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Without a Trace…Metal Free PCI
Dr Aisha Gohar MD PhD, ST6 Interventional Fellow, Imperial College Healthcare NHS Trust
Key learning points:
Introduction
The field of interventional cardiology is constantly evolving. Bare metal stents (BMS) were initially introduced in the 1990s, overcoming the shortcomings of plain old balloon angioplasty (POBA) including acute vessel closure and vessel recoil. However, the full metal implants were found to cause neointimal hyperplasia with subsequent in-stent restenosis (ISR). (1) The introduction of drug eluting stents (DES) in 2002 was a game changer, providing the benefits of the metal layer of BMS and combining it with a polymer releasing an antiproliferative drug. (2) Despite the improvement of outcomes and the reduction in the required duration of dual antiplatelet therapy (DAPT) seen with newer generation DES, ISR has long remained its Achilles’ heel, occurring in 3-20% of patients. (1,3) Therefore there is always room in the market for new technologies that can overcome the shortfalls seen with DES.
Bioresorbable stents (BRS) were developed with the goal of reducing stent-related long term adverse events. The BRS consists of a temporary mechanical scaffold with a short-term site-specific release of antiproliferative agents before being degraded to inert end-products. Absorb is currently the only BVS with randomized trial data, however results have shown inferior efficacy and safety compared to DES during long term follow up, with a significantly increased risk of target lesion revascularisation and thrombosis. (4)
Drug coated balloon (DCB) catheters are made up of regular semi-compliant balloons and a matrix coating applied to the surface of the balloon comprised of two elements: a lipophilic active drug and a spacer which increase the solubility of the active drug which facilitates its transfer from the balloon surface to the vessel wall. They provide an attractive alternative to stent implantation, working by delivering an antiproliferative drug into the vessel wall with a single balloon inflation resulting in better vessel wall healing. DES releases the drug solely in between the stent struts and at the stent edges, whereas DCBs release the drug in a more even distribution avoiding an extra metallic layer. This metal free strategy allows for a reduction in the duration of DAPT required, with studies showing safety with a minimum of one month of therapy. (5)
Paclitaxel versus sirolimus eluting drug balloons
Paclitaxel was the first eluting drug showing efficacy in clinical trials and was recommended by NICE as treatment for BMS-ISR in 2010. (2) Its success was based on its higher lipophilic properties compared with limus-eluting DCBs, binding irreversibly to the microtubules resulting in excellent persistence of the drug. Newer generation sirolimus-eluting DCBs have recently been developed showing promising results in both ISR and de novo lesions. Magic Touch (Concept Medical, India) was the first sirolimus-eluting DCB (SCB) to be marketed in Europe in 2016. A recent combined analysis of two parallel randomized control trials showed non-inferiority of SCBs compared with paclitaxel-eluting DCBs (PCB) in ISR lesions. (6)
It is important to bear in mind that head to head randomized control trials comparing DCBs are lacking and a class effect of DCBs cannot be assumed.
Drug coated balloons for in-stent restenosis
ISR is defined by a significant reduction (>50%) of the lumen diameter within a stented segment or within 5 mm proximal or distal to the stent with BMS or DES. DCBs for ISR of BMS and DES have proven safety and efficacy outcomes with results comparable to DES, hence the high level of recommendation as class 1a in the latest ESC guidelines. (4) In this scenario, DCBs are beneficial over DES as they avoid the implantation of a second metallic layer. This is useful in cases when another metallic layer is undesirable, such as with multiple previous stent layers or the presence of a major side branch, as well as for patients at high bleeding risk. Even more so than with DES, lesion preparation prior to DCB use is of the utmost importance. The ISAR-DESIRE 4 trial highlighted the importance of neointimal modification with a greater minimal lumen diameter at 6-8 month follow up with lesions pre-dilated with scoring balloons compared to lesions pre-dilated with conventional balloons prior to DCB therapy. (7) It is therefore important to ensure adequate lumen expansion with the use of intravascular imaging in combination with adequate pre-dilatation with semi- or non- compliant balloons, plaque modification balloons such as cutting/scoring balloons and rotational/orbital atherectomy or intravascular lithotripsy in calcified lesions. Prior to DCB implantation, it is suggested to have < 30% residual stenosis with TIMI flow grade 3 and no flow limiting dissections. If lumen expansion is suboptimal, repeated DES should be considered.
