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Paclitaxel coated balloons, the time for awareness has come
International Journal of Cardiology 164 (2013) 1–2
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Paclitaxel coated balloons, the time for awareness has come Bernardo Cortese a,⁎, Gregory A. Sgueglia b, Juan F. Granada c a b c
Scientific Research Director, Interventional Cardiology, Humanitas Gavazzeni, Bergamo, Italy Interventional Cardiology, Ospedale S.M. Goretti, Latina, Italy Executive Director and Chief Scientific Officer, Skirball Center for Cardiovascular Research, Columbia University Medical Center, NY, United States
a r t i c l e
i n f o
Article history: Received 4 May 2012 Accepted 5 May 2012 Available online 1 June 2012 Keywords: Paclitaxel-coated balloon Drug-eluting balloon Restenosis Clinical research New device
a b s t r a c t Over the last decade, a myriad of small clinical studies using a wide variety drug coated balloons (DCB) has shown the potential efficacy profile of this technology in specific clinical settings, especially coronary instent restenosis and peripheral artery disease. However, also due to the negative results of some small clinical studies, a big sense of confusion and uncertainty still exists among device developers and clinicians on current DCB indications. The advantages of DCB consist in non-polymeric delivery of anti-proliferative drugs limited to the time of the highest activity of the neointimal restenotic process after vessel injury, maintenance of vessel anatomy and potential to decrease delayed healing. Moreover, this field is rapidly evolving and includes lower-dose formulations, dedicated drug delivery reservoirs and alternative drugs. As these technologies emerge, we hope that some of the lessons learned will bring to proper validation strategies and solid experimental and clinical experimentations. © 2012 Elsevier Ireland Ltd. All rights reserved.
“You, catholic, call him the tabernacle prisoner. And there you keep him in custody in his dark but golden jail.” Hans Urs Von Balthasar So far the churchgoer was charged in the nineteenth century due to his wicked lifestyle, where he seemed to remember of God only the Sunday during the mass, sixty minutes per week condensed in the church, then he came back to his life as a sinner. We fear that drug coated balloon (DCB) technologies will share the same destiny, if common awareness does not change current habits. Over the last decade, a myriad of small clinical studies using a wide variety of Paclitaxel coating formulations have shown the potential efficacy profile in specific clinical settings, specifically in coronary in-stent restenosis and superficial femoral artery disease [1,2]. In addition, experimental data has shown the unique pharmacokinetic, tissue safety and efficacy profile of this technology [3]. However, despite the increasing scientific and clinical interest aroused in our field, a big sense of confusion and uncertainty still exists among device developers and clinicians abroad. Over the last several years, we have seen a wide variety of clinical trial designs including lesion sub-sets (i.e., bifurcations, de novo lesions and STEMI) [4,5] (P. Stella, Results of the DEB AMI trial, TCT 2011, Washington DC, US), that have not been sufficiently studied ⁎ Corresponding author at: Interventional Cardiology, Humanitas Gavazzeni, Bergamo, Via Gavazzeni, 37, Bergamo, Italy. Tel.: +39 0354204351; fax: +39 0354204345. E-mail address: [email protected] (B. Cortese). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.037
at the experimental setting [1]. Some of these studies, usually small and not properly controlled, have yielded confusing efficacy and safety results thus tainting the clinical potential of this technology. Then, despite the fact that this technology has been already commercially introduced in some countries around the world and it is currently used in a wide variety of clinical settings, its clinical applicability is still unknown. The questions are still multiple and widely unanswered; “which patient benefits the most following DCB treatment? Which type of lesion would be better suited for DCB therapy? Is there a true competitive advantage over drug-eluting stents?” we would face a troubled answer. Notwithstanding, the interventional community appears to believe in the therapeutic and safety profile of this technology and seems to find the concept of local delivery of anti-proliferative drug without the need of a permanent polymeric implant appealing. In the last couple of years, DCB have become one of the most interesting technological developments in interventional cardiology. Indeed, DCB theoretically offer several advantages compared to drug eluting stents including single non-polymeric delivery of antiproliferative drugs limited to the time of the highest activity of the neointimal process following vessel injury caused by percutaneous intervention; maintenance of the original vessel anatomy and potential to decrease delayed healing owing to the lack of continuous presence of a polymer matrix [3]. There is already evidence that in specific clinical settings, the longterm clinical efficacy of the original Paccocath® formulation is maintained [6]. In addition, other technology followers using similar technological principles have shown comparable short-term results
2
Editorial
Fig. 1. Timeline of CE mark obtaining for drug-coated balloons currently available in Europe.
