Sex-Related Differences in Lower Extremity Peripheral Artery Disease

A review of differences in clinical presentation and outcomes after surgical revascularization and endovascular procedures in women as compared with men.

By Maureen P. Kohi, MD, FSIR; and John Fritz Angle, MD, FSIR
 

Lower extremity peripheral artery disease (PAD) is a growing epidemic, affecting approximately 8 to 12 million individuals in the United States and more than 200 million people worldwide.1,2 The prevalence of PAD in women has traditionally been considered to be less than or equal to that of men. However, recent studies demonstrate an expected rise in the total population burden of PAD in women.3 Yet, PAD remains underdiagnosed in women, and women have been underrepresented in several PAD revascularization trials.

The traditional risk factors for development of PAD include diabetes mellitus, cigarette smoking, advanced age, dyslipidemia, and hypertension.4 Although these conventional risk factors result in PAD development in women similarly as they do in men, a growing body of evidence has demonstrated additional comorbidities that are prevalent in women with PAD, such as depression and inflammation.5 Such risk factors are not routinely evaluated in PAD studies, and future trials are necessary to determine whether an association exists between these “novel” risk factors and the development of PAD in women.

Intermittent claudication is considered the hallmark symptom of PAD, but women may often be asymptomatic or present with atypical symptoms (eg, leg muscle symptoms at rest and with exercise).3 Also, women with PAD are more likely to be older at presentation compared to their male counterparts, present with critical limb ischemia (CLI), are less likely to undergo surgery, and are more likely to undergo amputations.6

OUTCOMES AFTER SURGICAL REVASCULARIZATION

After lower extremity bypass surgery, women have a higher rate of graft failure, wound complications, and limb loss when compared to men.7 Additionally, elevated baseline levels of C-reactive protein and fibrinogen have been shown to be associated with inferior vein graft patency in women. This suggests a potential interaction between sex and inflammation in the healing response of vein grafts after lower extremity bypass surgery.8 In clinical practice, women with elevated preoperative C-reactive protein and fibrinogen levels may benefit from more aggressive postoperative graft surveillance protocols.

ENDOVASCULAR OUTCOMES

Recent studies evaluating sex differences in endovascular treatment outcomes have demonstrated that women are older and more likely to present with CLI compared to men, who most commonly presented with claudication.9 In addition, women were more likely to have multilevel disease and required more femoropopliteal interventions. There does not seem to be a mortality difference between men and women after endovascular treatment for PAD. Some studies suggest increased periprocedural adverse events, including vascular complications (dissections), bleeding, transfusions, and embolism in women.9,10 However, a recent propensity score–matched analysis demonstrated higher complications in male patients, with only an increased rate of blood transfusions in women.11 This finding is particularly important because it demonstrates that although women may present with more advanced PAD, the outcomes may not differ when compared to their male counterparts, who tend to be younger and have a less advanced PAD. This only increases the need for earlier diagnosis and intervention for women who have PAD. In a different propensity score–matched analysis, women were 1.5 times more likely to require reintervention when compared with men.12 Although the exact reason for this is not known, it may be due to the difference in vessel size. In fact, it has been shown that the caliber of all vessels in the lower extremity of women are statistically significantly smaller than those in men.13 These findings argue for potentially more aggressive clinical follow-up with female patients after endovascular therapy for PAD.

OUTCOMES AFTER DCB ANGIOPLASTY

Prospective randomized controlled trials have demonstrated superior outcomes for the treatment of femoropopliteal lesions with drug-coated balloon (DCB) angioplasty versus percutaneous transluminal angioplasty (PTA).14,15 However, the US Food and Drug Administration summary of safety and effectiveness data from the LEVANT 2 trial demonstrated a reduced treatment effect in women as compared with men.16 Interestingly, in the German subgroup analysis of the LEVANT 2 trial, women benefited more from treatment with DCB angioplasty compared to men.17 Other studies also demonstrate conflicting results and show female sex as a prognostic indicator for restenosis after DCB angioplasty.18,19 Further investigation is necessary in order to detect a potential sex-related difference with respect to outcomes following DCB angioplasty.

CASE EXAMPLE

A 47-year-old woman presented with left lower extremity claudication. On angiography, she was found to have near occlusion of the distal left superficial femoral artery (SFA) (Figure 1). The SFA occlusion was crossed in the subintimal plane using a 5-F catheter and 0.035-inch angled hydrophilic guidewire. After PTA to 4 mm, using a low compliance balloon, there was a non–flow-limiting dissection (Figure 2).

The patient returned 18 months later with recurrent symptoms. Two 6-mm nitinol self-expanding bare-metal stents (Protege, Medtronic) were placed from the femoral bifurcation to the adductor canal (Figure 3). Three years later, she required two reinterventions, including laser atherectomy and placement of a self-expanding covered stent (Viabahn, Gore & Associates) in the proximal popliteal artery (Figure 4).