Drug coated balloons for other indications including de novo lesions
More recently, the indications of DCBs have been extended to include de novo lesions, mainly of small vessel coronary artery disease. (8) Wan et al. reported the first-in-human outcomes of the SCB on a crystalline coating (SeQuent 4 μg/mm2, B. Braun Medical) as compared to a clinically proven PCB (SeQuent Please, 3 μg/mm2) for the treatment of de novo coronary lesions. Both DCB types showed similar angiographic courses with very low lumen loss in the treatment of DES after 6 months indicating that SCBs are as effective as PCBs. (9)
In contrast to ISR lesions, guidelines currently do not currently recommend DCBs for the treatment of de novo lesions. (4)
The use of DCBs for STEMI was investigated in the REVELATION trial which did not find any significant difference in fractional flow reserve (FFR) 6 months post primary PCI. (10) As of yet, there is little evidence for the use of DCB for larger vessels (>3.0 mm diameter).
The future of drug coated balloons
Other DCB using different limus-analogues drugs are currently being tested such as biolimus A9 in the REFORM randomized trial (Biolimus A9™). Their results will shed light on the potential of these drugs for the treatment of ISR and small vessels. The TRANSFORM II trial is an on going international randomized control trial enrolling patients with de novo disease of vessels between 2.0 – 3.0 mm in diameter, comparing sirolimus-eluting DCB with DES with a primary end point of target lesion failure at 4 years.
DCBs for very long lesions and chronic total occlusions will be assessed in the PICCOLETO III trial, an international randomized control trial comparing DES to paclitaxel- or sirolimus-eluting DCBs.
The “hybrid” approach is an interesting concept involving the use of both DES, for focal “spot” stenting, and DCB for longer segments of disease in smaller vessels. This approach is currently being assessed in registries.
Conclusions
There is a role for DCB for the treatment of ISR, which is also advocated by current guidelines. Although not recommended by current guidelines, there is growing evidence for their use in de novo lesions especially in small vessel disease. Despite the advantages of DCBs over DES, it is important to understand their limitations, recognise the appropriate indications and know when to still use DES if appropriate as a direct strategy or as a bailout strategy.
References
1) Giustino G. et al. Coronary In-Stent Restenosis. JACC State-of-the-Art Review. Journal of the American College of Cardiology.2022;80(4).
2) Eccleshall S. et al. The NICE recommendation for drug-coated balloons and its global impact. Therapeutic Advances in Cardiovascular Disease. 2015;9(3):87-94.
3) Alfonso F. et al. Management of in-stent restenosis. EuroIntervention 2022;18:e103-e123. DOI: 10.4244/EIJ-D-21-01034.
4) Franz-Josef Neumann et al. ESC Scientific Document Group, 2018 ESC/EACTS Guidelines on myocardial revascularization, European Heart Journal, Volume 40, Issue 2, 07 January 2019, 87–165.
5) Musumeci, G. et al. Drug-coated balloon angioplasty and 1 month DAPT strategy: Insights from the real world. Catheter Cardiovasc Interv. 2020; 96: 1021–1022.
6) Scheller B. et al. Combined Analysis of Two Parallel Randomized Trials of Sirolimus-Coated and Paclitaxel-Coated Balloons in Coronary In-Stent Restenosis Lesions. Circulation: Cardiovascular Interventions. 2022;15(9).
7) Kufner S. et al. Neointimal Modification with Scoring Balloon and Efficacy of Drug-Coated Balloon Therapy in Patients With Restenosis in Drug-Eluting Coronary Stents: A Randomized Controlled Trial. JACC Cardiovascular Interventions.2017;10(13): 1332-1340
8) Jeger R. et.al. for the BASKET-SMALL 2 Investigators. Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial. Lancet. 2020;396:1504–1510.
9) Wan Ahmad W.A., Nuruddin A.A., Abdul Kader M.A.S.K., et al. “Treatment of coronary de novo lesions by a sirolimus- or a paclitaxel-coated balloon”. J Am Coll Cardiol Intv 2022;15:7: 770-779.
10) Vos NS, Fagel ND, Amoroso G, Herrman J-PR, Patterson MS, Piers LH, van der Schaaf RJ, Slagboom T, Vink MA. Paclitaxel-coated balloon angioplasty versus drug-eluting stent in acute myocardial infarction: the REVELATION Randomized Trial. JACC Cardiovasc Interv 2019;12:1691–1699.