"I know I've made life more difficult
for many of you in the last few months," Dr Steven Nissen
of the Cleveland Clinic told a meeting of the American
Diabetes Association four weeks ago. Few in the room
disagreed with his assessment.
Dr Nissen well and truly put the
cat among the pigeons with his meta-analysis of cardiovascular
safety of diabetes blockbuster rosiglitazone in the
New England Journal of Medicine in May. His review
of 42 published trials involving over 27,000 patients
found a 43% increased risk of heart attack in patients
taking the drug.
On July 5 in the NEJM, interim
results from RECORD, the manufacturer GSK's own post-marketing
study of rosiglitazone's heart risks, were rushed to
print. The results — largely inconclusive —
do little to soften the blow dealt by the earlier meta-analysis.
STUDY
SHOCKWAVES
Primed by the flap over rofecoxib — whose cardiovascular
risks were also highlighted by Dr Nissen — the
media pounced on the Cleveland cardiologist's findings.
So did Congress, whose most famous terrier of accountability,
Rep Henry Waxman, held hearings that drew out a twisted
tale of warnings dating back to 1999 that were suppressed
or ignored. Diabetes specialists were besieged by worried
patients, and prescriptions of the drug, still climbing
up to that point, began to plummet. They have fallen
by 20% since Dr Nissen's paper came out.
Dr Nissen is a former president
of the American College of Cardiology, and when he warns
of heart risk, people listen. But he is not exactly
being feted as a hero in endocrine circles. Many of
those at the ADA meeting voiced fears that patients
would stop taking their diabetes medicine on their own
— a recipe for disaster. Dr Nissen countered, accurately
enough, that he had specifically warned against that,
instead counselling patients to consult their doctor.
But other voices have also accused
him of alarmism, including the editors of The Lancet.
"To avoid unnecessary panic among patients, a calmer
and more considered approach to the safety of [rosiglitazone]
is needed. Alarmist headlines and confident declarations
help nobody," they pronounced in an editorial.
WHOSE
RESPONSIBILITY?
Dr Nissen argues that the US's official drug regulator
left him no choice when it failed to do its job. "There
were alternate routes for this information to come before
the medical community, and all those routes failed,"
he said. He accused the FDA of rushing the drug's approval,
noting that early trial data from the drug's manufacturer
carried "a strong signal of excess myocardial infarction"
that regulators ignored.
It's certainly a sign of the times
that the dispute has become a question of partisan politics
in a bitterly divided Washington. The President of the
Center for Medicine in the Public Interest accused Dr
Nissen of co-ordinating an attack on the FDA with Democratic
Congressman Waxman, who is accused by Republicans of
using the episode as a stick to beat the Bush administration.
BROKEN
RECORD
So much for the politics. But where does this leave
Canadian doctors and patients who worry about rosiglitazone?
It doesn't look as if the dark
clouds gathering over rosiglitazone are going to dissipate
anytime soon. GSK was running a large open-label, randomized,
controlled, non-inferiority trial of the drug in Europe,
called RECORD, one of whose goals was to examine cardiovascular
risk. In response to Dr Nissen's meta-analysis, the
RECORD investigators decided to publish interim results
from RECORD, with an average follow-up of 3.75 years,
rather than the six years planned for the complete trial.
The results have done nothing to
alleviate concerns about cardiovascular risk. Three
accompanying editorials — one co-authored by NEJM
editor Jeffrey Drazen — essentially conclude that
not only do RECORD's interim results fail to reassure,
they actually point to a flawed study that is never
going to resolve this question even when completed.
Basically, RECORD is statistically
underpowered, and hugely so. The expected cardiovascular
event rate in both arms, 11%, never materialized. In
fact the event rate was just 2.5%. This was coupled
with a rapid loss of patients to follow-up that leaves
the researchers with nowhere near enough events to draw
robust conclusions.
Moreover, the data, as Dr Drazen
notes, "are consistent with as much as a 7% decrease
in cardiovascular risk and as much as a 32% increase
in risk." This means that RECORD's 95% confidence intervals
for cardiovascular risk actually overlap those of the
Dr Nissen meta-analysis, and do so in the area of increased
risk.
It's always been known and acknowledged
that rosiglitazone and the whole class of thiazolidinediones
increase the risk of heart failure. The new worries
centre on the risk of heart attack. Yet RECORD only
looked at a primary endpoint of "death or hospitalization
from cardiovascular causes."
WARNING
SIGNS
Dr Drazen notes that Dr Nissen's findings do not actually
stand alone. A patient-level analysis performed by GSK
themselves, and submitted to the FDA and European Medicines
Agency in August 2006, found a 31% increase in myocardial
ischemic events. The EMA responded by giving the drug
a black box warning. The FDA did not.
In fact, the FDA is about to give
rosiglitazone a black box warning, and will do the same
to its chemical cousin pioglitazone. But bizarrely,
the only cardiovascular risk that the warnings will
mention will be the heart failure risk that the FDA
already knew about in 1999.
The situation may yet change, as
the FDA has an advisory committee studying further label
changes this summer.
THE
WAITING GAME
A further meta-analysis, this one by the Cochrane Collaboration,
appears set to put another nail in the coffin of the
drug's cardiovascular safety profile.
Pooled data from 18 randomized
controlled trials including more than 8,000 participants
will not only corroborate Dr Nissen's findings of cardiovascular
risk, they will also report increased risk of weight
gain (a known problem), edema and fractures. Alarmingly,
lead author Bernd Richter, of Heinrich-Heine University
in Germany, counsels finding another diabetic medication
if possible, not only because of heart risk, but also
because of bone risk in women.
Worse still, they question the
drug's benefits, pointing out that it was approved on
the basis of its undeniably good glycemic control, rather
than on clinical endpoints of actual patient health.
GSK has correctly noted that waiting for such data in
diabetic patients would take about ten years. They add
that the previous generation of anti-diabetic medicines
were also approved on the basis of glycemic control,
with the actual clinical benefits becoming apparent
a decade later.
And this is the quandary that lies
at the root of the controversies that have overtaken
rosiglitazone, and rofecoxib before it. As an NEJM
editorial notes, "rosiglitazone represents a major failure
of the drug-use and drug-approval processes in the United
States."
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