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“Everything started with balloon inflations in the coronary arteries,” reflects Raban Jeger (University Hospital Basel, Basel, Switzerland), discussing the evolution of percutaneous coronary intervention (PCI). The history begins with Andreas Grüntzig—the godfather of modern interventional cardiology—who performed the first-in-man coronary angioplasty in Zürich in 1977.
Skipping ahead to the modern era, the field of PCI has become dominated by stents, with drug-eluting stents (DES) utilised in the vast majority of cases. However, the use of latest-generation drug-coated balloons (DCB)—which offer the opportunity to deliver potent antiproliferative drugs into the coronary artery whilst “leaving nothing behind” in the vessel after deployment—is increasingly gaining traction in certain anatomic and clinical situations. This represents a return to the roots of coronary interventions as envisioned by Grüntzig decades ago.
Stent implantation can often precede complications over the long-term, Jeger opines, offering stent thrombosis and in-stent restenosis as the primary complications of concern. “With balloons you might have a problem at the beginning, but afterwards it stays stable,” he says. Jeger describes drug-coated balloons as being “complementary” to drug-eluting stents, noting that, with good technique and lesion preparation, positive results after predilatation mean that the need to leave a permanent structure behind within the vessel is removed.
Up to now, use of DCBs in the coronary arteries has mainly been targeted towards in-stent restenosis (ISR) where they have been shown to be highly effective and are acknowledged as a standard of care, underscored in current European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines, carrying a class I recommendation with evidence type A. A DCB-only approach in de novo lesions of coronary small-vessel disease is also seen as an alternative to a drug-eluting stent strategy, if current recommendations regarding optimal balloon angioplasty and subsequent DCB delivery are adequately followed. And, there is a growing body of evidence pointing to other clinical scenarios in which using a DCB may be beneficial, including bifurcation lesions, PCI in large coronary vessels, or complex coronary interventions.
“Drug-coated balloons work the best in situations where there is an anatomical or clinical complexity of the patients,” says Jeger, pointing to small vessels, long lesions or bifurcations as the predominant ‘anatomical’ situations to consider, and the presence of diabetes, renal failure or a history of bleeding complications as the predominant ‘clinical’ factors.
As one of the leading researchers into the efficacy of DCBs in de novo lesions, Jeger was the primary author of BASKET-SMALL 2, the largest trial to date to assess the use of DCBs in de novo coronary lesions, which compared 758 patients with lesions less than 3mm in diameter receiving either a DCB or a drug-eluting stent. “We had similar results for both treatments and therefore I would say that this is the biggest trial with the most influence in the field up until now,” says Jeger of the study’s results, which were published in The Lancet in 2018, and showed the non-inferiority of the DCB versus the drug-eluting stent, with similar levels of major adverse cardiovascular events (MACE; 7.5% for the DCB group vs 7.3% for the drug-eluting stent group, hazard ratio [HR] 0·97 [95% CI 0.58–1.64], p=0.9180) between the two groups.
He also highlights DEBUT, authored by Tuomas Rissanen (North Karelia Central Hospital, Joensuu, Finland), which investigated the use of DCBs for treatment of de novo lesions in patients with high bleeding risk. A total of 208 patients were enrolled in the trial, which reported that at nine months MACE had occurred in one patient (1%) in the drug-coated balloon group and in 15 patients (14%) in the bare-metal stent group.
RESTORE study programme
Of the more recent studies to add to the totality of DCB evidence is the RESTORE clinical programme, consisting of the RESTORE ISR China and RESTORE SVD China randomised trials, investigating the use of the Restore (Cardionovum) DCB in a variety of clinical scenarios, including coronary in-stent restenosis and de novo small vessel disease. Results to date have been positive, with a five-year analysis of RESTORE SVD China, presented at the 2022 Transcatheter Cardiovascular Therapeutics meeting (TCT, 16–19 September, Boston, USA), demonstrating equivalent long-term safety and efficacy compared to DES in a small vessel disease.