(A. Colombo, Results of the BELLO trial, JIM 2012, Rome, Italy). However, due to the size and nature of these studies, it is premature and challenging to compare head to head the relative efficacy of these different technological approaches. Based on current data, the best clinical scenario in the coronary territory seems to be in-stent restenosis [7]. However, its relative efficacy in drug eluting stent restenosis is still unclear. In addition, although the data in de novo coronary lesions is scarce and controversial, the potential use of this technology in this particular application is quite appealing. Differences in drug transfer and tissue pharmacokinetics will make a difference regarding the safety and efficacy profile of these particular clinical scenarios. The field of DCB technologies is rapidly evolving and includes lower-dose formulations, dedicated drug delivery reservoirs and alternative drugs (J. Granada, Second generation DCB, TCT 2011, Washington DC, US). These emerging technologies may offset the technical and biological challenges seen with first generation DCB technologies. As these technologies emerge, it is important that some of the lessons learned during the early development of DCB technologies are adopted thus avoiding the premature introduction of immature technologies. Finally, the unique technological make up of these devices require that proper validation strategies bring together technological expertise and solid experimental and clinical background data. Unfortunately, to date, the rush of investigators to prematurely test new
DCB technologies has regrettably weakened rather than increased the knowledge on some specific clinical settings. In conclusion, in this emerging field all involved parties should work together to properly validate and introduce DCB into the clinical arena (Fig. 1). It is important that industry carefully design the studies and consequently their commercialization strategies based on large randomized controlled trials. At the early stages of development, so many negative or inconclusive studies produce harm instead of providing further support for the development of this technology. In addition, although early human clinical studies are important as a preliminary step of the technology development cycle, it is also important that clinical investigators select the proper clinical scenarios and outcomes based on solid technological and experimental data. Due to these facts, DCB are now reserved as a second-line of therapy in the coronary territory. However, many believe they have much to offer for the treatment of lesions other than in-stent restenosis. What we now need is that beyond the hype created by a new technological bubble, a new level of awareness occurs among researchers and clinicians working on this field toward the design of well balanced, statistically robust and, mostly, clinically relevant randomized controlled trials aiming to seek the proper clinical place of DCB in the interventional armamentarium. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Cortese B, Bertoletti A. Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data. Int J Cardiol Nov. 1 2012;161(1):4–12. [2] Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med Feb. 14 2008;358(7):689–99. [3] Gray WA, Granada JF. Drug-coated balloons for the prevention of vascular restenosis. Circulation Jun. 22 2010;121(24):2672–80. [4] Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart Aug. 2010;96(16):1291–6. [5] Mathey DG, Wendig I, Boxberger M, Bonaventura K, Kleber FX. Treatment of bifurcation lesions with a drug-eluting balloon: the PEPCAD V (Paclitaxel Eluting PTCA Balloon in Coronary Artery Disease) trial. EuroIntervention May 2011;7(Suppl. K): K61–5. [6] Scheller B, Clever YP, Kelsch B, et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. J Am Coll Cardiol Interv Mar. 2012;5:323–30. [7] Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med Nov. 16 2006;355(20): 2113–24.
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Paclitaxel coated balloons, the time for awareness has come Bernardo Cortese a,⁎, Gregory A. Sgueglia b, Juan F. Granada c a b c
Scientific Research Director, Interventional Cardiology, Humanitas Gavazzeni, Bergamo, Italy Interventional Cardiology, Ospedale S.M. Goretti, Latina, Italy Executive Director and Chief Scientific Officer, Skirball Center for Cardiovascular Research, Columbia University Medical Center, NY, United States
a r t i c l e
i n f o
Article history: Received 4 May 2012 Accepted 5 May 2012 Available online 1 June 2012 Keywords: Paclitaxel-coated balloon Drug-eluting balloon Restenosis Clinical research New device
a b s t r a c t Over the last decade, a myriad of small clinical studies using a wide variety drug coated balloons (DCB) has shown the potential efficacy profile of this technology in specific clinical settings, especially coronary instent restenosis and peripheral artery disease. However, also due to the negative results of some small clinical studies, a big sense of confusion and uncertainty still exists among device developers and clinicians on current DCB indications. The advantages of DCB consist in non-polymeric delivery of anti-proliferative drugs limited to the time of the highest activity of the neointimal restenotic process after vessel injury, maintenance of vessel anatomy and potential to decrease delayed healing. Moreover, this field is rapidly evolving and includes lower-dose formulations, dedicated drug delivery reservoirs and alternative drugs. As these technologies emerge, we hope that some of the lessons learned will bring to proper validation strategies and solid experimental and clinical experimentations. © 2012 Elsevier Ireland Ltd. All rights reserved.
