Transcript The TRIUMPH Study - Clinical Trial Results

The Tilarginine Acetate Injection in a
Randomized International Study in Unstable
Acute Myocardial Infarction Patients with
Cardiogenic Shock (TRIUMPH)
Judith S. Hochman
on behalf of TRIUMPH Investigators
TRIUMPH was supported by ArgiNOx Pharmaceuticals, Inc.
New York University received a research grant from ArgiNOx for TRIUMPH
Judith S. Hochman, MD served as a consultant to Datascope
TRIUMPH report can be found at jama.ama-assn.org
Background

The incidence of cardiogenic shock
complicating STEMI has remained
stable at ~8%

Despite the reduction in mortality
resulting from early revascularization,
early mortality rates remain high (50%
at 30 days)
Background

A systemic inflammatory response
syndrome (SIRS) may be triggered by a
large MI, with elevation of inflammatory
cytokines (e.g.,IL-6), as seen in septic
shock

High cytokine levels are associated with
the development of cardiogenic shock

Inflammatory cytokines increase
expression of inducible nitric oxide
synthase (iNOS) leading to high levels of
nitric oxide (NO)
Background

Experimental data demonstrate that high
levels of nitric oxide:

Reduce contractility

Reduce catecholamine responsivity

Induce inappropriate systemic vasodilation

Excess NO may play a role in the genesis
and persistence of cardiogenic shock

Preliminary studies suggested a beneficial
effect of isoform non-selective NOS
inhibition on hemodynamics, renal function,
and survival in persistent cardiogenic shock
LINCS - Single Center
Randomized Study of NOS inhibitor L-NAME
Marked Survival Benefit
L-NAME
1mg/kg bolus and
1mg/kg/hour X 5 hours
Usual care
Cotter et al. EHJ (2003)
SHOCK 2 - Phase 2 Multi Center Study
Early BP Effect
50
Change in MAP at 15 Minutes
All p values are vs. placebo
Dzavik et al, EHJ in press
40
30
20
10
4.0
3.0
4.3
6.3
0
0
-2.0
P=0.0004
-10
P=0.013
P=0.02
-20
P=0.012
-30
Placebo
0.15
mg/kg
0.50
mg/kg
Urine Output
cc/24 h
Median Overall Change=3.33
2400
2400
2000
2000
1600
1600
1.0
mg/kg
1.5
mg/kg
TRIUMPH Hypothesis
The NOS inhibitor tilarginine
{L-N-monomethyl arginine (L-NMMA)}
compared with placebo would reduce
30-day all-cause mortality by 25%
in patients with MI complicated by
cardiogenic shock persisting after
successful opening of the infarct artery.
TRIUMPH Eligibility
Myocardial Infarction
Ischemic
symptoms ≥ 30
minutes with:

Cardiac markers
or

ST-segment
elevation or left
bundle branch
block
+
Refractory Shock
Peripheral signs of
tissue hypoperfusion
and
SBP <100 mmHg
despite
Vasopressor Rx
 Dopamine ≥7 mcg/kg/min
 Norepinephrine ≥0.15 mcg/kg/min
 Epinephrine ≥0.15 mcg/kg/min
+
Persistent after PCI
 Patency of the
infarct artery
(<70% stenosis)
 LVEF <40%
 Shock persisting
≥1 hour after
infarct artery
patency
and
Clinical or hemodynamic
evidence of ↑LV EDP
Hemodynamics and requirement for vasopressor treatment were
reconfirmed just prior to study drug administration to exclude patients
with rapidly resolving shock
Major Exclusion Criteria

Severe valvular heart disease / acute MR

Severe RV dysfunction of any cause

Suspected or documented infection

Serum Cr >3.0 mg/dl (>264 μmol/l) or dialysis

Adult respiratory distress syndrome

Anoxic brain injury / irreversible multisystem failure

Recent thoracic or abdominal surgery

Need for emergency CABG within 24 hours
Endpoints
Primary Outcome:
All-cause mortality at 30 days among patients who
received any study medication


