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Original Contribution |

Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock:  The TRIUMPH Randomized Controlled Trial FREE

The TRIUMPH Investigators*
[+] Author Affiliations

TRIUMPH Writing Committee:John H. Alexander, MD (Duke University, Durham, NC); Harmony R. Reynolds, MD (New York University, New York, NY); Amanda L. Stebbins, MS (Duke Clinical Research Institute, Durham, NC); Vladimir Dzavik, MD (University of Toronto, Toronto, Ontario); Robert A. Harrington, MD (Duke University, Durham, NC); Frans Van de Werf, MD (University Hospital of Gasthuisberg, Leuven, Belgium); and Judith S. Hochman, MD (New York University, New York, NY).

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JAMA. 2007;297(15):1657-1666. doi:10.1001/jama.297.15.joc70035.
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Context Cardiogenic shock complicating acute myocardial infarction (MI) remains a common and lethal disorder despite aggressive use of early revascularization. Systemic inflammation, including expression of inducible nitric oxide synthase (NOS) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal function, and survival in patients with cardiogenic shock.

Objective To examine the effects of an isoform-nonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery.

Design, Setting, and Patients International, multicenter, randomized, double-blind, placebo-controlled trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock [TRIUMPH]) with planned enrollment of 658 patients at 130 centers. Participants were enrolled between January 2005 and August 2006 when the study was terminated early.

Intervention Tilarginine (L-NG-monomethylarginine [L-NMMA]), 1-mg/kg bolus and 1-mg/kg per hour 5-hour infusion, vs matching placebo.

Main Outcome Measures The primary outcome was 30-day all-cause mortality among patients who received study medication. Secondary outcomes included shock resolution and duration, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality.

Results Enrollment was terminated at 398 patients based on a prespecified futility analysis. Six-month follow-up was completed in February 2007. There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92-1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo;  = .31) and duration of shock (median, 156 [interquartile range, 78-759] hours tilarginine vs 190 [100-759] placebo;  = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo;  = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo;  = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79-1.36; P = .80).

Conclusions Tilarginine, 1-mg/kg bolus and 5-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. Early mortality rates in this patient group are high. Further research is needed to develop effective therapies for patients with cardiogenic shock following acute MI.

Trial Registration clinicaltrials.gov Identifier: NCT00112281

Trial Registration Published online March 26, 2007 (doi:10.1001/jama.297.15.joc70035).

Figures in this Article

Cardiogenic shock is the leading cause of death among hospitalized patients with acute myocardial infarction (MI), with mortality rates in excess of 50%.18 Early revascularization improves survival; however, early mortality rates remain high, particularly among patients with continued shock after revascularization.9 The understanding of the pathophysiology of cardiogenic shock complicating MI has recently evolved toward an appreciation of the role of systemic inflammation, including cytokine release and expression of inducible nitric oxide synthase (NOS).1012 Excessive NOS results in high levels of nitric oxide that, in turn, lead to inappropriate systemic vasodilatation, progressive systemic and coronary hypoperfusion, and myocardial depression.1012

Inhibition of NOS is a theoretically appealing approach to treatment of this high-risk population. Early single-center studies with isoform-nonselective NOS inhibitors were promising and suggested a substantial beneficial effect on survival.1214 The phase 2, dose-ranging trial SHOCK-2 (Should We Inhibit Nitric Oxide Synthase in Cardiogenic Shock 2) investigated the safety and tolerability of L-NG-monomethylarginine (L-NMMA) (tilarginine acetate injection; ArgiNOx Pharmaceuticals, Redwood Shores, Calif) in this population.15 In SHOCK-2, tilarginine was given as a bolus (0.15 to 1.5 mg/kg) followed by 5-hour infusion (0.15 to 1.5 mg/kg per hour) and resulted in modest early changes in hemodynamic parameters.15 There was no effect on survival; however, SHOCK-2 was not powered to assess the effect of tilarginine on mortality.

The Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock (TRIUMPH) trial was designed to test the effect of NOS inhibition with tilarginine on mortality due to persistent cardiogenic shock complicating MI despite an open infarct artery.

Study Design

TRIUMPH was a prospective, international, multicenter, randomized, double-blind, placebo-controlled trial that tested the hypothesis that tilarginine compared with placebo would reduce by 25% 30-day all-cause mortality in patients with MI complicated by cardiogenic shock despite successful revascularization of the infarct artery.

Patient Population

TRIUMPH was conducted at 130 centers in 8 countries in North America and Europe. Participants, or their legally authorized representatives, provided written informed consent. Institutional review board or ethics committee approval was obtained at all sites. Inclusion required all of the following: (1) MI, confirmed by ischemic symptoms for at least 30 minutes with elevated cardiac markers and/or ST-segment elevation or left bundle-branch block; (2) patency (<70% stenosis) of the infarct artery, either occurring spontaneously and confirmed at angiography or after percutaneous revascularization; (3) refractory cardiogenic shock of less than 24 hours’ duration, confirmed by peripheral signs of tissue hypoperfusion and systolic blood pressure less than 100 mm Hg despite vasopressor therapy (dopamine ≥7 μg/kg per minute or norepinephrine or epinephrine ≥0.15 μg/kg per minute) continuing longer than 1 hour after infarct artery patency; (4) clinical or hemodynamic evidence of elevated left ventricular filling pressures; and (5) left ventricular ejection fraction of less than 40%. Hemodynamics and requirement for vasopressor treatment were reconfirmed after randomization just prior to study drug administration; patients with resolving shock were excluded.

