Therapies Take on In-Stent Restenosis with Mixed Results

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NEW ORLEANS, LA—Two studies took on the challenge of in-stent restenosis therapy at this year’s American College of Cardiology Annual Scientific Session/i2 Summit, both of which were presented on April 3, 2011. One showed promising outcomes with a paclitaxel-eluting balloon following predilatation, while the other found that brachytherapy and sirolimus-eluting stents were surprisingly equivalent treatments over the long-term.

Predilatation Key with Paclitaxel Balloons

For the PEPPER (Paclitaxel-Eluting balloon in Patients PresEnting with in-stent Restenosis) trial, Christoph Hehrlein, MD, of the University Medical Center (Freiburg, Germany), and colleagues studied the effects of the paclitaxel-eluting Pantera Lux balloon (Biotronik, Vilvoorde, Belgium) in 81 patients with in-stent restenosis (53.1% BMS and 46.9% DES) who were enrolled at 9 European clinical sites between August 2009 and April 2010. The majority of patients (72.8%) presented with stable angina.

The Pantera Lux balloon combines known and novel technologies. Much like similar devices, it elutes paclitaxel (3.0 µg/mm²), “but it uses a new [lipophilic] excipient to keep the paclitaxel in a micro-crystalline structure,” said Dr. Hehrlein. Although the product has CE mark in Europe, it is not for sale in the United States.

In all, 81 lesions were first predilated with an uncoated balloon and then treated with a Pantera Lux balloon. Dual antiplatelet therapy was administered for 3 months following treatment.

Device success was high at 98.8%; in 1 case, the initial drug-eluting balloon was too short to cover the entire lesion, so a second balloon was used. Minimal lumen diameter was increased and percent diameter stenosis was reduced immediately after treatment. By 6 months, the primary endpoint of in-stent late-lumen loss was low and the treatment effect on percent diameter stenosis was largely maintained (table 1).

Table 1. QCA Results: In-Stent

In-segment results also were favorable after treatment and at 6 months, although the post-procedural reference vessel diameter was slightly lower in-segment than in-stent (2.79 ± 0.43 mm vs. 2.86 ± 0.39 mm), indicating some vasoconstriction.

The overall MACE rate at 6-month follow-up was 7.8%, with no cardiac deaths, 1 nonfatal MI within 24 hours of the procedure (1.3%), 4 cases of clinically driven TLR (5.2%), and 1 case of clinically driven TVR in a distal lesion (1.3%).

Treatment with the Pantera Lux balloon results in “very effective reduction of in-stent restenosis, regardless of whether BMS or DES restenosis were treated,” Dr. Hehrlein concluded, adding that a subanalysis of results according to stent type and data on 12-month clinical outcomes are forthcoming. “At least for focal lesions, I think a randomized trial of Pantera Lux against drug-eluting stents for in-stent restenosis should be conducted,” he added.

Session co-chair Roxana Mehran, MD, of Mount Sinai Medical Center (New York, NY), pointed out that the “stellar” PEPPER results come on the heels of another drug-eluting balloon from an earlier presentation that showed “horrible” outcomes. She suggested that perhaps PEPPER involved more focal lesions.

“It’s true that focal lesions are much easier to treat with a drug-eluting balloon, and the results will be much better,” Dr. Hehrlein replied, adding that in PEPPER, “every lesion was precisely predilated. I think that’s a mandatory task for application of a drug-eluting balloon.” The reason being that this step prepares the vessel wall to take up the drug, he explained.

Brachytherapy, SES Converge Over Time

During the same session, Oluseun Alli, MD, of the Mayo Clinic (Rochester, MN), presented 5-year follow-up from the SISR (SIrolimus-eluting Stents versus vascular brachytherapy for in-Stent Restenosis) trial, which randomized 384 patients with BMS in-stent restenosis to receive intravascular brachytherapy (n = 125) or sirolimus-eluting Bx Velocity stents (SES; Cordis, Miami Lakes, FL; n = 259). Baseline characteristics were similar with the exception of renal insufficiency, which was higher in patients who underwent stenting than in those treated with brachytherapy (9.3% vs. 3.2%; P = 0.04). Full follow-up data were available for nearly 90% of patients in each group.

