SirPAD: Sirolimus-Coated Balloons Cut Amputation and Revascularization in Infrainguinal PAD
核心洞察
The phase 3 SirPAD trial randomized 1,252 patients with symptomatic infrainguinal peripheral artery disease (搜索) to sirolimus-coated or uncoated balloon angioplasty.
At one year, the primary composite endpoint of major target-limb amputation or target-lesion revascularization for chronic limb-threatening ischemia (搜索) occurred in 8.8% versus 15%.
The key secondary composite endpoint of any unplanned amputation or revascularization occurred in 23% with sirolimus-coated balloons versus 30.8% with uncoated balloons.
Sirolimus-coated balloon (搜索) angioplasty significantly reduced major limb events compared with conventional uncoated balloon angioplasty in patients with symptomatic infrainguinal peripheral artery disease (搜索) (PAD), according to results of the investigator-initiated, multicenter, phase 3 SirPAD (Sirolimus-Coated Balloon for Peripheral Artery Disease) trial conducted in Switzerland.
The trial enrolled 1,252 patients (median age 75 years; 35.1% women) who were randomly assigned 1:1 to angioplasty with either a sirolimus-coated balloon (搜索) or an uncoated balloon. By Fontaine classification, 34.2% of patients had chronic limb-threatening ischemia (搜索) (CLTI) of the target limb (Fontaine stages III and IV), and 9.8% presented with acute limb ischemia. The median lesion length was 150 mm, 57.1% of patients had total occlusion of the target lesion, and disease extended below the knee in approximately 30% of patients — a substantially more complex population than that included in many prior drug-coated balloon (DCB) studies. Intravascular imaging was not required and was left to the operator's discretion.
The study adopted an all-comer design with minimal exclusion criteria, enhancing its real-world applicability. It employed blinded outcome adjudication and a prespecified hierarchical testing strategy, first assessing noninferiority and subsequently superiority.
Primary and Secondary Outcomes
At 1 year, the primary composite endpoint of major target-limb amputation or target-lesion revascularization (TLR) for CLTI occurred in 8.8% of patients treated with sirolimus-coated balloons compared with 15% of those treated with uncoated balloons (absolute risk difference, -4.9 percentage points; 95% confidence interval [CI], -8.5 to -1.3; pnoninferiority < 0.001; psuperiority = 0.009).
The key secondary composite endpoint — any unplanned amputation (major or minor) or TLR for critical or noncritical limb ischemia — occurred in 23% versus 30.8% (absolute risk difference, -7.8 percentage points; 95% CI, -12.7 to -2.9; p = 0.002). The reduction was driven by concordant effects on both individual components: unplanned major amputation occurred in 1.3% versus 2.7% (absolute risk difference, -1.4 percentage points; 95% CI, -3.1 to 0.2), and TLR for CLTI occurred in 8.3% versus 13.3% (absolute risk difference, -5 percentage points; 95% CI, -8.4 to -1.5). Kaplan-Meier curves for the primary outcome separated early and maintained divergence throughout the follow-up period.
The trial authors emphasized that although restenosis, patency, and TLR remain important procedural outcomes, patients and clinicians are ultimately concerned with limb preservation, symptom relief, and avoidance of repeat interventions. The SirPAD findings demonstrate that the benefits of DCB technology can translate into outcomes that matter directly to patients.
Safety Profile and the Paclitaxel Context
Safety remains a critical consideration for drug-coated technologies, given concerns regarding late mortality associated with paclitaxel-coated devices. The SAFE-PAD (Safety Assessment of Femoropopliteal Endovascular Treatment with Paclitaxel-Coated Devices) study, described as the largest real-world analysis to date, evaluated 168,553 Medicare beneficiaries with up to 9 years of follow-up and found no increased mortality associated with drug-coated devices (adjusted HR, 0.98; 95% CI, 0.97-0.99). These conflicting findings have fueled interest in alternative antiproliferative platforms.
In the SirPAD trial, 1-year all-cause mortality was similar between the sirolimus-coated and uncoated-balloon groups (11.8% vs. 12.8%; p = 0.67), with no evidence of excess mortality. Longer-term follow-up is ongoing.
Unlike paclitaxel, which exerts cytotoxic effects through microtubule disruption, sirolimus inhibits the mammalian target of rapamycin (mTOR (搜索)) pathway and acts cytostatically, suppressing neointimal hyperplasia while potentially preserving vascular healing. Sirolimus has an established safety profile in coronary interventions. Additional support for sirolimus-coated balloon (搜索) technology comes from the SIRONA (Sirolimus- vs Paclitaxel-Drug Coated Balloons in Patients With Peripheral Artery Disease (搜索)) trial, which demonstrated comparable clinical outcomes between sirolimus-coated and paclitaxel-coated balloons in femoropopliteal disease. Emerging systematic reviews report favorable efficacy and safety across diverse lesion complexities, supporting sirolimus-coated balloons as a viable therapeutic platform.