This case demonstrates the small size of the arteries in women and the tendency to experience complications such as dissection. The case also exemplifies the need for additional endovascular procedures, as women typically require more interventions as compared with men.

Figure 1. Angiogram showing near occlusion of the distal left SFA.

Figure 2. Angiogram showing a non–flow-limiting dissection after PTA using a low compliance balloon.

Figure 3. Eighteen months later, two 6- X 150-mm nitinol stents were placed in the left SFA.

Figure 4. CTA 2 years later, after placement of a 5- X 50-mm self-expanding covered stent in the proximal popliteal artery.

CONCLUSION

Sex-related differences are present in the development, presentation, and outcomes of PAD. Women with PAD are more likely to present with more advanced disease and are older at the time of diagnosis. This is due to the absence of routine PAD screening in women and potentially different risk factors and presenting symptoms.

Outcomes after endovascular treatment in women are promising. More research is necessary to determine whether women and men have similar outcomes after DCB angioplasty and to identify the potential subgroup of women who may require more aggressive follow-up and reintervention. Awareness of these differences can help identify more women who may be at risk for PAD, with intervention performed earlier. Further clinical trials are needed to identify the key sex-related differences that may explain the difference in outcomes between men and women with PAD.

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2. Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329-1340.

3. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012;125:1449-1472.

4. Barochiner J, Aparicio LS, Waisman GD. Challenges associated with peripheral arterial disease in women. Vasc Health Risk Manag. 2014;10:115-128.

5. Grenon SM, Cohen BE, Smolderen K, et al. Peripheral arterial disease, gender, and depression in the Heart and Soul Study. J Vasc Surg. 2014;60:396-403.

6. 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;22:31-37.

7. Egorova N, Vouyouka AG, Quin J, et al. Analysis of gender-related differences in lower extremity peripheral arterial disease. J Vasc Surg. 2010;51:372-8.e1.

8. Hiramoto JS, Owens CD, Kim JM, et al. Sex-based differences in the inflammatory profile of peripheral artery disease and the association with primary patency of lower extremity vein bypass grafts. J Vasc Surg. 2012;56:387-395.

9. Jackson EA, Munir K, Schreiber T et al. Impact of sex on morbidity and mortality rates after lower extremity interventions for peripheral arterial disease: observations from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. J Am Coll Cardiol. 2014;63:2525-2530.

10. Rieß HC, Debus ES, Heidemann F, et al. Gender differences in endovascular treatment of infrainguinal peripheral artery disease. Vasa. 2017;46:296-303.

11. Doshi R, Shah P, Meraj P. Gender disparities among patients with peripheral arterial disease treated via endovascular approach: a propensity score matched analysis [published online August 16, 2017]. J Interv Cardiol.

12. Jeon-Slaughter H, Tsai S, Kamath P, et al. Comparison of lower extremity endovascular intervention outcomes in women versus men. Am J Cardiol. 2017;119:490-496.

13. Czyzewska D, Ustymowicz A, Krysiuk K, et al. Ultrasound assessment of the caliber of the arteries in the lower extremities in healthy persons—the dependency on age, sex and morphological parameters of the subjects. J Ultrason. 2012;12:420-427.

14. Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014;7:10-19.

15. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015;131:495-502.

16. US Food and Drug Administration. PMA P130024: FDA summary of safety and effectiveness data. https://www.accessdata.fda.gov/cdrh_docs/pdf13/P130024B.pdf. Accessed November 19, 2017.

17. Scheinert D, Schmidt A, Zeller T, et al. German center subanalysis of the LEVANT 2 global randomized study of the Lutonix drug-coated balloon in the treatment of femoropopliteal occlusive disease. J Endovasc Ther. 2016;23:409-416.

18. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty. Evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012;5:831-840.

19. Schmidt A, Piorkowski M, Görner H, et al. Drug-coated balloons for complex femoropopliteal lesions: 2-year results of a real-world registry. JACC Cardiovasc Interv. 2016;9:715-724.

Maureen P. Kohi, MD, FSIR
Associate Professor
Department of Radiology and Biomedical Imaging
University of California San Francisco
San Francisco, California
maureen.kohi@ucsf.edu
Disclosures: None.

John Fritz Angle, MD, FSIR
Professor of Radiology
Director of Interventional Radiology
Department of Medical Imaging
University of Virginia Health System
Charlottesville, Virginia
jfa3h@virginia.edu
Disclosures: Consultant to Proteon Therapeutics, Terumo Interventional Systems, Daiichi Sankyo; speaker for Cook Medical, Medtronic, and Gore & Associates; unrestricted grants from Siemens Healthcare.

 

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