Buflomedil to reduce clinical complications of peripheral artery disease? Maybe, maybe not

Shelley Wood

March 11, 2005

Orlando, FL - Investigators for the Limbs International Medical Buflomedil (LIMB) trial group believe they have the first proof that buflomedil (Fonzylane®, Cephalon), a vasoactive agent, can reduce clinically important complications of peripheral arterial occlusive disease (PAOD). Dr Alain Leizorovicz (University of Lyon, France) presented the results of the trial at the American College of Cardiology (ACC) 2005 Scientific Sessions and says they are the first to show that the drug, already used as a treatment for peripheral vascular disease in Europebut not available in the UScan also have an impact on morbidity and mortality.

Dr Jeffrey W Olin (Mount Sinai School of Medicine, New York, NY), however, who discussed the trial results following the late-breaking session, found "serious" flaws in the study design that, he says, make it impossible to put the trial findings in perspective.

"The results of this study mandate a confirmatory study with the methods clearly defined before we accept this agent as efficacious," he stated.

Buflomedil is an alpha-adrenoceptor inhibitor that likely works by a variety of mechanisms, improving microcirculation in impaired vascular beds, inhibiting platelet aggregation, improving red-cell deformability, and reducing whole-blood and plasma viscosity. It has been used for years in Europe as a treatment for claudication, despite what Olin referred to as "underwhelming" evidence supporting efficacy.

Buflomedil to reduce clinical complications?

The LIMB study enrolled patients over age 40 with documented PAOD and an ankle brachial index (ABI) between 0.80 and 0.30. Patients were randomized to one of two doses of buflomedil (300 mg bid or 150 mg bid, based on creatinine clearance) or placebo. Antithrombotic, statin, and antihypertensive drugs were encouraged, but other peripheral vasodilators were discontinued. In total, 2078 patients were enrolled in the trial and followed for a median of 2.75 years.

The main composite outcome of the trialdefined as clinical deterioration (surgery or angioplasty or IV treatment for intermittent claudication); and/or fatal and nonfatal cardiovascular complications; and/or amputationoccurred in 9.1% of buflomedil-treated patients, compared with 12.4% of placebo-treated patients, a 26% relative risk reduction (95% CI 0.57-0.95; adjusted log rank p=-0.019). There were no significant differences, however, in secondary clinical outcomes, mainly the independent components of the primary end point: amputation, MI, stroke, CV death, and all deaths, although the investigators saw a trend toward reduced symptomatic deterioration of PAOD (3.6% vs 5.2%; p=0.09).

Leizorovicz et al also reported a 49% improvement in median relative change in initial claudication distance from baseline in the buflomedil-treated patients, whereas they saw no change in the placebo-treated group. Median relative change in absolute claudication distance from baseline to last visit also improved in the treatment group, but not in the placebo controls. Likewise, median relative ABI improved in the buflomedil-treated patients by 9.2% but actually declined in the placebo group by 3.6%. No significant differences were seen in adverse events between the two groups.

"The vasoactive agent buflomedil, given long term to PAOD patients, not only provided a sustained improvement of claudication but also reduced by 26% clinically important complications," Leizorovicz said in his concluding remarks, noting that this is the first time a vasoactive agent has been shown to reduce clinically meaningful complications in PAOD patients with claudication. Should further studies confirm the LIMB study results, buflomedil could potentially be tested in atherosclerosis, he added.

Results questioned

Olin began his dissection of the LIMB study by saying, "I was excited to see such a positive clinical trial in patients with PAOD," particularly with such large numbers. Previous trials of the drug have rarely used meaningful end points or have shown mixed results supporting relief from claudication in PAOD patients. And while the published trials, in sum, would seem to support use of the drug for claudication, this may be due to publication bias, said Olin, since several known studies of buflomedil have never appeared in print.

One of Olin's concerns with the LIMB study is that roughly 62% of the trial participants were enrolled in Russia, with the rest distributed among the Czech Republic, France, and Hungary. It is not known whether the results would have been the same had the participants been more evenly distributed, he noted.

An even bigger issue, he pointed out, was that the results on relative change in initial claudication distance from baseline in LIMB were "concerning" and "difficult to assess," since only median values were presented.

Particularly "bothersome" was the fact that the placebo group showed no improvement in claudication distance whatsoever over the course of the trial. In an interview with heart wire , Olin explained: "There's never been a study on any medication for claudication that had a zero placebo effect. All of these studies have a significant placebo effect. So that makes me think that there were some problems with the way the treadmill was done. We just conducted a large-scale trial on a gene therapy for claudication, and we got a 30% placebo effect. In studies of cilostazol, for exampleand there have been six or eight of themevery one of them had a placebo effect. So the fact that there was zero placebo effect in this trial means there's something wrong."

Olin had similar concerns about how ABI was measured in the LIMB study, given that, here, too, the placebo-group data seemed atypical. "No other study that has looked at vasoactive agents has ever shown that the ABI goes down with placebo, nor have they usually shown an improvement with active therapy. So there are just too many inconsistencies in this trial with what has been reported in the past."

Since the initial claudication distance data, in particular, were so difficult to understand, and since symptomatic deterioration of PAOD appeared to drive the primary end point of the trial, the trial's conclusions are "hard to accept," Olin concluded.

Responding to some of the discussant's concerns in an email interview with heart wire , Leizorovicz provided mean data for the absolute claudication distance that echoed the median values he'd presented at the ACC meeting. He also stated that, in fact, treadmill tests were not used in the LIMB study, an assumption made by the discussant. In fact, he said, they were "clinically estimated," although a substudy performed using treadmill tests in 200 patients was performed at six months "and the results are confirmatory for initial claudication and absolute claudication distance."

Leizorovicz also defended the fact that there was no obvious placebo effect in the LIMB study by explaining that while the histograms showing changes in initial claudication distance and absolute claudication distance did demonstrate an early placebo effect, this had "disappeared at the end of the follow-up, probably because of the length of the study." As well, he said, "ABI is an indicator of the severity of the stenosis of the arteries. LIMB was a long-term study, and aggravation due to the progression of atherosclerosis is expected to be seen within this time frame," a factor that would explain the decreased ABI in placebo-treated patients by the study's conclusion.

Skepticism remains

To heart wire , Olin said he hopes that a clearer explanation of the study's methods will come out when the results are published. In the meantime, he says, he does not think the results are promising, nor does he think they'll attract too much attention from vascular specialists.

"I don't think this drug will make it in the US. It certainly won't make it based on this study, and the issue is, what made the company fund a study of this size, especially for peripheral vascular disease? When I was asked to discuss this paper, I was very excited to see such a large peripheral-vascular-disease study, but there is much more information that needs to provided. If the authors can clarify some of the outstanding questions, maybe the results could be more acceptable, but as they stand right now, I'm skeptical that this could be an effective therapy."

Cephalon, the maker of buflomedil, was the trial sponsor; it is marketed in Europe and Japan.


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