Trial Strengths and Limitations
The SirPAD trial's strengths include its large sample size, all-comer population, clinically relevant hard endpoints, blinded adjudication, and hierarchical statistical design. The use of hard clinical outcomes rather than solely anatomical or procedural measures represents a particularly important advance.
Several limitations warrant consideration. Follow-up was limited to 1 year, and durability of benefit beyond this time frame remains uncertain. The open-label design may have influenced reintervention decisions, particularly for less severe ischemic events. The trial was conducted within a single-country health care system with a predominantly white population, limiting generalizability. In addition, the study compared sirolimus-coated balloons with uncoated balloons rather than with paclitaxel-coated devices, which remain widely used in contemporary practice — leaving the direct comparative effectiveness question unanswered.
Long-Term Real-World Data in Diabetic PAD
Complementary evidence on the paclitaxel platform comes from the BIOLUX P-III registry, a prospective, international, multicenter, post-market, all-comers registry evaluating the Passeo-18 Lux (搜索) DCB in infrainguinal atherosclerotic disease. Between October 2014 and January 2017, 882 patients were enrolled at 47 centers worldwide, and 877 underwent treatment with the device. Of these, 418 (47.7%) had diabetes mellitus (搜索) (DM) and 459 (52.3%) did not. Follow-up compliance exceeded 80% through 24 months and was 31.3% at 60 months.
Patients with DM formed a higher-risk subgroup with a greater cardiometabolic burden and more advanced PAD at presentation, including more severe ischemia by Rutherford class and more target-limb ulceration. They had a significantly higher prevalence of infrapopliteal (crural) disease (22.8% vs 11.8%; P = 0.0007) and heavy calcification (17.9% vs 13.2%), and were more likely to have prior ipsilateral minor amputation (11.6% vs 1.1%) or active ulceration (37.6% vs 17.8%; both P < 0.0001). Patients with DM were treated with smaller-diameter balloons (mean 4.5 ± 1.2 mm vs 4.8 ± 1.0 mm; P < 0.0001) and therefore received a lower cumulative paclitaxel dose (7.1 ± 5.5 mg vs 7.7 ± 5.7 mg; P = 0.0007).
At 5 years, freedom from major adverse events (MAEs) was significantly lower among patients with DM: 71.2% (95% CI: 64.2-77.1) versus 74.7% (95% CI: 68.3-80.0) in those without DM (P = 0.0359), driven by higher rates of major amputation and all-cause mortality. Freedom from clinically driven TLR (CD-TLR) was high and did not differ by diabetes status (79.8% vs 79.6% at 60 months; P = 0.535). Overall survival at 60 months was 56.3% (95% CI: 48.4-63.5) in patients with DM versus 73.8% (95% CI: 67.1-79.3) in those without DM (P < 0.0001). Freedom from major target-limb amputation at 60 months was 92.4% (95% CI: 88.3-95.1) in the DM group versus 98.8% (95% CI: 97.2-99.5) in the non-DM group (P < 0.0001), and amputation-free survival was 53.0% (95% CI: 45.4-60.1) versus 73.6% (95% CI: 67.0-79.1; P < 0.0001). Most amputations occurred within the first 6 months following the index procedure.
The investigators concluded that the poorer long-term survival and limb outcomes in patients with DM are more appropriately explained by their greater baseline burden of CLTI, tissue loss, renal insufficiency, coronary artery disease, ulceration, and prior amputation than by a device-specific effect. They noted that the registry was not designed to assess the long-term safety of paclitaxel-coated devices and lacked a non-paclitaxel comparator arm, so the results neither confirm nor exclude a device-related contribution to late mortality. Analyses were unadjusted and exploratory, with no multivariable adjustment, propensity-based analysis, or competing-risk modeling performed.
Clinical Implications
For practicing clinicians, the SirPAD investigators state that sirolimus-coated balloon (搜索) angioplasty offers superior limb-related outcomes compared with conventional balloon angioplasty — not just vessel patency — in an unselected, real-world population. Ongoing 5-year follow-up and future head-to-head trials against paclitaxel-coated devices in broader populations will be essential to define the long-term role of this technology.
The BIOLUX P-III analysis supports integrating endovascular revascularization with aggressive cardiovascular risk reduction, optimized glycemic management, structured wound surveillance, infection control, and coordinated limb-preservation pathways, particularly during the early post-procedural period when amputation risk appears greatest.