- Email: [email protected]
The Breakthrough Balloon for Critical Limb Ischemia?⁎
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
The Breakthrough Balloon for Critical Limb Ischemia?* Michael R. Jaff, DO Boston, Massachusetts
A true medical breakthrough represents “a sudden advance especially in knowledge or technique” (1). In the field of vascular medicine, such a breakthrough is welcome, because many of the treatments we have for peripheral artery disease (PAD) are limited. Of the patients with PAD, the subgroup with the highest risk of limb loss and mortality are those with critical limb ischemia (CLI) (ischemic rest pain, nonhealing ischemic ulcerations, gangrene). With the explosive epidemic of diabetes mellitus, it is likely that the prevalence of CLI will increase as well in years to come (2). Historically, the standard treatment of CLI has been complex surgical reconstruction using autologous saphenous vein from a proximal inflow artery to a healthy distal target artery, often located in the distal calf or foot. Despite excellent technical results with acceptable limb salvage rates, patient comorbidities often result in serious postoperative complications, including incisional infection, myocardial infarction, stroke, and death. See page 1105
In a meta-analysis of distal surgical bypass grafts among patients with CLI performed at centers with expertise in such revascularization procedures, the limb salvage rate was 78% (3). However, among such patients, 25% wound complication rates were reported (4). Perhaps the most sobering of statistics among patients with CLI is the dramatic reduction in survival. The Transatlantic Intersociety Consensus for the Management of Peripheral Arterial Disease reports that 20% of patients die within the first year of seeking treatment for CLI (5). Primary medical therapy, particularly for patients at prohibitive risk of serious complications with surgery, or without a suitable revascularization option, is very limited. Although some investigators have suggested that spinal cord stimulation
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Massachusetts General Hospital, Boston, Massachusetts. Dr. Jaff is a noncompensated advisor to Abbott Vascular, Boston Scientific, Covidien Corporation, Cordis Endovascular, and Medtronic Vascular; a compensated advisor for Arsenal Medical and Micell; an equity shareholder of Vascular Therapies; and a board member of VIVA Physicians, Inc. (a not-for-profit 501(c)3 education and research organization).
Vol. 58, No. 11, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.06.009
is an effective alternative among patients without a suitable revascularization option, a recent review of the published literature has demonstrated no real usefulness in these patients (6). With the recent lack of evidence of efficacy using angiogenesis therapy (7), investigators have demonstrated interest in stem cell and progenitor cell therapy (8) as future options for patients with nonrevascularizable PAD and CLI. Given the mortality rates and complications associated with surgical revascularization, many clinicians have suggested that endovascular therapy is a safer and equally effective alternative. Primary revascularization using percutaneous transluminal angioplasty (PTA) for CLI has been reported in multiple single-center observations (9). As patient selection and technology have become more sophisticated, results have improved, with a recent meta-analysis demonstrating 82.4% limb salvage rates at 3 years (10). The most important modern randomized study of surgical revascularization compared with PTA is the BASIL (Bypass Versus Angioplasty in Severe Ischaemia of the Leg) trial. In a final report of the primary intention-to-treat outcome, rates of amputation-free survival and overall survival were no different between the 2 treatments. However, among patients who survived at least 2 years after randomization, those patients treated with surgical revascularization lived 7 months longer (11). This study raises further confusion regarding the optimal strategy for patients with CLI. Varu et al. (12) suggest that surgical revascularization should be the principal revascularization strategy among patients with more diffuse infrapopliteal disease, whereas others suggest that advances in technology have expanded the population of patients with CLI who would be best treated with PTA (13). Schmidt et al. (14) have distinguished themselves as among the most prolific of clinical vascular researchers of the modern era, and their contribution to this issue of the Journal is no exception. The authors demonstrated, for the first time, impressive results of endovascular intervention using an angioplasty balloon coated with paclitaxel and a novel spacer, urea. Although there have been preliminary reports of the efficacy of drug-coated balloons in PAD (15), this particular study demonstrated impressive results with much longer anatomic lesions in the most challenging of arterial beds, the infrapopliteal arteries. In this single-center series of 104 patients and 109 limbs enrolled over 13 months, 82.6% had CLI at presentation (approximately 65% with minor or major tissue loss). The demographics of the study population highlight the major comorbidities associated with CLI: 71% with diabetes mellitus, 46% with chronic kidney disease, and 46% with coronary artery disease. The mean lesion length was 17.3 mm. At 3 months, angiography performed on 74 patients (79 limbs) demonstrated primary patency of 72.6%. Of those with restenosis, complete reocclusion developed in 8.3%, whereas the remainder demonstrated more focal stenosis. The authors previously defined a much higher restenosis rate with PTA balloons without drug coating of almost 70% at 3 months in lesions of similar lengths (16).
