The The Tilarginine Acetate Injection in a Tilarginine Acetate Injection in a Randomized International Study in Unstable Randomized International Study in Unstable

Acute Myocardial Infarction Patients with Acute Myocardial Infarction Patients with Cardiogenic Shock Cardiogenic Shock (TRIUMPH) (TRIUMPH)

Judith S. HochmanJudith S. Hochmanon behalf of TRIUMPH Investigatorson 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

BackgroundBackground

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)

BackgroundBackground 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)

BackgroundBackground 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 Single Center Randomized Study of NOS inhibitor L-NAMERandomized Study of NOS inhibitor L-NAME

Marked Survival BenefitMarked Survival Benefit

Cotter et al. EHJ (2003)

Usual care

L-NAME1mg/kg bolus and1mg/kg/hour X 5 hours

2400

2000

1600

2400

2000

1600Uri

ne

Ou

tpu

tcc

/24

h

SHOCK 2 - Phase 2 Multi Center Study SHOCK 2 - Phase 2 Multi Center Study Early BP EffectEarly BP Effect

-30

-20

-10

0

10

20

30

40

50

0

Median Overall Change=3.33

-30

-20

-10

0

10

20

30

40

50

0

Median Overall Change=3.33

-2.0

3.0 4.0 4.3 6.3

All p values are vs. placebo

P=0.013

P=0.012

P=0.02P=0.0004

Dzavik et al, EHJ in press

Ch

ang

e in

MA

P a

t 15

Min

ute

s

1.5 mg/kg

1.0 mg/kg

0.50 mg/kg

0.15 mg/kg

Placebo

TRIUMPH HypothesisTRIUMPH 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.

Ischemic symptoms ≥ 30 minutes with:

Cardiac markers or ST-segment

elevation or left bundle branch block

TRIUMPH EligibilityTRIUMPH EligibilityRefractory Shock+ +Myocardial Infarction

Hemodynamics and requirement for vasopressor treatment were reconfirmed just prior to study drug administration to exclude patients with rapidly resolving shock

Peripheral signs of tissue hypoperfusion

Patency of the infarct artery (<70% stenosis)

LVEF <40%

Shock persisting ≥1 hour after infarct artery patency

Persistent after PCI

and

SBP <100 mmHg

Vasopressor Rx Dopamine ≥7 mcg/kg/min Norepinephrine ≥0.15 mcg/kg/min Epinephrine ≥0.15 mcg/kg/min

despite

Clinical or hemodynamicevidence of ↑LV EDP

and

Major Exclusion CriteriaMajor 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 multi-system

failure Recent thoracic or abdominal surgery Need for emergency CABG within 24 hours

EndpointsEndpointsPrimary 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 ConsiderationsStatistical 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 InterventionsStudy 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 TerminationStudy 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 PatientsAcute MI with

Cardiogenic Shockentered in screening log

206 Tilarginine 190 Placebo

201 (97.6%) received study drugSBP no longer qualifying (n=5)

180 (94.7%) received study drugSBP no longer qualifying (n=10)

197 (98.0%) 30-d follow-up complete Lost to 30-d follow-up (n=4)

178 (98.9%) 30-d follow-up completeLost to 30-d follow-up (n=2)

186 (94.4%) 6-m follow-up completeLost to 6-m follow-up (n=11)

162 (91.0%) 6-m follow-up complete Lost to 6-m follow-up (n=16)

398 Eligible, enrolled ≥1hr after IRA patency

documented

Treatment Assignment unknown (n=2) 30 days: 1 died/1 survived

CANADA(20 sites)

51 subjects

USA(102 sites)

130 subjects

Enrollment

On average, 3.65 patients (0.25 patients per site per month) were enrolled at 130

centers in 8 countries

BELGIUM(3) 12

GERMANY(13) 54

CZECH REP(10)10

AUSTRIA(4) 39

POLAND(16) 78

HUNGARY(7) 22

Baseline Characteristics (1)Baseline Characteristics (1)

Tilarginine(n=206)

Placebo(n=190)

PValue

Age, years 67 68 0.98

Age ≥ 75 years, % 27 27 0.96

Male, % 74 70 0.40

White, % 92 91 0.68

Hypertension, % 56 60 0.43

Diabetes, % 36 31 0.23

Creatinine, mg/dL* 1.3 1.4 0.32

* Baseline creatinine available in only 40% of patients

Baseline Characteristics (2)Baseline Characteristics (2)

Tilarginine(n=206)

Placebo (n=190)

PValue

Prior HF, % 22 21 0.94

NYHA Class before randomization of those with HF, %

I 14 8

0.59 II 39 32

III 27 29

IV 21 32

LAD Infarct artery (IRA), % 61 56

ST-segment Elevation, % 79 76 0.43

Tilarginine(n=206)

Placebo(n=190)

