“Promising” results have been reported from the DANCE (Dexamethasone delivered to the adventitia to enhance clinical efficacy) trial, which is studying the Bullfrog (Mercator MedSystems) delivery of anti-inflammatory GR-agonist (dexamethasone) after atherectomy to inhibit restenosis.
Christopher Owens, University of California, San Francisco, USA, presented the data at the 2016 Leipzig Interventional Course (LINC; 26–29 January, Leipzig, Germany). He reported that post-atherectomy Bullfrog delivery of dexamethasone reduced the production of pro-inflammatory cytokines and acute phase reactants when compared with atherectomy alone.
Owens is the national co-principal investigator for the DANCE trial, an open-label, single-arm trial that is now fully enrolled. All patients had reported Rutherford classifications of 2–4 in the superficial femoral or popliteal arteries and exhibited de novo or restenotic lesions of ≤15cm length to be eligible for this study.
The Bullfrog catheter (which is FDA 510(k) cleared and CE marked) used in this trial has a needle to infuse the drug directly into the arterial wall. The drug is made up of 80% dexamethasone with 20% contrast to allow for visual confirmation of on-target drug delivery. The investigators’ hypothesis was that the dexamethasone drug delivery could inhibit inflammatory molecules that occur due to injury, thus “truncating” the injury process and resulting restenosis, Owens said.
The primary efficacy endpoint was 12-month patency (measured with duplex ultrasound and defined as peak systolic velocity ratio ≤2.4 and a lack of clinically-driven target lesion revascularisation) while the primary safety endpoint was the rate of major adverse limb events out to 12 months and post-operative death out to 30 days.
Owens said that the trial ran in parallel with two other trials, one was a percutaneous transluminal angioplasty arm and the other was an atherectomy arm. It was the first 100 patients enrolled in the atherectomy arm that were the focus of the LINC presentation, of whom 73 were analysed for primary patency and target lesion revascularisation endpoints.
The patient population was primarily enrolled in the southern US states, a fact which, Owens says, is reflected in the relatively high body mass index (31.6kg/m2±18.1kg/m2), high inflammation (high-sensitivity C-reactive protein [CRP] 5.2mg/dL±5.4mg/dL) and high proportion of black patients (20.5%) who generally have higher rates of re-stenosis. Lesion characteristics were “similarly challenging”, with a high representation (15.1%) of Rutherford 4 severe calcification, popliteal involvement (20.5%) and TASC II classification (36% A, 59% B and 6% C).
The trial was “a very safe trial”, with no device- or drug-related serious adverse events at one year. There were two major adverse limb events (both bypass) and five deaths at one year (but none at 30 days).
For efficacy, Owens reported 85% primary patency at one year and 81.5% patent at 390 days. He said that compared to other previous trials, lesion length was relatively long, the rate of Rutherford 4 classification was high, the number of TASC II B and C lesions was high and severe calcification was more common. Despite this, the trial achieved comparable or higher 12-month patency than several of these past trials. Rutherford classification and walking impairment questionnaire scores also showed statistically significant improvement (p<0.05) at 12 months when compared with the baseline screening exam.
Biomarkers used were high sensitivity C -reactive protein and monocyte chemoattractive protein-1 (MCP-1). CRP levels rise in response to local triggers such as inflammation, and Owens told the audience previous studies have indicated that elevated levels are tied to restenosis. This is also the case for MCP-1, which recruits inflammatory cells to the site of injury. Significant reductions in both were seen in the 24 hours after intervention with dexamethasone when compared with existing data from non-dexamethasone interventions. In fact, after it was shown to fall by almost 50% from baseline, Owens said that “I have never seen MCP-1 go down like this.”
“The early results of GR-agonist microinfusion in peripheral arteries at the time of atherectomy appear promising,” Owens continued, “particularly given the inherent safety profile of currently approved steroids.”
“It is a proof of principle study, but I do think it makes you think about a paradigm shift in anti-restenotic thought away from the intimal delivery platforms, towards adventitial delivery of an anti-inflammatory approach,” Owens told delegates. “We think that the adventitial delivery of powerful GR-agonist therapy results in nuclear immunomodulation of the vascular injury response to reduce restenosis while permitting the unimpeded re-establishment of vascular endothelium.”