Drug-coated balloon (DCB) technology: A pioneer’s view of the historical evolution and future directions

In this article, Bruno Scheller explores advances in local drug delivery, from drug-coated balloons to novel antiproliferative agents. These innovations aim to reduce restenosis, minimize permanent implants, and pave the way for patient-specific coronary artery disease treatments.

Coronary stenting overcomes the major limitations of balloon angioplasty, namely, acute recoil, dissections, abrupt vessel closure and longer-term negative vessel remodelling. However, restenosis may be accelerated due to continued or increased neointimal proliferation associated with the permanent implant. Local intravascular drug delivery by drug-eluting stents (DES) has successfully addressed this cellular basis of restenosis in the coronary territory. However, even with the latest generation of DES, device-associated annual event rates of 2 to 3 % are seen beyond the first year^1,2. The risk of long-term events increases with the number and length of DES¹. Therefore, new alternative concepts aim at local drug delivery without permanent scaffolding.

The addition of a contrast agent that led to a surprising discovery

Antiproliferative agents such as paclitaxel are suitable for the prevention of local intravascular restenosis due to their high lipophilicity and tight binding to various cell constituents³. The addition of a contrast agent surprisingly resulted in the solubility of paclitaxel and its analogues far beyond the concentrations applied in previous investigations^4. In the porcine coronary model, the intracoronary bolus administration of a taxane-contrast medium formulation led to a significant reduction of neointimal formation after experimental coronary stent implantation despite the short application time^5,6. The surprising discovery was that sustained drug release is not a precondition for long-lasting restenosis inhibition.

In 2001, the basic premise of a more lesion-specific method of intramural drug delivery became embodied in the concept of a drug-coated balloon (DCB)⁷. By coating paclitaxel onto the surface of a conventional angioplasty balloon in combination with an excipient an effective local drug concentration was achieved with very low systemic exposure⁸. Basically, a proper solubilising agent such as iopromide or urea are mandatory in balloon-based local drug delivery⁹. For long-term anti-restenotic efficacy, the irreversible binding of paclitaxel to microtubules¹⁰ resulting in long persistence in the vascular cell¹¹ and favourable cell-specific effects¹² is helpful.

Ongoing investigations

Several alternative drugs to paclitaxel have been investigated¹³. Sirolimus and its analogues reversibly bind to FKBP12, forming a complex with the mammalian target of rapamycin (mTOR), thus blocking cell cycle progression at the juncture of the G1 and S phases¹⁴. In the case of DES, sirolimus must be released over a period of several months for an effective inhibition of neointimal proliferation¹⁵. Some additional challenges influence the local delivery of sirolimus DCB compared with traditional paclitaxel DCB, primarily the need for an efficient technology to transfer sirolimus into the vessel wall¹⁶. Specific measures are required to facilitate a controlled drug release without having a stent platform¹⁷.

Attempts to deliver sirolimus and its analogues include both nano-encapsulated sirolimus via a porous balloon and phospholipid encapsulated sirolimus nanocarriers via drug-coated balloons, however resulting in a rapid decline in tissue levels^18,19. Another crystalline coating with 4 μg sirolimus per mm² balloon surface allowed for a high drug delivery and, at the same time, sufficient tissue persistence of up to 50% after 4 weeks¹⁷. Early clinical data report comparable short-term efficacy to paclitaxel DCB in in-stent restenosis (ISR)^20,21. For de novo lesions, a phospholipid encapsulated sirolimus DCB did not achieve non-inferiority primary when compared to a proven paclitaxel DCB²² whereas a highly crystalline SCB was non-inferior to the paclitaxel DCB. However, late lumen enlargement generally seems to be more frequent with paclitaxel DCB than sirolimus DCB^20,23.

Eliminating the need for permanent implants

There are also major challenges in the clinical application of DCB. We started the first clinical studies in patients with ISR²⁴ and lesions in the superficial femoral artery (SFA)²⁵, which ultimately led to DCB becoming the standard therapy in the SFA worldwide. In the meantime, DCBs had the highest level of recommendation for ISR in the European guidelines, which was withdrawn in the current CCS guidelines for reasons that are difficult to understand.

References

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The Essentials - Drug-Coated Balloons

Author

Bruno Scheller

@bruno_scheller

Interventional cardiologist / Cardiologist

Homburg, Germany

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