- Email: [email protected]
Intermediate Outcomes of Femoropopliteal Stenting in Women: 3-Year Results of the DURABILITY II Trial
Intermediate Outcomes of Femoropopliteal Stenting in Women: 3-Year Results of the DURABILITY II Trial Daniel K. Han, Peter L. Faries, Christine Chung, Marvin V. Weaver, Rami O. Tadros, Windsor Ting, and Ageliki G. Vouyouka, New York, New York
Background: This study investigated the effects of gender on the 3-year outcomes of the StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent System II (DURABILITY II) trial. Methods: A total of 287 patients enrolled in the DURABILITY II trial (prospective and nonrandomized trial) were stratified by gender and evaluated for primary, primary assisted, and secondary patency at 3 years. Clinical scores including changes in ankle-brachial index (ABI) and walking impairment questionnaire (WIQ) scores were evaluated. Results: Overall 190 male and 97 female patients were included for analysis. The 3-year primary, assisted primary, and secondary patency rates for women versus men were 62.5% vs. 58.8%, 68.5% vs. 64.9%, and 72.1% vs. 67.2%, respectively (P < 0.05). Although ABIs at presentation were similar between women versus men (0.64 vs. 0.65, P < 0.05), women had lower ABI scores at 3 years compared with men (0.85 vs. 0.92, P ¼ 0.03). Women versus men had inferior walking distance scores at presentation (13.6 vs. 25.7, P < 0.001), scores were equalized by 2 years (51.6 vs. 60.8, P < 0.05); however, 3-year follow-up demonstrated less durable results for women versus men (37.3 vs. 58.8, P < 0.05). In addition, women had worse WIQ scores for pain, walking speed, and stair climbing. However, the relative change in scores between men and women were comparable, with both groups seeing similar improvements from baseline for these parameters. Conclusions: Women continue to see clinical improvement after intervention, achieving comparable ABIs and walking distance to men at 2 years. These benefits are diminished at 3-year follow-up with women achieving lower absolute ABI and WIQ parameters compared with men, but improved overall compared with scores at presentation.
INTRODUCTION The patient populations evaluated in the landmark trials in vascular surgery that guide today’s practice
Division of Vascular Surgery, Department of Surgery, Mount Sinai Hospital, New York, NY. Correspondence to: Ageliki G.Vouyouka, MD, Division of Vascular Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 4th Floor, Box 1273, New York, NY 10029, USA; E-mail: [email protected] Ann Vasc Surg 2016; 30: 110–117 http://dx.doi.org/10.1016/j.avsg.2015.10.005 Ó 2016 Elsevier Inc. All rights reserved. Manuscript received: June 17, 2015; manuscript accepted: October 27, 2015; published online: November 14, 2015.
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are predominantly composed of men. The last decade has seen an increased understanding of differences in vascular disease regarding presentation, pattern, and responses after intervention in women versus men. The quest for better understanding of sex-related differences of vascular disease and its outcomes in women has gained significant popularity because women account for most of our aging population and develops arterial disease as their male counterparts do.1e3 Therefore, several studies have emerged over the last decade evaluating and adding important knowledge on the differential outcomes between women and men after lowerextremity revascularization.4e11 However, these studies were all performed in retrospective fashion
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and lacked prospective, comprehensive evaluation of peripheral endovascular outcomes in women versus men that would include both objective and quality of life outcomes. The StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II (DURABILITY II) trial is a prospective, multicenter, and single-arm study being conducted under an investigational device exemption by the US Food and Drug Administration. The trial began its enrollment in 2007 to evaluate the safety and efficacy of primary stenting in the femoropopliteal region in patients with symptomatic lifelimiting claudication (Rutherford categories 2e4) using the Protege Everflex Self-Expanding Peripheral Stent System (Covidien, Plymouth, MN). The DURABILITY II trial offers an opportunity for prospective subanalysis on the impact of sex on the outcomes after primary stenting for femoropopliteal lesions in claudicants. We previously reported sexstratified 1-year results demonstrating that women presented at a later age than men with worse, more significant disease.12 Although women accomplished comparable patency rates at 1 year, they had inferior life quality outcomes with worse pain scores compared with men. Data on long-term results for primary stenting in women, however, remain scarce in today’s literature. The goal of this study was to evaluate the intermediate outcomes at 3 years in men versus women after primary stenting for femoropopliteal lesions including not only differences in objective findings such as patency rates but also gender-related differences in symptom resolution and other subjective parameters associated with ambulation and quality of life.
METHODS The detailed DURABILITY II study protocol, including inclusion and exclusion criteria has been previously published.13 The trial collected data for patency as assessed by duplex ultrasonography and ankle-brachial indices (ABIs). Clinical outcomes were evaluated through objective assessments of absolute walking distance, walking speed, and stair climbing scores determined by treadmill testing. At last, the trial collected patient responses on the walking impairment questionnaire (WIQ) to determine subjective changes in symptoms. Inclusion and exclusion criteria for the DURABILITY II trial have previously been published.12,13 Patients that were at least 18 years old with stenotic, restenotic, or occluded lesions of the superficial
Intermediate outcomes of femoropopliteal stenting in women 111
femoral artery (SFA) and proximal popliteal arteries with moderate to severe claudication were included in the study. Patients were enrolled when an exchangeable guidewire was traversed across the target lesion and met all preoperative criteria. Patients were uniformly predilated with an angioplasty balloon before deployment of the EverFlex stent. The diameter and length of stent used in the procedure was chosen at the investigator’s discretion. As part of the study protocol, all patients were standardized to receive antiplatelet therapy (aspirin 81 or 325 mg before and after the procedure; clopidogrel 75 mg for 7 days, 300 mg for 3 days, or 600 mg 1 day before procedure and 75 mg daily for 4 weeks after the procedure). Patients in the DURABILITY II trial were stratified by sex and information regarding patency, ABI, clinical walking scores, and WIQ questionnaire were collected. The primary end points included primary patency at 3 years evaluated by duplex ultrasonography and clinically driven target lesion restenosis (TLR) determined by an adjudicated core laboratory (VasCore Ultrasound Core Laboratory, Boston, MA). Loss of primary patency was defined as a doubling of the peak systolic velocity (PSV) in the treated segment with a PSV ratio between the treated segment and proximal artery of greater than or equal to 2.0. TLR was defined as >50% stenosis in a patient with recurrent symptoms, >70% stenosis in a patient with decreased ABI >0.15 from baseline, major amputation leading to limb loss, and all-cause mortality. Secondary end points included primaryassisted patency, secondary patency, changes in ABI, results of treadmill testing including absolute walking distance, walking speed, and stair climbing score, and change in WIQ scores at 3 years. Outcomes in women versus men were compared using t-tests for continuous variables, Fisher’s exact test for binary variables, and chi-squared test for ordinal outcomes. P < 0.05 was determined to be statistically significant. Patency rates were evaluated using KaplaneMeier curves and compared using the log-rank test.
