Cox-2 vs traditional NSAIDs Cardio vascular risk

From ACR abstracts. Note this is an extremely large study nearly
35,000 people.

Purpose: COX-2 selective inhibitors (coxibs) increase the risk of
cardiovascular (CV) events vs. placebo, but a study designed with the
primary goal of assessing the relative CV risk of coxibs vs.
traditional NSAIDs has not been reported. The MEDAL Program was
designed to provide a precise estimate of the CV event rates of the
coxib etoricoxib and the traditional NSAID diclofenac.
Methods: The MEDAL Program (N=34,701) was comprised of 3 randomized,
double-blind trials (MEDAL study [N= 23,504], EDGE [N = 7,111], EDGE
II [N = 4,086]) comparing etoricoxib (60 or 90 mg daily) and
diclofenac (150 mg daily) in patients with OA (71.8%) or RA (28.2%).
The primary hypothesis was that the rate of thrombotic CV events
(confirmed by blinded adjudication) with etoricoxib was non-inferior
to the rate with diclofenac (non-inferiority defined as upper bound of
the 95% CI of the RR <1.30). As recommended for non-inferiority
comparisons, the primary analysis used the per protocol population
(from Day 1 to 14 days after discontinuation of study drug);
intent-to-treat (ITT) analyses were also done. Low-dose aspirin and
proton pump inhibitor use were actively encouraged in high CV or
gastrointestinal (GI) risk patients. Congestive heart failure and GI
clinical events were also adjudicated blindly.
Results: The mean duration of therapy was 18 months; 21,395 and 12,854
patients received ³12 and ³24 months of therapy. In the prespecified
primary analysis, the relative risk (RR) for thrombotic CV events with
etoricoxib vs. diclofenac was 0.95 (95% CI: 0.81, 1.11), meeting the
prespecified criterion of non-inferiority. An ITT analysis following
all patients through the end of each respective trial (including
events in patients who discontinued study drug early) yielded a RR of
1.05 (95% CI: 0.93, 1.19). Renovascular endpoints were also assessed
in the MEDAL study by dose and disease. The incidence of
discontinuations due to hypertension was significantly higher for
etoricoxib than diclofenac, and the incidence of discontinuations due
to edema was significantly higher for etoricoxib 90 mg but not 60 mg
compared to diclofenac. There was a non-significant trend toward a
higher incidence of congestive heart failure with etoricoxib 90 mg
compared to diclofenac.
Conclusion: This double-blind randomized trial of over 34,000 patients
with osteoarthritis or rheumatoid arthritis treated for up to 3.5
years shows that the CV risk was comparable with the coxib etoricoxib
and the traditional NSAID diclofenac. Data from MEDAL Program, the
largest randomized clinical trial ever conducted in arthritis
patients, should be useful to physicians in choosing the optimal
therapy for their patients with arthritis.



Author(s):

Loren Laine1, Sean P. Curtis2, Claire Bombardier3, Michael E.
Weinblatt4, Amarjot Kaur2, Christopher P. Cannon5. 1Univ Southern
California, Los Angeles, CA; 2Merck & Co., Rahway, NJ; 3Univ Toronto,
Toronto, ON, Canada; 4Brigham & Women's Hospital, Boston, MA; 5TIMI
Study Group, Boston, MA