“You, catholic, call him the tabernacle prisoner. And there you keep him in custody in his dark but golden jail.” Hans Urs Von Balthasar So far the churchgoer was charged in the nineteenth century due to his wicked lifestyle, where he seemed to remember of God only the Sunday during the mass, sixty minutes per week condensed in the church, then he came back to his life as a sinner. We fear that drug coated balloon (DCB) technologies will share the same destiny, if common awareness does not change current habits. Over the last decade, a myriad of small clinical studies using a wide variety of Paclitaxel coating formulations have shown the potential efficacy profile in specific clinical settings, specifically in coronary in-stent restenosis and superficial femoral artery disease [1,2]. In addition, experimental data has shown the unique pharmacokinetic, tissue safety and efficacy profile of this technology [3]. However, despite the increasing scientific and clinical interest aroused in our field, a big sense of confusion and uncertainty still exists among device developers and clinicians abroad. Over the last several years, we have seen a wide variety of clinical trial designs including lesion sub-sets (i.e., bifurcations, de novo lesions and STEMI) [4,5] (P. Stella, Results of the DEB AMI trial, TCT 2011, Washington DC, US), that have not been sufficiently studied ⁎ Corresponding author at: Interventional Cardiology, Humanitas Gavazzeni, Bergamo, Via Gavazzeni, 37, Bergamo, Italy. Tel.: +39 0354204351; fax: +39 0354204345. E-mail address: [email protected] (B. Cortese). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.037
at the experimental setting [1]. Some of these studies, usually small and not properly controlled, have yielded confusing efficacy and safety results thus tainting the clinical potential of this technology. Then, despite the fact that this technology has been already commercially introduced in some countries around the world and it is currently used in a wide variety of clinical settings, its clinical applicability is still unknown. The questions are still multiple and widely unanswered; “which patient benefits the most following DCB treatment? Which type of lesion would be better suited for DCB therapy? Is there a true competitive advantage over drug-eluting stents?” we would face a troubled answer. Notwithstanding, the interventional community appears to believe in the therapeutic and safety profile of this technology and seems to find the concept of local delivery of anti-proliferative drug without the need of a permanent polymeric implant appealing. In the last couple of years, DCB have become one of the most interesting technological developments in interventional cardiology. Indeed, DCB theoretically offer several advantages compared to drug eluting stents including single non-polymeric delivery of antiproliferative drugs limited to the time of the highest activity of the neointimal process following vessel injury caused by percutaneous intervention; maintenance of the original vessel anatomy and potential to decrease delayed healing owing to the lack of continuous presence of a polymer matrix [3]. There is already evidence that in specific clinical settings, the longterm clinical efficacy of the original Paccocath® formulation is maintained [6]. In addition, other technology followers using similar technological principles have shown comparable short-term results
2
Editorial
Fig. 1. Timeline of CE mark obtaining for drug-coated balloons currently available in Europe.
(A. Colombo, Results of the BELLO trial, JIM 2012, Rome, Italy). However, due to the size and nature of these studies, it is premature and challenging to compare head to head the relative efficacy of these different technological approaches. Based on current data, the best clinical scenario in the coronary territory seems to be in-stent restenosis [7]. However, its relative efficacy in drug eluting stent restenosis is still unclear. In addition, although the data in de novo coronary lesions is scarce and controversial, the potential use of this technology in this particular application is quite appealing. Differences in drug transfer and tissue pharmacokinetics will make a difference regarding the safety and efficacy profile of these particular clinical scenarios. The field of DCB technologies is rapidly evolving and includes lower-dose formulations, dedicated drug delivery reservoirs and alternative drugs (J. Granada, Second generation DCB, TCT 2011, Washington DC, US). These emerging technologies may offset the technical and biological challenges seen with first generation DCB technologies. As these technologies emerge, it is important that some of the lessons learned during the early development of DCB technologies are adopted thus avoiding the premature introduction of immature technologies. Finally, the unique technological make up of these devices require that proper validation strategies bring together technological expertise and solid experimental and clinical background data. Unfortunately, to date, the rush of investigators to prematurely test new
DCB technologies has regrettably weakened rather than increased the knowledge on some specific clinical settings. In conclusion, in this emerging field all involved parties should work together to properly validate and introduce DCB into the clinical arena (Fig. 1). It is important that industry carefully design the studies and consequently their commercialization strategies based on large randomized controlled trials. At the early stages of development, so many negative or inconclusive studies produce harm instead of providing further support for the development of this technology. In addition, although early human clinical studies are important as a preliminary step of the technology development cycle, it is also important that clinical investigators select the proper clinical scenarios and outcomes based on solid technological and experimental data. Due to these facts, DCB are now reserved as a second-line of therapy in the coronary territory. However, many believe they have much to offer for the treatment of lesions other than in-stent restenosis. What we now need is that beyond the hype created by a new technological bubble, a new level of awareness occurs among researchers and clinicians working on this field toward the design of well balanced, statistically robust and, mostly, clinically relevant randomized controlled trials aiming to seek the proper clinical place of DCB in the interventional armamentarium. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Cortese B, Bertoletti A. Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data. Int J Cardiol Nov. 1 2012;161(1):4–12. [2] Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med Feb. 14 2008;358(7):689–99. [3] Gray WA, Granada JF. Drug-coated balloons for the prevention of vascular restenosis. Circulation Jun. 22 2010;121(24):2672–80. [4] Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart Aug. 2010;96(16):1291–6. [5] Mathey DG, Wendig I, Boxberger M, Bonaventura K, Kleber FX. Treatment of bifurcation lesions with a drug-eluting balloon: the PEPCAD V (Paclitaxel Eluting PTCA Balloon in Coronary Artery Disease) trial. EuroIntervention May 2011;7(Suppl. K): K61–5. [6] Scheller B, Clever YP, Kelsch B, et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. J Am Coll Cardiol Interv Mar. 2012;5:323–30. [7] Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med Nov. 16 2006;355(20): 2113–24.