Major exclusion criteria included suspected or documented infection, other causes of shock (tachyarrhythmia or bradyarrhythmia, hypovolemia, hemorrhage, or anaphylaxis), shock due to acute mitral regurgitation or rupture of the ventricular septum or free wall, severe valvular heart disease, predominant right ventricular failure or severe right ventricular dysfunction of any cause, serum creatinine level greater than 3.0 mg/dL (>264 μmol/L) or end-stage renal disease requiring dialysis, adult respiratory distress syndrome, anoxic brain injury precluding survival, irreversible multisystem failure, recent thoracic or abdominal surgery, primary pulmonary hypertension, and the need for emergency coronary artery bypass graft surgery within 24 hours.

Participants had to be aged at least 18 years and both men and women were eligible. Self-reported race was collected to perform a subgroup analysis based on race for regulatory reporting.

Study Interventions

Eligible patients were randomized 1:1 to receive either tilarginine, 1.0 mg/kg intravenous bolus followed by 1.0 mg/kg per hour of intravenous infusion for 5 hours, or matching placebo. This dose was chosen based on prior studies that suggested an association with improved survival.13,14 The protocol strongly recommended avoiding a decrease in vasopressor doses during study drug infusion. Eligible patients were randomized, at least 1 hour after infarct artery patency, via an interactive voice-response system. Randomization was blocked with block sizes of 2 or 4 and stratified by site and by patient age (<75 or ≥75 years).

Other than administration of study drug and the recommendation regarding vasopressor dosing, patients were managed at the discretion of the treating physician based on current standards of care as recommended by the American College of Cardiology, American Heart Association, European Society of Cardiology, and Canadian Cardiovascular Society guidelines.1620

Study Outcomes

The primary outcome was all-cause mortality at 30 days overall and stratified by age (<75 or ≥75 years) among patients who received any study medication. Additional secondary outcome measures included the number of participants with resolution of shock, duration of shock, duration of mechanical ventilation, duration of intra-aortic balloon pump support, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality. Resolution of shock was defined as discontinuation of vasopressors, other than low-dose dopamine, and cessation of intra-aortic balloon pump support for at least 24 hours.

Statistical Methods

The planned sample size of 658 treated patients had 90% power to detect a 25% relative reduction in mortality from a projected placebo mortality rate of 50% at an α level of .05.1315 Interim efficacy and futility analyses were planned at 50% and 75% enrollment. A recommendation to stop the trial for efficacy was to be based on an O’Brien-Fleming-type boundary and Lan-DeMets α spending function. Futility analyses were performed to determine the conditional probability of reaching a statistically significant result at the final analysis. A conditional power of 20% or less at either the first or second interim analysis was to trigger a recommendation to stop the trial. The α for the final primary analysis was .044.

The primary prespecified analysis was based on a modified intent-to-treat cohort composed of all randomized patients who received any study medication. An intent-to-treat analysis was performed on all randomized patients as a sensitivity analysis. All other analyses were conducted on the intent-to-treat population.

Dichotomous outcomes are expressed as numbers and frequencies. Continuous variables are expressed as medians (interquartile range [IQR]). All discrete analyses were performed using the Cochran-Mantel-Haenszel or χ2 test. All continuous analyses were performed using the general linear model (GLM) with the exception of duration of shock. Assumptions for using continuous variables in the GLM were evaluated; only duration of shock was in violation. Duration of shock was not normally distributed, and no transformation was found to make it such. It was therefore analyzed using the log-rank statistic, with time measured from randomization to the resolution of shock. For patients who died prior to resolution of shock, assigned duration of shock was the longest reported duration of shock plus 1 hour.

Mortality at 30 days was analyzed using logistic regression. Mortality at 6 months was analyzed using the log-rank statistic, with calculation of a hazard ratio and 95% confidence interval (CI) by Cox proportional hazards modeling. Patients with missing data were not included in relevant analyses. Logistic regression modeling was used to assess the relationship between change in systolic blood pressure and mortality. Changes in systolic blood pressure were reported as a linear spline with different slopes at less than or equal to 0 and greater than 0. Other than the primary analysis of 30-day mortality, all other analyses should be considered hypothesis-generating. We considered P<.01 as strong evidence of an association. All analyses were performed using SAS software version 8.0 (SAS Institute Inc, Cary, NC).

