Keywords
clinical trial - ticagrelor - clopidogrel - death - infections - pneumonia - sepsis
Introduction
The relations between infections, hemostasis, and potency of antithrombotic therapy
are intertwined but important, especially after utilization of current aggressive
dual antiplatelet strategies following coronary revascularization.[1] Indeed, such complex interventions per se often require use of numerous devices
into and out of the arterial circulation, and these procedures may cause bacteremia[2] or even septicemia.[3] Since already established shortcomings following clopidogrel may include impaired
wound healing and increased postsurgery infections,[4]
[5] more powerful antiplatelet strategies could present even greater risks. The mechanism
responsible for such harmful association is probably indirect and involves weakening
of platelet–neutrophil–endothelial cross-talk necessary to combat infections, and/or
keep inflammation from spreading. However, the comparative risks of infections including
sepsis among adverse events in such patients have not been identified. The first alarming
signal that potent long-term antiplatelet therapy may cause excess of infections that
was observed in the prasugrel arm of TRITON-TIMI 38 trial.[6] Consistently, ticagrelor in PLATO caused more infections but surprisingly less sepsis-related
deaths (SRD) than clopidogrel.[7] The details of the Food and Drug Administration (FDA) review[7] are outlined in [Table 1].
Table 1
FDA analyses of infections and sepsis-related deaths in PLATO
|
Infection
|
Ticagrelor
|
Clopidogrel
|
|
Upper respiratory
|
947 (10.25%)
|
882 (9.6%)
|
|
Lungs
|
233 (2.52%)
|
245 (2.67%)
|
|
Urinary tract
|
184 (2.0%)
|
161 (1.8%)
|
|
Viral
|
466 (5.05%)
|
415 (4.52%)
|
|
Bacterial
|
506 (5.48%)
|
492 (5.36%)
|
|
Any infection
|
1,488 (16.11%)
|
1,438 (15.65%)
|
|
Fever
|
331 (3.58%)
|
318 (3.46%)
|
|
Sepsis-related deaths
|
7 (0.1%)
|
23 (0.2%)
|
Abbreviation: FDA, Food and Drug Administration.
The data outlined in the [Table 1] strongly suggest that more profound platelet inhibition with ticagrelor causes a
slightly greater risk for infections than after clopidogrel. Such observation may
be related to the fact that ticagrelor PLATO regiment was more potent. However, how
could the reduction of SRD reported after ticagrelor therapy be reconciled? With details
unavailable for public these numbers should be independently verified, despite some
preliminary attempts to explain this paradox.[8]
[9]
[10] We recently gained access to the detailed FDA-issued dataset of 938 PLATO deaths
which has been matched with local patient-level data from sites controlled by the
sponsor revealing that actual existence, the precise dates, and the proper causes
of some deaths in PLATO were inaccurately reported in favor of ticagrelor.[11] Moreover, there is a massive discrepancy between primary death causes reported to
the FDA, and those utilized by the PLATO Investigators for numerous secondary overoptimistic
reports published in top journals for over a decade.[12] Examining cancer deaths reveled that many clopidogrel events were misreported in
PLATO favoring ticagrelor as well.[13] Here, we disclose verified deaths from pneumonia and sepsis in PLATO, examining
their reporting patterns and validity.
Methods
Based on the Freedom of Information Act, BuzzFeed filed a legal complaint in U.S.
Federal Court, won an expedited order, and shared with us the complete PLATO death
list submitted to the FDA by the ticagrelor sponsor. The FDA spreadsheet contains
938 PLATO deaths with trial identification numbers, country, enrolling site, patient
age, gender, treatment assignments, discontinuations, outcome codes, dates, and precise
causes of trial exit. Each event contains whether the death cause was vascular (code
11), nonvascular (code 12), or unknown (code 97). There were 14 subcodes for vascular,
9 subcodes for nonvascular deaths, and universal code “99” which applied for “other”
causes. Among infections, the spreadsheet contains primary deaths' codes for pneumonia
(12–2) and SRD (12–8) only. Most of the data were controlled and reported by PLATO
sponsor, with the exception of the United States, Russia, Georgia, and most (sites
5101–5106) of Ukraine. The entire United States was monitored by ReSearch Pharmaceutical
Services, (Wort Washington, Pennsylvania, United States;
http://www.rpsweb.com
). All Russian, Georgian, and most Ukrainian sites were monitored by Evidence CRP,
now Worldwide Clinical Trials, (Morrisville, North Carolina, United States;
http://wwctrials.com/
). The FDA-issued list contains 18 precisely detailed pneumonia deaths and 30 SRD.
