INTERVENTIONAL/SURGERY

ATOLL seen as Supporting Enoxaparin Over Standard

Heparin in Primary PCI
AUGUST 30, 2010 | Steve Stiles

Stockholm, Sweden - More than two decades into the era of primary PCI, alternatives to
unfractionated heparin (UFH) as the procedure's antithrombin adjuvant have been explored far
less thoroughly than, say, what form of antiplatelet therapy might be best during the procedure.
Now a prospective, randomized trial appears to strengthen observational evidence that the low-
molecular-weight heparin (LMWH) enoxaparin (Lovenox, Sanofi-Aventis) may be superior to the
heparin "classic" in PCI for STEMI.

The STEMI Treated With Primary Angioplasty and Intravenous Lovenox or Unfractionated
Heparin (ATOLL) study, presented here today at the European Society of Cardiology 2010
Congress, randomized about 900 patients undergoing PCI for acute STEMI to receive either IV
enoxaparin or UFH with the procedure. The two groups' subsequent 30-day rates of a complex
composite primary end point that included death and major bleeding were not significantly different,
although the enoxaparin group showed a favorable trend. Also, the LMWH roundly outperformed
UFH for most of the trial's prospectively defined secondary end points, which generally were
composites of serious clinical events.

That was a big reason the trial's investigators as well experts who spoke with heartwire see
ATOLL as supporting IV enoxaparin over the traditional primary-PCI mainstay UFH, despite the
"missed" primary end point. But even if the drugs were equal clinically and in terms of safety,
inherent advantages of enoxaparin over UFH include bolus dosing and no need for measuring
coagulation times.

ATOLL was also a reliable test of enoxaparin because the trial entered an especially
high-risk primary PCI population, one that closely reflected the kind of patients treated in the "real
world," Dr Gilles Montalescot (Hpital Piti-Salptrire, Paris, France) told heartwire. "We
included patients in shock, in cardiac arrest. We had no age limit."

When formally presenting ATOLL at the meeting, Montalescot observed that PCI was performed
with radial-artery access in two-thirds of cases. Radial access, which has yet to catch on in the US
but is common in Europe, poses a much smaller risk of access-site bleeding compared with
femoral-artery access. "That's probably why the [difference in the] primary end point wasn't
significant," he said.

As the featured discussant following the ATOLL presentation, Dr Harvey White (Green
Lane Hospital, Auckland, New Zealand) lauded ATOLL as "a contemporary trialin fact, a
supercontemporary trialin terms of the use of radial access and the high rate of use of evidence-
based therapies. They've shown that enoxaparin is safe and may have an important clinically
relevant effect on ischemic end points in patients undergoing primary PCI." Still, he cautioned, "it
missed its primary end point."

The trial randomized 910 patients undergoing PCI for STEMI at 43 centers in Austria, France,
Germany, and the US, who did not receive any previous anticoagulation, to also receive either:

IV enoxaparin at 0.5 mg/kg, whether or not GP IIb/IIIa inhibitors are used (at physicians'
discretion) without coagulation monitoring.
UFH at 50 to 70 IU/kg with or 70 to 100 IU without GP IIb/IIIa inhibitors, with dosage titrated
to coagulation monitoring.

ATOLL: 30-day outcomes, IV enoxaparin vs unfractionated heparin in primary PCI

End point UFH Enoxaparin RR p

(n=460), % (n=450), % reduction, %

Death/MI complications*/procedural failure/major 33.7 28.0 17 0.07

bleeding (primary clinical end point)

Death/recurrent MI or ACS/urgent revascularization 11.3 6.7 41 0.01

Death/MI complications* 12.4 7.8 37 0.02

Death/recurrent MI/urgent revascularization 8.5 5.1 40 0.04

Non-CABG major bleeding (primary safety end point) 4.9 4.5 NS

Death/MI complications*/major bleeding (net clinical 15 10.2 32 0.03

benefit)

*MI complications=Death, resuscitated cardiac arrest, recurrent MI or ACS, urgent revascularization, stroke,
peripheral/pulmonary embolism.

The relative risk of death from any cause was 40% lower (p=0.08) and the composite rate of death
or resuscitated cardiac arrest fell 42% (p<0.05) in the enoxaparin group compared with those who
received UFH.
 Dr Clyde Yancy (Baylor University Medical Center, Dallas, TX), who wasn't connected
with ATOLL, commented for heartwire on why he sees the trial as supporting the use of
enoxaparin in primary PCI, even though the primary-end-point difference wasn't significant. One of
the quirks of combining multiple end points into one composite end point, he said, is that they can
be hard to interpret if they change in different directions. "If you have one or two that don't move,
you can lose a signal that might be important."

That didn't happen here. "In the current trial, the secondary end points were clinically relevant, and
I believe that gives us sufficient rationale to say it's persuasive. And, it's in the context of everything
else we know," Yancy said.

Indeed, ATOLL isn't an island, in spite of its name. Its primary-end-point results that fell
short of significance must be considered along with earlier trials and observational evidence
pointing to enoxaparin advantages over UFH in primary PCI, agreed Dr Robert Harrington (Duke
Clinical Research Institute, Durham, NC), who wasn't connected to the trial.

"Sometimes we get stuck in the evidence trap that every trial must stand on its own to tell us what
we know about that drug. That's sillywe need to put it into context with everything we already
know," he told heartwire.

Enoxaparin, he observed, is almost never used instead of UFH in primary PCI in the US, where
changes in practice can be slow. "It's hard to get American doctors out of standard operating
procedure." In fact, he added, ATOLL will probably speak loudest to clinicians who have already
accepted switching from UFH to enoxaparin. "There is there is a hurdle of comfort that has to be
overcome."

Montalescot reports receiving research grants from Abbott Vascular, Bristol-Myers Squibb, Cordis, Eli Lilly,
Pfizer, and Sanofi-Aventis and consulting for AstraZeneca, Bayer, Biotronik, Boehringer-Ingelheim, Bristol-
Myers Squibb, Merck, Novartis, Pfizer, Portola, Sanofi-Aventis, and Schering Plough. White reports receiving
research grants from Sanofi-Aventis, Eli Lilly, the Medicines Company, Pfizer, Roche, Johnson & Johnson,
Schering Plough, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, and Bristol-
Myers Squibb and consulting for Regado Biosciences.