A prespecified futility analysis was performed by the data and safety monitoring board when data were available on approximately 50% of the planned sample. Based on the recommendation of the board, recruitment into the trial was discontinued following an assessment of less than 10% conditional power to meet the specified primary objective of the trial. When the trial was stopped, data collection and cleaning ceased, resulting in some missing data. All participating centers were closed by the trial sponsor. Academic study leadership subsequently attempted to ascertain 6-month vital status on all randomized patients. Despite the withdrawal of financial support by the sponsor and the initial closure of the protocol at many sites, we were able to obtain nearly complete 6-month follow-up (through February 2007).

Patient Population

Of 1611 patients with MI complicated by cardiogenic shock entered into the TRIUMPH screening database between January 2005 and August 2006, 398 met the study inclusion criteria and were enrolled (Figure 1). On average, 3.65 patients (0.25 patients per site per month) were enrolled at each of 130 centers in 8 countries.

Figure 1. Patient Enrollment and Follow-up
Graphic Jump Location

MI indicates myocardial infarction.

Baseline characteristics of the population are shown in Table 1. All baseline characteristics were well balanced between the treatment groups. More than one quarter of the population was older than 75 years; the majority were male and of white race. More than half of the patients had hypertension and one third had diabetes; 84 (21%) had a history of heart failure and almost a third of those had advanced heart failure symptoms in the 6 weeks prior to enrollment. A quarter of the patients had baseline creatinine levels of 1.7 mg/dL (150 μmol/L) or higher.

Table Graphic Jump LocationTable 1. Baseline Patient Characteristics*

The median supported blood pressure just prior to study drug administration was 88/52 mm Hg. Most patients were supported with a single vasopressor at the time of study drug administration (Table 2). The majority of patients presented with anterior, ST-segment elevation MI with left anterior descending infarct artery location. Percutaneous coronary intervention was performed in nearly all patients to achieve the requirement for less than 70% infarct artery stenosis before study entry.

Study Interventions

A total of 15 (3.8%) randomized patients (5 [2.4%] tilarginine and 10 [5.3%] placebo, P = .14) did not receive study drug because their hemodynamics prior to study drug administration were no longer consistent with entry criteria. Study drug administration was interrupted in 5 (2.5%) patients assigned to tilarginine and 6 (3.3%) patients assigned to placebo (P = .62), and the mean duration of study drug use was similar (4.7 vs 4.4 hours; P = .06).

In-hospital procedures are shown in Table 3. Almost all patients were treated with intra-aortic balloon counterpulsation and mechanical ventilation, most before randomization, with no difference in use or duration between groups. Forty-seven (12%) patients received left ventricular assist device support after a median of 69 (IQR, 15-117) hours; however, only a minority of these ultimately underwent cardiac transplantation. Coronary artery bypass graft surgery was performed during hospitalization in 37 (9.3%) patients.

Concomitant medication use both between randomization and 24 hours after randomization and between 24 hours after randomization and 7 days after randomization is shown in Table 4. There was no statistically significant or clinically meaningful difference in the use of any nonstudy medication between groups. Most patients were treated with multiple antiplatelet and anticoagulant agents including aspirin, thienopyridines, glycoprotein IIb/IIIa inhibitors, and heparin. Most patients had heparin administered through 7 days. All patients received vasopressor therapy at randomization; in most cases, vasopressors were continued through at least 7 days. There was substantial use of early antiarrhythmic therapy, which increased further by day 7. A small number of patients received β-blockers and/or angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers early in the course despite having hypotension that required vasopressor support. By day 7, roughly half of patients were treated with β-blockers despite the fact that a substantial percentage had continued administration of sympathomimetic amines. A total of 229 (69%) patients received insulin therapy during the study period.

Study Outcomes

Hemodynamic outcomes are shown in Table 5. Patients assigned to tilarginine had a greater increase in systolic blood pressure at 2 hours compared with patients assigned to placebo (12.0 mm Hg vs 7.0 mm Hg; P = .001). This effect tended to be more evident in patients aged 75 years or older than those younger than 75 years (interaction P = .02). Timing of resolution of shock was similar among groups; the duration of shock was shorter in patients assigned to tilarginine, but this was not statistically significant (P = .16) (Figure 2). Similar findings were observed when duration of shock was assessed only in survivors. There was no effect of tilarginine on renal function.

Figure 2. Kaplan-Meier Curve of Duration of Cardiogenic Shock
Graphic Jump Location

Major clinical outcomes at 30 days are shown in Table 6. There was no difference in the primary outcome of all-cause, 30-day mortality between patients who received tilarginine and those who received placebo (97/201 [48%] vs 76/180 [42%]; risk ratio, 1.14; 95% CI, 0.92-1.41; P = .24). These results were unchanged when the 15 patients who did not receive study drug were included in the analysis. Also, when we adjusted for baseline differences in the use of vasopressors (Table 2), the results were unchanged (odds ratio, 1.27; 95% CI, 0.84-1.94; P = .26)

