Drug-coated balloon angioplasty vs up-front stenting for de novo CAD: 3-year follow-up of REC-CAGEFREE I trial

Selected in JACC by A. N. Calik , M. Gökalp

The 3-year follow-up of the REC-CAGEFREE I trial demonstrated that a DCB-based strategy with rescue stenting was associated with a significantly higher rate of DOCE compared with contemporary DES implantation in patients with de novo, non-complex coronary artery disease.

Reviewers

Ali Nazmi Calik

@ANazmiCalik

Interventional cardiologist / Cardiologist

Dr. Siyami Ersek Göğüs Kalp Ve Damar Cerrahisi Eğitim Ve Araştırma Hastanesi - Istanbul, Türkiye

Murat Gökalp

Interventional cardiologist / Cardiologist

Dr. Siyami Ersek Göğüs Kalp Ve Damar Cerrahisi Eğitim Ve Araştırma Hastanesi -

Our Comment

This study reports the 3-year follow-up results of the REC-CAGEFREE I trial, an investigator-initiated, prospective, open-label, randomised, multicenter, non-inferiority trial conducted across 43 centers in China.

The trial compared a drug-coated balloon (DCB)-based strategy with up-front drug-eluting stent (DES) implantation in patients presenting with de novo, non-complex coronary artery disease (CAD), irrespective of vessel diameter.

The primary endpoint was the device-oriented composite endpoint (DOCE), defined as cardiovascular death, target-vessel myocardial infarction (TV-MI), or clinically and physiologically indicated target-lesion revascularization (CPI-TLR).

The trial was originally powered to assess non-inferiority at 2 years, whereas the 3-year outcomes reported here represent prespecified follow-up analyses that were not powered.

Infographic summarising key information from the 3-year follow-up of the REC-CAGEFREE I study - courtesy of Ali Nazmi Calik & Murat Gökalp

Infographic summarising key information from the 3-year follow-up of the REC-CAGEFREE I study - courtesy of Ali Nazmi Calik & Murat Gökalp

Why this study – the rationale/objective?

DES remain the standard of care for percutaneous coronary intervention (PCI) in patients with de novo coronary artery disease¹. However, permanent metallic scaffolds are associated with an ongoing annual risk of stent failure and often require prolonged dual antiplatelet therapy, increasing bleeding risk in selected patients^2,3. DCBs, by delivering antiproliferative therapy without leaving a permanent implant, have emerged as an attractive alternative particularly in in-stent restenosis and small vessel disease⁴. While prior randomised trials have demonstrated non-inferiority of DCBs compared with DES in small vessel lesions, robust data in de novo lesions without vessel size restriction have been limited.

The REC-CAGEFREE I trial was designed to address this gap by comparing a DCB-based strategy with contemporary DES implantation in patients with de novo, non-complex coronary lesions, irrespective of vessel diameter, and to evaluate whether a “leave-nothing-behind” approach could provide comparable mid-term clinical outcomes.

How was it executed? The methodology

The REC-CAGEFREE I trial was an investigator-initiated, open-label, randomised, non-inferiority trial conducted across 43 sites in China. The trial was powered for non-inferiority at 2 years; the present report provides prespecified 3-year clinical outcomes.

The study enrolled patients ≥ 18 years of age with acute or chronic coronary syndromes, requiring PCI for de novo, non-complex coronary lesions, irrespective of vessel diameter. Importantly, randomisation was performed only after successful lesion predilation, defined as TIMI 3 flow, ≤ 30 % residual stenosis, and absence of major (type D-F) dissections. Using a centralised web-based system, 2,272 patients were randomized in a 1:1 ratio to either a DCB-based strategy (with provisional rescue stenting if required) or up-front second-generation sirolimus-eluting stent (DES) implantation. After DCB angioplasty, rescue stenting, using the same stent platform as in the DES group, was mandated in the presence of NHLBI type D, E, or F dissections, TIMI flow grade < 3, or residual diameter stenosis > 30% by visual assessment.

• The primary endpoint was the device-oriented composite endpoint (DOCE), defined as cardiovascular death, target-vessel myocardial infarction, or clinically and physiologically indicated target-lesion revascularisation.
• Secondary endpoints included individual components of DOCE, patient-oriented composite outcomes (all-cause death, stroke, any myocardial infarction, or any revascularisation), major bleeding (BARC type 3 or 5), net adverse clinical events, and definite or probable device thrombosis.

What is the main result?

Between February 2021 and May 2022, a total of 2,902 patients with de novo coronary artery disease were screened for eligibility. Following successful lesion predilation, 2,272 patients were randomized to either a DCB-based strategy (n = 1,133) or up-front DES implantation (n = 1,139). Rescue stenting was required in 9.4 % of patients assigned to the DCB arm. Three-year follow-up was available in 97.3 % of participants.

