By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCES: Habara S, et al. Late restenosis after paclitaxel-coated balloon angioplasty occurs in patients with drug-eluting stent restenosis. J Am Coll Cardiol 2015;66:14-22.
Alfonso F, et al. A prospective randomized trial of drug-eluting balloons vs everolimus-eluting stents in patients with in-stent restenosis of drug-eluting stents: The RIBS IV Randomized Clinical Trial. J Am Coll Cardiol 2015;66:23-33.
Drug-eluting stents have revolutionized the invasive treatment of obstructive coronary artery disease. The development of drug-coated balloons, most utilizing the anti-microtubule agent paclitaxel, seemed to have similar potential for treatment of specific lesion subsets. As early as 2006, well-publicized studies1 have focused on in-stent restenosis (ISR) as a target with clear advantages for such a device, potentially combining low recurrence rates with avoidance of the need for additional layers of stents. Outside of the United States, this technology has been in clinical use for several years. In the United States, however, the FDA has not approved drug-coated balloons for use in the coronary vessels, though approval has come recently for peripheral arterial use. Two new studies dampen the enthusiasm for this technology among interventional cardiologists.
In the first of these reports, Habara and others followed the intermediate and late-term results of angioplasty with paclitaxel-coated balloons for treatment of in-stent restenotic lesions. In this prospective protocol, 468 patients with 550 ISR lesions were followed both clinically and through planned routine angiographic follow-up at 6 and 18 months. Of the 550 lesions in the trial, 114 involved restenosis of bare-metal stents (BMS), while 436 involved drug-eluting stents (DES). Clinical follow-up was obtained for 99% of patients at 18 months, while the majority (89% at 6 months and 88% at 18 months) underwent follow-up angiography.
At the 6-month time point, 13 lesions (13%) in the BMS group and 82 lesions (21%) in the DES group had developed recurrent restenosis. Repeat intervention was then performed in seven lesions (7%) from the BMS group and 54 lesions (14%) in the DES group. Among the remaining lesions for which there was not restenosis at 6 months, 18-month angiography demonstrated significant restenosis in only two patients (2.5%) in the BMS group, but for 50 lesions (16.8%) in the DES group. This late restenosis occurring in the DES group was the most striking finding of the study, and calls into question the durability of the response of ISR lesions to drug-coated balloon angioplasty. In addition, the results of repeat intervention were clearly poorer when the initial stent had been a DES, as compared with a BMS.
The study by Alfonso et al was a randomized trial comparing paclitaxel-coated balloon angioplasty with restenting to everolimus-eluting stents for treatment of ISR. All patients in this study had developed ISR from drug-eluting stents. This multi-institution trial, carried out at 23 centers in Spain, randomized 309 ISR patients to either drug-coated balloon angioplasty (n = 154) or to repeat stenting (n = 155). Clinical-follow up at 1 year was complete for all patients, and demonstrated a significant reduction in the composite endpoint of cardiac mortality, myocardial infarction (MI), and target vessel revascularization in the repeat stenting group vs the drug-coated angioplasty group (10% vs 18%; P = 0.04). As expected, this difference was primarily accounted for by a lower need for target vessel revascularization (8% vs 16%; P = 0.035). The majority (90%) of patients underwent follow-up angiography at a median of 247 days, showing that patients in the restenting arm had significantly larger minimal lumen diameter, net lumen gain, and lower percent diameter stenosis and binary restenosis rate as compared with the drug-coated balloon patients.
Taken together, these results suggest superior clinical as well as angiographic results with a strategy of repeat stenting, as compared with using drug-coated balloons for treatment of in-stent restenosis.
Stent restenosis remains a vexing clinical problem, even in the era of the latest generation of drug-eluting stents. Plain balloon angioplasty of these ISR lesions carries a high recurrence rate. Other approaches are needed.
The observational drug-coated balloon study, which included a mix of BMS and DES restenosis, confirmed something that on further reflection seems to make sense: ISR of DES is harder to treat and has a worse overall prognosis. Presumably, this is because DES ISR already has been treated with one of the best available devices and drugs, and is less likely to respond fully the second time around. In this series of drug-coated balloon treatment, the more interesting finding was the development of late restenosis in a significant proportion of patients between 6 and 18 months. When both early and late failure are taken into account, more than 30% of patients had developed repeat restenosis by 18 months following drug-coated balloon treatment.
When compared with restenting with a standard everolimus-eluting stent, patients with a paclitaxel-coated balloon clearly fared worse both clinically and angiographically in the randomized trial. Repeat stenting with DES should, for now, be considered the default treatment for ISR. For those of us practicing in the United States, these results may provide some reassurance that the best available treatment is among the options currently approved by the FDA. Nevertheless, there is considerable potential to do better in this arena, and newer devices (drug-eluting balloons using sirolimus analogues, bioresorbable scaffolds, etc.) certainly will be studied as they become available.
- Scheller B et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355:2113-2124.