Table Graphic Jump LocationTable 6. Clinical Outcomes at 30 Days

Tilarginine had no effect on 30-day mortality in any prespecified subgroup including those based on age, sex, diabetes status, infarct artery location, left ventricular ejection fraction, or history of heart failure. When renal function was assessed as a continuous function, patients with higher creatinine levels tended to have worse outcomes with tilarginine (interaction P = .07) (Figure 3). The proximate cause of death was cardiac in 135 patients (78%) in both groups, with 67 (50%) of these due to pump failure. Tilarginine had no effect on the rate of 30-day myocardial reinfarction or 30-day New York Heart Association (NYHA) heart failure class. At 30 days, 64 (17%) surviving patients remained hospitalized. At 6 months, 58% of patients assigned to tilarginine and 59% of patients assigned to placebo had died (hazard ratio,  1.04; 95% CI, 0.79-1.36; P = .80) (Figure 4). These results were unchanged when the 15 patients who did not receive study drug were excluded from the analysis, and there was no interaction between treatment and age.

Figure 3. Effect of Tilarginine vs Placebo on 30-Day Mortality in Patient Subgroups
Graphic Jump Location

Because of substantial missing data and a very small number of patients with creatinine levels ≥1.9 mg/dL, renal dysfunction was defined as a baseline creatinine level ≥1.7 mg/dL (top-most quartile) rather than ≥1.9 mg/dL as prespecified in the statistical analysis plan. CI indicates confidence interval.

Figure 4. Kaplan-Meier Mortality Over 6 Months of Follow-up
Graphic Jump Location

A post-hoc analysis revealed that changes in systolic blood pressure between baseline and 2 hours were predictive of 30-day mortality; different relationships were observed for decreases and increases in blood pressure. In patients who manifested a decrease in systolic blood pressure between baseline and 2 hours, larger decreases in systolic blood pressure were associated with higher 30-day mortality (hazard ratio,  1.07 [95% CI, 1.04-1.11], χ2 = 17.3; P<.001) with no interaction by treatment (interaction P = .62). Increases in systolic blood pressure, however, were not associated with lower 30-day mortality (hazard ratio,  1.00 [95% CI, 0.98-1.01]; χ2 = 0.66; P = .42).

There were a total of 274 serious adverse events reported (130 in the placebo group and 144 in the tilarginine group) (Table 7). No significant differences in safety were found.

Table Graphic Jump LocationTable 7. Serious Adverse Events by Study Group*

In this international, multicenter, randomized trial, isoform-nonselective NOS inhibition with tilarginine (L-NMMA) did not reduce 30-day or 6-month mortality rates in patients with MI complicated by cardiogenic shock persisting after the infarct artery was patent, either in the overall group or when stratified by age. The observation of higher mortality rates among patients with baseline renal dysfunction treated with tilarginine may be due to chance but requires further investigation. Overall, tilarginine was well tolerated but had no effect on the resolution of cardiogenic shock, on reinfarction, or on renal function.

There was, however, a significant increase in blood pressure with tilarginine. This hemodynamic effect of NOS inhibition in patients with hypotension refractory to sympathomimetic amines supports the hypothesis that excess nitric oxide may play a role in the genesis and/or persistence of cardiogenic shock. However, the modest increase in systemic arterial pressure did not translate into improvement in outcome, even though higher blood pressure is well known to be associated with survival in individuals with cardiogenic shock.21,22 Perhaps isoform-nonselective NOS inhibition, with endothelial as well as inducible NOS inhibition, is not the optimal treatment to reverse the effects of excess inducible NOS–generated nitric oxide. The discordant findings for blood pressure response and survival serve as a reminder that there may be no adequate surrogate outcome or marker for mortality in cardiogenic shock complicating MI. This poses enormous challenges for the development of new therapies, particularly dose finding, in the treatment of this critical illness because each new therapy must be tested in randomized clinical trials with mortality as the end point. An adaptive, event-driven trial design might be best in this setting.23 Such a design would require a commitment on the part of sponsors to provide funding for enrollment of an uncertain number of patients, which is likely to exceed the number needed based on traditional designs. This study did establish the feasibility of conducting an adequately powered, multicenter, international randomized trial of a pharmacologic agent in persistent cardiogenic shock with a mortality end point.

Patients enrolled in TRIUMPH were selected for particularly high risk, based on the persistence of shock despite vasopressor/inotropic support for at least 1 hour after successful percutaneous revascularization. This patient subset was similar to that studied in the phase 1, single-center trials of NOS inhibition in cardiogenic shock, and the dose and duration of NOS inhibition were the same as in these studies.13,14 However, as is often the case, these early experiences with NOS inhibition in cardiogenic shock were conducted at a single institution without rigorous randomized trial methods. It is unlikely that the use of L-nitroarginine-methylester (L-NAME) in one of these studies accounted for the different results, because similar beneficial effects were seen in the other study in which L-NMMA was used.13,14 There remains the possibility that a higher dose, longer duration, or alternative dosing regimen of tilarginine could have a more pronounced effect on hemodynamics and/or survival; however, this seems unlikely in the absence of any signal of benefit in the present study. Furthermore, the SHOCK-2 phase 2 study of a 10-fold dose range of L-NMMA for cardiogenic shock found no benefit with the highest dose of 1.5-mg/kg bolus and infusion.15 Prior studies of prolonged NOS inhibition in patients with septic shock showed hemodynamic toxicity and excess mortality at higher doses with increases in pulmonary vascular resistance that would be expected to be prohibitive in the treatment of cardiogenic shock.24 In addition, animal models of cardiogenic shock have shown that higher-dose treatment with NOS inhibition is associated with an increase in afterload with no change in contractility.25