• The primary endpoint (DOCE) occurred in 8.2 % of patients in the DCB group and 5.0 % in the DES group (absolute difference 3.21 %; 95 % CI 1.17-5.26; p = 0.002), demonstrating a significantly higher event rate with DCB-based strategy. This difference was mainly driven by a higher rate of clinically and physiologically indicated target-lesion revascularisation (4.2 % vs 1.6 %). Rates of cardiovascular death (3.0 % vs 2.5 %) and target-vessel myocardial infarction (2.0 % vs 1.8 %) were similar between groups.
• Landmark analysis showed that the largest difference occurred during the first year, with progressively smaller absolute differences beyond 1 year.
• In vessels ≥ 3.0 mm, DOCE was notably higher with DCB (9.2 % vs 4.3 %), whereas in small-vessel disease the difference was less pronounced (7.0 % vs 5.8 %).
• Major bleeding (BARC 3 or 5) was numerically lower in the DCB group (1.4 % vs 2.6 %), but this did not reach clear statistical significance.

Overall, DES was associated with fewer device-oriented events at 3 years, primarily due to lower rates of repeat revascularisation.

Critical reading and the relevance for clinical practice:

The 3-year follow-up of the REC-CAGEFREE I trial demonstrated that a DCB-based strategy with rescue stenting was associated with a significantly higher rate of DOCE compared with contemporary DES implantation in patients with de novo, non-complex coronary artery disease. This difference was primarily driven by an increased incidence of clinically and physiologically indicated target-lesion revascularisation, while cardiovascular death and target-vessel myocardial infarction rates were similar between groups. Notably, the largest divergence occurred within the first year, with the gap narrowing thereafter, suggesting that early procedural or lesion-related factors may explain the excess revascularisation rather than late adverse remodeling.

These findings contrast with prior evidence supporting DCB use in small vessel disease. In the BASKET-SMALL 2 trial, DCB angioplasty was non-inferior to second-generation DES in de novo small-vessel CAD, with sustained safety and efficacy up to 3 years⁴. However, unlike BASKET-SMALL 2, the REC-CAGEFREE I trial included lesions irrespective of vessel diameter, and more than half of treated vessels were ≥ 3.0 mm. In this subgroup, DES clearly outperformed DCB, indicating that extrapolation of small-vessel data to larger vessels may not be appropriate.

Earlier randomised trials such as DEBUT, PEPCAD NSTEMI, and REVELATION suggested non-inferiority of DCB strategies compared with bare-metal stents or DES in selected ACS populations^3,5,6. However, these studies were smaller and often focused on surrogate endpoints or specific lesion subsets. REC-CAGEFREE I, by enrolling a substantially larger population and comparing DCB with contemporary thin-strut sirolimus-eluting stents, provides more definitive comparative data in de novo disease.

Safety considerations also deserve attention. Concerns regarding paclitaxel-coated devices, particularly following peripheral artery studies such as SWEDEPAD, have raised questions about long-term mortality⁷. In the present study, no excess all-cause or cardiovascular mortality was observed with paclitaxel-coated balloons, consistent with prior coronary meta-analyses. Thus, the limitation of DCB in this setting appears to relate to durability rather than safety.

From a clinical standpoint, these findings reinforce current guideline recommendations that DES remains the preferred strategy for de novo coronary lesions, especially in larger vessels. While DCB may retain a role in small-vessel disease or in carefully selected high-bleeding-risk patients where shorter antiplatelet regimens are desirable, the present data do not support routine adoption of a “leave-nothing-behind” strategy in unselected de novo CAD. This study therefore meaningfully refines the boundaries of DCB use in contemporary interventional practice.

References

1. Writing Committee M, Lawton JS, TamisHolland JE, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79: e21-e129.
2. Madhavan MV, Kirtane AJ, Redfors B, et al. Stent-related adverse events >1 year after percutaneous coronary intervention. J Am Coll Cardiol. 2020;75:590-604.
3. Rissanen TT, Uskela S, Eranen J, et al. Drug coated balloon for treatment of de novo coronary- artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, noninferiority trial. Lancet. 2019;394:230-239.
4. Jeger RV, Farah A, Ohlow MA, et al. Drugcoated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised noninferiority trial. Lancet. 2018;392:849-856.
5. Scheller B, Ohlow MA, Ewen S, et al. Bare metal or drug-eluting stent versus drug-coated balloon in non-ST-elevation myocardial infarction: the randomised PEPCAD NSTEMI trial. EuroIntervention. 2020;15:1527-1533.
6. Vos NS, Fagel ND, Amoroso G, et al. Paclitaxel-coated balloon angioplasty versus drugeluting stent in acute myocardial infarction: the REVELATION randomized trial. JACC Cardiovasc Interv.2019;12:1691-1699.
7. Nordanstig J, James S, Andersson M, et al. Paclitaxel-coated versus uncoated devices for infrainguinal endovascular revascularisation in patients with intermittent claudication (SWEDEPAD 2): a multicentre, participant-masked, registry-based, randomised controlled trial. Lancet. 2025;406(10508):1115-1127.