Over the last several decades a number of cardiovascular trials have provided unexpected findings that did not fit the pharmacological effects of what is known for a particular compound. The scientific community finds this very unsettling and usually within a few months there are a plethora of “potential” reasons for these unexpected findings. Dr. Frank Harrell, a noted biostatistician, some 20 years ago stated that “medical scientists are programmed to provide a plausible scientific explanation for an observation even if there is none, while biostatisticians try to determine if the observation is real in statistical terms.” In this issue of Thrombosis and Haemostasis Dr. Serebruany (1) has attempted to provide plausible “scientific” answers for some unusual observations from the PLATelet inhibition and clinical Outcomes (PLATO) trial (2) published in 2009. In this trial there was a significant reduction in cardiovascular (CV) mortality as part of a composite clinical endpoint (death, stroke and myocardial infarction). Using a hierarchical statistical testing strategy for the primary endpoint, to preserve statistical power, they concluded that the ticagrelor was superior to clopidogrel in acute coronary syndrome (ACS) for the composite endpoint, and the individual components myocardial infarction (MI) and CV mortality, but not for stroke. All-cause mortality was numerically lower as well, but statistically could not be inferred for the primary endpoint, as then adjustments had to be made to account for the multiple statistical tests that were performed. Dr. Serebruany has focused on the all-cause mortality rate which he notes was higher in the PLATO trial compared with other ACS trials. There are several flaws with his arguments as will be pointed out. The argument that the all-cause mortality observed in the PLATO trial is not consistent with other ACS trials cannot be made for many reasons. First, none of the trials quoted have included the same type of ACS patients. The PLATO trial (2) enrolled 40% ST-segment elevation myocardial infarction (STEMI) patients (with known high early mortality), while CURE (3) and ACUITY (4) included none; CHARISMA (5) was a chronic prevention trial where stable patients were enrolled (about 30% up to one year after MI (not necessarily STEMI)) and CREDO (6) was a PCI trial with only a portion of ACS patients. It is therefore expected that the overall mortality rates should be substantially different in these trials, particularly as patients were enrolled in different countries over the last decade. Second, we do not believe it is appropriate to compare the conduct and, specifically, the monitoring of the PLATO trial with other trials and to suggest that problems with these processes contributed to the mortality rates observed in the PLATO trial. Experienced clinical trial researchers understand that the operational conduct of a large, global cardiovascular trial is very complex and cannot be adequately judged or evaluated by outside “experts” who have little experience in these matters, and specifically, no role in the operational conduct of the trial in quesCorrespondence to: Prof. Magnus Ohman, MB, FRCPI, FESC, FACC Duke University Medical Center Box 3126 DUMC Durham, NC 27710, USA Tel.: +1 919 681 2069, Fax: +1 919 681 6443 E-mail: ohman001@mc.duke.edu