Drug-Eluting Balloon Fails for Below-the-Knee Lesions in Critical Limb Ischemia Patients

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In patients with critical limb ischemia (CLI), below-the-knee revascularization with a drug-eluting balloon (DEB) is as effective as standard balloon angioplasty, although DEB use is linked with a nominally higher amputation rate, according to a study published in the October 14, 2014, issue of the Journal of the American College of Cardiology.

Because the IN.PACT Amphirion paclitaxel-eluting DEB (Medtronic; Santa Rosa, CA) failed to show superiority over angioplasty, the sponsor decided to “withdraw the [DEB] from the market,” write Krishna J. Rocha-Singh, MD, of the Prairie Heart Institute at St. John’s Hospital (Springfield, IL), and colleagues.

The IN.PACT DEEP trial, conducted at 13 European centers, randomized 358 patients with infrapopliteal arterial disease presenting with CLI in a 2:1 fashion to the DEB (n = 239) or standard balloon angioplasty (n = 119).
Although the groups were generally well matched at baseline, patients treated with the DEB had a shorter mean target lesion length (10.2 vs 12.9 cm) and shallower mean wound depth (0.84 vs 1.77 mm) and were more likely to have impaired inflow (40.7% vs 28.8%) and a history of prior target limb revascularization (32.2% vs 21.8%) compared with those who underwent standard angioplasty. In addition, predilation was used more frequently during the procedure in the DEB group (90.5% vs 36.0%).

No Differences in Efficacy, but Safety Concerns Arise

Clinically driven TLR through 12 months occurred at similar rates in the DEB and control groups (9.2% vs 13.1%; P = .291) in patients who did not undergo amputation. This finding was maintained when the analysis was expanded to the overall study population (11.9% vs 13.5%; P = .682).

Late lumen loss at 12 months (in the subgroup of patients who had a lesion length ≤ 10 cm and consented for angiographic follow-up) was similar in the DEB and control groups (mean, 0.61 vs 0.62 mm; P = .950). There also were no differences in the rates of binary restenosis or reocclusion.

The primary safety endpoint (composite of all-cause mortality, major amputation, or clinically driven TLR through 6 months) was numerically higher in the DEB group but met criteria for noninferiority compared with standard balloon angioplasty (17.7% vs 15.8%; P for noninferiority = .021).

There were stronger trends, however, toward a higher rate of major amputation (8.8% vs 3.6%; P = .080) and a lower rate of major amputation-free survival (81.1% vs 89.2%; P = .057) in the DEB arm at 12 months, despite the presence of longer lesions and deeper wounds in the patients who underwent standard balloon angioplasty.

Wound healing was similar in the 2 groups, but overall procedural complications were more common with the DEB (9.7% vs 3.4%; P = .035). “However, these complications were successfully managed and were not associated with a higher incidence of distal embolization or need for provisional stent deployment,” Dr. Rocha-Singh and colleagues write, noting that freedom from postprocedural dissection was higher with the DEB (87.7% vs 80.8%; P = .045).

Remaining Options for CLI

“While the IN.PACT DEEP trial may set a new benchmark with standard [balloon angioplasty] for the treatment of CLI patients due to the observed extremely low reintervention and amputation rates, alternative therapies, such as drug-eluting stents for short lesions or bypass for longer lesions, may still apply as valuable options in patients who are surgical candidates,” according to the researchers.

They stress, also, that the “results only apply to the specific [DEB] study device for [below-the-knee] revascularization. Positive results on the use of IN.PACT and other DEB technologies have been consistently reported for the femoropopliteal vascular territory, which may likely derive from known differences in the severity of vascular disease and DEB technologies.”

In an accompanying editorial, John R. Laird, MD, of the University of California, Davis Medical Center (Sacramento, CA), and Ehrin J. Armstrong, MD, of the University of Colorado School of Medicine (Aurora, CO), point out that the observed lack of efficacy conflicts with the benefits seen in earlier single-center studies using the same DEB in infrapopliteal lesions and larger studies of femoropopliteal interventions.

It is possible, they suggest, that this particular DEB failed to deliver a sufficient dose of paclitaxel resulting from the way it is coated—the drug is applied to the balloon after it is folded, so paclitaxel is not uniformly distributed on the surface. “The bulk of the adherent drug is in an exposed position (not protected by balloon folds) and subject to loss during advancement through the sheath and tracking to the lesion,” Drs. Laird and Armstrong write.

They add that it is premature to rule out a place for DEBs in treating infrapopliteal disease in patients with CLI.

“While the results of [standard balloon angioplasty] in this trial were remarkably good, there is still a need for a therapy that provides more durable patency in this vascular bed and reduces the need for repeat interventions,” they write. “[DEB]s that can deliver therapeutic levels of paclitaxel into the vessel wall may still play a role.”

Uncertainty Surrounds Higher Amputation Rate

Drs. Laird and Armstrong note that the reason for the elevated amputation rate in the DEB arm is unclear but say it could be explained by the excellent results in the control arm, in which the rate “is remarkably low and certainly an outlier compared to major amputation rates from previous studies of [percutaneous transluminal angioplasty] and other endovascular therapies for CLI. These outstanding PTA outcomes were achieved despite inclusion of a high percentage of Rutherford class 5 patients and likely reflect good PTA results followed by excellent wound care.”

Ali F. Aboufares, MD, of Columbia University Medical Center (New York, NY), agreed that there is no clear explanation for the higher amputation rate in the DEB arm, but he told TCTMD in a telephone interview that it is possible that DEBs cause more thrombosis compared with standard balloons. 

Other major remaining questions center around the discrepant results between studies of DEBs in the SFA and in below-the-knee vessels, whether the paclitaxel dose was too high or too low, and whether paclitaxel works on calcifications, which are common in patients with CLI, Dr. Aboufares said.

“These are high-risk patients because in general they are either poor surgical patients or have no surgical options,” he said. “We need a lot of work to really understand how to make this vascular territory more favorable from a device standpoint.”


1. Zeller T, Baumgartner I, Scheinert D, et al. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol. 2014;64:1568-1576.

2. Laird JR, Armstrong EJ. Drug-coated balloons for infrapopliteal disease: digging deep to understand the impact of a negative trial [editorial]. J Am Coll Cardiol. 2014;64:1577-1579.

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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The IN.PACT DEEP trial was funded by Medtronic.
  • Dr. Rocha-Singh reports serving as a consultant to Medtronic.
  • Dr. Laird reports serving as a consultant to and being on the advisory board for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Covidien, and Medtronic and receiving research support from WL Gore.
  • Drs. Aboufares and Armstrong report no relevant conflicts of interest.