD
Long-term
outcomes trial
Randomization
Oral Tolvaptan 30 mg QD
Trial B
n=2085
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)
12
Combined Outcome Trial Design
Safety
Follow-up
Randomization
<48 hrs
7 days
Oral Tolvaptan 30 mg QD (n=2072)
Hospitalization
for worsening HF
Placebo QD (n=2061)
1065
Deaths
Dual Primary Endpoints:
• Improvement / non-inferiority in All-cause Mortality
• Improvement in CV death or HF hospitalization
13
Gheorghiade, et al. J Card Fail. 2005;11:260-269.
Sample Size Analysis
1. All-Cause Mortality
–
–
–
=0.0402
For superiority: 90% power for HR = 0.81
For non-inferiority: assuming no between group
difference, 90% power to exclude HR ≥1.25
2. CV Mortality or Hospitalization for HF
–
–
14
=0.009;
90% power for HR = 0.82
Trial Population
Tolvaptan
Placebo
(n=2072)
(n=2061)
65.9 (11.7)
65.6 (12.0)
Gender (% Male)
73.4
75.4
Race (% Caucasian)
85.3
85.7
27.5 (8.0)
27.5 (8.2)
NYHA Class III/IV (%)
60/40
59/41
Ischemic etiology (%)
65.1
65.9
Hypertension Hx (%)
70.8
71.1
AF Hx (%)
43.6
43.2
Diabetes (%)
39.8
37.6
Renal Insuf. (%)
26.5
27.1
Age, mean (SD) (yrs)
EF, mean (SD) (%)
15
Baseline Characteristics
Tolvaptan
Placebo
(n=2072)
% of patients
(n=2061)
% of patients
Diuretics
97.1
96.6
ACEi / ARB
84.3
84.1
β-blocker
70.8
69.6
Aldo blocker
53.6
54.7
IV inotrope
4.0
4.3
Nesiritide
4.2
5.1
Dyspnea
90.9
91.1
Edema
79.3
79.3
JVD ≥ 10 cm H2O
27.0
26.9
Serum Na+ <134 mEq/L
7.9
8.0
Baseline Meds
Baseline HF Characteristics
16
Short-Term Clinical Status Trials
17
Clinical Status Trials: Primary
Composite Endpoint
Change from baseline at day 7 or hospital discharge
Patient global
assessment (VAS)
Body
weight
&
Rank sum analysis:
18
TRIAL A
TRIAL B
Benefit with Tolvaptan
P=0.0004
Benefit with Tolvaptan
P<0.0001
Composite Components
(Day 7 or Discharge)
Change in Body Weight
Change in Global Clinical Status
Tolvaptan
Placebo
P=0.51
Additional weight loss
0.6 kg
0.9 kg
P=0.52
20
15
P<0.0001
P<0.0001
0
n=997 n=1007
mm
1
10
n=1031 n=1008
5
-1
kg
n=903
n=910
n=931
n=900
0
-2
Trial A
Trial B
-3
No difference in GCS
improvement
-4
-5
Trial A
19
Trial B
Secondary Endpoints: Day 1
Trial A
Tolvaptan
Δ in BW (kg)
Difference
Trial B
Placebo
Tolvaptan
Placebo
– 1.7
– 1.0
– 1.8
– 0.9
± 1.8
± 1.8
± 2.0
± 1.9
0.7 kg
Both trials
P<0.001
0.9 kg
80
Improved
Δ in
Dyspnea
(% of pts with
baseline
dyspnea)
60
11
14
11
24
24
25
40
20
0
worsened
–20
20
16
23
37
35
33
31
–2
Tolvaptan
(n=894)
–3
Placebo
(n=915)
–2
–3
Placebo
(n=914)
Tolvaptan
(n=941)
Both trials
P<0.001
Markedly better
Moderately better
Minimally better
Worse
Secondary Endpoint: Day 7 or DC
Δ in Edema Score
(% of patients with baseline edema)
100%
75%
Trial A
Trial B
P=0.07
P=0.02
9
8
27
26
7
33
7
27
improved
50%
37
36
33
25%
0%
21
36
17
22
18
19
9
8
7
10
Tolvaptan
Placebo
Tolvaptan
Placebo
(n=772)
(n=790)
(n=828)
(n=805)
–4
–3
–2
–1
0
1
2
worsened
Physician-assessed Signs and Symptoms
(% Patients with Improvement)
Tolvaptan
100
*
80
*
100
