Prognostic Factors and Predictors of Mortality in Patients with Critical Limb Ischemia: A Current Clinical Perspective

Moniruddin Chowdhury^1,2, Syeda Humayra², Sohel Mahmud³, Yukihito Higashi⁴, YD Singh¹

PAD and its impact in physical impairment or mortality.

Abstract

Critical limb ischemia (CLI) is an end-stage peripheral arterial disease (PAD). Mortality, limb loss, pain, and diminished health-related quality of life are highly prevalent in CLI patients. 20 to 50% CLI Mortality is intensely observed within the first six months to five years of CLI diagnosis, respectively. Prognostic treatments, including autologous bone marrow mononuclear cell implantation (BMMNCI), low-intensity pulsed ultrasound (LIPUS) technology, and medication therapy using Cilostazol, are available. In addition, required prognostic factors such as timely access to medical care can control the death. Impaired mobility, old age, low BMI, CKD (end-stage), T2DM, COPD (oxygen-dependent), HF, smoking, high Wound, Ischemia, and Foot Infection are the additional predictors for CLI-related mortality. Due to the poor survival and prognosis, it is crucial to identify the prognostic factors that will lead to better clinical benefits, including amputation-free survival rate and improved quality of life. This review highlights the current clinical perspective on the prognostic factors and predictors of mortality in CLI patients.

Keywords: Amputation, Critical limb ischemia, mortality, peripheral arterial disease, prognosis

References

Akagi, D., Hoshina, K., Akai, A., & Yamamoto, K. (2018). Clinical Study Outcomes in Patients with Critical Limb Ischemia due to Arteriosclerosis Obliterans Who Did Not Undergo Arterial Reconstruction. International Heart Journal, 59, 1041–1046.

Azuma, N., Takahara, M., Kodama, A., Soga, Y., Terashi, H., Tazaki, J., Yamaoka, T., Koya, A., & Iida, O. (2019). Predictive Model for Mortality Risk Including the Wound, Ischemia, Foot Infection Classification in Patients Undergoing Revascularization for Critical Limb Ischemia. Circulation: Cardiovascular Interventions, 12(12), 1–8.

Barc, P., Antkiewicz, M., Fraczkowska-Sioma, K., Kupczynska, D., Lubieniecki, P., Witkiewicz, W., ... & Skóra, J. P. (2022). Two-Stage Gene Therapy (VEGF, HGF and ANG1 Plasmids) as Adjunctive Therapy in the Treatment of Critical Lower Limb Ischemia in Diabetic Foot Syndrome. International Journal of Environmental Research and Public Health, 19(19), 12818.

Baser, O., Verpillat, P., Gabriel, S., & Wang, L. J. V. D. M. (2013). Prevalence, incidence, and outcomes of critical limb ischemia in the US Medicare population. Vasc Dis Manag, 10(2), E26-E36.

Beckman, J. A., & Creager, M. A. (2014). Critical limb ischemia and intermediate-term survival. JACC: Cardiovascular Interventions, 7(12), 1450–1452.

Biancari, F. (2013). Meta-analysis of the prevalence, incidence and natural history of critical limb ischemia. The Journal of Cardiovascular Surgery, 54(6), 663-669.

Brahmanandam, S. M., Messina, L. M., Belkin, M., Conte, M. S., & Nguyen, L. L. (2009). PP44. Determinants of Hospital Disposition after Lower Extremity Bypass Surgery. Journal of Vascular Surgery, 49(5), S27.

Chowdhury, M. (2017). Role of Cell Therapy for Patients with Chronic Critical Limb Ischemia to Prevent Amputation. Journal of Embryology & Stem Cell Research, 1(1), 1–3.

Chowdhury, M., Islam, R., & Chowdhury, A. (2020). Prevention of Amputation among the Cases of Chronic Critical Limb Ischaemia with Limited Treatment Option: Current Modalities of Therapy and Future Perspectives. Clinical and Experimental Anatomy, 3(8), 19–22.

Davies, M. G. (2012). Criticial limb ischemia: epidemiology. Methodist DeBakey Cardiovascular Journal, 8(4), 10–14.

Duff, S., Mafilios, M. S., Bhounsule, P., & Hasegawa, J. T. (2019). The burden of critical limb ischemia: A review of recent literature. Vascular Health and Risk Management, 15, 187–208.

Fagundes, C., Fuchs, F. D., Fagundes, A., Poerschke, R. A., & Vacaro, M. Z. (2005). Prognostic factors for amputation or death in patients submitted to vascular surgery for acute limb ischemia. Vascular Health and Risk Management, 1(4), 345–349.

Fereydooni, A., Gorecka, J., & Dardik, A. (2020). Using the epidemiology of critical limb ischemia to estimate the number of patients amenable to endovascular therapy. Vascular Medicine, 25(1), 78-87.

Furuyama, T., Onohara, T., Yamashita, S., Yoshiga, R., Yoshiya, K., Inoue, K., Morisaki, K., Kyuragi, R., Matsumoto, T., & Maehara, Y. (2018). Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia. Vascular, 26(6), 626–633.

Harwood, A. E., Pugh, C. J., Steward, C. J., Menzies, C., Thake, C. D., & Cullen, T. (2021). A systematic review of the role of heat therapy for patients with intermittent claudication due to peripheral artery disease. Vascular Medicine, 26(4), 440-447.

Idei, N., Soga, J., Hata, T., Fujii, Y., Fujimura, N., Mikami, S., Maruhashi, T., Nishioka, K., Hidaka, T., Kihara, Y., Chowdhury, M., Noma, K., Taguchi, A., Chayama, K., Sueda, T., & Higashi, Y. (2011). Autologous Bone-Marrow Mononuclear Cell Implantation Reduces Long-Term Major Amputation Risk in Patients With Critical Limb Ischemia A Comparison of Atherosclerotic Peripheral Arterial Disease and Buerger Disease. Circulation: Cardiovascular Interventions, 4(1), 15–25.