RESULTS Across 44 participating centers in the United States, a total of 287 patients (190 men and 97 women) were enrolled in the DURABILITY II trial. A total of 146 of the 190 (76.8%) men completed their 3year follow-up visits. Among the 44 men without completion, 18 died, 15 were lost to follow-up, and 11 withdrew from the study. Seventy-four of the 97 (76.3%) women completed their 3-year
112 Han et al.
follow-up visits. Among the 23 women without completion, 8 died, 6 were lost to follow-up, and 9 withdrew from study. Patient demographics and preoperative comorbidities have previously been described.12 Briefly, women were older than men at presentation (71.3 ± 11.2 years vs. 65.9 ± 9.9 years, respectively) and less likely to have hyperlipidemia (79.4% vs. 89.5%), but otherwise, all demographics and preoperative characteristics were comparable between the 2 groups (Table I). Overall, 6.3% (12 of 190) of men and 11.3% (11 of 97) of women were on cilostazol. There was no statistically significant difference (P ¼ 0.17). More women (64.9%) presented with severe claudication versus men (51.1%, P ¼ 0.03). Although lesion lengths were comparable between women versus men, both preprocedure vessel diameter (4.4 vs. 5.0 mm, P < 0.001) and postprocedure lumen diameters (3.6 vs. 4.2 mm, P < 0.001) were noted to be smaller in women. Finally, men had lesions with more severe degree of calcification than women. The stents used for intervention were similar in length for men and women (127.4 ± 53.8 mm vs. 137.0 ± 54.8 mm, P ¼ 0.17) but were slightly bigger in men than women (6.6 ± 0.6 mm vs. 6.3 ± 0.5 mm, P < 0.001). Dissection occurred in 6 men (3.2%) and 2 women (2.1%; P ¼ 0.72). Additional stenting was used in 18 men (9.5%) and 15 women (15.5%; P ¼ 0.17). For patency, women had slightly higher primary (62.5% vs. 58.8%), primary assisted (68.5% vs. 64.9%), and secondary (72.1% vs. 67.2%) patency rates than men at 3 years, but this did not reach statistical significance (Fig. 1). Freedom from TLR for women versus men was also comparable at 3 years (67.4% vs. 70.9%, P < 0.05). Overall survival rates were equivalent in women versus men (90.7% vs. 90.1%, P < 0.05; Fig. 2). Limb salvage at 3 years was also comparable between women versus men (98.9% vs. 99.4%, P < 0.05). Both women and men saw significant improvements in ABIs compared with baseline after intervention out to 3 years (Table II). When evaluating absolute ABIs, men were able to achieve higher absolute ABI scores at 3 years versus women (0.92 ± 0.18 vs. 0.85 ± 0.21, P ¼ 0.03) despite comparable baseline ABIs. At 3 years, 85.2% of men and 78.8% of women maintained improvements in their ABIs compared with baseline (P < 0.05). Fifty-two of the 190 (27.4%) men had reinterventions. Among the 52 men with reinterventions, 34 had a single reintervention and 18 had more than 1. Five men had open revascularization and the rest had percutaneous procedures. Thirty of the 97 (30.9%) women had reinterventions. Among the 30 women with reinterventions,
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8 had a single reintervention and 22 had more than 1. One woman had open revascularization, and the rest had percutaneous procedures. After intervention, significant improvements in WIQ pain, aching, and cramping scores were seen for both men and women, sustained out to 3 years. These improvements were noted to be more gradual in women, who had significantly lower pain scores compared with men at 1 year (68.0 ± 32.8 vs. 78.7 ± 26.2, respectively, P ¼ 0.017). By the second year, these differences were nullified with pain scores of 76.4 ± 29.2 for women versus 75.0 ± 31.8 for men. Similar results were noted at 3 years with pain scores of 72.8 ± 33.4 for women which were comparable to 75.2 ± 29.4 for men (Fig. 3A). For treadmill testing, women consistently performed worse than men in all parameters including walking distance, walking speed, and stair climbing scores (Fig. 3BeD). It is important to note that women also started with significantly lower scores at baseline. Although achieving lower scores than men, women saw significant improvements at 3 years versus baseline after intervention for walking distance (37.3 ± 36.7 vs. 13.6 ± 18.4, P < 0.0001), walking speed (27.9 ± 21.6 vs. 15.3 ± 14.9, P ¼ 0.0004), and stair climbing (42.5 ± 35.8 vs. 25.3 ± 27.5, P ¼ 0.0137).
