Almost 16 months after an FDA hearing into drug-eluting stent (DES)
safety emphasized the need for a randomized clinical trial to
determine, once and for all, the optimal duration of clopidogrel
(Plavix, Sanofi-Aventis) plus aspirin after DES implantation,
researchers, government agencies, and industry sponsors cannot agree
on how it should move ahead.

The clinical trial proposed by Dr Mitchell Krucoff and colleagues at
the Duke Clinical Research Institute and dubbed Clopidogrel: Optimal
Duration of Antiplatelet Therapy (CODA) is currently in limbo while
the various parties try to agree on key aspects of trial design,
duration, and who should head up the study.

In an interview with heartwire, Krucoff explained that the CODA
trial, designed with a patient-oriented end point of death, MI, and
stroke vs bleeding, was developed within the larger private-public
partnership between the FDA and Duke University, dating back to a
2006 'memorandum of understanding' that created a collaborative
Cardiovascular Safety and Research Consortium, originally to
evaluate drug effects on cardiac repolarization. According to
Krucoff, apart from answering the public-health question of optimal
duration of clopidogrel therapy post-DES, CODA, as designed, will
also help fill a key gap in the "regulatory landscape": namely, how
to test drugs necessary for the safe use of drug-device combinations.

Companies not convinced by CODA

Despite the urgent nature of the question--with roughly 10 million
DES-treated patients worldwide and no clear answers as to how long
they should take clopidogrel and aspirin--CODA has stalled. Krucoff
and colleagues, on the FDA's advice, have filed an investigational
device exemption (IDE) for the trial, and they've held "think-tank
meetings" with the four major DES manufacturers as well as smaller
DES companies; thienopyridine developers Sanofi-Aventis/Bristol-
Myers Squibb and Eli Lilly (responsible for clopidogrel and the next-
generation thienopyridine, prasugrel, respectively); the National
Institutes of Health, and the FDA. Ideally, all of these parties
would be funding the CODA trial.

But the device companies have balked at the notion of coughing up
support for a trial with a patient-oriented end point that won't
specifically establish the safety of a DES or determine the ability
of dual antiplatelet therapy to reduce the risk of late stent
thrombosis and how long such therapy is warranted to mitigate this
risk. The CHARISMA study, for example, suggested that long-term dual
antiplatelet therapy in patients with vascular disease reduces
death, MI, and stroke, but that benefit may not be specific to DES.
Acting via their umbrella trade organization, Advamed, the companies
have met with the FDA to propose changes to the CODA trial design.

"We have not yet seen the Advamed proposal," Krucoff told
heartwire. "My understanding is that the Advamed proposal [seeks to]
change the primary end point from what the current CODA IDE
submission proposes. We tried to make CODA a big, simple, clinical
trial because there is nobody tumbling head over heels to fund this.
Our goal was to make this as logistically feasible and inexpensive
as possible and have it still provide some prospective insights, on
an expedited basis, as to what we should be doing with the 10
million people with DES in their hearts. Our understanding is that
the Advamed proposed trial would be a more complex, slightly larger
trial, with a more device-specific rather than patient-oriented end
point."

Advamed and its member companies are pushing for a primary end point
of late stent thrombosis, as defined by the Academic Research
Consortium, which would require a larger trial and more funding.
Given the uncertainty over just how long the stent-thrombosis risk
endures, trial follow-up would likely also need to be extended.
Sources also tell heartwire that the DES manufacturers are also
calling for a bare-metal-stent arm, since the risk of late stent
thrombosis following bare-metal-stent implantation is also unknown.

"Such a trial would, indeed, be feasible if the device industry is
willing to put up additional funds," Krucoff said. "Our hope is that
these will not go forward as separate efforts but as a collaborative
effort with both the short-term issue of what to do with the
millions of patients with DES and also the longer-term issue of
helping us try to rearrange the regulatory landscape so that it is
more accommodating and defined for this drug-device interaction."

Heading up the trial

A separate issue is whether Duke would still head up the trial if
the CODA trial design is rejiggered. Krucoff believes that, given
the FDA-Duke collaboration already in place, Duke should have a key
role to play. Others have told heartwire that the sponsors are
asking the FDA to reopen the decision as to which research group
would lead the trial and permit other academic research centers to
bid.