It has been postulated that inhibition of the systemic inflammatory response, which may be triggered by a large MI via different pathways, would reduce the occurrence of shock. A phase 2 trial of the complement inhibitor pexelizumab suggested that baseline cytokine levels were predictive of cardiogenic shock onset and that complement inhibition might reduce the incidence of shock and death.26,27 This action was believed to involve, at least in part, a reduction in production of nitric oxide by iNOS. However, a large randomized trial of pexelizumab in patients with MI undergoing reperfusion showed no effect on mortality.28 Unfortunately, the promise shown in small initial studies of new therapies is too often not borne out in appropriately powered multicenter randomized trials.29,30

Recent reports have suggested that outcomes have improved over time with advances in percutaneous intervention and supportive care, and the mortality rates for persistent cardiogenic shock in our study are consistent with this trend.6,3133 The death rate was 39% for those patients younger than 75 years. Importantly, the majority of survivors were in NYHA functional class I or II at 30 days. Furthermore, the mortality rate between 1 and 6 months was low, even in this very high-risk cohort. This is consistent with findings from the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial and reinforces how essential and rewarding it is to treat these most critically ill patients early in their hospital course.9 Aggressive treatment in this cohort included percutaneous revascularization, treatment with multiple vasopressors at moderate to high doses, inotropic therapy, intra-aortic balloon counterpulsation, mechanical ventilation, anticoagulant and antiplatelet therapy, as well as insulin in many cases. The use of very early vasodilator therapy (angiotensin-converting enzyme inhibition, angiotensin II receptor blockade, nitrates) and β-blockade in a small percentage of patients is surprising. These treatments are the mainstay of secondary prevention following MI in these highest-risk patients but should be reserved for the period after shock resolution.

Tilarginine, at the dose and duration studied, had no effect on mortality in patients with MI complicated by refractory cardiogenic shock. The increase in blood pressure in response to NOS inhibition suggests that excess nitric oxide may play a role in the pathophysiology of cardiogenic shock. Additional innovations in therapy and improved health care delivery systems are needed to establish earlier reperfusion to prevent shock following MI and to reduce the high short-term mortality rate of patients who develop cardiogenic shock.

Corresponding Author: Judith S. Hochman, MD, Car diovascular Clinical Research Center, New York University School of Medicine, 530 First Ave HCC-1170, New York, NY 10016-9196 (judith.hochman@med.nyu.edu).

Published Online: March 26, 2007 (doi:10.1001 /jama.297.15.joc70035).

Author Contributions: Dr Alexander and Ms Stebbins had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Alexander, Reynolds, Dzavik, Harrington, Van de Werf, Hochman.

Acquisition of data: Alexander, Reynolds, Dzavik, Harrington, Van de Werf, Hochman.

Analysis and interpretation of data: Alexander, Reynolds, Stebbins, Dzavik, Harrington, Van de Werf, Hochman.

Drafting of the manuscript: Alexander, Reynolds, Stebbins, Hochman.

Critical revision of the manuscript for important intellectual content: Alexander, Reynolds, Dzavik, Harrington, Van de Werf, Hochman.

Statistical analysis: Alexander, Stebbins.

Obtained funding: Dzavik, Harrington, Hochman.

Administrative, technical, or material support: Alexander, Reynolds, Dzavik, Harrington, Van de Werf, Hochman.

Study supervision: Alexander, Reynolds, Dzavik, Harrington, Van de Werf, Hochman.

Financial Disclosures: All members of the writing committee (Drs Alexander and Reynolds, Ms Stebbins, and Drs Dzavik, Harrington, Van de Werf, and Hochman) received institutional research support from ArgiNOx Pharmaceuticals for their work on TRIUMPH. Dr Hochman reported receiving honoraria from ArgiNOx and Procter and Gamble and performed consulting for Datascope. Dr Dzavik reported receiving honoraria from Datascope.

Funding/Support: This study was sponsored by ArgiNOx Pharmaceuticals Inc. The ArgiNOx study team included David Hathaway, MD, Steve Bell, Grendel Burrell, and Kenneth Drazan, MD.

Role of the Sponsor: ArgiNOx was involved in the design and conduct of the study and in the collection and management of the data; however, the sponsor played no role in the analysis or interpretation of the data or in the preparation, review, or approval of the manuscript. All statistical analyses in this article were performed by Ms Stebbins with oversight from Dr Alexander.

TRIUMPH Executive Steering Committee: J. S. Hochman (study chair), R. A. Harrington, F. Van de Werf, V. Dzavik, D. Hathaway (ArgiNOx).

