Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy
Authors: Kawarada Osami , Zen Kan , Hozawa Koji , Obara Hideaki , Matsubara Kentaro , Yamamoto Yoshito , Doijiri Tatsuki , Tamai Nozomu , Ito Shigenori , Higashimori Akihiro , Kawasaki Daizo , Doi Hideki , Matsushita Kensuke , Tsukahara Kengo , Noda Katsuo , Shimpo Masahisa , Tsuda Yuki , Sonoda Shinjo , Taniguchi Takuya , Waseda Katsuhisa , Munehisa Masato , Taguchi Eiji , Kinjo Tatsuya , Sasaki Yohei , Yuba Kenichiro , Yamaguchi Shinichiro , Nakagami Takuo , Ayabe Shinobu , Sakamoto Shingo , Yagyu Takeshi , Ogata Soshiro , Nishimura Kunihiro , Motomura Hisashi , Noguchi Teruo , Ishihara Masaharu , Ogawa Hisao , Yasuda Satoshi 
Published: November 2022

Purpose: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). Materials and Methods: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. Results: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950–3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999–3.909, p=0.05). Conclusions: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. Clinical Impact The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.