Long-term Data Support Paclitaxel-Coated Balloons for In-Stent Restenosis

Long-term follow-up of patients treated for drug-eluting stent restenosis following an initial PCI suggests that a drug-coated balloon (DCB) is just as safe and effective as a second round of stenting.

At 10 years, the balloon and stent, both paclitaxel-based, each offered comparable incidence of the primary composite endpoint of cardiac death, target-vessel MI, target-lesion thrombosis, or target-lesion revascularization. Both the DCB and DES—an early-generation device—were superior to plain balloon angioplasty alone for preventing repeat target lesion revascularization, report investigators.

“Overall, it’s important to stress that at 10 years, the drug-based-treatment strategies—the drug-coated stent and the drug-coated balloon—resulted in a significant reduction in target lesion revascularization rates,” senior investigator Sebastian Kufner, MD (Deutsches Herzzentrum, Munich, Germany), told TCTMD.

“I think that’s noteworthy because you have a situation where a brief, 1-minute inflation of a drug-coated balloon results in a significant 43% relative risk reduction [versus plain balloon angioplasty] in target lesion revascularization at 10 years,” he said. “For the European doctors, for which drug-coated balloons are part of daily practice, the high efficacy is reassuring. You have a higher efficacy compared with plain-old balloon angioplasty, but the same efficacy as drug-eluting stents, all without a trade-off in safety out to 10 years.”  

Data from the US suggest that the incidence of in-stent restenosis in unselected patients undergoing midterm angiographic follow-up is around 10%, said Kufner. Additionally, registry data have previously shown that among 5 million patients undergoing PCI between 2009 and 2017, more than 10% were procedures that included treatment of in-stent restenosis.

“It’s a very common problem,” said Kufner. “We also know that patients presenting with in-stent restenosis are more challenging compared with patients with native coronary artery disease. This is particularly true for patients with drug-eluting stent in-stent restenosis. Compared with bare-metal stent in-stent restenosis, in-stent restenosis with a drug-eluting stent is more difficult to treat.”

In Europe, operators have several options to treat in-stent restenosis: plain-old balloon angioplasty, DCB angioplasty, and DES. Based on the 2018 European myocardial revascularization guidelines, both DCB and DES are recommended strategies (class I, level of evidence A) for treating patients with either BMS or DES in-stent restenosis. In the US, however, there are as yet no Food and Drug Administration-approved DCBs for coronary in-stent restenosis, although the agency has granted breakthrough device designation to several devices.

“In Europe, drug-coated balloons are very, very common,” said Kufner. “Specifically in Germany, drug-coated balloons are a very common treatment for in-stent restenosis.”

At 10 years, the new analysis is the longest follow-up to date looking at use of DCBs for the treatment of in-stent restenosis. Its results were recently published in the European Heart Journal.

Good News for Interventional Cardiologists

The ISAR-DESIRE 3 trial included 402 patients with in-stent restenosis following PCI with a DES and randomized them to plain-balloon angioplasty alone, DCB angioplasty (SeQuent Please; B. Braun), or DES (Taxus Liberté; Boston Scientific). The 3-year results, which were published in 2015, showed that the DCB produced sustained antirestenotic benefit compared with this early-generation DES.

The 10-year results showed similar outcomes. The primary composite endpoint occurred in 72% patients assigned to balloon angioplasty, 55.9% treated with DCB, and 62.4% of patients treated with DES (P < 0.001). In a pair-wise comparison, there was no significant different in the primary endpoint between DCB and DES (HR 1.10; 95% CI 0.80-1.51), while both strategies were superior to balloon angioplasty alone.

The possibility to treat in-stent restenosis in a patient with stent failure, without implanting another stent layer, with a drug-coated balloon with proven 10-year efficacy is good news for interventional cardiologists. Sebastian Kufner

Similarly, there was no significant difference between DCB and DES with respect to the composite safety endpoint of cardiac death, target-vessel MI, or target-lesion revascularization (HR 1.29; 95% CI 0.84-1.98). As individual endpoints, there was no difference between DCB and DES when it came to target lesion revascularization, cardiac death, target-vessel MI, or target-lesion thrombosis at 10 years.

Kufner noted that ISAR-DESIRE 3 saw patients treated with an older-generation DES, one with relatively thicker struts compared with today’s devices. By contrast, the RIBS IV trial, a newer-generation everolimus-eluting stent (Xience Prime; Abbott Vascular), outperformed the DCB in patients with in-stent restenosis. Kufner believes that both current-generation DES and DCB are good treatment options for today’s patients presenting with in-stent restenosis, and while newer-generation limus-eluting stents may be slightly more efficacious than DCBs, the advantage is avoiding a second stent in the coronary arteries.

“The possibility to treat in-stent restenosis in a patient with stent failure, without implanting another stent layer, with a drug-coated balloon with proven 10-year efficacy is good news for interventional cardiologists who will be faced with this problem more and more in the time to come,” said Kufner.

The present study, say the researchers, also confirms that DES for in-stent restenosis is associated with worse rates of target lesion revascularization compared with DES for de novo disease. At 10 years, the rates were 44% and 39% with DCB and DES, respectively. In 10-year follow-up of the ISAR-TEST studies, which included patients treated for de novo CAD, the rates of target lesion revascularization ranged from 18% to 22.5%.        

Landmark Analysis

The researchers also performed a landmark analysis looking at the risk of events between 0-5 and 5-10 years. Here, they observed a higher risk of cardiac death, target-vessel MI, or target-lesion thrombosis with DES compared with DCB in the first 5 years (HR 2.27; 95% CI 1.06-4.84). The risk of all-cause and cardiac mortality was also more than twofold higher with DES compared with DCB during this earlier timepoint, as was the risk of target-lesion thrombosis.

To TCTMD, Kufner said the 3-year results hinted at a higher rate of mortality with the paclitaxel-eluting stent. The higher risk remained until 5 years but then diminished beyond that time point. He stressed caution when interpreting the findings, noting that the higher risk of death with DES might be a chance finding, particularly since there was no difference between DES and DCB at 10 years. Kufner also noted that they don’t think this finding has any link with the late safety concerns with paclitaxel-eluting stents used in peripheral artery disease. In ISAR-DESIRE 3, the early mortality signal with DES versus DCB was seen even though both strategies used paclitaxel.    

In an editorial, Domitilla Gentile, MD (Vita-Salute San Raffaele University, Milan, Italy), Mario Iannaccone, MD (San Giovanni Bosco Hospital, Turin, Italy), and Alaide Chieffo, MD (IRCCS San Raffaele Scientific Institute, Milan), noted that the safety of paclitaxel-coated balloons has been observed in meta-analyses, including one in patients treated for in-stent restenosis. Like the researchers, they say it’s possible the early mortality signal with the paclitaxel-eluting stent might be a chance finding.

They note that DCBs have been proposed as treatment for patients with small-vessel disease, patients at high risk for bleeding, and other indications, such as bifurcation lesions. “The long-term results of the ISAR-DESIRE 3 trial may be considered as a milestone in the treatment of ISR with DCBs, yet further studies are needed to evaluate the role of DCBs in different clinical subsets and lesion anatomies,” write the editorialists.