Overall
Stratified by age (<75 or ≥75 years)
Other outcome measures:






Shock duration
Shock resolution
Blood pressure change at 2 hours
NYHA functional class at 30 days
Reinfarction
6-month mortality
Statistical Considerations


Planned sample size of 658 treated patients

90% power to detect 25% relative reduction in
mortality

Projected placebo mortality rate of 50%

Alpha = 0.05

Blocked randomization, stratified by site and age
Futility analysis

Conditional power of 20% was to trigger a
recommendation by the DSMB to stop the trial at
either the 50% or 75% review of the planned
sample
Study Interventions

Random 1:1 assignment to

Tilarginine (LNMMA) 1mg/kg bolus followed by 1
mg/kg/hr infusion X 5 hours

Matching placebo bolus and 5 hour infusion

Decrease in vasopressor doses was
discouraged during study drug infusion

IABP strongly recommended

Otherwise, patients were managed at the
discretion of the treating physician based on
ACC/AHA, ESC, and CCS guidelines
Study Termination

At the 50% review, the conditional power to
meet the primary objective was <10% and the
DSMB recommended termination

The sponsor quickly terminated trial
operations, resulting in some missing
baseline data

The academic leadership requested site
investigators attempt to collect 6 month vital
status
1611 Patients
Acute MI with
Cardiogenic Shock
entered in screening log
398 Eligible, enrolled
≥1hr after IRA patency
documented
206 Tilarginine
190 Placebo
201 (97.6%) received study drug
180 (94.7%) received study drug
SBP no longer qualifying (n=5)
SBP no longer qualifying (n=10)
197 (98.0%) 30-d follow-up complete
178 (98.9%) 30-d follow-up complete
Lost to 30-d follow-up (n=4)
Lost to 30-d follow-up (n=2)
186 (94.4%) 6-m follow-up complete
162 (91.0%) 6-m follow-up complete
Lost to 6-m follow-up (n=11)
Lost to 6-m follow-up (n=16)
Treatment Assignment unknown (n=2) 30 days: 1 died/1 survived
Enrollment
CANADA
(20 sites)
51 subjects
USA
(102 sites)
130 subjects
GERMANY
(13) 54
BELGIUM
(3) 12
POLAND
(16) 78
CZECH REP
(10)10
AUSTRIA
(4) 39 HUNGARY
(7) 22
On average, 3.65 patients (0.25 patients
per site per month) were enrolled at 130
centers in 8 countries
Baseline Characteristics (1)
Tilarginine
(n=206)
Placebo
(n=190)
P
Value
Age, years
Age ≥ 75 years, %
Male, %
67
27
74
68
27
70
0.98
0.96
0.40
White, %
Hypertension, %
Diabetes, %
92
56
36
91
60
31
0.68
0.43
0.23
Creatinine, mg/dL*
1.3
1.4
0.32
* Baseline
creatinine available in only 40% of patients
Baseline Characteristics (2)
Tilarginine
(n=206)
Placebo
(n=190)
P
Value
22
21
0.94
I
14
8
II
39
32
III
27
29
IV
21
32
LAD Infarct artery (IRA), %
61
56
ST-segment Elevation, %
79
76
Prior HF, %
NYHA Class before
randomization of those
with HF, %
0.59
0.43
Baseline Characteristics (3)
Tilarginine
(n=206)
Placebo
(n=190)
P
Value
Systolic, mmHg
88
89
0.69
Diastolic, mmHg
50
53
0.54
1
61
70
2
30
24
3
4.4
4.2
4
3.4
2.1
Dopamine, μg/kg/min
10.0
8.3
0.57
Norepinephrine, μg/kg/min
0.2
0.2
0.80
Epinephrine, μg/kg/min
0.2
0.2
0.47
Phenylephrine, μg/kg/min
1.1
1.3
0.95
Shock to open IRA, hrs
1.2
1.6
0.21
Open IRA to randomization, hrs
5.1
5.1
0.81
Blood Pressure*
Vasopressors, %
0.49
Time Intervals
* All blood pressures recorded on support measures
In-Hospital Procedures
Tilarginine
(n=206)
Placebo
(n=190)
P
Value
PCI, %
97
95
0.50
CABG, %
8.3
10.5
0.44
IABP, %
89
91
0.56
LV Assist Device, %
11.2
12.6
0.65
Cardiac Transplantation, %
0.5
0.6
>0.99
Primary Endpoint
30-day Mortality
70%
Mortality
60%
Tilarginine
50%
48%
42%
40%
30%
20%
10%
0%
0
Placebo
Tilarginine: Placebo
RR: 1.14
95% CI: 0.92-1.41
P=0.24
5
10
15
20
25
Days from randomization
30
Systolic Blood Pressure
change from baseline to 2 hours
ALL
< 75 years
≥ 75 years
Interaction p=0.02
2 hr change in SBP
mmHg
20
20
P=0.001
15
10
5
12
12
11
11
77
7
3.5
0
Tilarg Placebo
N=286
Tilarg Placebo
N=207
* All blood pressures recorded on support measures
Tilarg Placebo
N=77
Blood Pressure Change and Mortality

