Paclitaxel-coated balloon catheter for in-stent restenosis (ISR)

1) Background

In-stent restenosis (ISR) after coronary percutanous intervention (PCI) still occurs with a frequency between 15 and 20% depending on the treated patient population, vessel size, and complexity of the lesion [1].

The introduction of drug eluting stents (DES) represents a major clinical advance and has significantly reduced the need for treatment of restenosis. However, the initial results of 0% restenosis have not been shown to be achievable under “real world” conditions [1].

Rates of restenosis after implantation of DES range between 13-22%. In addition, recent studies have demonstrated that the use of DES may be associated with a higher incidence of early and late stent thrombosis compared to the use of bare metal stents (BMS) [2-5]. The underlying molecular and cellular reason for late stent thrombosis seem to be due to a delayed reendothelialization process leaving the stents struts exposed to the circulation even 6 month after stent implantation. Stent thrombosis is associated with a high mortality and especially occurs after (premature) discontinuation of dual antiplatelet therapy.

The BASKET LATE study shows that :

• 4.9% of the patients with drug eluting stent suffer from cardiac death or acute myocardial infarction (AMI) in the subsequent year after termination of dual platelet inhibition compared to 1.3% in patients with implantation of a BMS (p=0.01) [4]. 

Furthermore, a meta-analysis of first generation drug eluting stents suggests :

• a highincidence of total mortality and AMI of 38% (Sirolimus eluting stent, SES) and 16% (Paclitaxel eluting stent, PES) compared to control BMS (p-value: SES vs BMS: 0.03 ; PES vs BMS. 0.68) [6].

Besides various other data underlining the safety of DES and weaknesses of the studies demonstrating increased rates of cardiovascular events after DES, there is a need for new treatment options for ISR even in the era of DES. In the following we present a new option for patients with the need for treatment of significant restenosis.

2) Paclitaxel-coated balloon catheter for in-stent restenosis

Scheller et al. recently investigated the effect of a paclitaxel – coated balloon in patients with ISR [7]. Paclitaxel is an anti-proliferative acting agent previously used for stent coating which inhibits proliferation of vascular smooth muscle cells. The PACCOCATH-ISR study included 52 patients with ISR. Patients were randomized in this double-blind multicenter trial either to receive :

• traditional treatment of their ISR using an uncoated angioplasty balloon or
• to the paclitaxel-coated balloon.

The primary endpoint of the study was late luminal loss in angiography.
Secondary endpoints included binary restenosis and major adverse cardiac events (MACE).

The authors demonstrated that :

• late luminal loss was 0.74±0.86mm in the uncoated balloon group vs. 0.03±0.48mm in the paclitaxel-coated balloon group (p=0.002).
• 43% of the uncoated balloon group suffered from restenosis whereas only 5% of the paclitaxel-coated balloon group displayed relevant restenosis (p=0.002).
• The rate of MACE was reduced in the treatment group to 4% vs. 31% in the control group (p=0.01) mainly due to a reduced rate of target lesion revascularization in the paclitaxel group.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

Apparently, the local delivery of an anti-proliferative drug after short contact with vascular smooth muscle cells (time of balloon inflation was 83.7±49.6 and 81.5±48.7 seconds for uncoated and paclitaxel-coated balloon, respectively) is sufficient to effectively inhibit vascular smooth muscle cell proliferation and concomitant re-restenosis of the target vessel.

The described procedure seems to have the advantage of providing uniformly effective concentrations of the anti-proliferative substance within a short timeframe compared to DES which are characterized by a more inhomogenous, slow-release of the drug over a much longer timeframe.

One may speculate that this novel strategy of short-term contact without any further drug release may result in an enhanced reendothelialisation process potentially preventing stent thrombosis.

In this context it is crucial to mention that both groups received only a 4-week regimen of dual platelet inhibition therapy. Despite the convincing results one has to keep in mind that the study has to be considered a pilot trial due to the limited patient number.

The challenging questions will be whether this concept is transferable to primary atherosclerotic lesion treatment and whether it is superior to DES implantation in ISR.