Clinical Role of Drug-Coated Peripheral-Artery Balloon Still Uncertain After LEVANT-2 Primary Publication

June 25, 2015

BOSTON, MA — One year after femoropopliteal-artery angioplasty for symptomatic disease, patients treated with a paclitaxel-coated balloon (Lutonix 035, Lutonix-Bard) as compared with a standard balloon showed superior target-vessel patency, and their results were "noninferior" for a composite safety end point that included amputation and limb-related death, in a single-blind randomized multicenter trial[1].

However, "we did not find a significant difference between the two trial groups in the clinically important end point of target-lesion revascularization [TLR] at 12 months," notes the primary report from the second Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis trial (LEVANT 2), published online June 24, 2015 in the New England Journal of Medicine. On the other hand, according to the authors, led by Dr Kenneth Rosenfield (Massachusetts General Hospital, Boston), the 476-patient trial wasn't sufficiently powered for TLR.

The 12-month primary patency rate was 65.2% for the Lutonix and 52.6% for a standard percutaneous transluminal angioplasty (PTA) balloon (P=0.02 for superiority), and the rate of freedom from primary safety end points was 83.9% and 79.0%, respectively (P=0.005 for noninferiority).

LEVANT 2, they write, "does not provide definitive guidance" on the potential clinical role of the Lutonix balloon. "Although the findings are encouraging, long-term follow-up will be useful in determining whether the [patency] benefit of this intervention is sustained, increased, or attenuated over time."

Indeed, as the Food and Drug Administration noted in briefing documents prepared for its June 2014 Circulatory System Devices panel meeting[2], subsequent analysis going beyond the positive 12-month primary LEVANT 2 findings saw a "diminished treatment effect at 24 months," although in a much reduced sample of the initial cohort.

"Perhaps it would have been wise to wait for the 2-year data to be included in the pivotal paper, despite that it was beyond the primary end point," observed Dr Ron Waksman(Washington Hospital Center, DC) for heartwire from Medscape on being shown the published primary analysis this week. According to unpublished 2-year LEVANT 2 data, which he says he's seen, the primary patency end point dropped sharply in the Lutonix arm from month 12 to month 24, "while the control arm changed very little." Still, he said, the paclitaxel-coated balloon's patency advantage remained significant at that late follow-up.

Even with the FDA's expressed concern over possibly diminished long-term effects, the advisory panel voted unanimously to support the device's approval for use in femoropopliteal-artery PTA, based on LEVANT 2. The agency followed with its formal approval in October 2014, all as covered by heartwire . The Lutonix 035 became the first drug-coated balloon for vascular disease available in the US, a treatment that had already been approved in Europe.

Waksman noted that all randomized trials of paclitaxel-delivering PTA balloons have compared the novel device with standard balloons, "a rather weak comparator" given that—for the kind of short lesions treated in LEVANT 2—second-generation bare-metal stents or paclitaxel-eluting PTA stents like the Zilver PTX (Cook Medical) "are also better than standard balloon angioplasty." A more relevant trial, he said, would compare PTA with drug-coated-balloon vs a drug-eluting peripheral-artery stent.

LEVANT 2 entered patients with moderate to severe intermittent claudication or ischemic pain at rest plus a >70 stenosis in one or both of the superficial femoral and popliteal arteries; the lesions had to be no longer than 15 cm. It randomized 316 to PTA with the drug-coated balloon and 160 to a standard-balloon procedure at 54 sites in Europe and the US.

Primary and Secondary End Points in LEVANT 2: Drug-Coated Balloon vs Standard Balloon in PTA

End points at 12 months Drug-coated balloon (%) Standard balloon (%) P
Primary, patencya 65.2 52.6 0.02
Primary, safetyb 83.9 79.0 0.005 for noninferiority
Target-lesion revascularization 12.3 16.8 0.21
a. Lack of restenosis by duplex ultrasound and freedom from TLR
b. Freedom from death from any cause within 30 days after the procedure and freedom at 12 months from index-limb amputation or reintervention and index-limb-related death

"Drug-coated balloons are pricey, and in order to justify their broad use, they must show reduction in revascularization," Waksman said. "Given the lack of clinical utility in the study, this may curb the enthusiasm of physicians, especially when price needs to be justified."

Although drug-coated balloons have been shown inferior to drug-eluting stents for de novo coronary stenoses, they are often used to treat coronary in-stent restenosis, Waksman noted. However, "this interesting application was not studied in LEVANT 2."

LEVANT-2 was funded by Lutonix-Bard. Rosenfield discloses grant support from Lutonix-Bard, Cordis, Atrium, and the National Institutes of Health; grant support and personal fees from Abbott Vascular; and personal fees from VIVA Physicians. Disclosures for the coauthors are listed on the journal website. Waksman said he has no relevant financial relationships.

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