DISCUSSION The options for endovascular interventions in the femoropopliteal region continue to grow. Several studies continue today to elucidate the long-term efficacy of these options, which include angioplasty with selective stenting, primary stenting, covered stenting, drug-eluted stents, and angioplasty with drug-coated balloons. Although technical success and short-term results have been reported, longitudinal outcomes evaluating these treatment strategies are still lacking in the literature. Specifically, identifying subsets of patients who will best benefit from the different endovascular interventions remains the goal of many clinical studies. This clinical study provides the first intermediate outcomes of primary stenting for femoropopliteal lesions in men versus women. Although overall patencies remain comparable, several interesting differences in clinical outcomes were observed in men versus women. The 3-year results of the DURABILITY II trial were recently reported.14 Primary stenting with a single Everflex stent resulted in acceptable and durable results with primary patency of 60.0%, assisted-primary patency of 66.1%, secondary
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Table I. Preoperative patient, clinical, and lesion characteristics Baseline demographic and clinical characteristics Subject characteristics
Age (years) Diabetes Hyperlipidemia Hypertension Renal insufficiency Current smoker Angina Arrhythmia Congestive heart failure Stroke Transient ischemic attack Myocardial infarction Nonhealing ischemic ulcer in the lower extremities Amputation of the lower extremities Previous interventions in the superficial femoral or popliteal arteries Clinical characteristics Rutherford clinical category 2 ¼ Moderate claudication 3 ¼ Severe claudication 4 ¼ Ischemic rest pain 5 ¼ Minor tissue loss Lesion characteristics Lesion length (mm) Preprocedure stenosis (%) ± SD Occlusion Preprocedure reference vessel diameter (mm) ± SD
Males (n ¼ 190)
65.9 ± 9.9 44.2% 89.5% 86.8% 11.1% 42.6% 16.8% 13.7% 7.9% 6.8% 4.7% 22.1% 1.6% 1.6% 38.9%
(190) (84/190) (170/190) (165/190) (21/190) (81/190) (32/190) (26/190) (15/190) (13/190) (9/190) (42/190) (3/190) (3/190) (74/190)
Males (n ¼ 190)
Females (97)
P value
71.3 ± 11.2 (97) 39.2% (38/97) 79.4% (77/97) 90.7% (88/97) 7.2% (7/97) 32.0% (31/97) 18.6% (18/97) 14.4% (14/97) 12.4% (12/97) 5.2% (5/97) 5.2% (5/97) 18.6% (18/97) 1.0% (1/97) 0.0% (0/97) 45.4% (44/97)
<0.001 0.38 0.03 0.44 0.40 0.096 0.74 0.60 0.30 1.00 1.00 0.54 1.00 0.55 0.31
Females (97)
P value
44.2% 51.1% 4.2% 0.5%
(84/190) (97/190) (8/190) (1/190)
29.9% 64.9% 5.2% 0.0%
(29/97) (63/97) (5/97) (0/97)
0.071 0.02 0.03 0.77 1.00
87.8 ± 43.9 85.5 ± 16.2 46.8% 5.0 ± 0.9
(190) (190) (89/190) (190)
91.6 ± 46.8 86.2 ± 16.2 50.5% 4.4 ± 0.8
(97) (97) (49/97) (97)
0.52 0.65 0.62 <0.001
SD, standard deviation.
patency of 68.8%, and freedom from target lesion revascularization of 69.7%. When subdivided into lesion lengths, lesions 80 mm and shorter did remarkably well with primary patency of 71.0%, assisted-primary patency of 76.3%, secondary patency of 78.1%, and freedom from TLR of 79.6% at 3 years. In addition, mean ABIs remained significantly improved at 3 years (0.89 ± 0.19) compared with baseline (0.65 ± 0.15) and patients saw major improvements across all parameters in the WIQ scores. In a retrospective study, Stavroulakis et al. recently reported sex-stratified 5-year outcomes after stenting of femoropopliteal peripheral artery disease.15 Four different stents including EverFlex reported in this article (Covidien, Mansfield, MA), Pulsar 18 (Biotronic, Berlin, Germany), Supera (IDEV Technologies Inc, Webster, TX), and the paclitaxel-coated Zilver PTX (Cook Medical, Bloomington, IN) were used in the study. The authors reported similar overall 5-year primary patency in
males versus females (64.3% vs. 58.1%, respectively). When subdivided into presentation, claudicants saw similar result in men versus women (62.8% vs. 58.2%, respectively), but male patients who presented with critical limb ischemia (CLI) experienced higher patency rates compared with their female counterparts (73.9% vs. 59.8%, respectively; P < 0.05). In addition, women who presented with Trans-Atlantic Inter-Society Consensus C and D lesions performed significantly worse than men with primary patency of 62.0% in women versus 39.8% in men at 5 years. Although not adjudicated by a core laboratory, these findings were interesting considering that several studies, including our own have reported that women were more likely to present with CLI compared with men. Interestingly, a subanalysis of stent types in the previously mentioned study resulted in worse outcomes in women versus men when drug-eluted stents were used, whereas bare metal stent results were comparable.15 Although sex-stratified
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Fig. 1. (A) KaplaneMeier curve for primary patency. (B) KaplaneMeier curve for assisted-primary patency. (C) KaplaneMeier curve for secondary patency.
outcomes of the commercially available Lutonix and IN. PACT balloon have yet to be studied, the THUNDER trial evaluating angioplasty balloons coated with paclitaxel at a dose of 3 mg/mm2 of balloon surface performed a subanalysis of men versus women and reported slightly inferior rates in women as well, with similar rates of late lumen loss at 6-month follow-up, but higher rates of TLR in women (38%) versus men (17%) at 5 years.16 Another study reported that for patients presenting with critical limb ischemia, women were more likely to have significant femoropopliteal disease versus men (77% vs. 67%, respectively) and concurrent multilevel femoropopliteal and infrageniculate disease (63% vs. 51%, respectively).17 A total of 48% of women and 41% of men in the study received stents in their treatment. At 1 year, no significant differences were noted between men versus women undergoing intervention for femoropopliteal lesions with primary patency rates of 49%
versus 53%, assisted-primary patency rates of 55% versus 56%, and secondary patency rates of 63% versus 65%, respectively. These findings highlight the need for further studies to better understand effects of newer endovascular technology in female patients. Our previously reported sex-stratified 1-year results discussed that women presented with more severe claudication at a later age than men.12 Despite this, results from this present study demonstrate that patency and TLR rates remain durable, sustainable, and comparable between men and women through 3 years. Interestingly, the difference in ABI between men versus women reached statistical significance at 3 years. The clinical implications of this difference remain unclear as both men and women experienced significant improvements from their baseline ABIs. One speculation is that women may have more diffuse tibial disease that, although does not warrant intervention during
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Intermediate outcomes of femoropopliteal stenting in women 115
Fig. 2. KaplaneMeier curve for 3-year survival.
