the results of the latest large trial in patients with cardiogenic shock ( cs ) , namely the triumph trial , were recently published in journal of the american medical association . about 6 to 9% of myocardial infarctions ( mis ) , mostly with st elevation , is complicated by cs , which is the leading cause of death .
the shock trial has shown the benefit of early revascularization in decreasing the rate of death , although the in - hospital and long - term mortality remains high . as long ago as 1939 , mi was shown to be associated with an inflammatory process , when mallory and white described the time - related appearance of infiltrating cells .
later , it was also reported that after being activated in vivo , macrophage cytotoxicity was mediating an l - arginine - dependent biochemical pathway that synthesized l - citrulline and nitric oxide ( no ) .
no is also a powerful vasodilator that may alter cardiac contractile function , with a positive inotropic effect at low level and negative at higher levels . in the shock trial , many patients had evidence , at shock onset , of systemic inflammatory response syndrome with fever , leukocytosis and decreased systemic vascular resistance confirming the classic notion that cs leads to a compensatory vasoconstriction [ 6 - 8 ] .
this inappropriate systemic vasodilatation might be related to no overproduction that can contribute to a vicious cycle of aggravation of cs .
inhibition of no synthase ( nos ) was theoretically appealing , targeting a new pathophysiological approach of cs in mi .
the triumph study was a prospective , international , multi - center , randomized , double - blind , placebo - controlled trial testing the hypothesis that tilarginine ( a non - specific inhibitor of nos ) , when compared with placebo , would reduce 30-day mortality by 25% in patients with mi complicated by refractory cs despite successful revascularization of the infarct - related artery .
patients received a 1.0 mg / kg intravenous bolus of the drug followed by 5 hours of intravenous infusion of the drug at 1.0 mg / kg per hour or of a matching placebo .
the major outcome was 30-day all - causes overall mortality , and stratification by age ( less than 75 years or 75 years and over ) was performed .
the secondary outcome included duration and resolution of shock , new york heart association functional class at day 30 , and 6-month mortality .
the study was planned to include 658 treated patients in 130 centers for 90% power of detecting a 25% decrease in mortality . finally , the study stopped enrolment after 398 patients on the basis of interim efficacy and futility analyses planned at 50% and 75% of enrolment . although tilarginine increased systolic blood pressure by 5 mmhg ( 7 mmhg versus 12 mmhg ; p = 0.01 ) at 2 hours , no effect on mortality was observed at 30 days .
there was also no difference in secondary outcomes such as resolution or duration of the cs , new york heart association functional class and 6-month mortality .
there was , however , a 6% absolute increase in 30-day mortality in the tilarginine group ( 48% , versus 42% in the placebo ) that was qualified by ndrepepa and colleagues in their editorial in the same issue of jama as a disturbing event if this difference did not reach statistical significance ( p = 0.24 ) .
we can reasonably wonder whether this difference would have been significant if the total planned enrolment had been reached .
it is noteworthy that dzavic and colleagues recently published a study assessing the effect of the inhibition of nos on hemodynamics in patients with persistent cs after mi despite successful revascularization .
as opposed to the triumph study , this study , which used a bolus and 5-hour infusions of n - monomethyl - l - arginine ( 0.15 , 0.5 , 1.0 or 1.5 mg / kg per hour ) compared with placebo , did not increase the mean arterial pressure at 2 hours ( primary outcome ) . another international randomized placebo - controlled trial of n - monomethyl - l - arginine hydrochloride at a dose ranging from 0.5 to 20 mg / kg per hour for 7 or 14 days for septic shock was also stopped prematurely because of an increased 28-day mortality ( 59% versus 49% ; p < 0.001 ) .
all these randomized studies are disappointing because hope for a new therapeutic approach to cs had been raised by human pilot studies .
cotter and colleagues reported that inhibition of the no pathway reduces 30-day mortality from 67% to 27% in a small randomized study ( not placebo - controlled ) , with increased blood pressure and urine output ; this was the basis for the drug dosage and treatment duration for the triumph study .
this again proves that a placebo - controlled double - blind study remains mandatory for evaluating new treatment modalities and is what evidence - based medicine is all about .
furthermore , the tilarginine - induced increase in systolic blood pressure leads to questions about the use of systolic blood pressure as a surrogate endpoint to predict outcome in cs .
overall , treatments targeting the inflammatory cascade , especially the inhibition of the no pathway , remain as deceiving in mi as in sepsis .
this might be related to the use of a non - specific inhibitor of nos .
more importantly , our group showed recently that , in patients with various degrees of sepsis and inflammation , no overproduction leads to the very early production of peroxynitrite , which irreversibly inactivates proteins ( including contractile proteins ) , suggesting that inhibiting the no pathway probably comes too late and can not restore an already impaired contractile function .
the triumph study gave strong indications for stopping any further trial with non - specific nos inhibitors in cs and possibly also in all other cardiovascular diseases .
a better understanding of the physiopathology of the production of tissue - specific and systemic biomarkers is needed to develop new agents that have the potential to be effective in mi - induced cs .
while we wait for new treatment modalities , the prevention of cs with early acute mi primary angioplasty remains the gold standard .
percutaneous left - ventricle - assisting devices may serve as a bridge to recovery or final treatment , namely transplantation .
 the triumph study , recently published in journal of the american medical association , was a prospective randomized placebo - controlled trial testing the hypothesis that tilarginine ( a non - specific inhibitor of nitric oxide synthase ) , when compared with placebo , would reduce 30-day mortality by 25% in patients with myocardial infarction complicated by refractory cardiogenic shock despite successful revascularization of the infarct - related artery . 
 patients received an intravenous bolus of the drug followed by 5 hours of intravenous infusion of the drug or a matching placebo . 
 although tilarginine increased systolic blood pressure by 5 mmhg at 2 hours , no effect on mortality was observed at 30 days . 
 there was , however , a 6% absolute increase in 30-day mortality in the tilarginine group ( 48% , versus 42% in the placebo ) . 
 this definitive trial gave strong indications for stopping any further trial using non - specific inhibitors of nitric oxide synthase in cardiogenic shock and possibly also in any other cardiovascular area . 
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