"There's all kinds of levels of politics here, everything from ego,
to money, to whatever," Krucoff admitted. "As in any hot-topic area,
there may be some competition as to who runs the trial. That for me,
frankly, is a secondary issue. The important thing is for us to get
as immediate an answer as possible for patients and also help evolve
the landscape for evaluating these issues long term."

Asked if the CODA trial would still go ahead if the FDA agrees to a
new, Advamed-supported trial, headed by a different group, Krucoff
hedged.

"There are a lot of hypotheticals," he said. "If our trial were
totally redundant, and they had all the money and we had none, would
we go ahead? No. But what we're most enthusiastic about right now is
that these efforts are progressing. They are trying to achieve the
same definition and information, and our hope is that this will come
forward as a single, collaborative effort. . . . The details,
frankly, of who does what with regard to the trial itself I'm sure
are going to be subject to all of the usual issues that make people
decide to do a trial at this center or that center, or with this PI
or that PI, with this research organization or that research
organization. So nothing is written in stone."

MATRIX registry results

Results from the MATRIX registry study, presented at last week's
American College of Cardiology 57th Annual Scientific Session/i2
Summit-SCAI Annual Meeting, reinforced the need for a randomized
controlled trial to settle the DES-safety/clopidogrel-duration
issue. According to Dr George Dangas (Columbia University, New York,
NY), who presented the landmark analysis, patients treated with drug-
eluting stents who are no longer on clopidogrel after one year are
more likely to die than patients still taking the drug. But that
signal of increased risk is muddied somewhat by a lack of
information on patients who stopped and restarted the drug over the
study period, investigators for the study noted.

Among the 1510 patients treated with a sirolimus-eluting stent in
MATRIX, a low but measurable rate of clopidogrel discontinuation
over time was associated with higher all-cause mortality. At two
years, patients off clopidogrel had a statistically significant,
threefold higher increase in all-cause mortality and a twofold,
statistically significant increase in death/MI.

But the devil is in the details: patients still on clopidogrel at
one year were also more likely to have a target lesion
revascularization or target vessel revascularization--a chicken-and-
egg scenario that suggests some patients were taking clopidogrel at
one year or beyond because they had undergone repeat procedures.
Indeed, more than one-third of patients who were off clopidogrel at
30 days were back on it at six months and at one year; almost half
of the patients who were off clopidogrel at six months were back on
it at one year; while 44% of patients who were off at six months
were back on it at two years. Even more striking, one out of 10
patients who were off clopidogrel at one year were back on it at two
years. The numbers likely speak to patient-level finances, disease
progression, and comorbidities, as well as uncertainty among
physicians as to whether one year of dual antiplatelet therapy is
sufficient or whether a lifetime on both aspirin and a
thienopyridine may be the safest bet for avoiding stent thrombosis
post-DES. To confuse matters further, stent thrombosis after one
year occurred in 0.3% of patients still taking clopidogrel at 12
months, but in no patients not taking it at this cutoff.

Discussing the results after Dangas's presentation, Dr Bill Knopf
(Piedmont Hospital, Atlanta, GA) urged the audience to take the
findings with a grain of salt, since follow-up to date on the 1510
patients is incomplete: just 88% at one year and 70% at two years.
He called the lack of difference in late subacute stent-thrombosis
rates based on 12-month clopidogrel coupled with the higher rate of
death and MI "a bit of a disconnect" and said that the zigzagging of
patients on and off clopidogrel and the effect of this
pattern "needs to be sorted out."

"There is a higher death/MI rate with discontinuation of Plavix at
one year, leaving open the question of what is the optimal dosing of
Plavix and what is the mechanism for this death/MI-rate increase."
Knopf concluded. "At the end of the day, with a registry study, it
opens a lot of questions that don't all get answered, and that leads
us to larger randomized trials to determine what might be the
optimal strategy."

Also commenting on the MATRIX results, Dr Gregg Stone (Columbia
University), a coinvestigator for the MATRIX registry, emphasized
the difficulties of using a landmark analysis to address whether the
benefits of long-term clopidogrel outweigh bleeding risks in a group
of patients who go on and off the drug. In MATRIX, for example,
there was a trend toward being off clopidogrel being associated with
both cardiac and noncardiac deaths, suggesting that those patients
may just be sicker, Stone noted.

"Registries such as this, like the Duke/Eisenstein registry, suggest
that long-term Plavix may be beneficial and may be associated with
reduced mortality; however, given the potential for unmeasured
confounders to cloud the result, a large-scale randomized clinical
trial is clearly warranted if we're going to know the answer to this
very important question."