Non-linear relationship

Larger decreases in systolic blood
pressure were associated with higher
mortality (no interaction with treatment)

Increases in systolic blood pressure
were not significantly associated with
lower mortality (no interaction with
treatment)
Time to shock resolution
(hours)
70
Tilarginine
Patients (%)
60
Placebo
50
40
P=0.16
30
20
66% Tilarginine vs 61% Placebo
resolved shock
10
0
0
Hours
No. at risk:
Tilarginine: 201
Placebo:
177
72
144
216
288
360
158
151
103
108
84
80
74
76
70
74
Clinical Outcomes
Tilarginine
Placebo
Risk Ratio
(95% CI)
P
Value
48
51
0.93 (0.75–1.16)
0.51
Class I
26
33
Class II
47
42
Class III
17
10
0.99 (0.70–1.39)
0.27
Class IV
9
16
Myocardial
Reinfarction, %
4.0
3.9
1.02(0.59–1.77)
0.95
Hospitalization at 30 d, %
16
18
0.93 (0.71–1.22)
0.62
Heart Failure at 30 days %
NYHA class at 30 days
in those with HF %
Serious adverse events and causes of death were similar
Effect of Tilarginine on 30-day Mortality
Pre-specified Subgroup
Age <75
Age ≥75
Male
Female
Diabetes
No Diabetes
IRA LAD
IRA Other
LVEF <25%
LVEF ≥25%
Hx of CHF
No Hx of CHF
Renal Insufficiency*
No Renal Insufficiency
0.1
* Interaction p=0.07
1
Tilarginine
Better
10
Placebo
Better
6-month Mortality
70%
Tilarginine
Mortality
60%
Placebo
50%
40%
30%
P=0.80
20%
10%
0%
0
No. at risk:
Tilarginine:
Placebo:
30
60
90
120
150
180
Days from randomization
204
188
104
106
89
82
86
76
84
73
83
73
78
66
Conclusions

Tilarginine at the dose and duration studied
had no effect on mortality in patients with MI
complicated by refractory cardiogenic shock.
There may be an interaction of tilarginine and
renal insufficiency

Tilarginine significantly increased systemic
arterial blood pressure. This modest increase
in systemic arterial pressure did not
correlate with nor translate into improved
outcome
Conclusions

The observed increase in systemic arterial
pressure in response to NOS inhibition
suggests that excess nitric oxide plays a role
in the pathophysiology of cardiogenic shock

The simultaneous use of beta blockers and
vassopressors/inotropes is surprising. Beta
blockers should only be initiated for
secondary prevention in patients with acute
MI and heart failure after stabilization off
vasopressors.

