A possible association between the use of prasugrel, an ADP P2Y12
antagonist, and increased risk for cancer is cause for concern among the health
care community, according to a recent opinion published in the Archives
of Internal Medicine.
Prasugrel, which was
approved in July 2009 for patients with acute coronary
syndrome undergoing percutaneous coronary intervention, was approved based on
the results of the TRITON-TIMI 38 trial. However, trial results also indicated
an increase in solid tumors in patients assigned the drug.
“TRITON-TIMI 38 briefly mentioned a statistically significant
increase in colonic neoplasms with prasugrel use compared with clopidogrel (13
vs. 4 patients; P=.03),” wrote James S. Floyd, MD, and
Victor L. Serebruany, MD, PhD, in the opinion.
“However, a detailed analysis of cancer events performed by the FDA
and released for a Feb. 3, 2009, meeting of the Cardiovascular and Renal Drugs
Advisory Committee revealed an increase in multiple types of solid tumors with
prasugrel use.”
Floyd is from the Cardiovascular Health Research Unit, department of
medicine, University of Washington, Seattle. Serebruany is from HeartDrug
Research Laboratories, Towson, Md.
In their opinion, Floyd and Serebruany review the unpublished data
examining the link between prasugrel and cancer risk that was included in the
analysis conducted by FDA medical team leader Thomas A. Marciniak, MD.
Associated risk
Data from this analysis showed that although baseline malignant cancers
were balanced between the study arms, after excluding nonmelanoma skin cancers
and brain tumors, patients assigned prasugrel had 92 new solid tumors diagnosed
(1.4%) compared with 64 (0.9%) in the clopidogrel group (RR=1.44;
P=.02). The prasugrel group also had a higher rate of death in patients
with new cancers.
In response to the increased risk, it was posited that the increased
bleeding risk associated with prasugrel explained the difference in cancer
rates in patients assigned the drug, since “one might expect more occult
solid cancers to be detected through a bleeding event with prasugrel use than
with clopidogrel.”
However, even once data from cancers diagnosed by bleeding events were
excluded, the association persisted.
In an editorial that accompanied this opinion, Sanjay Kaul, MD,
of Cedars Sinai Medical Center and George A. Diamond, MD, of the David
Geffen School of Medicine, University of California, Los Angeles, wrote that
although definitive conclusions cannot be drawn from this data, the
“credible safety concern clearly merits careful scrutiny.”
When physicians currently consider the benefit-risk balance of
prescribing patients prasugrel the excess bleeding risk associated with the
drug is high on the assessment; however, if an increased risk for cancer exists
this would greatly alter the benefit-risk profile of prasugrel, according to
Kaul and Diamond.
“The benefit-risk balance of prasugrel with regard to ischemic
cardiovascular events and bleeding events shows that for every 1,000 patients
treated with prasugrel instead of clopidogrel, prasugrel is associated with 24
fewer ischemic events at the cost of 30 more bleeding events,” they wrote.
“Although an association between prasugrel and cancer has not been
firmly established, sufficient credible evidence has emerged to raise concerns
about a potential risk that arguably adversely alters the benefit-risk profile
of its long-term use.”
In the meantime
Because definitive conclusions cannot be drawn from the
TRITON-TIMI 38 trial, the FDA mandated that baseline cancer
history and cancer event data be collected as part of the Targeted Platelet
Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary
Syndromes trial (TRILOGY-ACS).
“To exclude a 50% increase in new cancers due to prasugrel use with
90% power, 256 new cancers will need to be observed. Assuming a 1% annual
incidence of new cancers in the clopidogrel group, this will require roughly an
average of 1 year of follow-up. Even longer follow-up will be required to
exclude a comparable increase in cancer mortality,” Floyd and Serebruany
wrote.
In addition, Floyd and Serebruany call on the FDA to require “as a
postmarketing requirement that TRILOGY-ACS be adequately powered to exclude a
clinically meaningful increase in new cancers, that outcomes be ascertained
rigorously, and that results be disclosed promptly.”
Until that time, given that the majority of prasugrel’s benefit on
ischemic cardiovascular events occurred within the first 30 days of follow-up
of TRITON-TIMI 38, Kaul and Diamond recommend limiting the use of prasugrel to
a few weeks rather than months in order to optimize the benefit-risk ratio.
Floyd JS. Arch Intern Med. 2010;170:1078-1080.
Kaul S. Arch Intern Med. 2010;170:1010-1012.
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