*
80
*
60
*
*
*
60
40
40
20
20
0
0
Day 1
Day 2
Day 3
Day 4
Dyspnea
Day 1
100
80
80
*
*
60
40
40
20
20
0
0
Day 1
Day 2
Day 3
Fatigue
Day 4
Day 2
Day 3
Day 4
Orthopnea
* P<0.05
100
60
22
Placebo
*
*
*
*
Day 1
Day 2
Day 3
Edema
Day 4
Long-Term Outcome Trial
23
Proportion Alive
Outcome Trial All-Cause Mortality
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR 0.98; 95%CI (.87-1.11)
Meets criteria for non-inferiority
Median follow-up 9.9 months
TLV 30 mg
PLACEBO
Peto-Peto Wilcoxon Test: P=0.68
2072
1812
1446
1112
859
589
404
239
97 TLV
2061
1781
1440
1109
840
580
400
233
95 PLC
0
3
6
9
12
15
18
21
Months In Study
24
24
Proportion Without Event
CV Mortality or HF Hospitalization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR 1.04; 95%CI (.95-1.14)
TLV 30 mg
PLACEBO
Peto-Peto Wilcoxon Test: P=0.55
2072
1562
1146
834
607
396
271
149
58 TLV
2061
1532
1137
819
597
385
255
143
55 PLC
0
3
9
12
15
18
21
6
Months In Study
25
24
Secondary Outcome Endpoints and
Components
26
Changes in Body Weight and Serum
Sodium by Visit
Inpatient
Outpatient
0
1998 1947
1997 1949
1899 1695
1887 1695
1485
1479
1285
1300
1059
1069
889
887
753
752
Day Day 7 or
1 Discharge
1 4
16
24
32
40
48
605 TLV
592 PLC
–1
Body Weight
(kg)
–2
–3
–4
8
56
12
Serum Na+
10
8
(mEq/L)
(baseline <134 mEq/L) 6
4
Tolvaptan
Placebo
2
0
–2
27
159
159
153
148
Day Day 7 or
1 Discharge
Inpatient
143
140
14
114
115
97
93
80
85
64
73
51
59
39
51
32 TLV
42 PLC
8
16
24
32
40
48
56
After Discharge (wk)
Changes in Renal Function
Inpatient
Outpatient
8
6
BUN
(mg/dL)
4
2
0
-2
-4
1980
1987
Day
1
1940
1951
Day 7 or
Discharge
1828
1820
14
1687
1674
1433
1434
1220
1247
1001
1014
851
853
713
706
558 TLV
559 PLC
8
16
24
32
40
48
56
0.6
Tolvaptan
Placebo
0.4
Serum Cr
(mg/dL)
0.2
0.0
-0.2
-0.4
1912
1925
Day
1
1864
1886
Day 7 or
Discharge
Inpatient
28
1755 1620
1761 1614
1381
1382
1168
1203
955
978
813
821
675
677
525 TLV
537 PLC
14
16
24
32
40
48
56
8
After Discharge (wk)
Adverse Events
29
Tolvaptan
Placebo
(n=2072)
(n=2061)
P-value
Renal failure
133 (6.4)
140 (6.8)
0.66
Hypotension
233 (11.3)
226 (11.0)
0.77
Ventricular tachycardia
123 (6.0)
118 (5.7)
0.79
Atrial fibrillation
116 (5.6)
122 (5.9)
0.69
Dry mouth
174 (8.4)
44 (2.1)
<0.001
Thirst
331 (16.0)
43 (2.1)
<0.001
Hyperkalemia
161 (7.8)
136 (6.6)
0.15
Hypokalemia
166 (8.0)
202 (9.8)
0.05
Hypernatremia
35 (1.7)
10 (0.5)
<0.001
Hypomagnesemia
21 (1.0)
39 (1.9)
0.02
Conclusions
1. 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 (d1) and edema (d7)
No effect on global clinical status (VAS) at d7/DC
Normalization of serum sodium
Maintenance of renal function.
2. Long-term treatment had no effect on long-term mortality or HF
morbidity.
3. Tolvaptan achieved short-term symptom benefit with a welldefined and acceptable long-term safety profile.
4. Future research should continue to clarify target patient
subsets and administration strategies to identify clinical
benefits of vasopressin receptor blockers.
30