GISTO MAJOR TRIAL

No high quality prospective studies were conducted initially to determine what effects these categories had on clinical outcomes, but they seemed reasonable and were for the most part accepted. The specific categories of each criteria were based on the investigator's determination of major vs. It is important to note that both these criteria were not so much derived as they were assembled. Both of these scores were invented by their respective study groups (TIMI and GUSTO) during the early thrombolytic ACS trials. In ACS research the most well-known are the TIMI and GUSTO bleeding criteria( Table 1). These scores were intended to categorize bleeding into levels of severity. More subtle tools are needed to identify bleeding that may have some clinical impact but would go unnoticed in trials too underpowered to detect any change in mortality. Obviously the simplest way is to examine if the bleeding caused by such intervention increases patient’s mortality, thereby eliminating any benefits its anticoagulant properties may have provided. Since we began examining ACS interventions to inhibit clot formation and promote clot degredation, the need for a standardized method of evaluating bleeding severity has been paramount. The most important question is how clinically relevant is the degree of bleeding the authors claim their drug prevents? This places us, as physicians, in a clinical dilemma, which do we prefer more bleeding or more recurrent MIs? It is, of course, never this simple.

GISTO MAJOR TRIAL

So what initially appeared to be an intriguingly genuine comparison of anticoagulants for ACS, ends up being yet another attempt of a drug company sponsored trial to manipulate the various surrogate endpoints in their favor. In other words, in a smaller-than-expected cohort the authors worried the decrease in irrelevant bleeding would not statistically overpower the increase in irrelevant myocardial infarctions, leading to a statistically negative trial.

They justify this methodologic faux pas by stating their enrollment was slower than anticipated and they feared their study was no longer powered to detect a difference in their initial endpoint. So much so that halfway through the trial they modified their primary endpoint from death, major bleeding and myocardial infarction to include just death and major bleeding. The authors were obviously aware of this. Since the initial trials performed on bivalirudin there has been a consistent decrease in the incidence of bleeding with a concurrent increase in myocardial infarction and stent restenosis (2,3,4). Neither the decreased bleeding or increased rate of infarction was serious enough to affect mortality. In this randomized open label trial they found that patients given bivalirudin experienced less bleeding, but slightly more recurrent MIs and early stent restenosis. This trial, entitled “The European Ambulance Acute Coronary Syndrome Angiography Trial”, given the unfortunate nickname EUROMAX, compares heparin or enoxaparin to bivalirudin when started in prehospital patients undergoing a ST-elevation MI. This was not done out of an overpowering ethical concern for transparency, but rather based off of the knowledge that highlighting bleeding risk as the primary outcome measure would lead to the most positive study. Simultaneously downplaying the importance of recurrent MI, normally a primary outcome in these types of trials, here was demoted to a secondary consideration. In contrast to the majority of trials examining novel anticoagulants for ACS, Steg et al chose to focus on the bleeding risk caused by their drug, bivalirudin, when compared to heparin or enoxaparin. A recent article published in the NEJM by Steg et al demonstrates that it is not the efficacy of an intervention that determines the success or failure of a trial, but rather the definition of its endpoints (1).

Gisto major