The main analysis of the study, which was powered for 9-month outcomes, found a rate of target vessel failure of 21.6% with brachytherapy vs. 12.4% with SES (P = 0.02). By 5-year follow-up, however, the gap had narrowed, such that TVF rates were 36.8% for brachytherapy and 33.6% for SES, primarily driven by TVR.

Survival curves for MACE, TVF, TLR, and all-cause mortality indicated that both treatments produced similar outcomes at 5 years. However, freedom from MI was lower with SES than with brachytherapy at 88.3% vs. 96.6% (P = 0.012).

Both Q-wave MI (3.5%) and non-Q-wave MI (8.9%) rates were high for SES patients, mainly affecting target vessels. In brachytherapy patients, the rates were “unusually low” at 0 and 3.2%, respectively.

The study, initiated in 2003 and 2004, reflects its era, said Dr. Alli, noting that only 3 months of dual antiplatelet therapy were required at that time. At 2 years only 40% were on dual therapy, but by 5 years, that number had increased to approximately 55%.

Major bleeding rates were low through 5 years at 1.9% for SES and 0.8% for brachytherapy. Academic Research Consortium-defined definite and probable stent thrombosis, however, was numerically higher at the end of follow-up in the SES group (4.2%) compared with the brachytherapy group (2.4%; P = 0.055). Most events were very late, and there were no reports of acute or subacute stent thrombosis in either study arm.

“These data provide long-term follow-up on sirolimus-eluting stents for the very difficult problem of in-stent restenosis. These are very unique insights into the long-term performance of sirolimus-eluting stents, even though this trial was not designed or powered for 5-year follow-up,” Dr. Alli noted. Important questions raised include whether long-term use of dual antiplatelet therapy after brachytherapy affects outcomes, and whether ‘stent-in-stent’ treatment within the SES arm had downstream consequences. In addition, 90% of patients in the brachytherapy arm ultimately received DES during the 5-year follow-up period.

“But sirolimus-eluting stents remain a viable treatment option for the treatment of BMS in-stent restenosis,” he concluded.

Dr. Mehran commented that SISR demonstrates how little therapies have progressed. “This is a very important study showing us the late catch-up of sirolimus-eluting stents in the treatment of in-stent restenosis,” she said. “Whether or not there was crossover or other limitations, the fact is [that with] the strategy of using sirolimus-eluting stents vs. brachytherapy, I think that you’ll find at the end of the day at 5 years we’re back where we started.”

In short, “we should eat some humble pie,” Dr. Mehran noted.

Co-chair Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), also seemed troubled by late catch-up and its impact. “There is a worrisome accumulation of events in the late phase, [so] I think we need to be cautious about [interpreting] the rates of dual antiplatelet therapy,” he said. “The fluctuations that you see are more often a result of repeat events, such that patients get placed back on dual antiplatelet therapy when they have an event that is usually treated with PCI. So it doesn’t necessarily reflect an intention to treat, so to speak, as much as a reaction to what has happened.”

 

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Sources:
1. Hehrlein C. European multicenter first in man trial of a novel paclitaxel eluting balloon in patients presenting with in-stent restenosis. Presented at: American College of Cardiology Annual Scientific Session/i2 Summit; April 3, 2011; New Orleans, LA.

2. Alli O. Five-year follow-up of the SISR trial: A multicenter, randomized study of the sirolimus-eluting Bx Velocity stent versus intravascular brachytherapy in the treatment of patients with in-stent restenotic coronary artery lesions. Presented at: American College of Cardiology Annual Scientific Session/i2 Summit; April 3, 2011; New Orleans, LA.

 

 

Related Stories:

• Paclitaxel-Eluting Balloon Effective for DES Restenosis
• PEPCAD II: Paclitaxel Balloon Matches Taxus for Treating In-Stent Restenosis
• SISR at 3 Years: Is SES Superior to Brachytherapy for BMS Restenosis?