Therapy Directed Against Platelets Does Not Significantly Reduce Painful Crises in Sickle Cell Disease
December 08, 2015
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are among the outlets that covered this study.
study in 13 developed and developing nations is one of the largest and
geographically broadest trials
BOSTON, MA, and
OAKLAND, CA – Treatment with the antiplatelet agent prasugrel does not significantly reduce
the rate of pain crises or severe lung complications in children with sickle
cell disease, according to a report published in the New England Journal of Medicine describing
one of the largest and most geographically diverse international clinical
trials on sickle cell disease to date.
Effects of Platelet Inhibition of Vaso-Occlusive Events
(DOVE) trial (ClinicalTrials.gov NCT01794000) was a
double blind, randomized, placebo-controlled phase 3 clinical trial held at 51
sites across 13 nations in the Americas, Europe, the Middle East, Asia and
Africa. Led by researchers at Dana-Farber/Boston Children's
Cancer and Blood Disorders Center and UCSF Benioff
Children's Hospital Oakland, the goal of the trial was to determine whether
prasugrel, a medication used in adult patients to reduce thrombotic
cardiovascular events, could also significantly reduce the rate of rate of
vaso-occlusive crises (VOCs) -- defined as pain crises or acute chest syndrome
-- in children with sickle cell disease.
Sickle cell disease affects
approximately 100 million children and adults globally, largely in sub-Saharan
Africa, the Middle East and India. In the United States, where it affects only
about 100,000 children and adults, primarily of African-American descent, it is
classified as an orphan disease. Patients with this inherited blood disorder
often experience repeated pain crises related to interrupted blood flow in
small vessels triggered by the complicated interactions among stiff, sticky,
sickle-shaped red blood cells; infection-fighting white blood cells;
clot-producing platelets; and the endothelial cells lining blood vessel walls.
These crises starve downstream tissues of oxygen and trigger pain and
inflammation. Over time, recurrent crises lead to tissue damage and chronic inflammation.
To date, the Food and Drug
Administration has only approved a single drug, hydroxyurea, for the treatment
of and reduction of crisis risk due to sickle cell disease. However,
hydroxyurea does not work for all patients, and, although it is often
prescribed for children, it is only approved for use in adult patients.
"Sickle cell disease has
a very complex, multisystem pathophysiology," said Matthew
M. Heeney, MD, clinical director of the Blood Disorders Center at
Dana-Farber/Boston Children's and co-lead investigator of the DOVE trial.
"As we learn more about this disease, we are finding that other blood
cells beyond red blood cells, including platelets, have significant parts to
play in the development of VOCs. There likely are additional routes by which we
“Although we were
disappointed that prasugrel does not appear to ease the suffering of children
with sickle cell disease, the fact that this study incorporated patients in the
wide range of countries where the disease occurs is hugely significant,” added Carolyn
Hoppe, MD, a pediatric hematologist/oncologist at UCSF Benioff Children's
Hospital Oakland and DOVE co-lead investigator. “The logistical challenges that
we addressed in designing and implementing the study can serve as a model for
— developed and marketed by Daiichi Sankyo Company, Ltd., and Eli Lilly and
Company under the brand name Effient® — prevents platelets from aggregating by
blocking an enzyme called P2Y12. This oral drug is approved for use in adult
cardiac patients in the U.S. to reduce the risk of clots following angioplasty
or insertion of an arterial stent.
DOVE trial enrolled 341 children with sickle cell disease, 170 of whom received
daily oral prasugrel for between nine and 24 months at individualized, blinded
doses intended to maintain a selected target range of platelet activity. The
remaining patients received a placebo. All patients were monitored for VOCs
prompting medical visits and for any increased risk of bleeding due to reduced
platelet activity. In addition, patients 4 years old and older kept a daily
electronic pain diary to aid in the reporting of painful events between visits.
To conduct the study
successfully on such a broad geographical scale, the study team had to address
several obstacles, such as varying standards of care, local technological
resources and infrastructure challenges, such as a lack of reliable electrical
At the end of the study
period, the overall rate of VOCs among patients in the trial's prasugrel arm
was 2.3 episodes per person year. This rate did not differ significantly from
that among placebo-treated patients (2.8 per person-year; p = 0.12). In
addition, treatment with prasugrel did not have any significant effects on the
trial's secondary outcome measures (i.e., VOC-related hospitalization rate,
duration of hospitalization, time between VOCs, incidence of ischemic attack or
ischemic stroke, transfusion rate, rate of pain, intensity of pain, use of
analgesics or missed school due to sickle cell disease-related pain). The study
investigators noted no adverse safety events related to prasugrel.
The data did reveal a trend
toward reduced VOC rates among patients aged 12-18 years (p = 0.06) and among
patients who were not taking hydroxyurea (p = 0.06). However, these trends also
were not statistically significant and require further research to determine
"Even though prasugrel
did not achieve significant results, the findings should not detract from the
fact that this team successfully completed a rigorous, sophisticated trial in a
disease where the barriers to conducting large-scale international,
patient-focused research are quite high," said Heeney. "While we
designed the study to measure the overall effect of prasugrel alone on VOCs, it
may be that a different approach that incorporates anti-platelet treatment as a
component could potentially have an impact."
This study was supported by
Daiichi Sankyo Company, Ltd. and Eli Lilly and Company.