The burden of critical limb ischemia: a review of recent literature

Figures & data

Table 1 CLI prevalence and incidence

Publication	Country/region	Data source (years)	Population details	Methods	CLI prevalence (N or %)	CLI incidence (annual unless stated)
Baser (2013)^Citation19	United States	100% Medicare inpatient/outpatient/denominator files (2007–2008)	US Medicare population	ICD-9 and CPT codes used to identify CLI cases	Using ICD-9 codes only: Total—0.23% Using ICD-9 and CPT codes Total—0.54%	Using ICD-9 codes only: Total—0.20% Fontaine Stage III only—0.05% Fontaine Stage IV only—0.15% Using ICD-9 and CPT codes: Total—0.48%
Nehler (2014)^Citation17	United States	MarketScan database (2004–2008)	US population age ≥40	ICD-9 and CPT codes used to identify CLI cases	2008 Overall: 1.28% 2008 Commercial: 0.80% 2008 Medicaid: 2.57% 2008 Medicare: 2.01%	Total CLI: 0.35%
Mustapha (2018)^Citation20	United States	Medicare fee-for-service Parts A and B (2011–2015)	Adult US Medicare population	ICD-9 and CPT codes used to identify CLI cases	2011: 116,031 (0.32%)	Total CLI: 0.26%

Abbreviations: CLI, critical limb ischemia; CPT, Current Procedural Terminology^®; ICD-9, International Classification of Diseases 9th Revision.

Figure 1 US CLI readmission rates.

Abbreviation: CLI, critical limb ischemia.

Table 2 CLI readmission rates

Publication	Country/region	Data source (years)	Population details	Methods	Readmission rate ranges (see figure 1 for detail)
Reed (2016)^Citation70	Cleveland, OH	Cleveland Clinic (2011–2015)	CLI patients undergoing endovascular treatment	Retrospective analysis of medical records	30-day: 13.9% 6-month: 40.5%
Jones (2016)^Citation71	United States	ACS National Surgical Quality Improvement Program (2012–2014)	CLI patients undergoing open bypass for rest pain or tissue loss	CPT codes to identify cases	30-day: 16.5–18.8%
Agarwal (2017)^Citation29	States of CA, FL, and NY	State inpatient databases (2009–2013)	Patients with a principal diagnosis of CLI	ICD-9 diagnosis and procedure codes used to identify cases and procedures	30-day: 23.6–29.1% 6-month: 47.7–59.5%
Bodewes (2017)^Citation72	United States	ACS National Surgical Quality Improvement Program (2012–2014)	CLI patients undergoing infrainguinal endovascular treatment	CPT codes to identify cases	30-day: 16%
Kolte (2017)^Citation23	United States	Nationwide Readmissions Database (2013–2014)	CLI patients undergoing open or endovascular treatment	ICD-9 diagnosis and procedure codes used to identify cases and procedures	30-day: 14.8–25.0%
Martinez (2018)^Citation64	United States	Nationwide Readmissions Database (2013–2014)	CLI patients undergoing revascularization procedures	ICD-9 diagnosis and procedure codes used to identify cases and procedures	30-day: 19.3% Overall: 40.4%
Masoomi (2018)^Citation73	United States	Nationwide Readmissions Database (2013)	CLI patients with/without revascularization procedures	ICD-9 diagnosis and procedure codes used to identify cases and procedures	30-day: 5%^a

Notes: ^aPrimary readmission diagnosis of CLI (rather than all-cause).

Abbreviations: ACS, American College of Surgeons; CLI, critical limb ischemia; CPT, Current Procedural Terminology^®; ICD-9, International Classification of Diseases 9th Revision.

