Two-year results of the IN.PACT SFA randomised controlled trial demonstrate durability and continued superiority of the IN.PACT Admiral drug-coated balloon (Medtronic) over plain balloon angioplasty in superficial femoral artery and popliteal artery lesions. The investigators maintain that these positive results with the drug-coated device at two years have the potential to drive a paradigm shift in superficial femoral artery interventions.
The new data were presented at the Transcatheter Cardiovascular Therapeutics conference (TCT, 10–15 October, San Francisco, USA) and published simultaneously in the Journal of the American College of Cardiology (JACC). The announcement follows the one-year results from the IN.PACT SFA trial where the IN.PACT Admiral drug-coated balloon resulted in the highest rate of primary patency and the lowest rate of clinically-driven target lesion revascularisation at 12 months in a pivotal study of interventional treatments for peripheral arterial disease. At TCT, the two-year data were presented by John Laird, interventional cardiologist at UC Davis Medical Center, Sacramento, USA.
He told delegates: “Superficial femoral artery disease remains a challenge to manage with no evidence-based standard treatment defined. We know that percutaneous transluminal angioplasty is associated with a very high incidence of restenosis when used for anything but focal, non-complex lesions in the femoropopliteal segment. There have been randomised trials demonstrating superiority of stents over balloon angioplasty in the superficial femoral artery. Reported long-term patency rates with stents range from 60–75%, but concerns persist about in-stent restenosis and stent fractures. We have seen promising early results with drug-coated balloons in randomised trials, but longer-term results are lacking and questions remain about the durability of the treatment effect.”
The objective of the IN.PACT SFA trial was to assess the safety and efficacy of the IN.PACT Admiral paclitaxel-coated balloon vs. standard angioplasty for the treatment of superficial femoral and proximal popliteal artery disease due to claudication and rest pain. The study enrolled 331 patients at 57 sites across Europe and the United States. All patients, whose lesions were classified as Rutherford clinical category 2 to 4 and had lengths between 4 and 18cm or occlusions equal to or less than 10cm, were randomised to treatment with either the IN.PACT Admiral drug-coated balloon or standard balloon angioplasty.
The primary efficacy endpoint was primary patency at 12 months, defined as freedom from clinically-driven target lesion revascularisation and duplex ultrasound-derived restenosis (PSVR ≤2.4). The primary safety endpoint was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven target vessel revascularisation within 12 months. The two groups were very well matched with regard to their baseline clinical characteristics. In the IN.PACT group, the mean lesion length was 8.94±4.89cm and in the angioplasty group it was 8.81±5.12cm. These lesion lengths are longer than any seen in other superficial femoral artery drug-coated balloon trials, he said. Total occlusions were present in between 19.5% and 25.8% of cases.
The results showed that the treatment with the drug-coated balloon resulted in a primary patency of 78.9%, a result that was superior to the 50.1% achieved in the plain angioplasty group (p<0.001). “And there is no catch up after one year in the Kaplan-Meier analysis,” Laird noted. The drug-coated balloon group also had a lower clinically-driven target lesion revascularisation rate at two years, with 9.1% of patients requiring a repeat procedure, compared to 28.3% of patients in the plain angioplasty group (p<0.001). Primary sustained clinical improvement was greater with drug-coated balloon (76.9% vs. 59.2%, p=0.003).
For the primary safety endpoint, a composite of freedom from 30-day device- and procedure-related death, target limb major amputation and clinically-driven target vessel revascularisation rate at 12 and 24 months was 87.4% in the drug-coated balloon group and 69.8% in the angioplasty cohort. There were no major target limb amputations in either group (p>0.999) and there were low thrombosis rates of 1.5% in the drug-coated balloon group, compared to 3.8% in the plain angioplasty group (p=0.243).
