PLATO DEATHS LISTS
Lately our Task Force gained access to the detailed dataset of 938 PLATO
deaths reported to the FDA. We matched those records with local
patient-level data from sites controlled by the sponsor, and found that
the existence, precise dates and proper causes of some deaths in PLATO
were inaccurately reported. 7 Several clopidogrel
deaths were reported earlier than actual, while their causes were
switched from “non-vascular” or “unknown” to “vascular”. In
contrast, some ticagrelor deaths were reported later while other
vascular deaths were incorrectly entered in the FDA list as
“non-vascular” or “unknown”.7 We explore here any
differences between the FDA-issued death list (n=938) and the shorter
PLATO Investigators dataset (n=905). The overall numbers of fatalities
and some primary causes for both lists are presented in the Table.
With regard to the discrepancy in total PLATO deaths, it is our
understanding that the dataset we have in possession includes deaths
after the analysis period that are not counted in the primary efficacy
analysis, but the absolute majority of deaths (over 900) should match
precisely (Figure). Indeed, we identified several events when the
patient never received a single drug dose, serious enrollment mistakes,
and inclusion/exclusion errors, but the most common restriction was the
length of follow-up. In fact, the PLATO death count was restricted to no
more than 12 months follow-up duration. Any death within the analysis
period should be counted, although PLATO also excluded deaths after
“withdrawal of consent” or “volunteer discontinuations mostly for
ticagrelor patients.3,8 Importantly, there were some
PLATO patients who were still on drug and died 12-16 months after
enrollment while the trial was still active in the second half of 2008,
but these patients were excluded as being beyond the analysis timeframe.
Finally, we are skeptical that the reductions in the FDA-issued list
removed more ticagrelor (n=21) than clopidogrel (n=12) events for the
final count of 905 deaths used in all PLATO publications and affiliated
presentations.
Furthermore, we presumed that the precise death characteristics and
single primary causes of all remaining PLATO deceased patients should be
identical between the FDA and trial investigators. All 905 deceased
patients in the “official” trial dataset should be included in the
broader list submitted to the FDA. Since some of the 938 deaths were
reported inaccurately to the FDA, we started looking at which of the
erroneous records were transferred into the smaller revised PLATO pool
used in the original1 and over 90 peer-reviewed
secondary publications. Examining details of 2 high-quality secondary
PLATO publications 9,10 focused on mortality revealed
several fundamental problems outlined in the Table.
The well-structured and detailed data from the PLATO
Investigators, clearly indicate that Tables 5
(vascular) and 6 (non-vascular) reported primary causes of
deaths.9 The FDA list also identify a single primary
cause of death, perhaps “unknown” or “other” but just one cause.
However, looking at the PLATO Investigators’ statements reveals obvious
discrepancies. With regard to reported numbers of vascular deaths the
significant differences were observed between FDA- and trial
investigators lists. There were more sudden deaths in the shorter list
than in the FDA dataset (161 vs.138; p<0.03), post-AMI (373
vs.178; p<0.001) but fewer heart failure deaths (73 vs.109;
p=0.02). Stroke numbers match well (39 vs. 37; p=NS) with only 2
ticagrelor cases removed. Among non-vascular causes of deaths cancer
matched well (32 vs.31; p=NS), and sepsis cases were identical (30 vs.
30; P=NS). However, suicides deserve special attention. Two extra
cases9, in the shorter list are impossible to
comprehend. Not only suicide (PLATO code 12-5) is a valid primary death
cause, but both “missing” patients are from the clopidogrel arm. We
directly approached PLATO Investigators with the detailed specific
inquiry regarding these 2 suicides no reported to the FDA but got no
response or any explanation regarding the 2 extra deaths in the
Investigators’ list. Not solving such a simple issue raises questions
regarding not only vascular deaths prevention but also the claimed
all-cause mortality benefit of ticagrelor.