Vienna, Austria - Adding abciximab (ReoPro, Lilly) to standard adjuvant double-antiplatelet therapy may help prevent reocclusion after interventional therapy of long, chronic total femoropopliteal occlusions, but it will also raise the bleeding risk without providing much clinical benefit, suggests a randomized study in patients with stable peripheral vascular disease [1].

Dr Iris Baumgartner

Recent trials support the use of abciximab with peripheral interventions in patients with acute or subacute limb ischemia, in whom the prospect of limb salvage or other clinical benefit justifies the increased risk of bleeding, Dr Iris Baumgartner (University Hospital, Berne, Switzerland) told heartwire. But the ReoPro and Peripheral Arterial Intervention to Improve Clinical Outcome in Patients with Peripheral Arterial Disease (RIO) trial, she said, shows that the glycoprotein IIb/IIIa inhibitor shouldn't be used on top of aspirin and clopidogrel in stable patients like those entered into the trial. Baumgartner presented the RIO results here today at the European Society of Cardiology Congress 2007.

As the assigned discussant for Baumgartner's presentation, Dr Horst Sievert (CardioVascular Center, Frankfurt, Germany) speculated that the RIO results may mean that the clinical risk from acute thrombosis isn't as great as that from thrombotic complications later on, minimizing any incremental benefit from an early abciximab infusion. They mean that abciximab shouldn't be used in cases like those in RIO, he said, pointing also to the fivefold increase in severe bleeding complications with triple antiplatelet therapy.

Dr Horst Sievert

The bleeding complications were primarily at the catheter access site, Sievert noted. Although such bleeding is often manageable, "we have to remember that bleeding complications, especially bleeding complications related to the access site, are the most important cause of mortality in peripheral interventions."

In RIO, as reported by Baumgartner, 423 patients undergoing angioplasty of the difficult femoropopliteal lesions, with or without stenting, were randomized to receive either abciximab or placebo on top of a standard antithrombotic regimen that included aspirin, clopidogrel, and heparin. Patients with acute or subacute limb ischemia were excluded.

The target lesions consisted of total occlusions at least 5 cm in length (mean 16 cm in the abciximab group, 18 cm among controls) and at least six weeks old. Abciximab was initiated after the guidewire's successful crossing of the lesion with a standard 0.25-mg/kg bolus plus maintenance at 0.125 µg/kg per minute for 12 hours. Aspirin was given at 100 mg/day; clopidogrel was initiated with a preprocedure 300-mg bolus and continued at 75 mg/day for 28 days.

The interventional procedure trended shorter in the abciximab group, in which it averaged 75 minutes, compared with 106 minutes in the control group (p<0.066); it was judged successful in 99% and 97% of cases, respectively.

There was no significant difference in the trial's 30-day primary end point, a composite of all-cause mortality, amputation, target-vessel reocclusion, and repeat target-vessel intervention. Meanwhile, the risk of bleeding went up sharply with triple antiplatelet therapy.

Outcomes in patients available for follow-up at 30 days and six months in the RIO trial

End point	Abciximab, n=197 (%)	Placebo, n=195 (%)	p
30 d
Primary clinical end pointa	5.1	5.6	NS
Intracranial hemorrhage	0	0	NS
Severe bleeding	5.1	1.0	0.020
Other bleedingb	8.1	1.5	0.004
6 mo
Target vessel reocclusion	22	39	<0.001
Restenosis (>50% lesions)	56	68	0.026

In addition, distal embolization as defined by angiography occurred in 6.1% of patients in the abciximab group and 12.3% of controls (p=0.02); that represented a 55% decrease in adjusted risk associated with triple antiplatelet therapy.

The six-month rates of reintervention and of amputation were statistically similar in the two groups; there was only one death, a patient in the placebo group.

Before RIO was designed about six years ago, Baumgartner said to heartwire, the idea of even double antiplatelet therapy at peripheral interventions was controversial—widely considered too aggressive. As the trial's protocol was coming together, she said, the Clopidogrel for Reduction of Events During Observation (CREDO) trial showed that adding the thienopyridine to aspirin was clinically beneficial in coronary interventions. Those findings gave the RIO researchers the confidence to use both drugs as the "standard" background therapy for the peripheral interventions.

But they underestimated how many patients they'd need to show a significant difference in the primary end point from adding abciximab, she said. With their background therapy ahead of its time, they expected far more end points and thought about 400 patients would be enough. Actually, according to Baumgartner, perhaps 10 to 20 times more patients would have been needed to show an incremental effect from abciximab.

The investigator-initiated RIO trial was supported by a research grant from Lilly; Baumgartner reports receiving consulting fees or honoraria from Bristol-Myers Squibb, Sanofi-Aventis, Abbott, and Roche and research grants from Roche, Abbott, Lilly, Cordis, and Medtronic.