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Journal Club 22 August 2012

Papers

Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified
Viewpoint: Central adjudication of myocardial infarction in outcomedriven clinical trials – Common patterns in TRITON, RECORD, and PLATO?

Presenter

AC

Summary

Mortality PLATO

The PLATO trial revealed excess all-cause (4.5%) and vascular (4.0%)
mortality after experimental pyrimidine, ticagrelor, and even higher
death rates (5.9% and 5.1%, respectively) after clopidogrel, which have
never been seen in any previous acute coronary syndrome (ACS) trial.
The Food and Drug Administration (FDA) conducted, and recently released
the ticagrelor review outlining some paradoxical mortality patterns
in PLATO, including the existence of alive patient, who initially
was reported dead. The drug was recently approved in Europe, but repeatedly
delayed in the USA. The objective of this viewpoint article was
to evaluate extremely high death rates in PLATO by scrutinising FDA-released
evidence, and comparing mortality patterns in recent ACS trials.
These data were first presented as the analytical report submitted to
the FDA on October 26, 2010. The available evidence suggest that mortality
rates in PLATO, so as death benefit of ticagrelor over clopidogrel
are extreme, despite incomplete follow-up, short duration of the trial,
frequent preloading with clopidogrel, and gross mismatch between
conventional average myocardial infarction rates but disproportionally
frequent vascular fatalities, and heavily imbalanced sepsis-related
deaths. In contrast to the overall PLATO results, the deaths rates in the
USA were much lower (3.2% vs. 3.8%) not only favouring clopidogrel,
but more importanly matching very well with identical rates in TRITON
(3.2%), and one-year ACUITY (3.6%-3.9%) fatalities. Since the «play of
chance» cannot explain these discrepancies due to excess death rates
in both PLATO arms, and considering that study sponsor self-monitored
sites in most countries, but not in the USA, the mortality data are questionable,
and should be independently virified. It was concluded that
excess mortality rates and delayed timing of the benefit onset in PLATO
do not match with any recent ACS trial, and do not look natural. Reevaluation
of the survival, especially driven from the several high-volume
sponsor monitored sites in Eastern Europe may reveal discrepancies
between those reported in PLATO and actual vital records. Future
practice of self monitoring in pivotal indication-seeking clinical trials
should be completely banned.

Myocardial Infarction Adjudication

Central adjudication in randomised controlled outcome-driven trials
represents a traditional approach to maintain data integrity by applying
uniformed rules for assessment of clinical events. It was the purpose of
this investigation to determine the patterns of myocardial infarction
(MI) adjudication in the TRITON, RECORD, and PLATO trials. We were
matching centrally-adjudicated MI’s (CAMI’s) from the official trial
publication with the site-reported MI (SRMI’s) count from the Food and
Drug Administration’s secondary analyses for the investigational compounds
prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor
(PLATO). CAMI numbers showed a remarkable discrepancy to SRMI’s by
more than a doubling of the difference: from 72 to 145 events in TRITON
favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a
HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in
PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast,
in the RECORD trial, the CAMI count was less than the SRMI count (from
24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this
case diminishing cardiovascular hazards in favour of rosiglitazone. In
conclusion, central adjudication in the TRITON, the RECORD, and the
PLATO trial turned out to have a critical impact on study outcomes. Trial
publications should in the future include site-reported major efficacy
and safety endpoints to preserve data integrity. The regulatory authorities
should consider independent audits when there is a major disagreement
between centrally adjudicated and site reported events influencing
the results of a major clinical trial.

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