Jaff Breakthrough Balloon for Critical Limb Ischemia
JACC Vol. 58, No. 11, 2011 September 6, 2011:1110–1
In association with this procedural effectiveness, the limb salvage rate of patients with CLI was 95.6%. Of patients with ischemic ulcerations at baseline, 74.2% of these ulcerations healed completely at a mean follow up of 378 ⫾ 65 days. Despite these impressive findings, this study is limited by the single-center nature of the evaluation and the potential for selection bias by the investigators for patients whose anatomical features may be optimally suited for this specific intervention. Future prospective nonrandomized evaluations of specific endovascular treatments for patients with CLI should include major adverse limb events and mortality rates (17). However, the U.S. Food and Drug Administration commented that “certain novel device types, such as drug-device combination products may not be suitable for evaluation in a single arm study because historical data may not represent an adequate comparator due to technology and clinical practice. Randomized controlled trials may be necessary to evaluate these types of products” (18). Therefore, future trials of drug-coated balloons should be performed in prospective, randomized fashion. The authors identify 2 arteries in which ectasia developed during angiographic follow-up. Despite their reassurance, the concepts describing the mechanisms and impact of drug delivery by an angioplasty balloon catheter are still in their infancy, and this finding raises some concern. Future investigations will need to study the impact of this therapy on arterial wall integrity over time. Finally, the cost of this specific technology must be greater than so-called bare balloon catheters. If the clinical indication for use of drug-coated balloons is limb salvage via healing of ischemic ulcerations, it seems that despite the marked improvement in vessel patency, there is no clear advantage of the more expensive technology over PTA alone. The authors highlight the potential advantage that drug-coated balloons require fewer repeat interventions when compared with PTA, and this may result in a cost advantage of this technology. Formal cost-effectiveness analyses will be required to demonstrate the advantages of one therapy over the other; however, one must question whether costs will favor this technology in the era of healthcare reform. Of greatest impact, however, is the reported mortality rate of 16.3% among 104 patients included in this study at 12 months. This mortality is significantly higher than that for women with breast cancer (e.g., 24 per 100,000 women/year) (19), and underscores the importance of comprehensive attention to the identification and modification of atherosclerotic risk factors and established arterial diseases in other vascular beds (i.e., coronary, cerebrovascular). For any endovascular technology to represent a true breakthrough, not only must the treatment promote improvement in functional capacity and limb salvage, but also strategies to prolong overall survival must be even more effective. Without the latter, the relevance of patent limb arteries wanes.
1111
Reprint requests and correspondence: Dr. Michael R. Jaff, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: [email protected].