Table II. ABI in men versus women Mean ABI
Male (n ¼ 190)
Female (n ¼ 97)
P value
Baseline 1 Year 2 Year 3 Year
0.65 0.90 0.90 0.92
0.64 0.88 0.85 0.85
0.63 0.75 0.10 0.03
the index procedure, may account for overall decreased perfusion after stenting of femoropopliteal lesions. This hypothesis, however, needs further investigation. Looking at quality outcomes, women presented with lower clinical scores for all parameters with lower absolute ABIs and inferior WIQ scores compared with men. Improvement after intervention was noted to be more gradual in women. At 1 year, women continued to have worse pain, aching, and cramping scores compared with men. By the second year, women accomplished the same level of improvement as men with equivalent pain scores. These results were sustained at 3 years. It is possible that larger caliber vessels may provide more arterial in-flow allowing for more rapid symptom relief after intervention. In our study, a postprocedural lumen diameter of 3.6 mm was achieved in women versus 4.2 mm in men. This difference may
explain the more gradual symptom resolution accomplished by the women in this study compared with men. Another possible explanation is that other coexisting conditions in elderly women with peripheral arterial disease (PAD) such as arthritis and osteoporosis may contribute to inferior postprocedural pain scores and allow for slow gradual improvement in pain and walking distances. Finally, the preprocedural lower baselines seen for walking distance, speed, and stair climbing may be a reflection of lower peak muscle mass achieved in women than men which may factor into slower improvement after intervention. Again, these speculations need further confirmation with future studies. But while absolute clinical scores may be lower in women compared with men, it is important to note that both men and women had similar improvements from baseline across all parameters. As the overall goal of treatment is to improve a patient’s quality of life, the change in baseline may be the most important outcome measure. Although more information is needed to elucidate the underlying reasons for these differences, this study adds to the literature important longitudinal data on endovascular interventions in women. Our results demonstrate that primary stenting for femoropopliteal lesions in women is a viable and effective treatment modality resulting
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Fig. 3. (A) Score for pain, aching, cramps in calves, or buttocks. (B) Walking distance score. (C) Walking speed score. (D) Stair climbing score.
in durable vessel patency and improvements in quality of life.
achieving lower absolute ABI and WIQ parameters compared with men, but improved overall compared with scores at presentation.
LIMITATIONS This study has several limitations. DURABILITY II is an industry-sponsored, single-arm, nonrandomized design trial and as such, is subject to selection bias by the operator. Our results only reflect the use of primary stenting with one commercially available device and cannot be generalized to other endovascular products. Intermediate results are reported here, but long-term follow-up would provide more information on the longitudinal efficacy of primary stenting.
CONCLUSIONS Women continue to see clinical improvement after intervention, achieving comparable ABIs and walking distance to men at 2 years. These benefits are diminished at 3-year follow-up with women
The authors wish to thank Julie Messer for study management, Mei Jiang, PhD for statistical analysis, and Azah Tabah, PhD for technical review of the article.
REFERENCES 1. Chung C, Tadros R, Torres M, et al. Evolution of genderrelated differences in outcomes from two decades of endovascular aneurysm repair. J Vasc Surg 2015;61:843e52. 2. Jim J, Dillavou ED, Upchurch GR Jr, et al. Gender-specific 30-day outcomes after carotid endarterectomy and carotid artery stenting in the Society for Vascular Surgery Vascular Registry. J Vasc Surg 2014;59:742e8. 3. Pulli R, Dorigo W, Pratesi G, et al. Gender-related outcomes in the endovascular treatment of infrainguinal arterial obstructive disease. J Vasc Surg 2012;55:105e12. 4. DeRubertis BG, Vouyouka A, Rhee SJ, et al. Percutaneous intervention for infrainguinal occlusive disease in women: equivalent outcomes despite increased severity of disease
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5.
6.
7.
8.
9.
10.
11.
compared with men. J Vasc Surg 2008;48:150e7; discussion 157-8. Domenick N, Saqib NU, Marone LK, et al. Impact of gender and age on outcomes of tibial artery endovascular interventions in critical limb ischemia. Ann Vasc Surg 2012;26: 937e45. Egorova N, Vouyouka AG, Quin J, et al. Analysis of genderrelated differences in lower extremity peripheral arterial disease. J Vasc Surg 2010;51:372e8. e1; discussion 378-9. Gallagher KA, Meltzer AJ, Ravin RA, et al. Gender differences in outcomes of endovascular treatment of infrainguinal peripheral artery disease. Vasc Endovascular Surg 2011;45:703e11. Lo RC, Bensley RP, Dahlberg SE, et al. Presentation, treatment, and outcome differences between men and women undergoing revascularization or amputation for lower extremity peripheral arterial disease. J Vasc Surg 2014;59: 409e18. e3. Roddy SP, Darling RC 3rd, Maharaj D, et al. Gender-related differences in outcome: an analysis of 5880 infrainguinal arterial reconstructions. J Vasc Surg 2003;37(2):399e402. Tye A, Han DK, Tadros RO, et al. Percutaneous intervention for infrageniculate arterial disease in women may be associated with better outcomes when compared to men. J Vasc Surg 2013;57:706e13. Vouyouka AG, Egorova NN, Salloum A, et al. Lessons learned from the analysis of gender effect on risk factors
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12.
13.
14.
15.
16.
17.
and procedural outcomes of lower extremity arterial disease. J Vasc Surg 2010;52:1196e202. Tadros RO, Faries PL, Rocha-Singh KJ, et al. The impact of sex on angioplasty and primary stenting for femoropopliteal occlusive disease: results of the DURABILITY II trial. Ann Vasc Surg 2014;28:1e9. Matsumura JS, Yamanouchi D, Goldstein JA, et al. The United States StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II (DURABILITY II). J Vasc Surg 2013;58: 73e83. e1. Rocha-Singh K, Bosiers M, Schultz G, et al. A single stent strategy in patients with lifestyle limiting claudication: 3-year results from the Durability II trial. Catheter Cardiovasc Interv 2015;86(1):164e70. Stavroulakis K, Donas KP, Torsello G, et al. Gender-related long-term outcome of primary femoropopliteal stent placement for peripheral artery disease. J Endovasc Ther 2015;22:31e7. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoralpopliteal arteries with drug-coated balloons: 5-year followup of the THUNDER trial. JACC Cardiovasc Interv 2015;8(1 Pt A):102e8. McCoach CE, Armstrong EJ, Singh S, et al. Gender-related variation in the clinical presentation and outcomes of critical limb ischemia. Vasc Med 2013;18:19e26.