Global Steering Committee: Executive Steering Committee and J. H. Alexander, G. Fonarow, W. B. Gibler, J. Hare, R. J. Lipicky, E. M. Ohman, J. Parrillo, J. L. Vincent, H. L. Dauerman, H. R. Reynolds, A. Geppert, S. Janssens, P. Widimsky, K. Werdan, A. Ronaszeki, W. Ruzyllo, G. Cotter, D. Hathaway.

Clinical Coordinating Centers: Office of the Study Chair–New York University Coordinating Center (New York, NY): J. S. Hochman, H. R. Reynolds, A. Roberts. European Coordinating Center–Leuven Coordinating Center (Leuven, Belgium): F. Van de Werf; A. Luyten, K. Vandenberghe. Duke Clinical Research Institute (Durham, NC): J. H. Alexander, A. Stebbins, G. Rankin, E. King.

Data and Safety Monitoring Board: J. Alpert (chair), E. Antman, P. W. Armstrong, D. DeMets, G. Francis, C. Hamm, H. Katus.

Site and Data Management: Hesperion Ltd.

TRIUMPH Investigators (No. of patients enrolled; countries and sites are listed in order of the average per-site enrollment rate): Austria (39 patients): Country leader: A. Geppert; 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): Country leader: W. Ruzyllo; 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 Śl Akademii Medycznej: M. Tendera, A. Ochala (5); Klinika Chorób Wewnetrznych: W. Banasiak, D. Kustrzycka-Kratochwil (4); Klinika Kardiologii, Wojskowy Instytut Medyczny: J. Adamus, M. Zarński (4); Śl 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): Country leader: K. Werdan; 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): Country leader: A. Ronaszeki; 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): Country leader: S. Janssens; 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): Country leader: V. Dzavik; 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). United States (131 patients): Country leader: R. Harrington; 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). Czech Republic (10 patients): Country leader: P. Widimsky; General University Hospital, Prague: J. Belohlavek, J. Horák (2); Kardio-Troll, s.r.o., Dept. of Invasive Cardiology: I. Varvaŕovský, J. Matějka (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).

Acknowledgment: We gratefully acknowledge the dedication and hard work of the TRIUMPH study coordinators and investigators.