REFERENCES
1. Merriam-Webster, Inc. “Breakthrough.” Available at: http:// www.merriam-webster.com/dictionary/breakthrough. Accessed May 23, 2011. 2. Moxey PW, Gogalniceanu P, Hinchliffe RJ, et al. Lower extremity amputations: a review of global variability in incidence. Diabetes Med 2011 Mar 9 [E-pub ahead of print]. 3. Albers M, Romiti M, Brochado-Neto FC, De Luccia N, Pereira CAB. Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia. J Vasc Surg 2006;43:498 –508. 4. Chung J, Bartelson BB, Hiatt WR, et al. Wound healing and functional outcomes after infrainguinal bypass with reversed saphenous vein for critical limb ischemia. J Vasc Surg 2006;43:1183–90. 5. Norgren L, Hiatt WR, Dormondy JA, Nehler MR, Harris KA, Fowkes FGR, on behalf of the TASC II Working Group. InterSociety Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5A– 67A. 6. Klomp HM, Steyerberg EW, Habbema JDF, van Urk H. What is the efficacy of spinal cord stimulation in (subgroups of) patients with critical limb ischemia. Ann Vasc Surg 2009;23:355– 63. 7. Hiatt WR, Baumgartner I, Nikol S, et al. NV1FGF gene therapy on amputation-free survival in critical limb ischemia: phase 3 randomized double-blind placebo-controlled trial. Circulation 2010;122:2218. 8. Lawall H, Bramlage P, Amann B. Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg 2011;53: 445–53. 9. Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal (outflow) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five year follow-up. Circulation 2001;104: 2057– 62. 10. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg 2008;47:975– 81. 11. Bradbury AW, on behalf of the BASIL trial investigators and participants. Final results of the BASIL trial (Bypass versus Angioplasty in severe ischemia of the legs.) J Vasc Surg 2010;51 Suppl:1S–75S. 12. Varu VN, Hogg ME, Kibbe MR. Critical limb ischemia. J Vasc Surg 2010:51:230 – 41. 13. Yan BP, Moran D, Hynes BG, Kiernan TJ, Yu CK. Advances in endovascular treatment of critical limb ischemia. Circulation J 2011; 75:756 – 65. 14. Schmidt A, Piorkowski M, Werner M, et al. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis-rate and clinical outcome. J Am Coll Cardiol 2011;58:1105–9. 15. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2006;355:689 –99. 16. Schmidt A, Ulrich M, Winkler B, et al. Angiographic patency and clinical outcome for balloon-angioplasty for extensive infrapopliteal arterial disease. Cath Cardiovasc Interv 2010;76:1047–54. 17. Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 2009;50:1462–73. 18. Kumar A, Brooks SS, Cavanaugh K, Zuckerman B. FDA perspective on objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 2009; 50:1474 – 6. 19. National Cancer Institute. Surveillance Epidemiology and End Results Stat Fact Sheets: Breast Cancer. Available at: http://www.seer. cancer.gov/statfacts/html/breast.html. Accessed May 23, 2011. Key Words: drug-coated balloons y peripheral artery disease.
EDITORIAL COMMENT
The Breakthrough Balloon for Critical Limb Ischemia?* Michael R. Jaff, DO Boston, Massachusetts
A true medical breakthrough represents “a sudden advance especially in knowledge or technique” (1). In the field of vascular medicine, such a breakthrough is welcome, because many of the treatments we have for peripheral artery disease (PAD) are limited. Of the patients with PAD, the subgroup with the highest risk of limb loss and mortality are those with critical limb ischemia (CLI) (ischemic rest pain, nonhealing ischemic ulcerations, gangrene). With the explosive epidemic of diabetes mellitus, it is likely that the prevalence of CLI will increase as well in years to come (2). Historically, the standard treatment of CLI has been complex surgical reconstruction using autologous saphenous vein from a proximal inflow artery to a healthy distal target artery, often located in the distal calf or foot. Despite excellent technical results with acceptable limb salvage rates, patient comorbidities often result in serious postoperative complications, including incisional infection, myocardial infarction, stroke, and death. See page 1105
In a meta-analysis of distal surgical bypass grafts among patients with CLI performed at centers with expertise in such revascularization procedures, the limb salvage rate was 78% (3). However, among such patients, 25% wound complication rates were reported (4). Perhaps the most sobering of statistics among patients with CLI is the dramatic reduction in survival. The Transatlantic Intersociety Consensus for the Management of Peripheral Arterial Disease reports that 20% of patients die within the first year of seeking treatment for CLI (5). Primary medical therapy, particularly for patients at prohibitive risk of serious complications with surgery, or without a suitable revascularization option, is very limited. Although some investigators have suggested that spinal cord stimulation
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Massachusetts General Hospital, Boston, Massachusetts. Dr. Jaff is a noncompensated advisor to Abbott Vascular, Boston Scientific, Covidien Corporation, Cordis Endovascular, and Medtronic Vascular; a compensated advisor for Arsenal Medical and Micell; an equity shareholder of Vascular Therapies; and a board member of VIVA Physicians, Inc. (a not-for-profit 501(c)3 education and research organization).