Early mortality in cardiogenic shock
complicating acute MI is high but those who
survive to 30 days have relatively low 6
month mortality and good functional status
Implications

There may be no adequate surrogate
outcome or marker for mortality in
cardiogenic shock complicating MI

Additional innovations in therapy are
needed

There are challenges for development
of new therapies because each one
must be tested in randomized clinical
trials with mortality as the endpoint
SPONSOR
Arginox Pharmaceuticals, Inc.
DATA SAFETY
MONITORING BOARD
J Alpert, Chair
E Antman, P Armstrong,
D DeMets,
G Francis, C Hamm, H
Katus
CLINICAL COORDINATING
CENTERS
NYU Cardiovascular Clinical
Research Center, New York, NY
J Hochman, Study Chair
H Reynolds, A Roberts
European Coordinating Center,
Leuven, Belgium
F Van de Werf
Duke Clinical Research Institute,
Durham, NC
R Harrington, J Alexander, A Stebbins,
G Rankin, E King
EXECUTIVE COMMITTEE
J Hochman, Chair,
R Harrington, F Van de Werf,
V Dzavik, D Hathaway
(Arginox)
INVESTIGATOR SITES
Principal Investigators
and Clinical Research
Coordinators
SITE AND DATA
MANAGEMENT
Hesperion Ltd
GLOBAL STEERING COMMITTEE
Executive Steering committee
and
J Alexander, G Fonarow, W Gibler, J
Hare, R Lipicky, E Ohman, J
Parrillo, J Vincent, H Dauerman, H
Reynolds, G Cotter, D Hathaway
and
country leaders:
A Gepert (Austria), W Ruzyllo
(Poland), K Werdan (Germany), A
Ronaszeki (Hungary), S Janssens
(Belgium), V Dzavik (Canada), R
Harrington (USA), P Widimsky
(Czech Rep)
Sites Recognition
Austria (39 patients) 0.88 pt/site/mo:
Universitätsklinik für Innere Medizin II AKH Wien: G. Heinz (18); 3.Medizinische Abteilung mit
Kardiologie Wilhelminenhospital Vienna: A. Geppert, B. Fellner (13); Universitätsklinik für Innere
Medizin II mit Kardiologie Salzburg: I. Pretsch, K. Kopp (8).
Poland (78 patients) 0.49 pt/site/mo:
Klinika Choroby Wieńcowej i II: W. Ruzyllo, M. Kruk (15); Zakład Hemodynamiki i Angiokardiografii
Instytutu Kardiologii: K. Zmudka, T. Pawelec (11); Samodzielna Pracownia Diagnostyki Inwazyjnej
Chorób Układu Krążenia AM: D. Ciecwierz, R. Targonski (8); Pracownia Kardiologii Inwazyjnej CSK
AM: J. Kochman, A. Rdzanek (7); Klinika Kardiologii: W. Musial, I. Wojtkowska (6); Oddział Ostrych
Zespołów Wieńcowych: P. Buszman, A.Żurakowski (6); III Katedra i Klinika Kardiologii Ślą skiej
Akademii Medycznej: M. Tendera, A. Ochala (5); Klinika Chorób Wewnetrznych: W. Banasiak, D.
Kustrzycka-Kratochwil (4); Klinika Kardiologii, Wojskowy Instytut Medyczny: J. Adamus, M. Zarębiński
(4);Śląskie Centrum Chorób Serca: M. Zembala, M. Swierad (4); II Katedra i Klinika Kardiologii
Uniwersytetu Medycznego w Łodzi: M. Krzemińska-Pakuła, T. Jeżewski (3); Klinika Kardiologii, Szpital
Kliniczny Nr. 3: J.H. Goch, K. Chizynski (3); Klinika Kardiologii AM: T. Widomska-Czekajska, J. Drozd
(1); Pracownia Hemodynamiki CSK MSW: R. Gil (1).
Germany (55 patients) 0.41 pt/site/mo:
