By Krishna Rocha-Singh
How can we account for the lack of treatment effect of the IN.PACT Amphirion below-the-knee drug-eluting balloon (Medtronic) versus standard percutaneous transluminal angioplasty in the IN.PACT DEEP trial, the largest randomised controlled and independently adjudicated investigation of patients with critical limb ischaemia to date?
In the IN.PACT DEEP trial, 358 critical limb ischaemia patients were randomised 2:1 between the IN.PACT Amphirion drug-eluting balloon and standard percutaneous transluminal angioplasty at 13 European sites. After 12 months, including independent core lab adjudication of an angiographic cohort and independent core lab assessment of all wounds, the decision was made to recall the IN.PACT Amphirion drug-eluting balloon based on a trend toward a higher rate of major amputation in the drug-eluting balloon arm (8.8% vs. 3.6%, p=0.080) and no significant benefit (drug-eluting balloon vs. angioplasty) for the efficacy endpoints of clinically-driven target lesion revascularisation (11.9% vs. 13.5%, p=0.682), late lumen loss (0.605±0.775mm vs. 0.616±0.781mm, p=0.950), and binary restenosis (41% vs. 35.5%, p=0.609).
However, the same iteration of the IN.PACT Amphirion drug-eluting balloon had demonstrated promising results in two single-centre self-adjudicated studies. In a Leipzig registry of 104 patients (mean lesion length 17.6cm, 82.6% critical limb ischaemia), IN.PACT Amphirion binary restenosis was 27.4% at three months, and the target lesion revascularisation rate was 17.3% at one year. Those results for IN.PACT Amphirion compared favourably against findings of a three-month 68.8% restenosis rate and 50% one-year target lesion revascularisation rate in a historical standard angioplasty cohort with similar baseline characteristics. In the DEBATE-BTK randomised trial versus angioplasty in 132 diabetic critical limb ischaemia patients (mean lesion length 13cm), 12-month binary restenosis was 27% in the drug-eluting balloon arm versus 74.3% in the angioplasty arm, the target lesion revascularisation rate was 18% vs. 43%, and there was only one major amputation (in the angioplasty arm) (see Table).
Clearly, small single-centre studies and large multinational, multicentre trials may differ largely in terms of patient demographics and potential selection biases, variable technical expertise, use of ancillary devices to address matters such as pedal circulation, and non-uniformity of post-procedure wound care. Self-adjudicated single-centre trials often report larger treatment effects compared to large multicentre trials, with institution-specific practices resulting in superior outcomes that cannot be generalised to less-experienced practitioners at lower-volume sites.
For example, compared with the self-adjudicated DEBATE BTK trial, with its closely coordinated multidisciplinary team approach and intense wound care surveillance, wound management in IN.PACT DEEP trial was performed according to individual site protocols (23.5% of IN.PACT Amphirion patients and 29.4% of angioplasty patients received self-administered wound care). However, the IN.PACT DEEP trial was also 100% adjudicated by independent angiographic and wound core labs, with 100% source documentation, lending veracity to the trial conclusions.
A striking finding of the IN.PACT DEEP trial was that late lumen loss was identical in the drug-eluting balloon and angioplasty arms. This finding prompts the question whether the paclitaxel dosage contained on the IN.PACT Amphirion device actually reached and was retained within the target vessel wall.
Unlike the CE-marked IN.PACT Admiral drug-eluting balloon (Medtronic) designed for femoropopliteal use, the IN.PACT Amphirion device (for infrapopliteal use) was manually coated with the urea excipient and paclitaxel only after being folded, resulting in a non-uniform paclitaxel distribution on the balloon. The majority of the adherent paclitaxel was thus exposed during delivery, unprotected within the deflated balloon folds, and vulnerable to loss during transit to the vessel lesion. Also, the material used in the IN.PACT Amphirion below-the-knee balloon, when compared to the material used in the IN.PACT Admiral femoropopliteal balloon, had a higher surface energy, thereby providing less efficient paclitaxel release after inflation and contact with the vessel wall. In preliminary animal studies comparing the efficiency of drug release between the IN.PACT Amphirion drug-eluting balloon used for below-the-knee lesions in IN.PACT DEEP and the IN.PACT Admiral drug-eluting balloon used for femoropopliteal lesions, the more recent IN.PACT Admiral balloon design retained substantially less drug, thus delivering more paclitaxel to the vessel wall (see Figure).
Primary angioplasty below the knee is plagued by high rates of restenosis and the need for repeat interventions, which are associated with increased morbidity and drive cost. The rationale for drug-eluting balloon interventions is to increase primary patency rates above those typically associated with standard angioplasty, thereby promoting wound healing and limb preservation. The time to wound healing and the duration of benefit are likely to be further improved by the recently increased focus on addressing pedal run-off and pursuing pedal loop interventions to maximise perfusion into the foot after upstream drug-eluting balloon intervention.
Below-the-knee lesions associated with critical limb ischaemia are often long, occlusive, and associated with challenging inflow and run-off disease, presenting major obstacles to clinical success. With the insights provided by the IN.PACT DEEP trial, the goal of defining a more durable endovascular critical limb ischaemia treatment solution is far from dead. As such, we should remain optimistic about the eventual US approval of a drug-eluting balloon to treat below-the-knee lesions in critical limb ischaemia patients.
Krishna Rocha-Singh is chief scientific officer, Prairie Heart Institute, Springfield, USA