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The SAVAL Trial
Prompt endovascular or surgical revascularization is recommended to restore distal perfusion, minimize tissue loss, and maintain quality of life for patients with critical limb ischemia (CLI).1 The major advantage of endovascular treatment compared to surgical bypass is lower periprocedural morbidity and mortality, which is a concern in typical patients with CLI who are older, frail, and often present with systemic atherosclerosis, diabetes mellitus, and elevated risk for cardiovascular events. Patients with CLI presenting with infrapopliteal atherosclerotic lesions of the tibial or peroneal arteries are an especially challenging population because restoring vessel patency is considerably more difficult in infrapopliteal lesions compared to those in the femoropopliteal segment.
Despite the obvious advantages of an endovascular approach in patients with significant systemic comorbidities, percutaneous transluminal angioplasty (PTA) results remain suboptimal in infrapopliteal lesions.2 Short coronary drug-eluting stents (DESs) have been evaluated in infrapopliteal lesions in several randomized controlled trials, demonstrating superior patency and freedom from reintervention with DES compared to PTA,3-5 with a sustained clinical benefit through 5 years.6 However, no DES is indicated in the United States for infrapopliteal use, and coronary stents are not well suited for the hostile infrapopliteal segment. A DES for dedicated infrapopliteal applications should be available in longer lengths to accommodate long tortuous lesions, provide adequate radial force to prevent stent collapse and restenosis, yet remain flexible enough to avoid fracture when subjected to torque and extravascular compressive forces.
The SAVAL trial was designed to provide level 1 evidence of the clinical utility of a DES that is specifically intended for infrapopliteal applications. Investigation of this DES was arranged through the FDA Breakthrough Devices Program (formerly the Expedited Access Pathway), which is intended to facilitate development and expedite the review of breakthrough technologies.7
TRIAL DESIGN
A total of approximately 301 patients with CLI undergoing infrapopliteal endovascular treatment are planned to be enrolled in the SAVAL trial (NCT03551496), which includes two phases. The first phase is a global, prospective, multicenter, randomized investigation designed to evaluate the safety and effectiveness of an infrapopliteal DES (Saval™ DES BTK, Boston Scientific Corporation) in patients with CLI. Approximately 201 patients with CLI (Rutherford class 4 and 5) will be randomly assigned (2:1) to the DES or PTA arms at up to 50 centers in the United States, Europe, and Japan. The primary objective of the randomized study is to demonstrate superior effectiveness and acceptable safety of infrapopliteal DES treatment versus PTA in patients with CLI.
The second phase of the SAVAL trial is a nonrandomized, single-arm study of 100 patients treated with the Saval™ DES BTK. Enrollment for this phase will commence after enrollment is complete in the randomized phase, with identical participating centers, eligibility criteria, procedures, outcome measures, and follow-up assessments. The purpose of the nonrandomized phase of the trial is to collect additional safety and efficacy data on patients who undergo implantation of a Saval™ DES BTK.
PATIENT ELIGIBILITY
Key eligibility criteria include Rutherford class 4 or 5 disease, life expectancy > 1 year, no previous surgery in the target vessel, no previous or planned major amputation in the target limb, and absence of significant systemic comorbidities such as renal failure, New York Heart Association class IV heart failure, or symptomatic coronary artery disease. Importantly, limb hemodynamics will be collected at study enrollment and at all follow-up visits but not used as an inclusion or exclusion criteria. Inclusion criteria assessed intraprocedurally include the presence of one target lesion per vessel in no more than two infrapopliteal arteries in a single limb, reference vessel diameter of 2.5 to 3.75 mm, total lesion length ≤ 70 mm (≤ 140 mm after approval for stent overlap), and lesion location at least 4 cm above the ankle joint.
STUDY PROCEDURES AND FOLLOW-UP
Patients will be randomly allocated to undergo infrapopliteal treatment with the self-expanding, nitinol, paclitaxel-eluting Saval™ DES BTK or PTA. This DES is specifically designed to optimize flexibility, radial/compressive strength, and fatigue properties for durable performance in infrapopliteal arteries. Commercially available PTA balloons, selected at the investigator’s discretion, will be used as the comparator.
Adjunctive therapies for treating the target lesion, such as drug-coated balloons, atherectomy, or radiation therapy, are not permitted in the study. Anticoagulation and antiplatelet therapy will be administered before and during the procedure, according to the standard medication regimen at each center. Dual antiplatelet therapy is required in all patients for 6 months and is strongly recommended for 1 year in patients treated with the DES.
Patients will return for clinical and imaging follow-up at 1 month, 3 months, 6 months, and annually for 3 years.
OUTCOMES
The primary effectiveness endpoint of the randomized trial is primary patency at 6 months. Primary vessel patency will be evaluated by duplex ultrasound on a per-lesion basis. Primary patency is a binary endpoint determined by duplex ultrasound measurement of flow (vs no flow) in the absence of clinically driven target lesion revascularization (TLR) or bypass of the target lesion. The primary safety endpoint of this trial is freedom from major adverse limb events and postoperative death (MALE-POD) at 6 months. This is a composite outcome including MALE (above-ankle amputation of the index limb or major reintervention [eg, bypass or interposition graft, thrombectomy, thrombolysis]) and POD (death within 30 days of index procedure). The MALE outcome has been endorsed by the Society for Vascular Surgery and FDA, and it is a primary endpoint in the ongoing BEST-CLI trial.8-10 The single-arm study has a 12-month primary safety endpoint based on MALE-POD criteria, and efficacy information will also be collected.
