Problems Found in PLATO Trial Results
Published: Aug 5, 2013 | Updated: Aug 6, 2013
By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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Action Points
A look at FDA documents revealed concerns about the reliability of the published results of the PLATO trial, which led to the approval of ticagrelor for patients with ACS.
Point out that among the concerning findings was an increased likelihood for events submitted for adjudication to be considered "no event" when tied to a patient taking ticagrelor versus clopidogrel, and a tendency for sites that were monitored by the drug manufacturer, instead of an independent clinical research organization, to report more beneficial results for ticagrelor.
A look at FDA documents revealed concerns about the reliability of the published results of the PLATO trial, which led to the approval of ticagrelor (Brilinta) for patients with acute coronary syndrome (ACS), two investigators said.
The main results of the PLATO trial -- presented at the European Society of Cardiology meeting and published in the New England Journal of Medicine in 2009 -- showed that among patients with ACS, ticagrelor plus aspirin versus clopidogrel plus aspirin significantly reduced the rate of a composite of death from vascular causes, myocardial infarction (MI), or stroke (9.8% versus 11.7%, HR 0.84, 95% CI 0.77-0.92).
Among the findings that caused concern was an increased likelihood that events submitted for adjudication be considered "no event" when tied to a patient taking ticagrelor versus clopidogrel, according to James DiNicolantonio, PharmD, of Ithaca, N.Y., and Ales Tomek, MD, of Charles University in Prague.
Also, there was a tendency for sites that were monitored by the drug maker -- AstraZeneca -- instead of an independent clinical research organization to report more beneficial results for ticagrelor, DiNicolantonio and Tomek reported online in the International Journal of Cardiology.
"The FDA report highlights what appear to be multiple serious deficiencies in the reporting of the PLATO results, which clinicians will not have gleaned from the primary publication alone," they wrote. "Individual clinicians may therefore wish to carefully reconsider their practice of ticagrelor prescription for this indication. Guideline bodies should also evaluate the information in its totality."
PLATO PI Responds
Several prominent cardiologists declined to comment publicly on DiNicolantonio and Tomek's paper, but one of the principal investigators of the PLATO trial, Lars Wallentin, MD, PhD, of Uppsala Clinical Research Center in Sweden, weighed in.
"Since the publication ... of the PLATO trial results in August 2009 and the presentation of the FDA documents in 2011, Mr. DiNicolantonio and/or his collaborators have produced 25 to 30 manuscripts for various journals, criticizing the PLATO trial, its investigators, sponsor, and the regulators from similar perspectives without providing any new valid data as support for their allegations," Wallentin wrote in an email to MedPage Today.
He said the lead PLATO investigators have responded formally in several manuscripts and pointed to a recent publication in Stroke: Journal of the American Heart Association to provide their viewpoint on the positions of DiNicolantonio and his colleagues.
In it, Wallentin and colleagues wrote, "We do not and cannot support bad science propagated for reasons unclear to us except perhaps to engender publicity and media attention. Any reader of scientific articles should be able to review the results critically, draw conclusions, and translate the results for clinical practice. In doing so, the reader should be confident that the reported data derived from meticulously performed clinical trials are correct and reported with minimal bias. Unfortunately, DiNicolantonio and [Victor Serebruany, MD, PhD, a co-author one of the papers] report selected data derived from various sources using improper statistics. The data provided in the commentary are a biased selection of an extensively peer-reviewed and published series of articles."
Wallentin added in his email that "neither the previous nor the new manuscript by Mr. DiNicolantonio will in any way influence our interpretation of the results of the PLATO trial nor the unanimous international guideline recommendation to use ticagrelor as a first-line treatment in patients with [ACS]."
Questioning PLATO's Generalizability
Following publication of the main results of the trial, approval of the drug appeared inevitable, although there were some lingering issues, including the lack of a significant benefit for the drug in the patients enrolled in the U.S.
An FDA advisory committee recommended approval of the drug in 2010, but after delaying its decision, the agency told AstraZeneca that it would not approve the drug before getting additional analyses. The FDA was apparently satisfied by the additional information, and it approved ticagrelor in July 2011.
DiNicolantonio and Tomek examined the FDA's Complete Response Review to assess the reliability of the published PLATO results, and uncovered several issues.
During the trial, there were 864 primary endpoint events in the ticagrelor arm and 1,014 in the clopidogrel arm, a difference of 150. Of the events favoring ticagrelor, 46% came from two countries -- Poland and Hungary -- even though only 21.1% of the enrolled patients came from those areas.
That finding "[questions] the generalizability of the results of the PLATO trial to other geographical regions," DiNicolantonio and Tomek wrote.
Some of trial sites were monitored by AstraZeneca and some were monitored by an independent clinical research organization, Worldwide Clinical Trials.