Khaira, K. B., Brinza, E., Singh, G. D., Amsterdam, E. A., Waldo, S. W., Tong, K., Pandya, K., Laird, J. R., & Armstrong, E. J. (2017). Long-term outcomes in patients with critical limb ischemia and heart failure with preserved or reduced ejection fraction. Vascular Medicine, 22(4), 307–315.

Kobayashi, N., Hirano, K., Nakano, M., Ito, Y., Ishimori, H., Yamawaki, M., Tsukahara, R., & Muramatsu, T. (2015). Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy. Journal of Vascular Surgery, 61(4), 951–959.

Kondo, K., Yanishi, K., Hayashida, R., Shintani, S., Shibata, R., Murotani, K., Ando, M., Mizuno, M., Fujiwara, T., Murohara, T., Matoba, S., Higashi, Y., Saito, Y., Fukumoto, Y., Ikeda, U., Ishigami, T., Yoshimi, R., Fukumoto, S., & Fujimoto, K. (2018). Long-term clinical outcomes survey of bone marrow-derived cell therapy in critical limb ischemia in Japan. Circulation Journal, 82(4), 1168–1178.

Kuoppala, M., Franzén, S., Lindblad, B., & Acosta, S. (2008). Long-term prognostic factors after thrombolysis for lower limb ischemia. Journal of Vascular Surgery, 47(6), 1243–1250.

Levin, S. R., Arinze, N., & Siracuse, J. J. (2020). Lower extremity critical limb ischemia: A review of clinical features and management. Trends in cardiovascular medicine, 30(3), 125-130.

Lozano Navarro, L. V., Chen, X., Giratá Viviescas, L. T., Ardila-Roa, A. K., Luna-Gonzalez, M. L., Sossa, C. L., & Arango-Rodríguez, M. L. (2022). Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem Cell Research & Therapy, 13(1), 1-17.

Majmundar, M., Patel, K. N., Doshi, R., Anantha-Narayanan, M., Kumar, A., Reed, G. W., ... & Kalra, A. (2022). Comparison of 6-Month Outcomes of Endovascular vs Surgical Revascularization for Patients With Critical Limb Ischemia. JAMA network open, 5(8), e2227746-e2227746.

Mohamad Yusoff, F., Kajikawa, M., Matsui, S., Hashimoto, H., Kishimoto, S., Maruhashi, T., Chowdhury, M., Noma, K., Nakashima, A., Kihara, Y., Sueda, T., Higashi, Y., & Rahman, A. (2019). Review of the Long-term Effects of Autologous Bone-Marrow Mononuclear Cell Implantation on Clinical Outcomes in Patients with Critical Limb Ischemia. Scientific Reports, 9(1), 1–7.

Mohamad Yusoff, F., Kajikawa, M., Yamaji, T., Takaeko, Y., Hashimoto, Y., Mizobuchi, A., ... & Higashi, Y. (2021). Low-intensity pulsed ultrasound decreases major amputation in patients with critical limb ischemia: 5-year follow-up study. Plos one, 16(8), e0256504.

Roijers, J. P., Rakké, Y. S., Hopmans, C. J., Buimer, M. G., Ho, G. H., de Groot, H. G. W., Veen, E. J., Mulder, P. G. H., & van der Laan, L. (2020). A mortality prediction model for elderly patients with critical limb ischemia. Journal of Vascular Surgery, 71(6), 2065-2072.

Rutherford, R. B., Baker, J. D., Ernst, C., Johnston, K. W., Porter, J. M., Ahn, S., & Jones, D. N. (1997). Recommended standards for reports dealing with lower extremity ischemia: revised version. Journal of Vascular Surgery, 26(3), 517-538.

Shimizu, Y., Kondo, K., Hayashida, R., Sasaki, K. I., Ohtsuka, M., Fukumoto, Y., ... & Murohara, T. (2022). Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial. Angiogenesis, 25(4), 535-546.

Simons, J. P., Schanzer, A., Flahive, J. M., Osborne, N. H., Mills, J. L., Bradbury, A. W., & Conte, M. S. (2019). Survival prediction in patients with chronic limb-threatening ischemia who undergo infrainguinal revascularization. European Journal of Vascular and Endovascular Surgery, 58(1),120-134

Soga, Y., Iida, O., Takahaera, M., Hirano, K., Suzuki, K., Kawasaki, D., Miyashita, Y., & Tsuchiya, T. (2014). Two-year life expectancy in patients with critical limb ischemia. JACC: Cardiovascular Interventions, 7(12), 1444–1449.

Teraa, M., Conte, M. S., Moll, F. L., & Verhaar, M. C. (2016). Critical limb ischemia: Current trends and future directions. Journal of the American Heart Association, 5(2), 1–8.

Uccioli, L., Meloni, M., Izzo, V., Giurato, L., Merolla, S., & Gandini, R. (2018). Critical limb ischemia: current challenges and future prospects. Vascular Health and Risk Management, 14,63-74.

Varu, V. N., Hogg, M. E., & Kibbe, M. R. (2010). Critical limb ischemia. Journal of Vascular Surgery, 51(1), 230–241.

Yunir, E., Wisman, B. A., Antono, D., Mansjoer, A., Sarumpaet, A., Iswati, E., ... & Soewondo, P. (2022). Factors Affecting Mortality of Critical Limb Ischemia 1 Year after Endovascular Revascularization in Patients with Type 2 Diabetes Mellitus. Review of Diabetic Studies, 18(1), 20-26.