Additional outcomes to be assessed include unplanned readmissions through 30 days, as well as hemodynamic outcomes and health-related quality of life (EuroQoL five dimensions and Vascular Quality of Life Questionnaire) through 1 year. Patency, clinically driven TLR, wound assessment, major amputations, Rutherford classification, and adverse events will be evaluated through 3 years.
Wound characteristics will be documented at each follow-up visit in patients with minor tissue loss, ischemic ulcer, or focal gangrene (Rutherford class 5) and evaluated by an independent blinded reviewer.
DISCUSSION
Revascularization remains the cornerstone of therapy for CLI and is recommended by the professional guidelines.11,12 The ongoing BEST-CLI trial may provide further insight into selective treatment strategies for these challenging patients. Although the specific role of surgery versus endovascular therapy remains uncertain, an endovascular-first approach has been recently advocated.13
For patients undergoing endovascular intervention, there is currently no DES that is approved for infrapopliteal applications in the United States. The aim of the SAVAL trial is to determine if a DES specifically developed for the infrapopliteal segment offers superior patency and acceptable safety compared with the current standard of care (PTA). The regulatory application for this trial will receive priority review by the FDA given the novelty of the device and because of the need for more effective treatment options in this patient population.
It should be noted that after the SAVAL trial had begun enrollment, the meta-analysis by Katsanos et al voiced concern regarding increases in late mortality seen after the use of paclitaxel-coated balloons and paclitaxel-eluting stents in the femoral and popliteal arteries.14 This issue has been closely followed by the FDA and Boston Scientific Corporation. After the release of the updated FDA letter to treating physicians in March 2019,15 the SAVAL trial informed consent document is being modified to reflect the following: the acknowledgment of a potential increased rate of mortality associated with paclitaxel-coated devices used to treat peripheral artery disease, the impact that this mortality signal may have on benefit-risk considerations for patient participation in the trial, and the need for diligent review and follow-up of all trial participants by the Data and Safety Monitoring Board.
Conclusion
Given that CLI is underdiagnosed, increasing in prevalence, and responsible for significant risk to life and limb, considerable efforts are needed to raise disease awareness, refine diagnostic algorithms, and establish evidence-based treatment pathways. The SAVAL randomized trial is a first-of-its-kind study that utilizes a DES that is specifically developed for infrapopliteal applications.
1. Shishehbor MH, White CJ, Gray BH, et al. Critical limb ischemia: an expert statement. J Am Coll Cardiol. 2016;68:2002-2015.
2. Mustapha JA, Finton SM, Diaz-Sandoval LJ, et al. Percutaneous transluminal angioplasty in patients with infrapopliteal arterial disease: systematic review and meta-analysis. Circ Cardiovasc Interv. 2016;9:e003468.
3. Scheinert D, Katsanos K, Zeller T, et al. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial. J Am Coll Cardiol. 2012;60:2290-2295.
4. Spreen MI, Martens JM, Hansen BE, et al. Percutaneous transluminal angioplasty and drug-eluting stents for infrapopliteal lesions in critical limb ischemia (PADI) trial. Circ Cardiovasc Interv. 2016;9:e002376.
5. Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg. 2012;55:390-398.
6. Spreen MI, Martens JM, Knippenberg B, et al. Long-term follow-up of the PADI trial: percutaneous transluminal angioplasty versus drug-eluting stents for infrapopliteal lesions in critical limb ischemia. J Am Heart Assoc. 2017;6:e004877.
7. US Food and Drug Administration. Breakthrough devices program: draft guidance for industry and Food and Drug Administration staff. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM581664.pdf. Published December 18, 2018. Accessed March 28, 2019.
8. 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;50:1462-1473.
9. 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;50:1474-1476.
10. Menard MT, Farber A, Assmann SF, et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) trial. J Am Heart Assoc. 2016;5:e003219.
11. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006;47:1239-1312.
12. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33(suppl 1):S1-75.
13. Jaff MR, White CJ, Hiatt WR, et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: a supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): the TASC steering committee. Catheter Cardiovasc Interv. 2015;86:611-625.
14. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018;7:e011245.
15. US Food and Drug Administration. Update: Treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality–letter to health care providers. https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm633614.htm. Published March 15, 2019. Accessed April 3, 2019.
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Jihad A. Mustapha, MD, FACC, FSCAI
Associate Professor
Michigan State University
Advanced Cardiac & Vascular Amputation Prevention Centers
Grand Rapids, Michigan
jmustapha@acvcenters.com
Disclosures: Consulting agreements with Bard Peripheral Vascular, Inc., Boston Scientific Corporation, Cardiovascular Systems, Inc., Medtronic, Philips, and Terumo.
Patrick Geraghty, MD, FACS
Professor of Surgery and Radiology
Washington University School of Medicine
St. Louis, Missouri
geraghtyp@wustl.edu
Disclosures: Consulting/advisory board for Bard/BD, Boston Scientific Corporation, Intact Vascular, Inc.; equity holder in Euphrates Vascular.
Hans van Overhagen, MD, PhD, EBIR
Department of Radiology
Haga Teaching Hospital
The Hague, the Netherlands
h.voverhagen@hagaziekenhuis.nl
Disclosures: Consultant to Boston Scientific Corporation.
