Archive for August, 2012

Journal Club 22 August 2012


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?




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.

Categories: Journal Club

ACS Symposium Link

ACS Symposium Link (provided by AstraZeneca) (password: presentation)

Everolimus Eluting Stents in Diabetes

Bangalore et al have published a meta-analysis (Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22 844 patient years of follow-up from randomised trials)

A summary excerpt of the Bayesian analysis is shown below:


The supplementary material are available here: supplement 1, supplement 2.


Journal Club 8 August 2012


Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain



Summary (abstract from paper)


It is unclear whether an evaluation incorporating coronary computed tomographic
angiography (CCTA) is more effective than standard evaluation in the emergency
department in patients with symptoms suggestive of acute coronary syndromes.


In this multicenter trial, we randomly assigned patients 40 to 74 years of age with
symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic
changes or an initial positive troponin test to early CCTA or to standard
evaluation in the emergency department on weekdays during daylight hours between
April 2010 and January 2012. The primary end point was length of stay in the hospital.
Secondary end points included rates of discharge from the emergency department,
major adverse cardiovascular events at 28 days, and cumulative costs. Safety
end points were undetected acute coronary syndromes.


The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age
of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard
evaluation, the mean length of stay in the hospital was reduced by 7.6 hours
(P<0.001) and more patients were discharged directly from the emergency department
(47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes
and no significant differences in major adverse cardiovascular events at 28 days.
After CCTA, there was more downstream testing and higher radiation exposure.
The cumulative mean cost of care was similar in the CCTA group and the standardevaluation
group ($4,289 and $4,060, respectively; P = 0.65).


In patients in the emergency department with symptoms suggestive of acute
coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency
of clinical decision making, as compared with a standard evaluation in the
emergency department, but it resulted in an increase in downstream testing and
radiation exposure with no decrease in the overall costs of care.


There was general discussion around different diagnostic algorithms, definitions of acceptable risk, various accelerated diagnostic protocols, radiation exposure and stochastic risk (esp. cumulative exposures and ‘vulnerable’ group). [Cardiology and Emergency Physician input]

The editorial is available here

Troponin post noncardiac surgery and 30-day mortality

15133 patients   (age 45 years or older; 51.5% female) undergoing noncardiac surgery were enrolled in prospective VISION study (August 2007 to January 2011) were analysed (see reference below). The same troponin T assay was used for all patients. The relationship between troponin T level is graphically presented below. The vertical axis is logarithmic. The tooltips are absolute numbers (percentage of total population). The red labels above the bars are the percentage of patients  in each group dying (30 day mortality).

The Vascular Events in Noncardiac Surgery Patients Cohort Evaluation  (VISION)Study Investigators. Association between troponin levels and  30-day mortality among patients undergoing non-cardiac surgery. JAMA 2012 Jun 6; 307:2295