- Email: [email protected]
Favorable Angiographic Outcome After Treatment of Infrapopliteal Lesions With Drug-Coated Balloons Without Clinical Benefit
JACC: CARDIOVASCULAR INTERVENTIONS
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2016.03.005
EDITORIAL COMMENT
Favorable Angiographic Outcome After Treatment of Infrapopliteal Lesions With Drug Coated Balloons Without Clinical Benefit What We Learn From a Meta-Analysis* Thomas Zeller, MD,a Michael R. Jaff, DOb
D
espite significant improvements in clinical
(Biotronik AG, Buelach, Switzerland) (10). The 1 study
outcomes of patients suffering from femo-
where DES served as the control cohort was small in
ropopliteal peripheral artery disease treated
size, including only 25 patients into each study arm
with drug-eluting technologies, dedicated bare-metal
with limited follow-up to 6 months only (13).
stent designs, and atherectomy endovascular technol-
The authors conclude that DCBs result in superior
ogies (1–8), durability of endovascular treatment of
angiographic outcomes expressed as a lower late lumen
longer infrapopliteal lesions remains one of the last
loss (LLL) at a median follow-up of 1 year without
significant challenges (9–11). In this issue of JACC:
clinical outcome differences. Their explanation for the
Cardiovascular Interventions, Cassese et al. (12)
missing link between angiographic superiority and
include 5 randomized—only 2 of them independently
clinical benefit is the heterogeneity of the study pop-
controlled—trials in a meta-analysis comparing the
ulations in terms of disease severity and differences in
performance of drug-coated balloons (DCB) and either
clinical patient follow-up protocols in particular
uncoated
regarding wound care (12). Is this conclusion justified?
percutaneous
transluminal
angioplasty
(PTA) (4 trials) or drug-eluting stent (DES) (1 trial)
First of all, are the angiographic findings correct?
placement. Of note is that 4 of those 5 trials used the
Are DCB really superior in terms of LLL over uncoated
same DCB—the IN.PACT Amphirion balloon (Med-
PTA and DES? Interestingly, only the 3 uncontrolled
tronic, Brescia, Italy)—which was withdrawn from
studies using the IN.PACT Amphirion DCB resulted in
the market after releasing the negative outcomes of
superior LLL outcomes (13–15) whereas both inde-
the largest interventional RCT in infrapopliteal
pendently core laboratory adjudicated and fully in-
arterial disease to date, the IN.PACT DEEP study
dustry funded studies found identical LLL outcomes
(9,13–15). This leaves only 72 of 641 patients in the
for the DCB and PTA cohorts suggesting a lack of
analysis treated with a still commercially available
biological efficacy of both DCB brands examined in
study device in certain countries, the Passeo 18 Lux
those 2 studies (9,10). Are controlled and uncontrolled trial outcomes comparable in particular if uncontrolled single-center trials are typically borne
*Editorials published in JACC: Cardiovascular Interventions reflect the
“within highly expert endeavors, highly committed to
views of the authors and do not necessarily represent the views of JACC:
the cause, dedicated and enthusiastic”? Positive
Cardiovascular Interventions or the American College of Cardiology. From the aDepartment of Angiology, Universitäts-Herzzentrum FreiburgBad Krozingen, Bad Krozingen, Germany; and bVascular Medicine, Mas-
technical outcomes of those mostly self-reported, self-adjudicated trials may be affected by systematic
sachusetts General Hospital, Boston, Massachusetts. Dr. Zeller has served
(positive), unmeasured errors or confounders and
as a consultant and received consulting fees, speaker honoraria, and sup-
simply mirror the center’s practice resulting in
port for accommodation and traveling from Boston Scientific, Cook, Med-
limited generalizability. The most relevant bias
tronic, W.L. Gore, Veryan, Spectranetics, Trireme, and Terumo. Dr. Jaff has
results from unblinded quantitative angiographic
served as a noncompensated advisor for Medtronic and a compensated board member of VIVA Physicians, a 501c3 not-for-profit education and
measurements and data analysis as it has already
research organization, and is an equity investor of PQ Bypass.
shown for renal denervation studies (16).