The FDA documents showed that there was a significant advantage for ticagrelor over clopidogrel for the primary endpoint at sites monitored by the drug maker (odds ratio 0.74, 95% CI 0.64-0.85), but not among the sites monitored by the independent organization (OR 1.21, 95% CI 0.91-1.59), which included the U.S., Russia, and Georgia.
Also, among patients taking ticagrelor, those treated at sites monitored by AstraZeneca were less likely to have a primary endpoint event than those treated at sites monitored by the independent organization (OR 0.67, 95% CI 0.54-0.83)
"Thus, the study sponsor may have affected the results of the PLATO trial in a way that we cannot yet understand," DiNicolantanio and Tomek wrote.
Unbiased Adjudication?
The researchers also examined downgraded adjudications, which were events submitted for adjudication that were determined to be "no event."
They found that among the countries with the largest enrollments -- and thus the most events -- those with results showing the greatest benefit from ticagrelor also had downgrade rates most beneficial to ticagrelor: Czech Republic (9.2% difference in rates favoring ticagrelor), Hungary (6.3% difference), and Poland (0.9% difference). All of those countries were monitored by AstraZeneca.
In the U.S., where the trial was monitored by the independent organization, the difference in downgrade rates favored clopidogrel (1.7% difference).
The FDA reviewer noted, however, that "it does not appear that downgrades of investigator-reported events during adjudication were done in a manner that biased the outcome of the trial."
Call for Internal FDA Investigation
Another issue raised by DiNicolantonio and Tomek was that cardiac events that resulted in hospitalization and a discharge diagnosis of MI were more likely to be classified as MI after adjudication when the patients were taking clopidogrel instead of ticagrelor (91% versus 84%, P=0.01).
Looking just at events reported by the sites, the rate of MI was not significantly reduced with ticagrelor versus clopidogrel (5.4% versus 5.9%, P=0.13).
Furthermore, DiNicolantonio and Tomek wrote, "an estimated 23 definite or possible cardiovascular events or deaths on ticagrelor were either not submitted for adjudication, inactivated, deleted, or were downgraded to 'softer' endpoints (this was not shown in the FDA review for clopidogrel)."
"Even if explanations [for these findings] are given by the study sponsor," they wrote, "it would seem logical that an internal FDA investigation is required to truly understand the PLATO trial design, conduct and submission problems, as well as verification of deaths from the PLATO trial."
They noted that four of the 10 FDA reviewers (two medical officers, a statistician, and the medical team leader who acted as the primary efficacy reviewer) recommended against approving ticagrelor.
The authors reported that they had no conflicts of interest.
Published: Aug 5, 2013 | Updated: Aug 6, 2013
By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
save|AA
Action Points
A look at FDA documents revealed concerns about the reliability of the published results of the PLATO trial, which led to the approval of ticagrelor for patients with ACS.
Point out that among the concerning findings was an increased likelihood for events submitted for adjudication to be considered "no event" when tied to a patient taking ticagrelor versus clopidogrel, and a tendency for sites that were monitored by the drug manufacturer, instead of an independent clinical research organization, to report more beneficial results for ticagrelor.
A look at FDA documents revealed concerns about the reliability of the published results of the PLATO trial, which led to the approval of ticagrelor (Brilinta) for patients with acute coronary syndrome (ACS), two investigators said.
The main results of the PLATO trial -- presented at the European Society of Cardiology meeting and published in the New England Journal of Medicine in 2009 -- showed that among patients with ACS, ticagrelor plus aspirin versus clopidogrel plus aspirin significantly reduced the rate of a composite of death from vascular causes, myocardial infarction (MI), or stroke (9.8% versus 11.7%, HR 0.84, 95% CI 0.77-0.92).
Among the findings that caused concern was an increased likelihood that events submitted for adjudication be considered "no event" when tied to a patient taking ticagrelor versus clopidogrel, according to James DiNicolantonio, PharmD, of Ithaca, N.Y., and Ales Tomek, MD, of Charles University in Prague.
Also, there was a tendency for sites that were monitored by the drug maker -- AstraZeneca -- instead of an independent clinical research organization to report more beneficial results for ticagrelor, DiNicolantonio and Tomek reported online in the International Journal of Cardiology.
"The FDA report highlights what appear to be multiple serious deficiencies in the reporting of the PLATO results, which clinicians will not have gleaned from the primary publication alone," they wrote. "Individual clinicians may therefore wish to carefully reconsider their practice of ticagrelor prescription for this indication. Guideline bodies should also evaluate the information in its totality."
PLATO PI Responds
Several prominent cardiologists declined to comment publicly on DiNicolantonio and Tomek's paper, but one of the principal investigators of the PLATO trial, Lars Wallentin, MD, PhD, of Uppsala Clinical Research Center in Sweden, weighed in.
"Since the publication ... of the PLATO trial results in August 2009 and the presentation of the FDA documents in 2011, Mr. DiNicolantonio and/or his collaborators have produced 25 to 30 manuscripts for various journals, criticizing the PLATO trial, its investigators, sponsor, and the regulators from similar perspectives without providing any new valid data as support for their allegations," Wallentin wrote in an email to MedPage Today.
