Ranolazine, the first entrant
from the first genuinely new class of anti-anginal drugs to be introduced in 25
years, doesn't lead to arrythmias as many critics feared — but neither does
it help prevent major ischemic events. Those are the
main findings of the biggest study to date on the new angina treatment, which
is likely to become a major seller when it gains Canadian approval in the near
future. Ranolazine was approved as a second-line agent
for stable angina in the US early in 2006, but its approval is still on hold in
Canada and Europe. One reason for the delay was concern engendered by the drug's
tendency to prolong the QT interval in the heartbeat. Many experts worried that
this might lead to arrythmias — indeed one FDA scientist proposed a Black
Box warning to that effect. But the latest study, in
JAMA, appears to put those fears to bed. In fact, the authors, led by Dr
David Morrow of Brigham and Women's Hospital in Boston, even suggest the drug
might have a mild anti-arrythmic effect. Ranolazine is still not quite as well-tolerated
as standard anti-anginal drugs like beta-blockers, but its side effects appear
to pose more of a nuisance than a danger. ACS
NO-GO
The actual purpose of the MERLIN trial (Metabolic Efficiency With
Ranolazine for Less Ischemia in Non—ST-Elevation Acute Coronary Syndromes)
was not to prove safety but to look at the possible use of ranolazine in acute
coronary syndrome (ACS). It's believed that the drug's anti-anginal effect is
due to a reduction of ischemia in stable angina, so it seemed natural to ask if
it might prevent the more serious consequences of ischemia, such as death and
myocardial infarction. Since these endpoints are much
rarer than angina, this required a large study population (6,560 patients) and
a decent follow-up, about a year on average. The researchers realized that this
would roughly double the available safety data on the drug, so they tracked safety
carefully too. The shadow that hung over this drug —
QT prolongation — has now largely been removed. That will reassure the FDA,
who specified when they gave their approval that this question would need to be
revisited. It will probably also remove the remaining obstacle to ranolazine's
approval for angina here. MERLIN'S
MAGIC
The MERLIN trial began with an intense four-day program of intravenous
ranolazine or placebo, followed by a year or more of taking the drug orally. There
was almost no difference in the rate of arrythmias between the ranolazine and
placebo groups over the course of the whole study. "I
do find the results on arrythmia reassuring," says Dr John Cairns, a cardiologist
at Vancouver General and the former dean of UBC's school of medicine. "There's
been some concern on this front with ranolazine, and this study appears to lay
some of those fears to rest. There was, however, an unexplained association with
syncope that needs to be looked into further." The patients
in this study were not the healthiest, and even in the placebo group 2.3% had
an episode of unexplained fainting, but in the ranolazine group that figure was
3.3%, a statistically significant difference that suggests the drug is somehow
involved. What the mechanism might be, nobody knows or wants to speculate. Most
of the extra cases were diagnosed as vasovagal syncope. FIRST-LINE
POTENTIAL
The findings on the drug's efficacy in ACS are simpler to
relate — it didn't work, at least not to the point of statistical significance.
The primary end point (cardiovascular death, MI or recurrent ischemia) occurred
in 696 patients (21.8%) in the ranolazine group compared with 753 patients (23.5%)
in the placebo group. The study supports the FDA's
judgement in designating ranolazine as a second-line agent for stable angina,
says Dr Cairns. "If it had proved in the angina studies to be superior to existing
agents — atenolol, diltiazem, amlodipine — then it might make a new
first-line agent. But it hasn't shown that yet," he says. He
adds, "Of course, most of the patients in this study were also receiving other
anti-anginal drugs — 89% were taking beta-blockers — and it seems likely
that ranolazine will be used in combination as well as in substitution. That would
probably be typical in Canadian patients too, if it's approved here. In fact 310
of the patients in this study were Canadian. In cases where a patient fails to
respond to a beta-blocker, ranolazine might be added. Where a patient doesn't
tolerate the beta-blocker, it might be substituted."
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