2
Zeller and Jaff
JACC: CARDIOVASCULAR INTERVENTIONS VOL.
-, NO. -, 2016 - 2016:-–-
Drug-Coated Balloon Benefits
The
potentially
incorrect
interpretation
of
a
In summary, despite the superior angiographic
favorable angiographic outcome without a clinical
outcome
benefit in this meta-analysis might result in prob-
the performance of DCB in infrapopliteal lesions
defined
as
LLL
in
this
meta-analysis
lematic conclusions such as the one suggesting
remains controversial. In particular the independently
that patency does not matter in infrapopliteal
controlled studies did not result in any proof of efficacy
interventions in general. The YUKON-BTK (YUKON-
of short-term balloon-based paclitaxel release to the
Drug-Eluting Stent Below The Knee-Randomized
wall of infrapopliteal arteries. The only remaining
Double-Blind) study (17) comparing DES with BMS
commercially available DCBs with infrapopliteal indi-
resulted not only in a significantly reduced restenosis
cation analyzed in this meta-analysis, the Passeo 18 Lux
rate favoring the DES at 2 years of follow-up but as a
DCB, did not show any technical or clinical benefit over.
result of the improved patency also resulted in a
Thus, the conclusion drawn Cassese et al. that DCBs
reduced target vessel revascularization and amputa-
result in favorable angiographic outcome compared to
tion rate, underlining the relevance of a patent vessel
PTA or DES must be interpreted with caution. The re-
in the long run.
sults of this meta-analysis cannot be generalized to
The conclusion from this meta-analysis that DCBs
other commercially available DCBs without published
result in favorable angiographic outcome as compared
clinical study data or to those DCBs still under clinical
to DES is misinterpreting the outcome of the original
evaluation. As a result of the limited proof of efficacy
IDEAS study (13). In this study, DES significantly out-
for DCBs with infrapopliteal indication this technology
performed the DCB cohort with regard to the primary
is not reimbursed even in countries where dedicated
study endpoint of binary restenosis rate at 6 months
reimbursement is established for DCB treatment of
(28% vs. 57.9%; p ¼ 0.0457). The nonsignificantly
femoropopliteal lesions, such as Germany.
reduced LLL in the DCB cohort (1.15 0.3 mm vs. 1.35 0.2 mm; p ¼ 0.62) in this study was simply the result of
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
an acutely higher lumen gain in the DES cohort (9.6
Thomas Zeller, Universitäts-Herzzentrum Freiburg-
2.2% vs. 24.8 3.5%; p < 0.0001). LLL is not the
Bad Krozingen, Klinik für Kardiologie und Angiologie
appropriate study endpoint comparing a stent-based
II, Südring 15, 79189 Bad Krozingen, Germany. E-mail:
therapy with a balloon-based therapy.
[email protected].
REFERENCES 1. Dake M, Ansel GM, Jaff MR, et al. Sustained safety and effectiveness of paclitaxel-eluting stents for femoropopliteal lesions: two-year follow-up from the Zilver PTX randomized and single-arm clinical studies. J Am Coll Cardiol 2013;61:2417–27. 2. Tepe G, Laird J, Schneider P, et al., for the IN. PACT SFA Trial Investigators. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131:495–502. 3. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol 2015;66:2329–38. 4. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53.
late re-intervention in the femoropopliteal artery 2 year results from the randomized Mimics trial. Circulation Cardiovasc Intervent 2016. In press. 8. McKinsey JF, Zeller T, Rocha-Singh KJ, Jaff MR, Garcia LA. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. J Am Coll Cardiol Intv 2014;7:923–33. 9. Zeller T, Baumgartner I, Scheinert D, et al., IN.PACT DEEP Trial Investigators. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol 2014;64:1568–76. 10. Zeller T, Beschorner U, Pilger E, et al. Paclitaxel-coated balloon in infrapoplilteal arteries: 12month results from the BIOLUX P-II randomized trial. J Am Coll Cardiol Intv 2015;8:1614–22. 11. Schmidt A, Ulrich M, Winkler B, et al. Angio-
5. Tepe G, Schnorr B, Albrecht T, et al. Five-year follow-up data of the Thunder trial: angioplasty of femoro-popliteal arteries with drug-coated balloons. J Am Coll Cardiol Intv 2015;8:102–8.
graphic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease. Catheter Cardiovasc Interv 2010; 76:1047–54.