Background: This study investigated the effects of gender on the 3-year outcomes of the StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent System II (DURABILITY II) trial. Methods: A total of 287 patients enrolled in the DURABILITY II trial (prospective and nonrandomized trial) were stratified by gender and evaluated for primary, primary assisted, and secondary patency at 3 years. Clinical scores including changes in ankle-brachial index (ABI) and walking impairment questionnaire (WIQ) scores were evaluated. Results: Overall 190 male and 97 female patients were included for analysis. The 3-year primary, assisted primary, and secondary patency rates for women versus men were 62.5% vs. 58.8%, 68.5% vs. 64.9%, and 72.1% vs. 67.2%, respectively (P < 0.05). Although ABIs at presentation were similar between women versus men (0.64 vs. 0.65, P < 0.05), women had lower ABI scores at 3 years compared with men (0.85 vs. 0.92, P ¼ 0.03). Women versus men had inferior walking distance scores at presentation (13.6 vs. 25.7, P < 0.001), scores were equalized by 2 years (51.6 vs. 60.8, P < 0.05); however, 3-year follow-up demonstrated less durable results for women versus men (37.3 vs. 58.8, P < 0.05). In addition, women had worse WIQ scores for pain, walking speed, and stair climbing. However, the relative change in scores between men and women were comparable, with both groups seeing similar improvements from baseline for these parameters. Conclusions: Women continue to see clinical improvement after intervention, achieving comparable ABIs and walking distance to men at 2 years. These benefits are diminished at 3-year follow-up with women achieving lower absolute ABI and WIQ parameters compared with men, but improved overall compared with scores at presentation.
INTRODUCTION The patient populations evaluated in the landmark trials in vascular surgery that guide today’s practice
Division of Vascular Surgery, Department of Surgery, Mount Sinai Hospital, New York, NY. Correspondence to: Ageliki G.Vouyouka, MD, Division of Vascular Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 4th Floor, Box 1273, New York, NY 10029, USA; E-mail: [email protected] Ann Vasc Surg 2016; 30: 110–117 http://dx.doi.org/10.1016/j.avsg.2015.10.005 Ó 2016 Elsevier Inc. All rights reserved. Manuscript received: June 17, 2015; manuscript accepted: October 27, 2015; published online: November 14, 2015.
110
are predominantly composed of men. The last decade has seen an increased understanding of differences in vascular disease regarding presentation, pattern, and responses after intervention in women versus men. The quest for better understanding of sex-related differences of vascular disease and its outcomes in women has gained significant popularity because women account for most of our aging population and develops arterial disease as their male counterparts do.1e3 Therefore, several studies have emerged over the last decade evaluating and adding important knowledge on the differential outcomes between women and men after lowerextremity revascularization.4e11 However, these studies were all performed in retrospective fashion
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and lacked prospective, comprehensive evaluation of peripheral endovascular outcomes in women versus men that would include both objective and quality of life outcomes. The StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II (DURABILITY II) trial is a prospective, multicenter, and single-arm study being conducted under an investigational device exemption by the US Food and Drug Administration. The trial began its enrollment in 2007 to evaluate the safety and efficacy of primary stenting in the femoropopliteal region in patients with symptomatic lifelimiting claudication (Rutherford categories 2e4) using the Protege Everflex Self-Expanding Peripheral Stent System (Covidien, Plymouth, MN). The DURABILITY II trial offers an opportunity for prospective subanalysis on the impact of sex on the outcomes after primary stenting for femoropopliteal lesions in claudicants. We previously reported sexstratified 1-year results demonstrating that women presented at a later age than men with worse, more significant disease.12 Although women accomplished comparable patency rates at 1 year, they had inferior life quality outcomes with worse pain scores compared with men. Data on long-term results for primary stenting in women, however, remain scarce in today’s literature. The goal of this study was to evaluate the intermediate outcomes at 3 years in men versus women after primary stenting for femoropopliteal lesions including not only differences in objective findings such as patency rates but also gender-related differences in symptom resolution and other subjective parameters associated with ambulation and quality of life.
METHODS The detailed DURABILITY II study protocol, including inclusion and exclusion criteria has been previously published.13 The trial collected data for patency as assessed by duplex ultrasonography and ankle-brachial indices (ABIs). Clinical outcomes were evaluated through objective assessments of absolute walking distance, walking speed, and stair climbing scores determined by treadmill testing. At last, the trial collected patient responses on the walking impairment questionnaire (WIQ) to determine subjective changes in symptoms. Inclusion and exclusion criteria for the DURABILITY II trial have previously been published.12,13 Patients that were at least 18 years old with stenotic, restenotic, or occluded lesions of the superficial
Intermediate outcomes of femoropopliteal stenting in women 111
femoral artery (SFA) and proximal popliteal arteries with moderate to severe claudication were included in the study. Patients were enrolled when an exchangeable guidewire was traversed across the target lesion and met all preoperative criteria. Patients were uniformly predilated with an angioplasty balloon before deployment of the EverFlex stent. The diameter and length of stent used in the procedure was chosen at the investigator’s discretion. As part of the study protocol, all patients were standardized to receive antiplatelet therapy (aspirin 81 or 325 mg before and after the procedure; clopidogrel 75 mg for 7 days, 300 mg for 3 days, or 600 mg 1 day before procedure and 75 mg daily for 4 weeks after the procedure). Patients in the DURABILITY II trial were stratified by sex and information regarding patency, ABI, clinical walking scores, and WIQ questionnaire were collected. The primary end points included primary patency at 3 years evaluated by duplex ultrasonography and clinically driven target lesion restenosis (TLR) determined by an adjudicated core laboratory (VasCore Ultrasound Core Laboratory, Boston, MA). Loss of primary patency was defined as a doubling of the peak systolic velocity (PSV) in the treated segment with a PSV ratio between the treated segment and proximal artery of greater than or equal to 2.0. TLR was defined as >50% stenosis in a patient with recurrent symptoms, >70% stenosis in a patient with decreased ABI >0.15 from baseline, major amputation leading to limb loss, and all-cause mortality. Secondary end points included primaryassisted patency, secondary patency, changes in ABI, results of treadmill testing including absolute walking distance, walking speed, and stair climbing score, and change in WIQ scores at 3 years. Outcomes in women versus men were compared using t-tests for continuous variables, Fisher’s exact test for binary variables, and chi-squared test for ordinal outcomes. P < 0.05 was determined to be statistically significant. Patency rates were evaluated using KaplaneMeier curves and compared using the log-rank test.