Agress CM, Binder MJ. Cardiogenic shock.  Am Heart J. 1957;54:458-477
PubMed   |  Link to Article
Berger PB, Holmes DR, Stebbins AL, Bates ER, Califf RM, Topol EJ. Impact of an aggressive invasive catheterization and revascularization strategy on mortality in patients with cardiogenic shock in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial: an observational study.  Circulation. 1997;96:122-127
PubMed   |  Link to Article
Kuhn LA. The treatment of cardiogenic shock, I: the nature of cardiogenic shock.  Am Heart J. 1967;74:578-581
PubMed   |  Link to Article
Goldberg RJ, Samad NA, Yarzebski J, Gurwitz J, Bigelow C, Gore JM. Temporal trends in cardiogenic shock complicating myocardial infarction.  N Engl J Med. 1999;340:1162-1168
PubMed   |  Link to Article
Lindholm MG, Kober L, Boesgaard S, Torp-Pedersen C, Aldershvile J.Trandolapril Cardiac Evaluation Study Group.  Cardiogenic shock complicating acute myocardial infarction; prognostic impact of early and late shock development.  Eur Heart J. 2003;24:258-265
PubMed   |  Link to Article
Zeymer U, Vogt A, Zahn R.  et al.  Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI): results of the primary PCI registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK).  Eur Heart J. 2004;25:322-328
PubMed   |  Link to Article
Mehta RH, Sadiq I, Goldberg RJ.  et al.  Effectiveness of primary percutaneous coronary intervention compared with that of thrombolytic therapy in elderly patients with acute myocardial infarction.  Am Heart J. 2004;147:253-259
PubMed   |  Link to Article
Himbert D, Golmard JL, Juliard JM, Feldman LJ, Steg PG. Impact of smoking on the incidence and survival of cardiogenic shock complicating acute myocardial infarction treated with reperfusion therapy.  Am J Cardiol. 2002;89:73-75
PubMed   |  Link to Article
Hochman JS, Sleeper LA, Webb JG.  et al.  Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction.  JAMA. 2006;295:2511-2515
PubMed   |  Link to Article
Akiyama K, Suzuki H, Grant P, Bing RJ. Oxidation products of nitric oxide, NO2 and NO3, in plasma after experimental myocardial infarction.  J Mol Cell Cardiol. 1997;29:1-9
PubMed   |  Link to Article
Akiyama K, Kimura A, Suzuki H.  et al.  Production of oxidative products of nitric oxide in infarcted human heart.  J Am Coll Cardiol. 1998;32:373-379
PubMed   |  Link to Article
Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm.  Circulation. 2003;107:2998-3002
PubMed   |  Link to Article
Cotter G, Kaluski E, Milo O.  et al.  LINCS: L-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock.  Eur Heart J. 2003;24:1287-1295
PubMed   |  Link to Article
Cotter G, Kaluski E, Blatt A.  et al.  L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock.  Circulation. 2000;101:1358-1361
PubMed   |  Link to Article
Dzavik V, Cotter G, Reynolds HR.  et al.  Effect of nitric oxide synthase inhibition on hemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study.  Eur Heart JIn press
Arnold JM, Liu P, Demers C.  et al.  Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.  Can J Cardiol. 2006;22:23-45
PubMed   |  Link to Article
Hunt SA.American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure).  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure).  J Am Coll Cardiol. 2005;46:e1-e82
PubMed   |  Link to Article
Swedberg K, Cleland J, Dargie H.  et al.  Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology.  Eur Heart J. 2005;26:1115-1140
PubMed   |  Link to Article
Antman EM, Anbe DT, Armstrong PW.  et al.  ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).  Circulation. 2004;110:588-636
PubMed   |  Link to Article
Van de Werf F, Ardissino D, Betriu A.  et al.  Management of acute myocardial infarction in patients presenting with ST-segment elevation.  Eur Heart J. 2003;24:28-66
PubMed   |  Link to Article
Fincke R, Hochman JS, Lowe AM.  et al.  Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry.  J Am Coll Cardiol. 2004;44:340-348
PubMed   |  Link to Article
Hasdai D, Holmes DR Jr, Califf RM.  et al.  Cardiogenic shock complicating acute myocardial infarction: predictors of death: Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO).  Am Heart J. 1999;138:21-31
PubMed   |  Link to Article
Kuehn BM. Industry, FDA warm to “adaptive” trials.  JAMA. 2006;296:1955-1957
PubMed   |  Link to Article
López A, Lorente JA, Steingrub J.  et al.  Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.  Crit Care Med. 2004;32:21-30
PubMed   |  Link to Article
Nordhaug D, Steensrud T, Aghajani E, Korvald C, Myrmel T. Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure.  Eur J Heart Fail. 2004;6:705-713
PubMed   |  Link to Article
Théroux P, Armstrong PW, Mahaffey KW.  et al.  Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial.  Eur Heart J. 2005;26:1964-1970
PubMed   |  Link to Article
Granger CB, Mahaffey KW, Weaver WD.  et al.  Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the Complement Inhibition in Myocardial Infarction Treated With Angioplasty (COMMA) trial.  Circulation. 2003;108:1184-1190
PubMed   |  Link to Article
APEX AMI Investigators.  Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2007;297:43-51
PubMed   |  Link to Article
DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials: part I.  Circulation. 2002;106:746-751
PubMed   |  Link to Article
DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials: part II.  Circulation. 2002;106:880-886
PubMed   |  Link to Article
Dauerman HL, Goldberg RJ, White K.  et al.  Revascularization, stenting, and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock.  Am J Cardiol. 2002;90:838-842
PubMed   |  Link to Article
Klein LW, Shaw RE, Krone RJ.  et al.  Mortality after emergent percutaneous coronary intervention in cardiogenic shock secondary to acute myocardial infarction and usefulness of a mortality prediction model.  Am J Cardiol. 2005;96:35-41
PubMed   |  Link to Article
Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS.NRMI Investigators.  Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock.  JAMA. 2005;294:448-454
PubMed   |  Link to Article

Figures

Figure 1. Patient Enrollment and Follow-up
Graphic Jump Location

MI indicates myocardial infarction.

Figure 2. Kaplan-Meier Curve of Duration of Cardiogenic Shock
Graphic Jump Location
Figure 3. Effect of Tilarginine vs Placebo on 30-Day Mortality in Patient Subgroups
Graphic Jump Location

Because of substantial missing data and a very small number of patients with creatinine levels ≥1.9 mg/dL, renal dysfunction was defined as a baseline creatinine level ≥1.7 mg/dL (top-most quartile) rather than ≥1.9 mg/dL as prespecified in the statistical analysis plan. CI indicates confidence interval.

Figure 4. Kaplan-Meier Mortality Over 6 Months of Follow-up
Graphic Jump Location

