PAD clinical trials overview

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Research

PAD affects more than 8 million patients.1 The most common anatomic location is in the superficial femoral artery (SFA). Symptomatic SFA disease is treated with endovascular technologies including drug-coated balloon and stents. This update discusses the major randomized trials in the field.

Early trials in the mid-2000s investigated sirolimus-eluting stents coated onto bare metal stents. Since then, the drug-coated technology has moved to paclitaxel (PTX). The transition to PTX occurred with the THUNDER Trial.2 The THUNDER Trial enrolled 150 patients with femoral-popliteal stenotic or occlusive disease who were randomized to treatment with either PTX-coated catheters, uncoated catheters with PTX dissolved in contrast medium, or uncoated catheters (controls). This study demonstrated that PTX limited restenosis. Of note, in this study, there was no pre-dilatation performed of the lesion prior to drug delivery. The inflation time of the balloon in this trial was 1 minute. Most of the lesions treated were stenotic with 27% of the patients having total occlusions and 36% being restenotic. The average of length treated was 7.4 cm + 6.5 cm. In the control group, there were more patients who received a stent. Once the stent patients were removed from the analysis, the PTX-coated balloons were found to be superior to the control group, showing that PTX therapy may be efficacious for reducing restenosis in patients treated with SFA disease.

The FemPac study randomized 87 patients with femoral-popliteal arterial disease to either uncoated or PTX-coated balloons.3 The primary end point of this study was late lumen loss at 6 months. The average lesion length in this study was 4.7 cm for the control group and 4.0 cm for the PTX group. The 6-month follow-up angiographic data showed a significantly lower late lumen loss in PTX-coated balloons compared to controls (0.5 + 1.1 vs. 1.0 + 1.1 mm).

The PACIFIER Study enrolled 85 patients, 91 procedures, randomized in a multicenter trial using the IN.PACT balloon (44) compared to angioplasty (47).4 This study enrolled patients with an average lesion length of 7 cm in the IN.PACT and 6.6 cm in the control arm. Pre-dilatation of the stenosis was only performed in 6.4% of the patients in the control group and 13.6% of the patients in the drug-eluting balloon group. There was a reduction in late lumen loss with fewer binary restenosis occurring at 6 months (8.6% vs. 32.4%). This study was used to help design the LEVANT 1 and 2 studies.

The LEVANT 1 study enrolled 101 patients who were randomized to low-dose PTX-coated balloons (2 micrograms/mm2, Lutonix) or plain old balloon angioplasty (POBA).5 Pre-dilatation was performed. The average length treated was 80.5 mm. The primary endpoint was late lumen loss at 6 months and it was 0.46 mm in the Lutonix-treated arm VS. 1.09 mm in the control arm. The LEVANT 2 study enrolled 476 patients in a 2: (Lutinix vs. control).6 Patients presented with intermittent claudication or ischemic rest pain. The primary endpoint was 12-month primary patency of the target lesion. In the LUTONIX drug-coated arm, this was 65.2% compared to the control arm of 52.6% (P=0.02).

The IN.PACT SFA study7 enrolled 330 patients with intermittent claudication or ischemic rest pain involving the SFA and popliteal location. Patients were randomized to PTX-eluting balloon angioplasty (IN.PACT) or conventional angioplasty. The average lesion length in this study was 8.94 cm in the PTX-coated balloon arm and 8.81 cm in the angioplasty arm. 25.8% of the lesions had chronic total occlusions in the drug-coated balloon arm and 19.5% in the plain angioplasty. This study showed higher patency rate in IN.PACT arm of 82.2% vs. 52.4% at 12 months.

The Zilver PTX randomized trial studied the effect of the Zilver paclitaxel-coated stent (n=236) vs. angioplasty (n=238), with 91% of the patients having claudication and 9% with critical limb ischemia. The authors reported that the 1-year patency rates of drug-eluting stents were superior to angioplasty.8 Recently, 5-year data from this study showed a “clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% vs. 59.3%, P<0.01), patency (66.4% vs. 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% vs. 67.6%, P<0.01) for the overall DES group compared to standard care in nonrandomized comparisons.”

Recently, the IMPERIAL study conducted a head-to-head comparison between ELUVIA drug-eluting stent and the Zilver PTX stent (2:1).9 Both stents are polymer free and coated with PTX. This was a noninferiority trial with 12-month follow-up. This trial demonstrated no difference between the two stents with respect to primary patency (ELUVIA: 86.8% and Zilver PTX: 81.5%).

The ILLUMENATE Pivotal trial is being performed in Europe and it is investigating another PTX-coated balloon compared to POBA in SFA and popliteal disease.10 This trial is using the Stellarex 0.035-inch balloon, which has low dose of PTX. This trial is ongoing and 3-year results have been presented in abstract form only. The investigators reported 3-year patency of 64.2% in the DCB arm compared to 51% in the control arm.

References

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  2. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwalder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B and Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358:689–99.
  3. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U and Ricke J. Inhibition of restenosis in femoropopliteal arteries: Paclitaxelcoated versus uncoated balloon: Femoral paclitaxel randomized pilot trial. Circulation. 2008;118:1358–65.
  4. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB and Hanninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: Evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012;5:831–40.
  5. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S and Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovascular interventions. 2014;7:10–9.
  6. Rosenfield K, Metzger DC and Scheinert D. A paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 015;373:1785–6.
  7. Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, Metzger C, Scheinert D, Zeller T, Cohen DJ, Snead DB, Alexander B, Landini M, Jaff MR and Investigators IPST. Drugcoated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015;131:495–502.
  8. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, Machan LS, Snyder SA, O’Leary EE, Ragheb AO, Zeller T and Zilver PTXI. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation. 2016;133:1472–83; discussion 1483.
  9. Gray WA, Keirse K, Soga Y, Benko A, Babaev A, Yokoi Y, Schroeder H, Prem JT, Holden A, Popma J, Jaff MR, Diaz-Cartelle J, Muller-Hulsbeck S and investigators I. A polymer-coated, paclitaxeleluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, non-inferiority trial. Lancet. 2018;392:1541–1551.
  10. dicardiology.com/content/philips-shares-three-year-results-stellarex-035-drug-coated-balloon.