CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 5, September/October 2010
AFRICA
299
Anti-thrombotic trials in atrial fibrillation, the RELY study
Prof Michael Ezekowitz, Thomas Jefferson
Medical School, vice president of the
Lankenau Institute for Medical Research,
Pennsylvania
‘The strength of the RELY study of
dabigatran in stroke prevention resides
in two critical factors; (1) the scien-
tific integrity of the study despite being
unblinded to warfarin, and (2) the wide
range of patients at risk for stroke studied.’
This view was expressed by the
co-principal investigator of the study,
Prof Michael Ezekowitz in an interview
with the
Cardiovascular Journal of Africa
at the 2010 South African Heart Congress
in August at Sun City.
Dr Ezekowitz graduated from
the University of Cape Town Medical
School. After residency he proceeded
to London University (Imperial College)
on a British Council fellowship where
he was awarded a Doctor of Philosophy
degree. His fellowship in cardiology was
at Johns Hopkins Hospital. He has held
faculty appointments at the University of
Oklahoma and Yale University School of
Medicine.
In 2000 he moved to Philadelphia
as the June F Klinghoffer professor
and chairman of Medicine at Drexel
University School of Medicine. He is now
the vice president of Lankenau Institute
for Medical Research (LIMR) and vice
president of Clinical Research, Main
Line Hospitals, and professor at Jefferson
Medical College.
‘In retrospect, RELY was an amazing
study; we were surprised by the results,
on the upside!’ RELY was primarily
designed to determine the safety and effi-
cacy of dabigatran in patients with atrial
fibrillation at risk of stroke, compared to
the gold standard, warfarin. Warfarin had
already been shown to be superior to aspi-
rin and clopidogrel for stroke prevention
in the ACTIVE-W trial.
2
‘In RELY, the higher dose of dabigat-
ran, 150 mg bid, was shown to be signifi-
cantly and statistically superior to warfa-
rin with regard to its efficacy in stroke
prevention; while the lower dose (110
mg bid) equalled warfarin efficacy but
was significantly safer than warfarin’, Dr
Ezekowitz pointed out.
There was no price to pay with
regard to bleeding rates and surprisingly
there was between 60 and 70% reduc-
tion in intracranial haemorrhage in the
dabigatran-treated groups. A dose-related
response was seen in the two doses of
dabigatran used for efficacy and safety.
‘We had hoped to fast track the regis-
tration of this indication for dabigatran as
it has the potential to change clinical prac-
tice radically with regard to atrial fibrilla-
tion. However, the FDA, as it should, is
subjecting the data to rigorous evaluation.
I am personally confident that we will get
approval.’
Results of the RELY study were docu-
mented in a number of presentations at
the 2009 ESC congress in Barcelona to an
audience of 8 000 to 10 000 cardiologists
from around the world. Criticisms of the
study have been few, mainly directed at
the single-blinded warfarin arm and the
issue of differences in myocardial infarc-
tions, which were slightly higher in the
dabigatran group.
Dr Ezekowitz commented that the
design of the study was very carefully
considered, ‘The dabigatran dosage arms
were double blind, but the warfarin arm
was not. We made very important safe-
guards to maintain the scientific integ-
rity of the trial – all hospital admissions
were assessed blindly for both safety
and efficacy end-points. Questionnaires
were completed by every patient at every
visit to ensure that minor events and side-
effects were not missed.’
The increase in clinically manifested
myocardial infarctions (MI) of 0.2% per
year in the dabigatran arm compared to
the warfarin arm (with no difference in
fatal MI) was looked at more closely
after the announcement of the results.
‘Myocardial infarction rates were very
low throughout the study. When silent
ischaemia was included, there was no
statistical difference between the warfa-
rin and dabigatran-treated patients’, Dr
Ezekowitz noted.
Importantly, there was no evidence of
liver toxicity. This was one of the most
meticulously conducted aspects of the
RELY study, following the failure of an
earlier direct thrombin inhibitor, xymela-
gatran, as a result of liver toxicity. ‘I can
state unequivocally that this drug is not
toxic to the liver’, Dr Ezekowitz stressed.
Of importance is that patients at
lower risk of stroke, at a CHAD score
of 1, showed a striking benefit in stroke
reduction when treated with dabigatran
compared to warfarin. In patients (about
2 000) who underwent cardioversion,
overall complication rates were very low
and comparable to those on warfarin,
which should increase confidence in
using this effective strategy when patients
are on dabigatran.
There are limitations to the use of
dabigatran. It cannot be used at creati-
nine clearance levels
<
30 ml/min and
some patients are not able to tolerate the
dyspepsia. In the RELY study, 2.5% of
patients withdrew from the dabigatran
arm due to this side effect.
There are some drug interactions with
dabigatran, for example proton pump
inhibitors reduce absorption, but the only
drug truly contra-indicated for patients on
dabigatran is quinidine.
Dabigatran has shown that three out
of four potential strokes caused by atrial
fibrillation can be prevented. Atrial fibril-
lation patients eagerly await this drug.
J Aalbers, Special Assignments Editor
1. Drug Trends in Cardiology. Boehringer
launches first direct thrombin inhibitor:
dabigatran (Pradaxa
®
).
Cardiovasc J Afr
2010;
21
(3): 173–174.
2. Healey JS, Hart RG, Pogue J, Pfeffer
MA, Hohnloser SH, De Caterina R,
et al
.
Risks and benefits of oral anticoagulation
compared with clopidogrel plus aspirin in
patients with atrial fibrillation according to
stroke risk: the atrial fibrillation clopidogrel
trial with irbesartan for prevention of vascu-
lar events (ACTIVE-W).
Stroke
2008;
39
(5):
1482–1486. E-pub Mar 6 2008.