Vol. 58, No. 11, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.06.009
is an effective alternative among patients without a suitable revascularization option, a recent review of the published literature has demonstrated no real usefulness in these patients (6). With the recent lack of evidence of efficacy using angiogenesis therapy (7), investigators have demonstrated interest in stem cell and progenitor cell therapy (8) as future options for patients with nonrevascularizable PAD and CLI. Given the mortality rates and complications associated with surgical revascularization, many clinicians have suggested that endovascular therapy is a safer and equally effective alternative. Primary revascularization using percutaneous transluminal angioplasty (PTA) for CLI has been reported in multiple single-center observations (9). As patient selection and technology have become more sophisticated, results have improved, with a recent meta-analysis demonstrating 82.4% limb salvage rates at 3 years (10). The most important modern randomized study of surgical revascularization compared with PTA is the BASIL (Bypass Versus Angioplasty in Severe Ischaemia of the Leg) trial. In a final report of the primary intention-to-treat outcome, rates of amputation-free survival and overall survival were no different between the 2 treatments. However, among patients who survived at least 2 years after randomization, those patients treated with surgical revascularization lived 7 months longer (11). This study raises further confusion regarding the optimal strategy for patients with CLI. Varu et al. (12) suggest that surgical revascularization should be the principal revascularization strategy among patients with more diffuse infrapopliteal disease, whereas others suggest that advances in technology have expanded the population of patients with CLI who would be best treated with PTA (13). Schmidt et al. (14) have distinguished themselves as among the most prolific of clinical vascular researchers of the modern era, and their contribution to this issue of the Journal is no exception. The authors demonstrated, for the first time, impressive results of endovascular intervention using an angioplasty balloon coated with paclitaxel and a novel spacer, urea. Although there have been preliminary reports of the efficacy of drug-coated balloons in PAD (15), this particular study demonstrated impressive results with much longer anatomic lesions in the most challenging of arterial beds, the infrapopliteal arteries. In this single-center series of 104 patients and 109 limbs enrolled over 13 months, 82.6% had CLI at presentation (approximately 65% with minor or major tissue loss). The demographics of the study population highlight the major comorbidities associated with CLI: 71% with diabetes mellitus, 46% with chronic kidney disease, and 46% with coronary artery disease. The mean lesion length was 17.3 mm. At 3 months, angiography performed on 74 patients (79 limbs) demonstrated primary patency of 72.6%. Of those with restenosis, complete reocclusion developed in 8.3%, whereas the remainder demonstrated more focal stenosis. The authors previously defined a much higher restenosis rate with PTA balloons without drug coating of almost 70% at 3 months in lesions of similar lengths (16).
Jaff Breakthrough Balloon for Critical Limb Ischemia
JACC Vol. 58, No. 11, 2011 September 6, 2011:1110–1
In association with this procedural effectiveness, the limb salvage rate of patients with CLI was 95.6%. Of patients with ischemic ulcerations at baseline, 74.2% of these ulcerations healed completely at a mean follow up of 378 ⫾ 65 days. Despite these impressive findings, this study is limited by the single-center nature of the evaluation and the potential for selection bias by the investigators for patients whose anatomical features may be optimally suited for this specific intervention. Future prospective nonrandomized evaluations of specific endovascular treatments for patients with CLI should include major adverse limb events and mortality rates (17). However, the U.S. Food and Drug Administration commented that “certain novel device types, such as drug-device combination products may not be suitable for evaluation in a single arm study because historical data may not represent an adequate comparator due to technology and clinical practice. Randomized controlled trials may be necessary to evaluate these types of products” (18). Therefore, future trials of drug-coated balloons should be performed in prospective, randomized fashion. The authors identify 2 arteries in which ectasia developed during angiographic follow-up. Despite their reassurance, the concepts describing the mechanisms and impact of drug delivery by an angioplasty balloon catheter are still in their infancy, and this finding raises some concern. Future investigations will need to study the impact of this therapy on arterial wall integrity over time. Finally, the cost of this specific technology must be greater than so-called bare balloon catheters. If the clinical indication for use of drug-coated balloons is limb salvage via healing of ischemic ulcerations, it seems that despite the marked improvement in vessel patency, there is no clear advantage of the more expensive technology over PTA alone. The authors highlight the potential advantage that drug-coated balloons require fewer repeat interventions when compared with PTA, and this may result in a cost advantage of this technology. Formal cost-effectiveness analyses will be required to demonstrate the advantages of one therapy over the other; however, one must question whether costs will favor this technology in the era of healthcare reform. Of greatest impact, however, is the reported mortality rate of 16.3% among 104 patients included in this study at 12 months. This mortality is significantly higher than that for women with breast cancer (e.g., 24 per 100,000 women/year) (19), and underscores the importance of comprehensive attention to the identification and modification of atherosclerotic risk factors and established arterial diseases in other vascular beds (i.e., coronary, cerebrovascular). For any endovascular technology to represent a true breakthrough, not only must the treatment promote improvement in functional capacity and limb salvage, but also strategies to prolong overall survival must be even more effective. Without the latter, the relevance of patent limb arteries wanes.