Table 3 CLI amputation rates

Publication	Country/region	Data source (years)	Population details	Methods	Amputation rate or incidence
Marston^a (2006)^Citation74	Chapel Hill, NC	University of North Carolina Wound Management Center (1999–2005)	CLI patients with unhealed ulcers not candidates for revascularization	Retrospective analysis of prospectively collected data	1-Year 38%
Henry (2011)^Citation28	United States	Nationwide Inpatient Sample (2003–2007)	Hospitalized CLI patients except those with EVT plus amputation	ICD-9 diagnosis and procedure codes used to identify cases and procedures; multivariate regression analyses	During Admission 24.2% Significant Odds Ratios^b Black: 2.15 Native American: 2.00 Low income: 1.12–1.34 Private insurance: 0.74 Medicaid: 1.26
Peacock (2011)^Citation65	Minnesota	State-based hospital claims database (2005–2008)	Patients with lower limb ischemic amputation^c	ICD-9 diagnosis and procedure codes used to identify cases and procedures	Age-Adjusted Incidence All: 20.0/100,000 Rural: 21.4/100,000 Urban: 19.6/100,000
O’Brien-Irr (2012)^Citation25	New York State	SPARCS database (2001–2008)	CLI patients undergoing vascular intervention	ICD-9 diagnosis and procedure codes used to identify cases and procedures	During Admission Rutherford 4: 3.1% Rutherford 5: 26.7% Rutherford 6: 55.0%
Baser (2013)^Citation19	United States	100% Medicare inpatient/outpatient/denominator files (2007–2008)	US Medicare population	ICD-9 and CPT codes used to identify CLI cases	Annual Incidence Overall: 12.5% Asian: 3.6% Hispanic: 9.7% White: 11.7% Black: 20.5% DM-: 7.0% DM+: 19.4%
Abu Dabrh (2015)^Citation3	Multi-national	Published literature (1986–2013)^d	Natural history CLI patients not receiving revascularization	Meta-analysis of 8 RCTs and 5 case series	1-Year Major amputation: 22%
Howard (2015)^Citation75	United Kingdom (Oxfordshire)	Medical records (2002–2012)	CLI patients within the OXVASC study population (no age restriction)	Prospective, population-based study	1-Year 6.6% 5-Year 43.4%
Reinecke (2015)^Citation26	Germany	German health insurer data (2009–2011)	Hospitalized CLI patients	ICD-10 dx and German procedure (OPS) codes to identify cases and procedures	Index Hospitalization Rutherford 4: 1.6% Rutherford 5: 9.8% Rutherford 6: 42.0% 1-Year Rutherford 6: 59.6% 4-Year Rutherford 4: 12.1% Rutherford 5: 35.3% Rutherford 6: 67.3%
Agarwal (2016)^Citation22	United States	Nationwide Inpatient Sample (2003–2011)	Hospitalized CLI patients	ICD-9 diagnosis and procedure codes used to identify cases and procedures	Annual Major Amputation 2003: 16.7% 2011: 10.8%
Luders (2016)^Citation24	Germany	German health insurer data (2009–2012)	Hospitalized CLI patients (Rutherford 1–3 as reference group)	ICD-10 diagnosis and German procedure (OPS) codes to identify cases and procedures	Hazard Ratio vs Rutherford 1–3 (median follow-up =2.1 years) Rutherford 4: 3.0 Rutherford 5: 9.1 Rutherford 6: 28.3
Spreen (2016)^Citation27	The Netherlands	Pooled patient-level data from the PADI and JUVENTAS trials (2006-unknown)	CLI patients undergoing one of the PADI or JUVENTAS interventions	Analysis of pooled RCT data	Time: Major Amp. (DM-/DM+) 6 months: 11.4%/19.7% 1 year: 16.0%/23.8% 2 years: 17.8%/28.3% 3 years: 18.7%/29.2% 4 years: 20.4%/30.8% 5 years: 20.4%/34.1%
Baubeta Fridh (2017)^Citation76	Sweden	Swedish National Quality Register for Vascular Surgery (Swedvasc) (2008–2013)	CLI patients who had a revascularization treatment	Observational cohort study	Time: Major Amputation 6 months: 12.0% 1 year: 14.8% 2 years: 17.2% 3 years: 18.6%
Klaphake (2017)^Citation31	The Netherlands	Large teaching hospital (2006–2013)	CLI patients undergoing major amputation	Retrospective analysis of medical records	During Study Period Major Amputation: 26%
Martinez (2018)^Citation64	United States	Nationwide Readmissions Database (2013–2014)	CLI patients undergoing revascularization procedures	ICD-9 diagnosis and procedure codes used to identify cases and procedures	During Index Admission Amputation: 5.4%
Masoomi (2018)^Citation73	United States	Nationwide Readmissions Database (2013)	CLI patients with/without revascularization procedures	ICD-9 diagnosis and procedure codes used to identify cases and procedures	During Index Admission Major Amputation: 16.2%
Mustapha (2018)^Citation20	United States	Medicare fee-for-service Parts A and B (2011–2015)	Adult US Medicare population	ICD-9 and CPT codes used to identify CLI cases	During Index Admission Major Amputation: 6%

