Potential Benefits of Drug-Coated Balloons for Infrapopliteal Disease Remain Uncertain
Patients with advanced atherosclerotic disease of the infrapopliteal arteries have similar outcomes at 1 year whether they are treated with drug-coated balloons (DCBs) or with uncoated balloons or DES, a new meta-analysis of randomized data shows. However, DCBs do seem to reduce late lumen loss.
But even with the pooling of data from multiple trials, there is still insufficient evidence to draw firm conclusions, lead author Salvatore Cassese, MD, PhD (Deutsches Herzzentrum München, Munich, Germany), told TCTMD in an email. He said that the sample size was less than half what would be needed to detect whether DCBs are having a measurable effect on rates of repeat revascularization or amputation.
That uncertainty, which is compounded by the lack of standardized wound care management across the trials, “justifies further studies, and the results of ongoing RCTs are eagerly awaited,” Cassese said.
Although DCBs have been shown to improve angiographic and clinical outcomes compared with uncoated balloons in femoropopliteal arteries, their use in the infrapopliteal vasculature remains controversial. Early studies suggested some benefits, but those were not confirmed in the recent IN.PACT DEEP and BIOLUX P-II trials. Moreover, IN.PACT DEEP showed a nonsignificant trend toward a higher amputation rate in the DCB arm. The IN.PACT Amphirion paclitaxel-eluting balloon (Medtronic) used in that trial was withdrawn from the market.
To evaluate the impact of DCBs in patients with advanced infrapopliteal disease, the investigators pooled data from five randomized trials: IN.PACT DEEP, BIOLUX P-II, DEBATE BTK, DEBELLUM, and IDEAS. They included a total of 641 patients assigned to a DCB (n = 378) or either an uncoated balloon or DES (n = 263).
Nearly all patients (99.6%) had critical limb ischemia. About one-third of lesions were completed occluded and 20% had severe calcifications. Lesion length was slightly lower in the DCB arm (113.1 vs 127.0 mm).
As reported online April 27, 2016, ahead of print in JACC: Cardiovascular Interventions, use of a DCB vs an uncoated balloon/DES was associated with a numerically lower rate of TLR (primary efficacy outcome) though a median follow-up of 12 months, although the difference did not reach statistical significance (18.3% vs 29.1%; risk ratio 0.71; 95% CI 0.47-1.09). There were similarly no differences between groups in rates of clinically driven TLR, death, major adverse events, and Rutherford class 5-6.
As for safety, there were similar risks of amputation (primary safety endpoint), major amputation, and delayed wound healing in both groups.
Angiographic late lumen loss, which was assessed in a subset of patients, was reduced by 0.41 mm (P = .04) in the DCB arm.
Caution Interpreting Angiographic Endpoint
The reduction in late lumen loss with DCBs appears to be the result of inhibition of neointimal proliferation and positive vessel remodeling, according to Cassese and colleagues.
Addressing the apparent discrepancy between angiographic and clinical effects, Cassese said that “in patients with PAD, mechanistic measures of efficacy are not always associated with meaningful clinical improvement. . . . In the case of the infrapopliteal arterial district, the revascularization of patients with ulcer or gangrene is unable to reduce per se the risk of disease progression without a dedicated unit taking care of the foot with an established protocol of surveillance.”
But in an accompanying editorial, Thomas Zeller, MD (Universitäts-Herzzentrum Freiburg-Bad Krozingen, Germany), and Michael Jaff, DO (Massachusetts General Hospital, Boston, MA), question whether the meta-analysis can be used to conclude that late lumen loss actually was reduced with DCBs.
They note that all but one of the trials used the now-discontinued IN.PACT Amphirion balloon and that only 72 of the patients in the meta-analysis were treated with a balloon that is still available anywhere: the Passeo 18 Lux (Biotronik), which is not available in the United States. Also, only two of the trials had independent core lab adjudication, and in those, late lumen loss did not differ between groups.
“Positive technical outcomes of those mostly self-reported, self-adjudicated trials may be affected by systematic (positive), unmeasured errors or confounders and simply mirror the center’s practice, resulting in limited generalizability,” Zeller and Jaff write. “The most relevant bias results from unblinded quantitative angiographic measurements and data analysis, as [has been] shown for renal denervation studies.”
Thus, the conclusion that angiographic outcome is improved with DCBs should be interpreted with caution, they write, adding that the findings of the meta-analysis cannot be applied to other DCBs that are either commercially available or under investigation.
The study authors acknowledge that “larger randomized trials in this setting remain of paramount importance to disclose whether the efficacy and safety of DCB best other revascularization therapies, particularly in those cases with a huge plaque burden.”
Cassese S, Ndrepepa G, Liistro F, et al. Drug-coated balloon for revascularization of infrapopliteal arteries: a meta-analysis of randomized trials. J Am Coll Cardiol Intv. 2016;Epub ahead of print.
Zeller T, Jaff MR. Favorable angiographic outcome after treatment of infrapopliteal lesions with drug coated balloons without clinical benefit: what we learn from a meta-analysis. J Am Coll Cardiol Intv. 2016;Epub ahead of print.
- Cassese reports no relevant conflicts of interest.
- Zeller reports serving as a consultant to and receiving consulting fees, speaker honoraria, and support for accommodation and traveling from Boston Scientific, Cook, Medtronic, W.L. Gore, Veryan, Spectranetics, Trireme, and Terumo.
- Jaff reports serving as a non-compensated advisor for Medtronic, a compensated board member of VIVA Physicians, and an equity investor of PQ Bypass.