1111
Reprint requests and correspondence: Dr. Michael R. Jaff, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: [email protected].
REFERENCES
1. Merriam-Webster, Inc. “Breakthrough.” Available at: http:// www.merriam-webster.com/dictionary/breakthrough. Accessed May 23, 2011. 2. Moxey PW, Gogalniceanu P, Hinchliffe RJ, et al. Lower extremity amputations: a review of global variability in incidence. Diabetes Med 2011 Mar 9 [E-pub ahead of print]. 3. Albers M, Romiti M, Brochado-Neto FC, De Luccia N, Pereira CAB. Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia. J Vasc Surg 2006;43:498 –508. 4. Chung J, Bartelson BB, Hiatt WR, et al. Wound healing and functional outcomes after infrainguinal bypass with reversed saphenous vein for critical limb ischemia. J Vasc Surg 2006;43:1183–90. 5. Norgren L, Hiatt WR, Dormondy JA, Nehler MR, Harris KA, Fowkes FGR, on behalf of the TASC II Working Group. InterSociety Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5A– 67A. 6. Klomp HM, Steyerberg EW, Habbema JDF, van Urk H. What is the efficacy of spinal cord stimulation in (subgroups of) patients with critical limb ischemia. Ann Vasc Surg 2009;23:355– 63. 7. Hiatt WR, Baumgartner I, Nikol S, et al. NV1FGF gene therapy on amputation-free survival in critical limb ischemia: phase 3 randomized double-blind placebo-controlled trial. Circulation 2010;122:2218. 8. Lawall H, Bramlage P, Amann B. Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg 2011;53: 445–53. 9. Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal (outflow) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five year follow-up. Circulation 2001;104: 2057– 62. 10. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg 2008;47:975– 81. 11. Bradbury AW, on behalf of the BASIL trial investigators and participants. Final results of the BASIL trial (Bypass versus Angioplasty in severe ischemia of the legs.) J Vasc Surg 2010;51 Suppl:1S–75S. 12. Varu VN, Hogg ME, Kibbe MR. Critical limb ischemia. J Vasc Surg 2010:51:230 – 41. 13. Yan BP, Moran D, Hynes BG, Kiernan TJ, Yu CK. Advances in endovascular treatment of critical limb ischemia. Circulation J 2011; 75:756 – 65. 14. Schmidt A, Piorkowski M, Werner M, et al. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis-rate and clinical outcome. J Am Coll Cardiol 2011;58:1105–9. 15. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2006;355:689 –99. 16. Schmidt A, Ulrich M, Winkler B, et al. Angiographic patency and clinical outcome for balloon-angioplasty for extensive infrapopliteal arterial disease. Cath Cardiovasc Interv 2010;76:1047–54. 17. Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 2009;50:1462–73. 18. Kumar A, Brooks SS, Cavanaugh K, Zuckerman B. FDA perspective on objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 2009; 50:1474 – 6. 19. National Cancer Institute. Surveillance Epidemiology and End Results Stat Fact Sheets: Breast Cancer. Available at: http://www.seer. cancer.gov/statfacts/html/breast.html. Accessed May 23, 2011. Key Words: drug-coated balloons y peripheral artery disease.