“Cardionovum have to be congratulated that they have quite a large research programme and this is very important because not every drug-coated balloon is the same,” comments Jeger. “The RESTORE programme is very nice because they tested the balloon in different situations like in-stent restenosis and small vessel disease and always had good results.”
Hybrid approach: HYPER & HYPER II
Though much research to date has focused on DCB-only strategies, the use of the Restore DCB as part of a hybrid approach—in which the balloon is used alongside a new-generation DES to treat de novo diffuse coronary artery disease—is one strategy that is gaining traction, and may be particularly useful in cases with very long lesions involving small vessels or in diabetic patients. This approach is being studied through the HYPER study programme, consisting of the HYPER pilot study and the ongoing HYPER II trial.
“Stent length is known to independently predict in-stent restenosis and stent thrombosis,” Alfonso Ielasi (IRCCS Ospedale Galeazzi Sant’Ambrogio, Milan, Italy), the principal investigator in both studies, tells Cardiovascular News. “Stenting with long—more than 60mm—overlapping DESs as well as implanting two stents in a true bifurcation, is associated with an increased ischaemic risk”.
Ielasi explains that in de novo diffuse coronary artery disease—long lesions and bifurcations with different reference vessel diameters (RVDs)—the option of using a hybrid strategy has the power to combine the features of both the DCB and the DES, making it an alternative approach to limit total stent length and its associated risks.
The hybrid strategy involves overlapping or superimposing a DES implanted in the larger (defined as having RVD >2.75mm), more proximal part of the vessel, or in the main branch of the bifurcation, alongside DCB inflation for a contiguous small vessel disease (defined as an RVD ≥2mm to <2.75mm) located in the distal segment or at the side branch of a bifurcation.
The HYPER pilot study was a prospective, single-arm, multicentre study which aimed to assess the feasibility and efficacy of the hybrid approach with Restore and a new-generation DES, enrolling a total of 106 patients between April 2019 and December 2020 in five centres across Italy.
“Diffuse coronary artery disease is frequently encountered in everyday interventional practice,” comments Ielasi, noting the relevance of the trial population to his everyday work. Though the trial enrolled more patients with acute coronary syndrome (ACS) than one may typically expect, the HYPER pilot study population consisted of 32% of patients suffering diabetes, putting it in line with everyday practice, says Ielasi, while the left anterior descending artery was the vessel most frequently treated—another common feature in practice.
Ielasi presented one-year clinical results of the HYPER study at EuroPCR 2022 (17–20 May, Paris, France), reporting that a hybrid approach is feasible, associated with a high rate of procedural success, as well as a low incidence at one-year of the device-oriented composite endpoint (DOCE) of cardiac death, target vessel myocardial infarction (TV-MI) and ischaemia-driven target lesion revascularisation (ID-TLR) in DES or DCB-treated segments.
“Procedural success, defined as final DES and DCB delivery with a percentage diameter stenosis of less than 30% in the DCB target segment and less than 10% in the DES target segment was obtained in a very high percentage of patients—96%,” Ielasi tells Cardiovascular News. The primary endpoint—DOCE—was 3.7%, mainly related to the ischaemia-driven TLR, Ielasi goes on to explain, concluding that “these results are very encouraging and support the use of the hybrid approach for the treatment of de novo diffuse coronary artery disease”.
Taking this programme further, HYPER II will continue on to assess the performance of a hybrid approach in very long (>38 mm) de novo lesions, with a goal to enrol 500 patients internationally, assessing a primary endpoint of target lesion failure (TLF) as well as a composite of cardiac death, target vessel myocardial infarction (MI) and ischaemia driven target lesion revascularisation (TLR) at one year.
“In my opinion, data coming from the HYPER and—I hope—HYPER II, will support the use of this hybrid approach in patients with complex diffuse coronary artery disease in order to limit the total stent length approaching diffuse disease with segments of different RVDs with DCBs, in this case with Restore paclitaxel eluting balloon in the smaller distal segment and DES implantation in the larger more proximal segment,” says Ielasi.
Using this approach operator could combine the best features of two important tools used every day in interventional practice to manage complex coronary artery disease.