He said the lead PLATO investigators have responded formally in several manuscripts and pointed to a recent publication in Stroke: Journal of the American Heart Association to provide their viewpoint on the positions of DiNicolantonio and his colleagues.
In it, Wallentin and colleagues wrote, "We do not and cannot support bad science propagated for reasons unclear to us except perhaps to engender publicity and media attention. Any reader of scientific articles should be able to review the results critically, draw conclusions, and translate the results for clinical practice. In doing so, the reader should be confident that the reported data derived from meticulously performed clinical trials are correct and reported with minimal bias. Unfortunately, DiNicolantonio and [Victor Serebruany, MD, PhD, a co-author one of the papers] report selected data derived from various sources using improper statistics. The data provided in the commentary are a biased selection of an extensively peer-reviewed and published series of articles."
Wallentin added in his email that "neither the previous nor the new manuscript by Mr. DiNicolantonio will in any way influence our interpretation of the results of the PLATO trial nor the unanimous international guideline recommendation to use ticagrelor as a first-line treatment in patients with [ACS]."
Questioning PLATO's Generalizability
Following publication of the main results of the trial, approval of the drug appeared inevitable, although there were some lingering issues, including the lack of a significant benefit for the drug in the patients enrolled in the U.S.
An FDA advisory committee recommended approval of the drug in 2010, but after delaying its decision, the agency told AstraZeneca that it would not approve the drug before getting additional analyses. The FDA was apparently satisfied by the additional information, and it approved ticagrelor in July 2011.
DiNicolantonio and Tomek examined the FDA's Complete Response Review to assess the reliability of the published PLATO results, and uncovered several issues.
During the trial, there were 864 primary endpoint events in the ticagrelor arm and 1,014 in the clopidogrel arm, a difference of 150. Of the events favoring ticagrelor, 46% came from two countries -- Poland and Hungary -- even though only 21.1% of the enrolled patients came from those areas.
That finding "[questions] the generalizability of the results of the PLATO trial to other geographical regions," DiNicolantonio and Tomek wrote.
Some of trial sites were monitored by AstraZeneca and some were monitored by an independent clinical research organization, Worldwide Clinical Trials.
The FDA documents showed that there was a significant advantage for ticagrelor over clopidogrel for the primary endpoint at sites monitored by the drug maker (odds ratio 0.74, 95% CI 0.64-0.85), but not among the sites monitored by the independent organization (OR 1.21, 95% CI 0.91-1.59), which included the U.S., Russia, and Georgia.
Also, among patients taking ticagrelor, those treated at sites monitored by AstraZeneca were less likely to have a primary endpoint event than those treated at sites monitored by the independent organization (OR 0.67, 95% CI 0.54-0.83)
"Thus, the study sponsor may have affected the results of the PLATO trial in a way that we cannot yet understand," DiNicolantanio and Tomek wrote.
Unbiased Adjudication?
The researchers also examined downgraded adjudications, which were events submitted for adjudication that were determined to be "no event."
They found that among the countries with the largest enrollments -- and thus the most events -- those with results showing the greatest benefit from ticagrelor also had downgrade rates most beneficial to ticagrelor: Czech Republic (9.2% difference in rates favoring ticagrelor), Hungary (6.3% difference), and Poland (0.9% difference). All of those countries were monitored by AstraZeneca.
In the U.S., where the trial was monitored by the independent organization, the difference in downgrade rates favored clopidogrel (1.7% difference).
The FDA reviewer noted, however, that "it does not appear that downgrades of investigator-reported events during adjudication were done in a manner that biased the outcome of the trial."
Call for Internal FDA Investigation
Another issue raised by DiNicolantonio and Tomek was that cardiac events that resulted in hospitalization and a discharge diagnosis of MI were more likely to be classified as MI after adjudication when the patients were taking clopidogrel instead of ticagrelor (91% versus 84%, P=0.01).
Looking just at events reported by the sites, the rate of MI was not significantly reduced with ticagrelor versus clopidogrel (5.4% versus 5.9%, P=0.13).
Furthermore, DiNicolantonio and Tomek wrote, "an estimated 23 definite or possible cardiovascular events or deaths on ticagrelor were either not submitted for adjudication, inactivated, deleted, or were downgraded to 'softer' endpoints (this was not shown in the FDA review for clopidogrel)."
"Even if explanations [for these findings] are given by the study sponsor," they wrote, "it would seem logical that an internal FDA investigation is required to truly understand the PLATO trial design, conduct and submission problems, as well as verification of deaths from the PLATO trial."
They noted that four of the 10 FDA reviewers (two medical officers, a statistician, and the medical team leader who acted as the primary efficacy reviewer) recommended against approving ticagrelor.
The authors reported that they had no conflicts of interest.