The all-cause death rate was 8.1% in the drug-coated balloon group and 0.9% in the plain balloon angioplasty group (p<0.008). The deaths, including cardiac-related, malignancy-related, respiratory-related and other, were all adjudicated by the Clinical Events Committee as not being device- or procedure-related.
Subgroup analysis
In a subgroup analysis from the IN.PACT SFA trial, two-year results also showed clinical superiority and consistency across various patient types that have been proven difficult to treat based on historical data, including people with diabetes and the female population.
For people with diabetes, the drug-coated balloon group showed a higher restored blood flow rate of 73.3%, compared to 45.8% in the plain angioplasty group (p<0.001). In an evaluation of the female population, the drug-coated balloon group showed a restored blood flow rate of 76.7%, vs. 42.3% in the plain angioplasty group (p<0.001).
A subset of patients underwent a six-minute walk test after intervention and there was a significant increase in mean walking distance in both groups at 12 and 24 months. The drug-coated balloon patients achieved the same level of functional improvement with 58% fewer reinterventions. Quality of life and walking impairment was assessed with a walking impairment questionnaire and again there was an increase in the percentage indicating less walking impairment in both treatment groups at 12 and 24 months; the drug-coated balloon patients achieved this same level of functional improvement with significantly fewer reinterventions.
“The IN.PACT Admiral drug-coated balloon has produced consistently strong clinical results over the longer-term. At two years, the IN.PACT Admiral drug-coated balloon showed strong patency and very low target lesion revascularisation rates,” said Laird, co-principal investigator of the IN.PACT SFA trial and first author of the published results in JACC. “These data continue to validate this drug-coated balloon as the durable, safe and primary treatment option, and are poised to impact the current superficial femoral artery treatment paradigm.”
Asked about why a late catch-up between 12 and 24 months was not present in the study, Laird said that first of all it was important to note that not all drug-coated balloons are the same. He added, “We have seen some late catch-up with other trials of drug-coated balloons. With IN.PACT Admiral there is a paclitaxel dose of 3.5µg/mm2, whereas with other balloons the dose may be as low as 2µg/mm2. There is a different excipient molecule that allows the drug to come off the balloon and there is a different coating process, so all these things can impact the results and the impact of the durability of the treatment effect.”
Glass half full or half empty
Lawrence Garcia, chief, Interventional Cardiology at St Elizabeth’s Medical Center, Brighton, USA, an investigator in the IN.PACT SFA trial, told Vascular News he believes the two-year data is a great opportunity for “game changer” status with a “leave nothing behind” strategy. He commented: “The critical part of this is how you interpret the data. The outcomes based on 12 months have a primary patency of 89%. The 14-month window was at 79%. So at 24 months it was 79% with the 26-month patency at 73%. What is the point? Well, either the glass is half full or half empty. The glass half full is that even with the lowest number at 14 months the delta change to 26 months was only 10%… a very soft landing indeed. If we take the pessimistic view, it went from 89% to 79%, or a 10% drop. I would suspect that the glass half full approach makes the best overall read of the dataset.”
Garcia notes that a widespread adoption of drug-coated balloons will depend on whether interventionalists believe the data with lesions of approximately 10cm are robust enough to change their practice with patients presenting with 20–30cm lesions. He said, “I would suspect that according to most technologies these patency rates decline for a myriad of causes—one of which is lesion length. Further, the global registry that is being used to support the outcomes with drug-coated balloons are clearly different to the randomised controlled trial data, in particular with the use of stenting. So overall, it is hard to know where the paradigm shift will be. Will it be only with the moderate long lesions and not with the complex long lesions?”
He states that trials directly comparing drug-eluting technologies are lacking on the scientific landscape. “If drug-coated balloons are directly compared to drug-eluting stents or another technology and they win across a large type of patient population then this technology will become the ‘default’ therapy,” he says.
The IN.PACT Admiral drug-coated balloon received the CE mark in 2009 and approval by the FDA in December 2014. The IN.PACT SFA trial will follow patients for five years.