We have local verified records on four of such deaths (two each for pneumonia and
SRD) among 861 PLATO patients from 14 enrolling sites in eight countries and matched
those with what was reported to the FDA. We also assessed the reporting pattern of
deaths from infections issued by the FDA just scrolling down column “S” for the nonvascular
death causes.
Results
Among 18 FDA-reported pneumonia deaths in PLATO, those attributed to ticagrelor (n = 10) were numerically more than after clopidogrel (n = 8). We matched two PLATO patients with the local site data (one ticagrelor and
one clopidogrel). Both cases were reported correctly. With regard to SRD verification
in two clopidogrel cases, both primary death causes were reported incorrectly. As
reported by site the primary cause of death of one clopidogrel patient was multiorgan
failure (nonvascular subcode 9) but not SRD (subcode 8). Another patient is of significant
interest since sepsis was among the secondary diagnoses. However, site reported respiratory
failure (nonvascular subcode 1) as a primary death cause but not sepsis. Of the remaining
21 clopidogrel SRD, 6 were reported as three separate pairs repeating previous in
list patient record suggesting last minute addition of incorrect cases. In contrast,
four ticagrelor SRD has been accompanied by very close clopidogrel SRD entry in a
pattern to “compensate” or maintain ticagrelor sepsis advantage. See [Table 2] for details.
Table 2
FDA-issued dataset entries for questionable sepsis deaths in PLATO trial
|
ENTR
|
Country
|
Age
|
ETN
|
Gender
|
STUDYDY
|
TRTRTXT
|
NVASSCLS
|
|
22
|
Argentina
|
57
|
E1016xxx2DE
|
Female
|
37
|
Clopidogrel
|
8
|
|
24
|
Argentina
|
71
|
E1016xxx4DE
|
Male
|
8
|
Ticagrelor
|
8
|
|
76
|
Brazil
|
59
|
E1422xxx1DE
|
Male
|
52
|
Clopidogrel
|
8
|
|
78
|
Brazil
|
77
|
E1425xxx11DE
|
Female
|
147
|
Clopidogrel
|
8
|
|
86
|
Brazil
|
64
|
E1427xxx6DE
|
Female
|
56
|
Clopidogrel
|
8
|
|
88
|
Brazil
|
75
|
E1427xxx5DE
|
Male
|
34
|
Clopidogrel
|
8
|
|
193
|
Czech
|
67
|
E1804xxx9DE
|
Female
|
69
|
Ticagrelor
|
8
|
|
195
|
Czech
|
62
|
E1805xxx4DE
|
Female
|
51
|
Clopidogrel
|
8
|
|
436
|
India
|
74
|
E2717xxx37DE
|
Female
|
198
|
Clopidogrel
|
8
|
|
440
|
India
|
74
|
E2719xxx8DE
|
Female
|
83
|
Clopidogrel
|
8
|
|
467
|
Indonesia
|
52
|
E2805xxx1DE
|
Female
|
131
|
Ticagrelor
|
8
|
|
468
|
Israel
|
70
|
E2901xxx79DE
|
Female
|
169
|
Clopidogrel
|
8
|
|
650
|
Poland
|
73
|
E3625xxx45DE
|
Female
|
242
|
Ticagrelor
|
8
|
|
651
|
Poland
|
71
|
E3625xxx72DE
|
Female
|
17
|
Clopidogrel
|
8
|
Abbreviations: ENTR, patient number among 938 reported PLATO deaths, goes in alphabetical
order from Argentina to the United States, ending with 2 last deaths from Ukraine
after monitoring switch from CRO to the sponsor; ETN, event tracking number; FDA,
Food and Drug Administration; STUDYDY, Study days; TRTRTXT, randomization treatment
text; NVASCLS, subclassification of nonvascular death code.[12]
The surprising and highly unusual pattern of three pairs of close or next in line
clopidogrel patients marked as SRD can be easily detected by just scrolling down Excel
list column “S” among fatalities in Brazil and India. Repeated placement in pairs
of subcode 8 (SRD) for 6 clopidogrel patients could indicate database manipulation
or/and last-minute modifications to artificially worsen clopidogrel infection risks.