RESULTS Across 44 participating centers in the United States, a total of 287 patients (190 men and 97 women) were enrolled in the DURABILITY II trial. A total of 146 of the 190 (76.8%) men completed their 3year follow-up visits. Among the 44 men without completion, 18 died, 15 were lost to follow-up, and 11 withdrew from the study. Seventy-four of the 97 (76.3%) women completed their 3-year
112 Han et al.
follow-up visits. Among the 23 women without completion, 8 died, 6 were lost to follow-up, and 9 withdrew from study. Patient demographics and preoperative comorbidities have previously been described.12 Briefly, women were older than men at presentation (71.3 ± 11.2 years vs. 65.9 ± 9.9 years, respectively) and less likely to have hyperlipidemia (79.4% vs. 89.5%), but otherwise, all demographics and preoperative characteristics were comparable between the 2 groups (Table I). Overall, 6.3% (12 of 190) of men and 11.3% (11 of 97) of women were on cilostazol. There was no statistically significant difference (P ¼ 0.17). More women (64.9%) presented with severe claudication versus men (51.1%, P ¼ 0.03). Although lesion lengths were comparable between women versus men, both preprocedure vessel diameter (4.4 vs. 5.0 mm, P < 0.001) and postprocedure lumen diameters (3.6 vs. 4.2 mm, P < 0.001) were noted to be smaller in women. Finally, men had lesions with more severe degree of calcification than women. The stents used for intervention were similar in length for men and women (127.4 ± 53.8 mm vs. 137.0 ± 54.8 mm, P ¼ 0.17) but were slightly bigger in men than women (6.6 ± 0.6 mm vs. 6.3 ± 0.5 mm, P < 0.001). Dissection occurred in 6 men (3.2%) and 2 women (2.1%; P ¼ 0.72). Additional stenting was used in 18 men (9.5%) and 15 women (15.5%; P ¼ 0.17). For patency, women had slightly higher primary (62.5% vs. 58.8%), primary assisted (68.5% vs. 64.9%), and secondary (72.1% vs. 67.2%) patency rates than men at 3 years, but this did not reach statistical significance (Fig. 1). Freedom from TLR for women versus men was also comparable at 3 years (67.4% vs. 70.9%, P < 0.05). Overall survival rates were equivalent in women versus men (90.7% vs. 90.1%, P < 0.05; Fig. 2). Limb salvage at 3 years was also comparable between women versus men (98.9% vs. 99.4%, P < 0.05). Both women and men saw significant improvements in ABIs compared with baseline after intervention out to 3 years (Table II). When evaluating absolute ABIs, men were able to achieve higher absolute ABI scores at 3 years versus women (0.92 ± 0.18 vs. 0.85 ± 0.21, P ¼ 0.03) despite comparable baseline ABIs. At 3 years, 85.2% of men and 78.8% of women maintained improvements in their ABIs compared with baseline (P < 0.05). Fifty-two of the 190 (27.4%) men had reinterventions. Among the 52 men with reinterventions, 34 had a single reintervention and 18 had more than 1. Five men had open revascularization and the rest had percutaneous procedures. Thirty of the 97 (30.9%) women had reinterventions. Among the 30 women with reinterventions,
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8 had a single reintervention and 22 had more than 1. One woman had open revascularization, and the rest had percutaneous procedures. After intervention, significant improvements in WIQ pain, aching, and cramping scores were seen for both men and women, sustained out to 3 years. These improvements were noted to be more gradual in women, who had significantly lower pain scores compared with men at 1 year (68.0 ± 32.8 vs. 78.7 ± 26.2, respectively, P ¼ 0.017). By the second year, these differences were nullified with pain scores of 76.4 ± 29.2 for women versus 75.0 ± 31.8 for men. Similar results were noted at 3 years with pain scores of 72.8 ± 33.4 for women which were comparable to 75.2 ± 29.4 for men (Fig. 3A). For treadmill testing, women consistently performed worse than men in all parameters including walking distance, walking speed, and stair climbing scores (Fig. 3BeD). It is important to note that women also started with significantly lower scores at baseline. Although achieving lower scores than men, women saw significant improvements at 3 years versus baseline after intervention for walking distance (37.3 ± 36.7 vs. 13.6 ± 18.4, P < 0.0001), walking speed (27.9 ± 21.6 vs. 15.3 ± 14.9, P ¼ 0.0004), and stair climbing (42.5 ± 35.8 vs. 25.3 ± 27.5, P ¼ 0.0137).
