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The Tilarginine Acetate Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients

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.

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The Tilarginine Acetate Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients

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  1. The Tilarginine Acetate Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients with Cardiogenic Shock (TRIUMPH) Judith S. Hochmanon 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

  2. 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)

  3. 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)

  4. 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

  5. LINCS - Single Center Randomized Study of NOS inhibitor L-NAMEMarked Survival Benefit L-NAME 1mg/kg bolus and 1mg/kg/hour X 5 hours Usual care Cotter et al. EHJ (2003)

  6. SHOCK 2 - Phase 2 Multi Center Study Early BP Effect All p values are vs. placebo Dzavik et al, EHJ in press 6.3 4.0 4.3 3.0 Change in MAP at 15 Minutes -2.0 P=0.0004 P=0.02 P=0.013 P=0.012 1.5 mg/kg 0.50 mg/kg Placebo 0.15 mg/kg 1.0 mg/kg 2400 2000 1600 Urine Output cc/24 h

  7. 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.

  8. Patency of the infarct artery (<70% stenosis) • LVEF <40% • Shock persisting ≥1 hour after infarct artery patency Peripheral signs of tissue hypoperfusion SBP <100 mmHg • Vasopressor Rx • Dopamine ≥7 mcg/kg/min • Norepinephrine ≥0.15 mcg/kg/min • Epinephrine ≥0.15 mcg/kg/min TRIUMPH Eligibility + + Myocardial Infarction Refractory Shock Persistent after PCI Ischemic symptoms ≥ 30 minutes with: • Cardiac markers or • ST-segment elevation or left bundle branch block and despite 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

  9. 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 multi-system failure • Recent thoracic or abdominal surgery • Need for emergency CABG within 24 hours

  10. 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

  11. 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

  12. Study Interventions • Random 1:1 assignment to • Tilarginine (LNMMA) 1mg/kg bolus followed by1 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

  13. 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

  14. 1611 Patients Acute MI with Cardiogenic Shock entered in screening log 398 Eligible, enrolled ≥1hr after IRA patency documented 190 Placebo 206 Tilarginine 201 (97.6%) received study drug SBP no longer qualifying (n=5) 180 (94.7%) received study drug SBP 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 complete Lost to 30-d follow-up (n=2) 186 (94.4%) 6-m follow-up complete Lost to 6-m follow-up(n=11) 162 (91.0%) 6-m follow-up complete Lost to 6-m follow-up (n=16) Treatment Assignment unknown (n=2) 30 days: 1 died/1 survived

  15. Enrollment POLAND (16) 78 GERMANY (13) 54 CANADA (20 sites) 51 subjects BELGIUM (3) 12 CZECH REP (10)10 AUSTRIA (4) 39 HUNGARY (7) 22 USA (102 sites) 130 subjects On average, 3.65 patients (0.25 patients per site per month) were enrolled at 130 centers in 8 countries

  16. Baseline Characteristics (1) * Baseline creatinine available in only 40% of patients

  17. Baseline Characteristics (2)

  18. Baseline Characteristics (3) *All blood pressures recorded on support measures

  19. In-Hospital Procedures

  20. Primary Endpoint30-day Mortality 70% 60% Tilarginine 50% 48% 42% 40% Mortality Placebo 30% Tilarginine: Placebo RR: 1.14 95% CI: 0.92-1.41 20% 10% P=0.24 0% 0 5 10 15 20 25 30 Days from randomization

  21. Systolic Blood Pressure change from baseline to 2 hours ALL < 75 years ≥ 75 years Interaction p=0.02 P=0.001 2 hr change in SBP mmHg Tilarg Placebo N=207 Tilarg Placebo N=77 Tilarg Placebo N=286 *All blood pressures recorded on support measures

  22. 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 pressurewere not significantly associated with lower mortality (no interaction with treatment)

  23. Time to shock resolution (hours) 70 Tilarginine 60 Placebo 50 40 Patients (%) P=0.16 30 20 66% Tilarginine vs 61% Placebo resolved shock 10 0 0 72 144 216 288 360 Hours No. at risk: Tilarginine: 201 158 103 84 74 70 Placebo: 177 151 108 80 76 74

  24. Clinical Outcomes Serious adverse events and causes of death were similar

  25. Effect of Tilarginine on 30-day Mortality Pre-specified Subgroup Age <75Age ≥75 MaleFemale DiabetesNo Diabetes IRA LADIRA Other LVEF <25%LVEF ≥25% Hx of CHFNo Hx of CHF Renal Insufficiency*No Renal Insufficiency * Interaction p=0.07 0.1 1 10 TilarginineBetter PlaceboBetter

  26. 6-month Mortality 70% Tilarginine 60% Placebo 50% 40% Mortality 30% P=0.80 20% 10% 0% 0 30 60 90 120 150 180 Days from randomization No. at risk: Tilarginine: 204 104 89 86 84 83 78 Placebo: 188 106 82 76 73 73 66

  27. 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

  28. 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 relativelylow 6 month mortality and good functional status

  29. 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

  30. SPONSOR Arginox Pharmaceuticals, Inc. DATA SAFETY MONITORING BOARD J Alpert, Chair E Antman, P Armstrong, D DeMets, G Francis, C Hamm, H Katus SITE AND DATA MANAGEMENT Hesperion Ltd EXECUTIVE COMMITTEE J Hochman, Chair, R Harrington, F Van de Werf, V Dzavik, D Hathaway (Arginox) 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 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) INVESTIGATOR SITES Principal Investigators and Clinical Research Coordinators

  31. 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).

  32. 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).

  33. 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).

  34. JAMA, Published online March 26, 2007 TRIUMPH report can be found at jama.ama-assn.org

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