References

Agress CM, Binder MJ. Cardiogenic shock.  Am Heart J. 1957;54:458-477
PubMed   |  Link to Article
Berger PB, Holmes DR, Stebbins AL, Bates ER, Califf RM, Topol EJ. Impact of an aggressive invasive catheterization and revascularization strategy on mortality in patients with cardiogenic shock in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial: an observational study.  Circulation. 1997;96:122-127
PubMed   |  Link to Article
Kuhn LA. The treatment of cardiogenic shock, I: the nature of cardiogenic shock.  Am Heart J. 1967;74:578-581
PubMed   |  Link to Article
Goldberg RJ, Samad NA, Yarzebski J, Gurwitz J, Bigelow C, Gore JM. Temporal trends in cardiogenic shock complicating myocardial infarction.  N Engl J Med. 1999;340:1162-1168
PubMed   |  Link to Article
Lindholm MG, Kober L, Boesgaard S, Torp-Pedersen C, Aldershvile J.Trandolapril Cardiac Evaluation Study Group.  Cardiogenic shock complicating acute myocardial infarction; prognostic impact of early and late shock development.  Eur Heart J. 2003;24:258-265
PubMed   |  Link to Article
Zeymer U, Vogt A, Zahn R.  et al.  Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI): results of the primary PCI registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK).  Eur Heart J. 2004;25:322-328
PubMed   |  Link to Article
Mehta RH, Sadiq I, Goldberg RJ.  et al.  Effectiveness of primary percutaneous coronary intervention compared with that of thrombolytic therapy in elderly patients with acute myocardial infarction.  Am Heart J. 2004;147:253-259
PubMed   |  Link to Article
Himbert D, Golmard JL, Juliard JM, Feldman LJ, Steg PG. Impact of smoking on the incidence and survival of cardiogenic shock complicating acute myocardial infarction treated with reperfusion therapy.  Am J Cardiol. 2002;89:73-75
PubMed   |  Link to Article
Hochman JS, Sleeper LA, Webb JG.  et al.  Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction.  JAMA. 2006;295:2511-2515
PubMed   |  Link to Article
Akiyama K, Suzuki H, Grant P, Bing RJ. Oxidation products of nitric oxide, NO2 and NO3, in plasma after experimental myocardial infarction.  J Mol Cell Cardiol. 1997;29:1-9
PubMed   |  Link to Article
Akiyama K, Kimura A, Suzuki H.  et al.  Production of oxidative products of nitric oxide in infarcted human heart.  J Am Coll Cardiol. 1998;32:373-379
PubMed   |  Link to Article
Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm.  Circulation. 2003;107:2998-3002
PubMed   |  Link to Article
Cotter G, Kaluski E, Milo O.  et al.  LINCS: L-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock.  Eur Heart J. 2003;24:1287-1295
PubMed   |  Link to Article
Cotter G, Kaluski E, Blatt A.  et al.  L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock.  Circulation. 2000;101:1358-1361
PubMed   |  Link to Article
Dzavik V, Cotter G, Reynolds HR.  et al.  Effect of nitric oxide synthase inhibition on hemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study.  Eur Heart JIn press
Arnold JM, Liu P, Demers C.  et al.  Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.  Can J Cardiol. 2006;22:23-45
PubMed   |  Link to Article
Hunt SA.American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure).  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure).  J Am Coll Cardiol. 2005;46:e1-e82
PubMed   |  Link to Article
Swedberg K, Cleland J, Dargie H.  et al.  Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology.  Eur Heart J. 2005;26:1115-1140
PubMed   |  Link to Article
Antman EM, Anbe DT, Armstrong PW.  et al.  ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).  Circulation. 2004;110:588-636
PubMed   |  Link to Article
Van de Werf F, Ardissino D, Betriu A.  et al.  Management of acute myocardial infarction in patients presenting with ST-segment elevation.  Eur Heart J. 2003;24:28-66
PubMed   |  Link to Article
Fincke R, Hochman JS, Lowe AM.  et al.  Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry.  J Am Coll Cardiol. 2004;44:340-348
PubMed   |  Link to Article
Hasdai D, Holmes DR Jr, Califf RM.  et al.  Cardiogenic shock complicating acute myocardial infarction: predictors of death: Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO).  Am Heart J. 1999;138:21-31
PubMed   |  Link to Article
Kuehn BM. Industry, FDA warm to “adaptive” trials.  JAMA. 2006;296:1955-1957
PubMed   |  Link to Article
López A, Lorente JA, Steingrub J.  et al.  Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.  Crit Care Med. 2004;32:21-30
PubMed   |  Link to Article
Nordhaug D, Steensrud T, Aghajani E, Korvald C, Myrmel T. Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure.  Eur J Heart Fail. 2004;6:705-713
PubMed   |  Link to Article
Théroux P, Armstrong PW, Mahaffey KW.  et al.  Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial.  Eur Heart J. 2005;26:1964-1970
PubMed   |  Link to Article
Granger CB, Mahaffey KW, Weaver WD.  et al.  Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the Complement Inhibition in Myocardial Infarction Treated With Angioplasty (COMMA) trial.  Circulation. 2003;108:1184-1190
PubMed   |  Link to Article
APEX AMI Investigators.  Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2007;297:43-51
PubMed   |  Link to Article
DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials: part I.  Circulation. 2002;106:746-751
PubMed   |  Link to Article
DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials: part II.  Circulation. 2002;106:880-886
PubMed   |  Link to Article
Dauerman HL, Goldberg RJ, White K.  et al.  Revascularization, stenting, and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock.  Am J Cardiol. 2002;90:838-842
PubMed   |  Link to Article
Klein LW, Shaw RE, Krone RJ.  et al.  Mortality after emergent percutaneous coronary intervention in cardiogenic shock secondary to acute myocardial infarction and usefulness of a mortality prediction model.  Am J Cardiol. 2005;96:35-41
PubMed   |  Link to Article
Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS.NRMI Investigators.  Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock.  JAMA. 2005;294:448-454
PubMed   |  Link to Article
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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