DISCUSSION The options for endovascular interventions in the femoropopliteal region continue to grow. Several studies continue today to elucidate the long-term efficacy of these options, which include angioplasty with selective stenting, primary stenting, covered stenting, drug-eluted stents, and angioplasty with drug-coated balloons. Although technical success and short-term results have been reported, longitudinal outcomes evaluating these treatment strategies are still lacking in the literature. Specifically, identifying subsets of patients who will best benefit from the different endovascular interventions remains the goal of many clinical studies. This clinical study provides the first intermediate outcomes of primary stenting for femoropopliteal lesions in men versus women. Although overall patencies remain comparable, several interesting differences in clinical outcomes were observed in men versus women. The 3-year results of the DURABILITY II trial were recently reported.14 Primary stenting with a single Everflex stent resulted in acceptable and durable results with primary patency of 60.0%, assisted-primary patency of 66.1%, secondary
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Table I. Preoperative patient, clinical, and lesion characteristics Baseline demographic and clinical characteristics Subject characteristics
Age (years) Diabetes Hyperlipidemia Hypertension Renal insufficiency Current smoker Angina Arrhythmia Congestive heart failure Stroke Transient ischemic attack Myocardial infarction Nonhealing ischemic ulcer in the lower extremities Amputation of the lower extremities Previous interventions in the superficial femoral or popliteal arteries Clinical characteristics Rutherford clinical category 2 ¼ Moderate claudication 3 ¼ Severe claudication 4 ¼ Ischemic rest pain 5 ¼ Minor tissue loss Lesion characteristics Lesion length (mm) Preprocedure stenosis (%) ± SD Occlusion Preprocedure reference vessel diameter (mm) ± SD
Males (n ¼ 190)
65.9 ± 9.9 44.2% 89.5% 86.8% 11.1% 42.6% 16.8% 13.7% 7.9% 6.8% 4.7% 22.1% 1.6% 1.6% 38.9%
(190) (84/190) (170/190) (165/190) (21/190) (81/190) (32/190) (26/190) (15/190) (13/190) (9/190) (42/190) (3/190) (3/190) (74/190)
Males (n ¼ 190)
Females (97)
P value
71.3 ± 11.2 (97) 39.2% (38/97) 79.4% (77/97) 90.7% (88/97) 7.2% (7/97) 32.0% (31/97) 18.6% (18/97) 14.4% (14/97) 12.4% (12/97) 5.2% (5/97) 5.2% (5/97) 18.6% (18/97) 1.0% (1/97) 0.0% (0/97) 45.4% (44/97)
<0.001 0.38 0.03 0.44 0.40 0.096 0.74 0.60 0.30 1.00 1.00 0.54 1.00 0.55 0.31
Females (97)
P value
44.2% 51.1% 4.2% 0.5%
(84/190) (97/190) (8/190) (1/190)
29.9% 64.9% 5.2% 0.0%
(29/97) (63/97) (5/97) (0/97)
0.071 0.02 0.03 0.77 1.00
87.8 ± 43.9 85.5 ± 16.2 46.8% 5.0 ± 0.9
(190) (190) (89/190) (190)
91.6 ± 46.8 86.2 ± 16.2 50.5% 4.4 ± 0.8
(97) (97) (49/97) (97)
0.52 0.65 0.62 <0.001
SD, standard deviation.
patency of 68.8%, and freedom from target lesion revascularization of 69.7%. When subdivided into lesion lengths, lesions 80 mm and shorter did remarkably well with primary patency of 71.0%, assisted-primary patency of 76.3%, secondary patency of 78.1%, and freedom from TLR of 79.6% at 3 years. In addition, mean ABIs remained significantly improved at 3 years (0.89 ± 0.19) compared with baseline (0.65 ± 0.15) and patients saw major improvements across all parameters in the WIQ scores. In a retrospective study, Stavroulakis et al. recently reported sex-stratified 5-year outcomes after stenting of femoropopliteal peripheral artery disease.15 Four different stents including EverFlex reported in this article (Covidien, Mansfield, MA), Pulsar 18 (Biotronic, Berlin, Germany), Supera (IDEV Technologies Inc, Webster, TX), and the paclitaxel-coated Zilver PTX (Cook Medical, Bloomington, IN) were used in the study. The authors reported similar overall 5-year primary patency in
males versus females (64.3% vs. 58.1%, respectively). When subdivided into presentation, claudicants saw similar result in men versus women (62.8% vs. 58.2%, respectively), but male patients who presented with critical limb ischemia (CLI) experienced higher patency rates compared with their female counterparts (73.9% vs. 59.8%, respectively; P < 0.05). In addition, women who presented with Trans-Atlantic Inter-Society Consensus C and D lesions performed significantly worse than men with primary patency of 62.0% in women versus 39.8% in men at 5 years. Although not adjudicated by a core laboratory, these findings were interesting considering that several studies, including our own have reported that women were more likely to present with CLI compared with men. Interestingly, a subanalysis of stent types in the previously mentioned study resulted in worse outcomes in women versus men when drug-eluted stents were used, whereas bare metal stent results were comparable.15 Although sex-stratified
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Fig. 1. (A) KaplaneMeier curve for primary patency. (B) KaplaneMeier curve for assisted-primary patency. (C) KaplaneMeier curve for secondary patency.
outcomes of the commercially available Lutonix and IN. PACT balloon have yet to be studied, the THUNDER trial evaluating angioplasty balloons coated with paclitaxel at a dose of 3 mg/mm2 of balloon surface performed a subanalysis of men versus women and reported slightly inferior rates in women as well, with similar rates of late lumen loss at 6-month follow-up, but higher rates of TLR in women (38%) versus men (17%) at 5 years.16 Another study reported that for patients presenting with critical limb ischemia, women were more likely to have significant femoropopliteal disease versus men (77% vs. 67%, respectively) and concurrent multilevel femoropopliteal and infrageniculate disease (63% vs. 51%, respectively).17 A total of 48% of women and 41% of men in the study received stents in their treatment. At 1 year, no significant differences were noted between men versus women undergoing intervention for femoropopliteal lesions with primary patency rates of 49%
versus 53%, assisted-primary patency rates of 55% versus 56%, and secondary patency rates of 63% versus 65%, respectively. These findings highlight the need for further studies to better understand effects of newer endovascular technology in female patients. Our previously reported sex-stratified 1-year results discussed that women presented with more severe claudication at a later age than men.12 Despite this, results from this present study demonstrate that patency and TLR rates remain durable, sustainable, and comparable between men and women through 3 years. Interestingly, the difference in ABI between men versus women reached statistical significance at 3 years. The clinical implications of this difference remain unclear as both men and women experienced significant improvements from their baseline ABIs. One speculation is that women may have more diffuse tibial disease that, although does not warrant intervention during
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Fig. 2. KaplaneMeier curve for 3-year survival.
