(Leipzig, Germany) January 29, 2020 -- Continuing the series of first-time data releases at LINC, Patrick J. Geraghty, MD (Washington University Medical School, and Barnes-Jewish Hospital in Saint Louis, MO) presented 12-month data of the Lutonix BTK trial1, including a subset analysis of complex patients.
The Lutonix BTK trial compares the performance of the Lutonix 014 BTK drug-coated balloon (DCB) (BD), which includes a 2 μg/mm2 density paclitaxel coating, to percutaneous transluminal angioplasty (PTA) in a 2:1 fashion.
Dr Geraghty is co-principal investigator of the trial alongside Jihad Mustapha, MD (Advanced Cardiac & Vascular Centers for Amputation Prevention, Grand Rapids, MI) and Marianne Brodmann, MD (Medical University of Graz, Austria).
A total of 442 patients were enrolled at 51 sites throughout the U.S., Europe, Canada, Japan, and Australia. International enrollment included 32 sites in the U.S. (n=275 patients), 14 sites in Europe and Canada (n=127), and five sites in Japan (n=40).
Independent analysis included angiographic and radiographic assessment by SynvaCor, duplex ultrasound follow-up by VasCore, a Clinical Events Committee adjudicating serious adverse events, and a Data Monitoring Committee assessing overall patient safety.
Key inclusion criteria included: the presence of arterial stenosis of ≥70% below the tibial plateau and above the tibiotalar joint; appropriateness for angioplasty as per operator visual assessment; Rutherford category 3–5; a cumulative lesion length of ≤320 mm; patent inflow artery from the aorta to the target lesion free from significant (≥50%) infra-malleolar outflow vessel; and target vessel diameter of 2–4 mm, treatable with available device sizes.
Key exclusion criteria included: severe medical comorbidities (e.g. untreated coronary artery disease or congestive heart failure) or metastatic cancer; ischemic ulceration extension >4 cm proximal to the digit-metatarsal skin crease of the target limb; gangrene extending proximal to the digit-metatarsal skin crease of the target limb; neurotrophic ulcer or heel pressure ulcer or ulcer potentially involving calcaneus in the target limb; planned major amputation, or prior major amputation if the patient is not independently ambulating; or acute limb ischemia, in-stent restenosis, or presence of thrombosis in the target lesion.
Mean patient age in the DCB arm was 72.9 ± 9.7 years, and 72.9 ± 9.7 years in the PTA arm. Mean body mass index was approximately 28 in both groups. Patients with lesions of Rutherford category 3–5 were recruited; 56.1% of lesions were Rutherford 5 in both DCB and PTA groups; and approximately 90% of all patients had chronic limb threatening ischemia (CLTI). The majority of patients had hypertension (DCB arm, 92.0%; PTA arm, 95.5%), dyslipidemia (DCB arm, 78.4%; PTA arm, 74.8%), and type II diabetes (DCB arm, 71.1%; PTA arm, 68.4%). Over half of all patients had undergone previous peripheral intervention.
Regarding lesion characteristics, mean lesion length was slightly longer in the DCB group relative to the PTA group (11.18 ± 9.26 cm vs 9.47 ± 8.54 cm; p = 0.03). CTO rates were significant, although similar between arms (DCB arm, 37.7%; PTA arm, 35.5%).
Primary endpoints of the study were 30-day safety, including 30-day freedom from major adverse limb events (MALE), which included significant reintervention and above-ankle amputation, and perioperative death (POD). The primary efficacy endpoint was six-month freedom from major amputation, target vessel occlusion (evaluated by duplex ultrasound) and clinically driven target lesion revascularization (TLR).
“During the course of the study, because of a period of prolonged enrollment, there was a change from a frequentist evaluation to a Bayesian approach,” Dr Geraghty said. “This allowed for interim assessments that determined the need for continuing enrollment. Unfortunately, each interim assessment brings a penalty of a more stringent P-value needed to reach statistical significance. Additionally, there was a decision made to look at different arterial distributions, and that also decreased the stringency of the P-value.
“The final result of this, as shown in our initial publication of the six-month results2, is that a composite efficacy measure of the full intention-to-treat population narrowly missed reaching the pre-specified Bayesian P-value of .0085.”
The 30-day primary safety endpoint of freedom from MALE-POD was 99.3% versus 99.4% for DCB versus PTA, respectively. This was non-significant between groups. The composite efficacy endpoint of primary patency and limb salvage at six months was 74.7% versus 64.2% for DCB and PTA, respectively. While this constituted a numerical difference of 10.5%, this was just short of statistically significant under Bayesian analysis (P=.02).
Discussing Kaplan-Meier analysis, Dr Geraghty noted that results were more encouraging: “This gives an overall better idea of efficacy going out to the full year,” he said. “At six months, by Kaplan Meier, we do see a statistically significant difference between treatment arms, with a 14% difference in the composite efficacy [P< .001]. These [curves] draw together at one year [P=.54].
“Looking at clinically driven TLR, we are getting the same look – with slightly smaller numbers of course – but a statistically significant difference of 8% at six months [P=.004] and, again, the curves drawing together at one year [P=.42].”
Moving on to further secondary observations in one-year data, he continued: “We looked at the cumulative burden of reintervention – not just if you get a single reintervention, because some patients might have had multiple reinterventions. At six months in particular, there is a statistically significant difference in favor of the DCB arm [8.5% vs 17.5%; P=.01]. Those numbers are no longer statistically significantly different at one year, although there is still a slight advantage for DCB [17.8% vs 21.8%; P=.39]. Toe brachial index improved in both groups and was consistent in terms of improvement through 12 months of follow-up.”
Dr Geraghty then presented preliminary data on wound assessment. Overall, wounds were present at baseline in 56% of patients in each arm. At six months, these figures dropped to 41.7% and 45.1%, respectively for DCB and PTA. At 12 months, these had dropped again to 29.7% and 25.9%, respectively.
In his concluding remarks, Dr Geraghty highlighted available safety data out to three-year follow-up, in light of the ongoing discussions regarding the safety of paclitaxel. “At this point, 66% of the enrolled patients have completed follow-up to three years. We looked at freedom from all-cause death, freedom from major amputation, and combined amputation-free survival.
“We see that through these three years of follow-up, there are no statistically significant differences in freedom from all-cause death between the two arms of this study [HR, 1.04]. Likewise, major amputation rates through three years are not statistically significantly different at any point [HR, 0.81]. Finally, the combined amputation-free survival endpoint also shows no differences throughout the three years [HR, 1.04].”
In addition to this, he added, a first look at available three-year efficacy data (valid as of October 2019) demonstrated no statistical difference between the two groups.
- Lutonix DCB Versus Standard Balloon Angioplasty for Treatment of Below-The-Knee (BTK) Arteries. ClinicalTrials.gov. Available online at https://clinicaltrials.gov/ct2/show/NCT01870401. Accessed January 29, 2020.
- Mustapha JA, Brodmann M, Geraghty PJ, et al; Lutonix BTK Study Investigators. Drug-coated vs uncoated percutaneous transluminal angioplasty in infrapopliteal arteries: six-month results of the Lutonix BTK trial. J Invasive Cardiol. 2019;31(8):205-211.