“Starting to close the door on the paclitaxel controversy”: Late-breaking trials presented at TCT 2020

Clockwise from top left: Sahil A Parikh, Frank Veith, Marc Bonaca, Connie N Hess, and Robert A Lookstein

Findings from a series of late-breaking trials in the endovascular field were presented recently at TCT Connect (14–18 October, virtual), the 32nd annual scientific symposium of the Cardiovascular Research Foundation (CRF). Sahil A Parikh (Columbia University Medical Center, New York, USA) and Frank Veith (New York University Medical Center, New York, USA) moderated the session, with Marc Bonaca (University of Colorado, Aurora, USA) and Robert A Lookstein (Mount Sinai Health System, New York, USA) on the panel.

First on the virtual podium was Connie N Hess (University of Colorado, Aurora, USA), who presented the results from a large subgroup analysis of the VOYAGER PAD randomised clinical trial. This showed neither a mortality risk nor benefit associated with the use of paclitaxel drug-coated devices in the treatment of peripheral arterial disease (PAD). The study also found that the benefit of rivaroxaban use on reducing ischaemic limb and cardiovascular outcomes was consistent regardless of whether a drug-coated device was used.

Hess and team’s analysis examined the long-term safety of drug-coated devices (DCDs). It also evaluated whether rivaroxaban 2.5mg twice daily plus low dose aspirin versus low dose aspirin alone was consistent, either with or without use of a DCD.

During the qualifying endovascular lower extremity revascularisation, DCD was used for 31% (n=1,358) of patients. Patients receiving DCD more frequently had prior endovascular lower extremity revascularisation, had higher baseline use of dual antiplatelet therapy and statins, and were more often treated for claudication than non-DCD patients.

In the unweighted analysis, lower associated mortality was observed among patients receiving DCD versus non-DCD (2.9 vs. 3.9 per 100 patient-years; 3.5-year Kaplan-Meier cumulative incidence of 10.2% vs.13.8%). After weighting, there was no association between DCD use and mortality (3.5-year cumulative incidence 12.1% vs. 12.6%, HR 0.95, 95% CI 0.83-1.09, p=0.49). The benefit of rivaroxaban 2.5mg twice daily with aspirin compared to aspirin alone on reducing ischaemic limb and cardiovascular outcomes was also consistent regardless of whether a DCD was used.

The VOYAGER PAD trial was funded by research grants to CPC Clinical Research from Bayer and Janssen.

IN.PACT 0.014 DCB may offer a clinical benefit in patients with CLI

Antonio Micari (University of Messina, Messina, Italy) presented first-ever results from Medtronic’s IN.PACT BTK study, a feasibility study assessing the safety and effectiveness of the company’s IN.PACT 0.014 drug-coated balloon (DCB) in critical limb ischaemia (CLI) patients with chronic total occlusion (CTO) in the infrapopliteal arteries.

The IN.PACT BTK study is a prospective, multicentre, 1:1, randomised feasibility study assessing the safety and effectiveness of the IN.PACT 0.014 DCB, a 3.5 μg/mmdose paclitaxel-coated balloon, versus conventional percutaneous transluminal angioplasty (PTA) for the treatment of CTOs in the infrapopliteal arteries. The study enrolled 50 patients at nine sites in Europe.

At nine months, patients in the DCB group experienced a reduction in sub-segmental late lumen loss compared to those in the PTA control group (0.59±0.94mm versus 1.26±0.81mm, respectively, p=0.017), a 53% lower late lumen loss than the PTA control group. Using the classic late lumen loss method, subjects in the DCB group experienced lower late lumen loss compared to those in the PTA control group at nine months (0.89±0.77mm versus 1.31±0.72mm respectively, p=0.07 ), a 32% lower late lumen loss than the PTA control group.

Historically, there has not been a DCB technology that has demonstrated effectiveness in this vessel bed. According to a Medtronic press release, the data presented at TCT demonstrate that IN.PACT 0.014 may offer a clinical benefit in patients with CLI.

The IN.PACT 0.014 DCB is an investigational device that is being evaluated in Europe. This device is not currently being evaluated in the USA.

ILLUMENATE Global: Four-year results support durable long-term outcomes with the Stellarex DCB

Andrew Holden (Auckland City Hospital, Auckland, New Zealand) reported on late safety and efficacy outcomes for the low-dose Stellarex DCB (Philips) in de novo and restenotic femoropopliteal lesions from a large cohort.

He revealed that four-year data from the trial show favourable safety and efficacy outcomes consistent with the ILLUMENATE randomised controlled trials, and also demonstrate similar efficacy in prespecified cohorts including different gender groups and diabetics.