6. IDEV. Supera Peripheral Stent System SSED
12. Cassese S, Ndrepepa G, Liistro F, et al. Drug-
(SUPERB). 2014. Available at: http://www.accessdata. fda.gov/cdrh_docs/pdf12/P120020b.pdf. Accessed February 23, 2016.
coated balloon for revascularization of infrapopliteal arteries. A meta-analysis of randomized trials. J Am Coll Cardiol Intv 2016;XX:XX.
7. Zeller T, Gaines PA, Ansel GM, Caro CG. A helical centerline stent improves patency and reduces
13. Siablis D, Kitrou PM, Spiliopoulos S, Katsanos K, Karnabatidis D. Paclitaxel-coated balloon
angioplasty versus drug-eluting stenting for the treatment of infrapopliteal long-segment arterial occlusive disease: the IDEAS randomized controlled trial. J Am Coll Cardiol Intv 2014;7:1048–56. 14. Liistro F, Porto I, Angioli P, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation 128:615–21. 15. Fanelli F, Cannavale A, Boatta E, et al. Lower limb multilevel treatment with drug-eluting balloons: 6-month results from the DEBELLUM randomized trial. J Endovasc Ther 2012;19:571–80. 16. Howard JP, Shun-Shin MJ, Hartley A, et al. Quantifying the 3 biases that lead to unintentional overestimation of the blood pressure-lowering effect of renal denervation. Circ Cardiovasc Qual Outcomes 2016;9:14–22. 17. Rastan A, Brechtel K, Krankenberg H, et al. Sirolimus-eluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared to bare-metal stents: long-term results from a randomized trial. J Am Coll Cardiol 2012;60: 587–91.
KEY WORDS angioplasty, drug-coated balloon, infra-popliteal artery, peripheral artery disease
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2016.03.005
EDITORIAL COMMENT
Favorable Angiographic Outcome After Treatment of Infrapopliteal Lesions With Drug Coated Balloons Without Clinical Benefit What We Learn From a Meta-Analysis* Thomas Zeller, MD,a Michael R. Jaff, DOb
D
espite significant improvements in clinical
(Biotronik AG, Buelach, Switzerland) (10). The 1 study
outcomes of patients suffering from femo-
where DES served as the control cohort was small in
ropopliteal peripheral artery disease treated
size, including only 25 patients into each study arm
with drug-eluting technologies, dedicated bare-metal
with limited follow-up to 6 months only (13).
stent designs, and atherectomy endovascular technol-
The authors conclude that DCBs result in superior
ogies (1–8), durability of endovascular treatment of
angiographic outcomes expressed as a lower late lumen
longer infrapopliteal lesions remains one of the last
loss (LLL) at a median follow-up of 1 year without
significant challenges (9–11). In this issue of JACC:
clinical outcome differences. Their explanation for the
Cardiovascular Interventions, Cassese et al. (12)
missing link between angiographic superiority and
include 5 randomized—only 2 of them independently
clinical benefit is the heterogeneity of the study pop-
controlled—trials in a meta-analysis comparing the
ulations in terms of disease severity and differences in
performance of drug-coated balloons (DCB) and either
clinical patient follow-up protocols in particular
uncoated
regarding wound care (12). Is this conclusion justified?
percutaneous
transluminal
angioplasty
(PTA) (4 trials) or drug-eluting stent (DES) (1 trial)
First of all, are the angiographic findings correct?