Martin Luther Universität Halle-Wittenberg, Innere Medizin III: K. Werdan, H. Ebelt, G. Soeffker (15);
Medizinische Klinik/Kardiologie, St. Antonius Hospital Eschweiler: U. Janssens, S. Reith (9); Clinic of
Internal Medicine 1, Friedrich-Schiller University, Jena: M. Ferrari, S. Utschig (6); Medizinische Klinik
Kardiologie Technische Universitat Dresden: R. H. Strasser, S. Hofmann (6); Herzzentrum Leipzig: G.
Schuler, H. Thiele (5); Carl-von-Basedow-Klinikum Merseberg: R. Prondzinsky, S. Burghard (4);
Herzzentrum Bad Krozingen: E. Stengele, S. Eble (4); University of Göttingen: B. Pieske,S. Rydberg
(2); University of Leipzig, Medical ICU: L. Engelmann, S. Petros (2); Kerckhoff Heart Center Bad
Nauheim: V. Mitrovic, A. Rieth (1); University of Saarland Homburg: M. Böhm, A. Link (1).
Hungary (22 patients) 0.36 pt/site/mo:
Semmelweis Egyetem, Ér-és Szívsebészeti Klinika: B. Merkely, L. Molnár (16); Gottsegen György
Országos Kardiologiai Intezet: P. Ofner, Z. Piróth (4); Zala Megyei Kórház: G. Lupkovics, A.Mihálcz
(2).
Belgium (12 patients) 0.35 pt/site/mo:
Virga Jesseziekenhuis: P. Vranckx, L. Vandebeek (5); U.Z. Gastuisberg: S. Janssens, K. Meeusen (4);
Imeldaziekenhuis Imeldalaan 9: J. Roosen, K. Muller (3)
Canada (51 patients) 0.25 pt/site/mo:
Vancouver Hospital and Health Sciences Centre: K. Ramanathan, N. Uchida (9); York PCI Group: S.
Miner, K. Stearns (7); Quebec Heart Institute: C.M. Nguyen, G. Rossignol (6); Hamilton Health
Sciences: J.Velianou, S. Brons (5); Toronto General Hospital: V. Dzavik, R. Ramsamujh (5); St. Paul’s
Hospital: K. Ramanathan, N. de Mesa (4); Calgary Heart Centre Alberta: M. Curtis, K. Parker (3);
Mississauga Cardiology Consultants: R. Watson, A. Carter (3); University of Ottawa: M. Labinaz, C.
Charlebois (3); Montreal Heart Institute: L. Bilodeau, N. Hardy (2); Victoria Heart Institute Foundation:
A. Della Siega, J. Joval (2); St. Michael’s Hospital Toronto: D. Fitchett, A. DiMarco (1); University of
Alberta: W. Tymchak, L. Harris (1).
Czech Republic (10 patients) 0.11 pt/site/mo:
General University Hospital, Prague: J. Belohlavek, J. Horák (2); Kardio-Troll, s.r.o., Dept. of Invasive
Cardiology: I. Varvaŕovsky, J. Matĕjka (2); University Hospital Krahlovske Vinohrasy: R. Jirmar, J.
Dvorak (2); Hospital Na Homolce: J. Matouskova (1); Massaryk’s Hospital Usti nad Labe: P. Cervinka,
J. Bednarova (1); University Hospital Hradec Králové: J. Vojaček, J. Bis (1); University Hospital St.
Anna in Brno: L. Groch, M. Rezek (1).
United States (131 patients) 0.16 pt/site/mo:
Newark Beth Israel Medical Center: D. Baran, A. Gonzales (8); The Sanger Clinic: T. Frank, C. Dellinger (8);
University of Southern California: A. Mehra (8); Washington Hospital Center: J. Panza, M. McNulty, S. Glaes (7);
University of Kansas Hospital:P.N. Tadros, C. Reitz (6); Allegheny General Hospital: D. Lasorda, C. Harter (4); John
H. Stroger, Jr. Hospital of Cook County: S. Nathan, G. Peacock (4); LDS Hospital: J.B. Muhlestein, P. Kennedy (4);