Interestingly, patients in between: on line 77 received ticagrelor but patient on
line 87 was on clopidogrel. However, that particular patient reported on line 87 experienced
a cardiogenic shock, the “precious” vascular cause of death potentially contributing
to PLATO primary efficacy outcome, and next in line 88 deceased clopidogrel patient
was reported as SRD.
Impression
The main finding of this report suggests that ticagrelor is not better than clopidogrel
with regard to risks of infections and affiliated deaths. Aside from possible misreporting,
and unsubstantiated claims that ticagrelor could prevent SRD in PLATO, the drug per
se probably do not cause direct inflammation effect but could negatively contribute
via excessive chronic platelet inhibition when used in full-dose long term. Assessing
infections signal after ticagrelor was tricky because of more infections, but over
three times, less SRD than after clopidogrel were reported in PLATO. In contrast to
the balanced and mildly concerned FDA report,[7] the secondary PLATO publications overoptimistically present the infections data
as somewhat a protective effect of ticagrelor.[8]
[9]
[10]
[14]
[15]
[16] Aside from reduction in ischemic cardiovascular events, the explanations for the
mortality benefits of ticagrelor by suggesting pleiotropic effects[17]
[18]
[19] cannot be sustained since PLATO deaths benefit has been never achieved in later
ticagrelor trials, making any extravagant explanation(s) meritless.
Long-term dual antiplatelet therapy may be associated with the unexpected but fatal
complications including bleeding, infections, and SRD. This is especially alarming
since modern antiplatelet strategies are often used off-label with regard to treatment
duration. Also, randomized evidence suggests that most vascular benefits emerge early
after coronary stenting but most complications including bleeding or/and infections
grow over time of exposure. Unfortunately, we will not be able to intelligently assess
the real rates of infections after dual antiplatelet therapy since the trials design
do not measure such adverse events. However, more recent trials suggested that shorter
antiplatelet strategies decrease bleeding risks without increased mortality.
The unremarkable and probably correct reporting of pneumonia deaths but possible increase
of clopidogrel SRD count in PLATO was no surprise to the Task Force since changes
of death dates, and especially their causes were already well-documented and previously
reported.[11] What is puzzling are the observation of three pairs of clopidogrel SRD in Brazil
and India justifying complete reassessment of PLATO deaths. Such misreporting of data
or error in late process of submission could not be detected by the independent researchers
or scientific executive committee. Furthermore, the FDA could pick-up such evidence
without an independent new monitoring of all deaths in PLATO. The observation that
such rare fatal outcomes as SRD are reported in pairs is highly questionable. Indeed,
SRD were reported as a primary cause of death in less than 3.2% PLATO fatalities making
these 3 pairs of clopidogrel deaths unusual and very unlikely. Such particular pattern
of death reporting is very similar to cancer misreporting in PLATO when clopidogrel
deaths were also entered in pairs.[12] There are few shortcomings of the present analyses limiting our abilities to draw
definite conclusions. In fact, within any large-scale world-wide clinical trial to
access the difference of 8 versus 10 fatal pneumonia events is challenging, and may
represent a play of chance. The numbers are simply way too small to make any qualifying
statements. The SRD misreporting will not necessarily change the direction of PLATO
trial results evaluation since numerous issues gave been already reported.[11]
[12]
[13] Together with the FDA, we are currently implementing the joint status report in
civil case number 21–572 based on the Freedom of Information Act in Washington, District
of Columbia, District Court focusing on PLATO late event adjudication and some submission
NDA 022433 evidence.
Conclusion
The pneumonia deaths were reported correctly, while many SRD were misreported in PLATO
favoring ticagrelor.