placement. Of note is that 4 of those 5 trials used the
Are DCB really superior in terms of LLL over uncoated
same DCB—the IN.PACT Amphirion balloon (Med-
PTA and DES? Interestingly, only the 3 uncontrolled
tronic, Brescia, Italy)—which was withdrawn from
studies using the IN.PACT Amphirion DCB resulted in
the market after releasing the negative outcomes of
superior LLL outcomes (13–15) whereas both inde-
the largest interventional RCT in infrapopliteal
pendently core laboratory adjudicated and fully in-
arterial disease to date, the IN.PACT DEEP study
dustry funded studies found identical LLL outcomes
(9,13–15). This leaves only 72 of 641 patients in the
for the DCB and PTA cohorts suggesting a lack of
analysis treated with a still commercially available
biological efficacy of both DCB brands examined in
study device in certain countries, the Passeo 18 Lux
those 2 studies (9,10). Are controlled and uncontrolled trial outcomes comparable in particular if uncontrolled single-center trials are typically borne
*Editorials published in JACC: Cardiovascular Interventions reflect the
“within highly expert endeavors, highly committed to
views of the authors and do not necessarily represent the views of JACC:
the cause, dedicated and enthusiastic”? Positive
Cardiovascular Interventions or the American College of Cardiology. From the aDepartment of Angiology, Universitäts-Herzzentrum FreiburgBad Krozingen, Bad Krozingen, Germany; and bVascular Medicine, Mas-
technical outcomes of those mostly self-reported, self-adjudicated trials may be affected by systematic
sachusetts General Hospital, Boston, Massachusetts. Dr. Zeller has served
(positive), unmeasured errors or confounders and
as a consultant and received consulting fees, speaker honoraria, and sup-
simply mirror the center’s practice resulting in
port for accommodation and traveling from Boston Scientific, Cook, Med-
limited generalizability. The most relevant bias
tronic, W.L. Gore, Veryan, Spectranetics, Trireme, and Terumo. Dr. Jaff has
results from unblinded quantitative angiographic
served as a noncompensated advisor for Medtronic and a compensated board member of VIVA Physicians, a 501c3 not-for-profit education and
measurements and data analysis as it has already
research organization, and is an equity investor of PQ Bypass.
shown for renal denervation studies (16).
2
Zeller and Jaff
JACC: CARDIOVASCULAR INTERVENTIONS VOL.
-, NO. -, 2016 - 2016:-–-
Drug-Coated Balloon Benefits
The
potentially
incorrect
interpretation
of
a
In summary, despite the superior angiographic
favorable angiographic outcome without a clinical
outcome
benefit in this meta-analysis might result in prob-
the performance of DCB in infrapopliteal lesions
defined
as
LLL
in
this
meta-analysis
lematic conclusions such as the one suggesting
remains controversial. In particular the independently
that patency does not matter in infrapopliteal
controlled studies did not result in any proof of efficacy
interventions in general. The YUKON-BTK (YUKON-
of short-term balloon-based paclitaxel release to the
Drug-Eluting Stent Below The Knee-Randomized
wall of infrapopliteal arteries. The only remaining
Double-Blind) study (17) comparing DES with BMS
commercially available DCBs with infrapopliteal indi-
resulted not only in a significantly reduced restenosis
cation analyzed in this meta-analysis, the Passeo 18 Lux
rate favoring the DES at 2 years of follow-up but as a
DCB, did not show any technical or clinical benefit over.
result of the improved patency also resulted in a
Thus, the conclusion drawn Cassese et al. that DCBs
reduced target vessel revascularization and amputa-
result in favorable angiographic outcome compared to
tion rate, underlining the relevance of a patent vessel
PTA or DES must be interpreted with caution. The re-
in the long run.
sults of this meta-analysis cannot be generalized to
The conclusion from this meta-analysis that DCBs
other commercially available DCBs without published
result in favorable angiographic outcome as compared
clinical study data or to those DCBs still under clinical
to DES is misinterpreting the outcome of the original
evaluation. As a result of the limited proof of efficacy
IDEAS study (13). In this study, DES significantly out-
for DCBs with infrapopliteal indication this technology
performed the DCB cohort with regard to the primary
is not reimbursed even in countries where dedicated
study endpoint of binary restenosis rate at 6 months
reimbursement is established for DCB treatment of
(28% vs. 57.9%; p ¼ 0.0457). The nonsignificantly
femoropopliteal lesions, such as Germany.
