Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified

Victor L. Serebruany

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)752-759
Number of pages8
JournalThrombosis and Haemostasis
Volume105
Issue number5
DOIs
StatePublished - May 2011

Fingerprint

clopidogrel
Mortality
United States Food and Drug Administration
Acute Coronary Syndrome
Blood Vessels
(1,2-diamino-4-nitrobenzene)dichloroplatinum(II)
Eastern Europe
Sepsis
Myocardial Infarction
Clinical Trials
Pharmaceutical Preparations

Keywords

  • Clinical trial
  • Mortality
  • Outcomes
  • Site monitoring
  • Ticagrelor

ASJC Scopus subject areas

  • Hematology

Cite this

Viewpoint : Paradoxical excess mortality in the PLATO trial should be independently verified. / Serebruany, Victor L.

In: Thrombosis and Haemostasis, Vol. 105, No. 5, 05.2011, p. 752-759.

Research output: Contribution to journalArticle

@article{107ad47d01484d38b9d66349808e45bc,
title = "Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified",
abstract = "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.",
keywords = "Clinical trial, Mortality, Outcomes, Site monitoring, Ticagrelor",
author = "Serebruany, {Victor L.}",
year = "2011",
month = "5",
doi = "10.1160/TH10-12-0807",
language = "English (US)",
volume = "105",
pages = "752--759",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer GmbH",
number = "5",

}

TY - JOUR

T1 - Viewpoint

T2 - Paradoxical excess mortality in the PLATO trial should be independently verified

AU - Serebruany, Victor L.

PY - 2011/5

Y1 - 2011/5

N2 - 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.

AB - 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.

KW - Clinical trial

KW - Mortality

KW - Outcomes

KW - Site monitoring

KW - Ticagrelor

UR - http://www.scopus.com/inward/record.url?scp=79955772062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955772062&partnerID=8YFLogxK

U2 - 10.1160/TH10-12-0807

DO - 10.1160/TH10-12-0807

M3 - Article

C2 - 21384079

AN - SCOPUS:79955772062

VL - 105

SP - 752

EP - 759

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 5

ER -