Table II. ABI in men versus women Mean ABI
Male (n ¼ 190)
Female (n ¼ 97)
P value
Baseline 1 Year 2 Year 3 Year
0.65 0.90 0.90 0.92
0.64 0.88 0.85 0.85
0.63 0.75 0.10 0.03
the index procedure, may account for overall decreased perfusion after stenting of femoropopliteal lesions. This hypothesis, however, needs further investigation. Looking at quality outcomes, women presented with lower clinical scores for all parameters with lower absolute ABIs and inferior WIQ scores compared with men. Improvement after intervention was noted to be more gradual in women. At 1 year, women continued to have worse pain, aching, and cramping scores compared with men. By the second year, women accomplished the same level of improvement as men with equivalent pain scores. These results were sustained at 3 years. It is possible that larger caliber vessels may provide more arterial in-flow allowing for more rapid symptom relief after intervention. In our study, a postprocedural lumen diameter of 3.6 mm was achieved in women versus 4.2 mm in men. This difference may
explain the more gradual symptom resolution accomplished by the women in this study compared with men. Another possible explanation is that other coexisting conditions in elderly women with peripheral arterial disease (PAD) such as arthritis and osteoporosis may contribute to inferior postprocedural pain scores and allow for slow gradual improvement in pain and walking distances. Finally, the preprocedural lower baselines seen for walking distance, speed, and stair climbing may be a reflection of lower peak muscle mass achieved in women than men which may factor into slower improvement after intervention. Again, these speculations need further confirmation with future studies. But while absolute clinical scores may be lower in women compared with men, it is important to note that both men and women had similar improvements from baseline across all parameters. As the overall goal of treatment is to improve a patient’s quality of life, the change in baseline may be the most important outcome measure. Although more information is needed to elucidate the underlying reasons for these differences, this study adds to the literature important longitudinal data on endovascular interventions in women. Our results demonstrate that primary stenting for femoropopliteal lesions in women is a viable and effective treatment modality resulting
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Fig. 3. (A) Score for pain, aching, cramps in calves, or buttocks. (B) Walking distance score. (C) Walking speed score. (D) Stair climbing score.
in durable vessel patency and improvements in quality of life.
achieving lower absolute ABI and WIQ parameters compared with men, but improved overall compared with scores at presentation.
LIMITATIONS This study has several limitations. DURABILITY II is an industry-sponsored, single-arm, nonrandomized design trial and as such, is subject to selection bias by the operator. Our results only reflect the use of primary stenting with one commercially available device and cannot be generalized to other endovascular products. Intermediate results are reported here, but long-term follow-up would provide more information on the longitudinal efficacy of primary stenting.
CONCLUSIONS Women continue to see clinical improvement after intervention, achieving comparable ABIs and walking distance to men at 2 years. These benefits are diminished at 3-year follow-up with women
The authors wish to thank Julie Messer for study management, Mei Jiang, PhD for statistical analysis, and Azah Tabah, PhD for technical review of the article.
REFERENCES 1. Chung C, Tadros R, Torres M, et al. Evolution of genderrelated differences in outcomes from two decades of endovascular aneurysm repair. J Vasc Surg 2015;61:843e52. 2. Jim J, Dillavou ED, Upchurch GR Jr, et al. Gender-specific 30-day outcomes after carotid endarterectomy and carotid artery stenting in the Society for Vascular Surgery Vascular Registry. J Vasc Surg 2014;59:742e8. 3. Pulli R, Dorigo W, Pratesi G, et al. Gender-related outcomes in the endovascular treatment of infrainguinal arterial obstructive disease. J Vasc Surg 2012;55:105e12. 4. DeRubertis BG, Vouyouka A, Rhee SJ, et al. Percutaneous intervention for infrainguinal occlusive disease in women: equivalent outcomes despite increased severity of disease
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5.
6.
7.
8.
9.
10.
11.
compared with men. J Vasc Surg 2008;48:150e7; discussion 157-8. Domenick N, Saqib NU, Marone LK, et al. Impact of gender and age on outcomes of tibial artery endovascular interventions in critical limb ischemia. Ann Vasc Surg 2012;26: 937e45. Egorova N, Vouyouka AG, Quin J, et al. Analysis of genderrelated differences in lower extremity peripheral arterial disease. J Vasc Surg 2010;51:372e8. e1; discussion 378-9. Gallagher KA, Meltzer AJ, Ravin RA, et al. Gender differences in outcomes of endovascular treatment of infrainguinal peripheral artery disease. Vasc Endovascular Surg 2011;45:703e11. Lo RC, Bensley RP, Dahlberg SE, et al. Presentation, treatment, and outcome differences between men and women undergoing revascularization or amputation for lower extremity peripheral arterial disease. J Vasc Surg 2014;59: 409e18. e3. Roddy SP, Darling RC 3rd, Maharaj D, et al. Gender-related differences in outcome: an analysis of 5880 infrainguinal arterial reconstructions. J Vasc Surg 2003;37(2):399e402. Tye A, Han DK, Tadros RO, et al. Percutaneous intervention for infrageniculate arterial disease in women may be associated with better outcomes when compared to men. J Vasc Surg 2013;57:706e13. Vouyouka AG, Egorova NN, Salloum A, et al. Lessons learned from the analysis of gender effect on risk factors
Intermediate outcomes of femoropopliteal stenting in women 117
12.
13.
14.
15.
16.
17.
and procedural outcomes of lower extremity arterial disease. J Vasc Surg 2010;52:1196e202. Tadros RO, Faries PL, Rocha-Singh KJ, et al. The impact of sex on angioplasty and primary stenting for femoropopliteal occlusive disease: results of the DURABILITY II trial. Ann Vasc Surg 2014;28:1e9. Matsumura JS, Yamanouchi D, Goldstein JA, et al. The United States StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II (DURABILITY II). J Vasc Surg 2013;58: 73e83. e1. Rocha-Singh K, Bosiers M, Schultz G, et al. A single stent strategy in patients with lifestyle limiting claudication: 3-year results from the Durability II trial. Catheter Cardiovasc Interv 2015;86(1):164e70. Stavroulakis K, Donas KP, Torsello G, et al. Gender-related long-term outcome of primary femoropopliteal stent placement for peripheral artery disease. J Endovasc Ther 2015;22:31e7. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoralpopliteal arteries with drug-coated balloons: 5-year followup of the THUNDER trial. JACC Cardiovasc Interv 2015;8(1 Pt A):102e8. McCoach CE, Armstrong EJ, Singh S, et al. Gender-related variation in the clinical presentation and outcomes of critical limb ischemia. Vasc Med 2013;18:19e26.