reduced LLL in the DCB cohort (1.15 0.3 mm vs. 1.35 0.2 mm; p ¼ 0.62) in this study was simply the result of
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
an acutely higher lumen gain in the DES cohort (9.6
Thomas Zeller, Universitäts-Herzzentrum Freiburg-
2.2% vs. 24.8 3.5%; p < 0.0001). LLL is not the
Bad Krozingen, Klinik für Kardiologie und Angiologie
appropriate study endpoint comparing a stent-based
II, Südring 15, 79189 Bad Krozingen, Germany. E-mail:
therapy with a balloon-based therapy.
[email protected].
REFERENCES 1. Dake M, Ansel GM, Jaff MR, et al. Sustained safety and effectiveness of paclitaxel-eluting stents for femoropopliteal lesions: two-year follow-up from the Zilver PTX randomized and single-arm clinical studies. J Am Coll Cardiol 2013;61:2417–27. 2. Tepe G, Laird J, Schneider P, et al., for the IN. PACT SFA Trial Investigators. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131:495–502. 3. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol 2015;66:2329–38. 4. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53.
late re-intervention in the femoropopliteal artery 2 year results from the randomized Mimics trial. Circulation Cardiovasc Intervent 2016. In press. 8. McKinsey JF, Zeller T, Rocha-Singh KJ, Jaff MR, Garcia LA. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. J Am Coll Cardiol Intv 2014;7:923–33. 9. Zeller T, Baumgartner I, Scheinert D, et al., IN.PACT DEEP Trial Investigators. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol 2014;64:1568–76. 10. Zeller T, Beschorner U, Pilger E, et al. Paclitaxel-coated balloon in infrapoplilteal arteries: 12month results from the BIOLUX P-II randomized trial. J Am Coll Cardiol Intv 2015;8:1614–22. 11. Schmidt A, Ulrich M, Winkler B, et al. Angio-
5. Tepe G, Schnorr B, Albrecht T, et al. Five-year follow-up data of the Thunder trial: angioplasty of femoro-popliteal arteries with drug-coated balloons. J Am Coll Cardiol Intv 2015;8:102–8.
graphic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease. Catheter Cardiovasc Interv 2010; 76:1047–54.
6. IDEV. Supera Peripheral Stent System SSED
12. Cassese S, Ndrepepa G, Liistro F, et al. Drug-
(SUPERB). 2014. Available at: http://www.accessdata. fda.gov/cdrh_docs/pdf12/P120020b.pdf. Accessed February 23, 2016.
coated balloon for revascularization of infrapopliteal arteries. A meta-analysis of randomized trials. J Am Coll Cardiol Intv 2016;XX:XX.
7. Zeller T, Gaines PA, Ansel GM, Caro CG. A helical centerline stent improves patency and reduces
13. Siablis D, Kitrou PM, Spiliopoulos S, Katsanos K, Karnabatidis D. Paclitaxel-coated balloon
angioplasty versus drug-eluting stenting for the treatment of infrapopliteal long-segment arterial occlusive disease: the IDEAS randomized controlled trial. J Am Coll Cardiol Intv 2014;7:1048–56. 14. Liistro F, Porto I, Angioli P, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation 128:615–21. 15. Fanelli F, Cannavale A, Boatta E, et al. Lower limb multilevel treatment with drug-eluting balloons: 6-month results from the DEBELLUM randomized trial. J Endovasc Ther 2012;19:571–80. 16. Howard JP, Shun-Shin MJ, Hartley A, et al. Quantifying the 3 biases that lead to unintentional overestimation of the blood pressure-lowering effect of renal denervation. Circ Cardiovasc Qual Outcomes 2016;9:14–22. 17. Rastan A, Brechtel K, Krankenberg H, et al. Sirolimus-eluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared to bare-metal stents: long-term results from a randomized trial. J Am Coll Cardiol 2012;60: 587–91.
KEY WORDS angioplasty, drug-coated balloon, infra-popliteal artery, peripheral artery disease