ILLUMENATE Global is a prospective, single-arm, multicentre study conducted in the EU. The patient population included those with Rutherford Clinical Classification (RCC) of 2–4  indicated for treatment of the superficial femoral artery (SFA) and/or popliteal artery for de novo or restenotic lesions. Follow-up office visits were at one, six, 12, 24, and 36-months post-procedure and included clinical, haemodynamic, and functional outcomes.

At four years, the rate of major target limb amputation was 0.8% and that of all-cause mortality was 8.1%. Clinically-driven target lesion revascularisation through four years was 75.6% at day 1,460 and the subgroup analysis revealed no difference in prespecified cohorts.

“The ILLUMENATE Global study supports durable long-term outcomes with the Stellarex DCB and is applicable to a complex population,” Holden told the TCT audience.

Bullfrog device shows promise in TANGO Registry

Ehrin J Armstrong (UCHealth Heart and Vascular Center, Aurora, USA) presented results of the TANGO Registry. This Phase 2 study aimed to assess the six-month efficacy and safety of the Bullfrog micro-infusion device (Mercator MedSystems) adventitial deposition of two escalating doses of temsirolimus in reducing angiographic neointimal hyperplasia and target lesion failure after revascularisation of below-the-knee (BTK) arteries.

This prospective, multicentre, dose-escalation, comparative, double-blinded study enrolled 61 patients undergoing endovascular revascularisation of ≥1 angiographically significant BTK lesions. Treatment was applied after completion of artery revascularisation, and divided into control (saline; 0.25–0.5mL/cm of lesion length), low-dose temsirolimus (0.1mg/mL; 0.025–0.05mg/cm of lesion length) or high-dose temsirolimus (0.4mg/mL; 0.1–0.2mg/cm of lesion length) groups in a dual-blinded, randomised fashion.

Primary and secondary efficacy endpoints were transverse-view vessel area loss percentage (TVAL%) of the target lesion and clinically relevant target lesion failure (CR-TLF) at six months, respectively. Primary safety endpoint was freedom from a major adverse limb event or perioperative death (MALE+POD) at 30 days.

Armstrong reported that superior primary efficacy of the treatment arm was apparent in the per protocol (PP) and PP-TASC B-D (excluding 15 subjects with TASC A lesions) subgroups, and that TVAL% reductions of 13.9% and 22.3% were seen in the PP and PP-TASC B-D subgroups at six months, respectively.

In addition, freedom from CR-TLF rates were substantially higher in those patients treated with temsirolimus, and differences between treatment and control for freedom from CR-TLF at six months were 27.1% and 39.2% in the PP and PP TASC B-D subgroups, respectively. Freedom from composite of 30-day MALE+POD was 100% in all groups.

“Findings suggest that adventitial deposition of temsirolimus using the Bullfrog micro-infusion device improves six-month vessel patency when applied to BTK arteries after successful endovascular revascularisation,” Armstrong concluded.

FLASH Registry: Acute haemodynamic improvement with percutaneous mechanical thrombectomy in a real-world pulmonary embolism population

Catalin Toma (University of Pittsburgh, Pittsburgh, USA) presented results from the FLASH Registry. FLASH is a 500-patient prospective, multicentre registry study to evaluate real-world outcomes after treatment of patients with intermediate and high risk PE with FlowTriever (Inari Medical).

Toma reported that mortality through 48 hours was 0% and that just three patients out of 320 (1.3%) experienced major adverse events—all of which were major bleeds.

Ablation of peri-arterial nerves in ARA should result in an additional blood pressure reduction

Yu Sato (CVPath Institute, Gaithersburg, USA) gave the final presentation of the session, on the anatomy of the human accessory renal artery peri-arterial renal sympathetic nerve for renal denervation.

Sato began by detailing that accessory renal arteries (ARAs) have been reported in about 30% of patients. Some renal denervation clinical trials excluded patients with ARAs, while others included such patients but excluded those with ARAs less than 3 or 4mm in diameter. Moreover, some studies have suggested that renal denervation for ARAs may have an additional advantage of blood pressure reduction. The aim of this study was to evaluate the anatomic distribution of peri-arterial nerves in human ARAs.

Sato concluded that ARAs have two-thirds the number of nerves as compared to dominant renal arteries, and that the number of nerves around the ARAs is dependent on the size of the renal arteries.

“Our results suggest that ablation of peri-arterial nerves in ARA should result in an additional blood pressure reduction,” he remarked, adding that future renal denervation clinical trials should consider including ablation of peri-arterial nerves in ARAs.

Closing the door on the paclitaxel controversy

“I think we are really starting to close the door on the paclitaxel controversy,” Lookstein commented at the end of the session. “There is clearly a lot more work that needs to be done for paclitaxel below the knee and it is encouraging to see that there is going to be work on that,” he added. “We are barely scratching the surface on drug-based delivery in the below knee circulation, so there is a lot more work to do.”


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