University of Massachusetts Medical School: J. Gore, S. Ball (4); Central Arkansas Cardiovascular Research Group:
L. Garza, F. Katkhordeh (4); Baylor Heart Clinic: V. Thohan, E. Bavouset (3); Duke University Medical Center: P.
Berger, J. Hervey (3); Fletcher Allen Healthcare: P. Gogo, F. Straight (3); Health First Clinical Research Institute: S.
Karas, N. Parker (3); Iowa Health, Des Moines: D. VerSteeg, K. Barkema (3); Los Angeles Cardiology Associates:
D. Shavelle, S. Mullin (3); Mercy General Hospital: W. Marquardt, S. Bordash (3); Stanford University School of
Medicine: M. B. Fowler, D. J. Christopherson (3); University of Kentucky:S. Steinhubl, L. Withrow (3); William
Beaumont Hospital: S. Dixon, J. Wegner (3); Asheville Cardiology Associates: M. Unks, S. Lingelbach (2); Brigham
and Women’s Hospital: J. Kirshenbaum, M. Lopez (2); Cooper Health System: S. Hollenberg, J.E. Parrillo (2);
Emory Crawford Long Hospital: H. A. Liberman, R. Cook (2); Florida Cardiovascular Research Center: J. Kieval, J.
Friderich (2); Saint Louis University: M. Lim, N. Elmore (2); University of Michigan Health Systems: E. Bates, A.
Luciano (2); University of Texas Medical School: R. W. Smalling, M. Vooletich (2); Beth Israel Deaconess Medical
Center: D. Cutlip, T. Bishop (1); Mayo Clinic Rochester: M. Bell, M. Grant (1); Maine Medical Center: M.E. Kellett, C.
Berg (1); Penn State Hershey Medical Center: I. Gilchrist, L. Seiders (1); Washington University School of Medicine
at Barnes Jewish Hospital: R. Bach, M. Palazzolo (1); Orlando Regional Medical Center: P. Giordano, R. Colern (1);
Baylor College of Medicine: N. Lakkis, J. Bobek (1); Cedars-Sinai Medical Center: B. Cercek, L. Defensor (1); South
Denver Cardiology Associates: J. Burchenal, D. Erickson (1); MidWest Cardiology Research Foundation: S.
Yakubov, K. Pethtel (1); Northeast Cardiology Associates: A. Wiseman, C. Adams (1); Lehigh Valley Hospital: M.
Matsumura, L. Phillips (1); Mt. Sinai Medical Center, Florida: G. Lamas, B.E. Restrepo (1); Johnson City Medical
Center: M. Chang, W. Fields (1); Ochsner Clinic Foundation: S. Ramee, B. Hirstius (1); University of Rochester
Medical Center: L. Chen, J. Schrack (1); Mount Sinai Medical Center, New York: M. Farkouh, E. J. Fernandez (1);
Fallon Cardiology: E. Ramsaran, P. Sigel (1); Forsyth Medical Center: D. Smull, W. Hobbs (1); Iowa Heart Center: A.
Chawla, J. Gehrke (1); Bryant LGH Heart Institute: S. Krueger, C. Orosco (1); The Miriam Hospital: P. Gordon, N.
Wright (1); Lahey Clinic: S. Waxman, P. Baum (1); University of Iowa Hospital: P. Horwitz, A. Ollinger (1); Trinity
Medical Center: S. Puri, C. Antonio (1); Watson Clinic, LLP: K. Browne, K. Prisoc (1); Munroe Regional Medical
Center: E. Santoian, S. Williams (1); UNC Chapel Hill School of Medicine: V. Menon, M. Cohen, K. Wood (1).
JAMA, Published online March 26, 2007
TRIUMPH report can be found at jama.ama-assn.org