PValue

Blood Pressure*

Systolic, mmHg 88 89 0.69

Diastolic, mmHg 50 53 0.54

Vasopressors, %

1 61 70

0.49 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

Time Intervals

Shock to open IRA, hrs 1.2 1.6 0.21

Open IRA to randomization, hrs 5.1 5.1 0.81

Baseline Characteristics (3)Baseline Characteristics (3)

* All blood pressures recorded on support measures

In-Hospital ProceduresIn-Hospital Procedures

Tilarginine(n=206)

Placebo(n=190)

PValue

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

0%0%

10%10%

20%20%

30%30%

40%40%

70%70%

00 55 1010 1515 2020 2525 3030Days from randomizationDays from randomization

Mo

rtal

ity

Mo

rtal

ity

PlaceboPlacebo

TilarginineTilarginine

60%60%

50%50%

Primary EndpointPrimary Endpoint 30-day Mortality30-day Mortality

Tilarginine: PlaceboTilarginine: Placebo RR: 1.14

95% CI: 0.92-1.41

P=0.24

48%48%

42%42%

Systolic Blood Pressure Systolic Blood Pressure change from baseline to 2 hours change from baseline to 2 hours

12

7

0

5

10

15

20

12

7

11

7

0

5

10

15

20

12

7

11

7

20

3.5

0

5

10

15

20

P=0.001

2 hr

cha

nge

in S

BP

2 hr

cha

nge

in S

BP

mm

Hg

mm

Hg

Tilarg PlaceboN=286

Tilarg PlaceboN=207

Tilarg PlaceboN=77

ALL < 75 years ≥ 75 years

* All blood pressures recorded on support measures

Interaction p=0.02

Blood Pressure Change and MortalityBlood 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 Time to shock resolution (hours)(hours)

No. at risk:No. at risk:Tilarginine:Tilarginine: 201201 158158 103103 8484 7474 7070Placebo:Placebo: 177177 151151 108108 8080 7676 7474

00

2020

4040

6060

7070

00 144144HoursHours

Pat

ien

ts (

%)

Pat

ien

ts (

%)

1010

3030

5050 PlaceboPlacebo

TilarginineTilarginine

2882887272 216216 360360

66% Tilarginine vs 61% Placebo 66% Tilarginine vs 61% Placebo resolved shockresolved shock

PP=0.16=0.16

Tilarginine PlaceboRisk Ratio

(95% CI)P

Value

Heart Failure at 30 days % 48 51 0.93 (0.75–1.16) 0.51

NYHA class at 30 days in those with HF %

Class I 26 33

0.99 (0.70–1.39) 0.27Class II 47 42

Class III 17 10

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

Clinical OutcomesClinical Outcomes

Serious adverse events and causes of death were similar

Age <75Age <75Age ≥75Age ≥75

MaleMaleFemaleFemale

DiabetesDiabetesNo DiabetesNo Diabetes

IRA LADIRA LADIRA OtherIRA Other

LVEF <25%LVEF <25%LVEF ≥25%LVEF ≥25%Hx of CHFHx of CHF

No Hx of CHFNo Hx of CHFRenal Insufficiency*Renal Insufficiency*

No Renal InsufficiencyNo Renal Insufficiency

TilarginineTilarginineBetterBetter

PlaceboPlaceboBetterBetter

0.10.1 11 1010

Effect of Tilarginine on 30-day Mortality Effect of Tilarginine on 30-day Mortality Pre-specified Subgroup Pre-specified Subgroup

* Interaction p=0.07

6-month Mortality6-month Mortality

0%0%

20%20%

40%40%

60%60%

70%70%

00 3030 6060 9090 120120 150150 180180

Days from randomizationDays from randomization

Mo

rtal

ity

Mo

rtal

ity PlaceboPlacebo

TilarginineTilarginine

10%10%

30%30%

50%50%

No. at risk: Tilarginine: 204 104 89 86 84 83 78Placebo: 188 106 82 76 73 73 66

P=0.80

ConclusionsConclusions

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

ConclusionsConclusions 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

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

ImplicationsImplications

SPONSORArginox Pharmaceuticals, Inc.

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 WerfDuke Clinical Research Institute,

Durham, NCR Harrington, J Alexander, A Stebbins, G Rankin, E King

EXECUTIVE COMMITTEEJ Hochman, Chair,

R Harrington, F Van de Werf, V Dzavik, D Hathaway

(Arginox)

INVESTIGATOR SITESPrincipal Investigators and Clinical Research

Coordinators

DATA SAFETY MONITORING BOARD

J Alpert, ChairE Antman, P Armstrong,

D DeMets, G Francis, C Hamm, H

Katus

GLOBAL STEERING COMMITTEEExecutive Steering committee

andJ 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)

SITE AND DATA MANAGEMENTHesperion Ltd

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).

Sites RecognitionSites Recognition

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).

TRIUMPH report can be found at jama.ama-assn.org

JAMA, Published online March 26, 2007