Notes: ^aAlthough the publication date criteria excluded studies prior to 2007, few papers document the natural history of CLI disease and, therefore, this paper was included within the review; ^bReference groups in the multivariate logistic regression: Race/ethnicity=white; median income quartiles=Q4 (highest income); payer=Medicare; ^cUnclear if entire population was CLI; ^dPublication dates listed; data used in the individual studies may be considerably older.

Abbreviations: Amp, amputation; CLI, critical limb ischemia; CPT, Current Procedural Terminology^®; DM, diabetes mellitus; EVT, endovascular treatment; ICD-9/10, International Classification of Diseases 9th/10th Revision; JUVENTAS, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation; OPS, Operationen und Prozedurenschlüssel [German procedure classification]; OXVASC, Oxford Vascular Study; PADI, Percutaneous Transluminal Balloon Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia; RCT, randomized clinical trial; SPARCS, Statewide Planning and Research Cooperative System.

Figure 2 Long-term CLI mortality rates.

Abbreviations: CLI, critical limb ischemia; OXVASC, Oxford Vascular Study.

Table 4 Long-term CLI mortality rates

Publication	Country/region	Data source (years)	Population details	Methods	Long-term mortality
Baser (2013)^Citation19	United States	100% Medicare inpatient/outpatient/denominator files (2007–2008)	US Medicare population	ICD-9 and CPT codes used to identify CLI cases	1-Year After CLI dx: 30.3% After CLI dx + amp: 40.4%
Soga (2014)^Citation77	Japan	Prospective, multicenter (n=17) database (2004–2011)	CLI patients undergoing endovascular treatment	Retrospective analysis of medical records	2-Year 41%
Abu Dabrh (2015)^Citation3	Multi-national	Published literature (1986–2013)^a	Natural history CLI patients not receiving revascularization	Meta-analysis of 8 RCTs and 5 case series	1-Year 18%-22%^b
Howard (2015)^Citation75	United Kingdom (Oxfordshire)	Medical records(2002–2012)	CLI patients within the OXVASC study population (no age restriction)	Prospective, population-based study	30-Day 7.4% 5-Year 29.2%
Reinecke (2015)^Citation26	Germany	German health insurer data (2009–2011)	Hospitalized CLI patients	ICD-10 diagnosis and German procedure (OPS) codes to identify cases and procedures	1-Year Rutherford 6: 34.2% 4-Year Rutherford 4: 37.7% Rutherford 5: 52.2% Rutherford 6: 63.5%
Luders (2016)^Citation24	Germany	German health insurer data (2009–2012)	Hospitalized CLI patients (Rutherford 1–3 as reference group)	ICD-10 diagnosis and German procedure (OPS) codes to identify cases and procedures	Hazard Ratio vs Rutherford 1–3 (median follow-up =2.1 years) Rutherford 4: 2.01 Rutherford 5: 2.46 Rutherford 6: 3.59
Spreen (2016)^Citation27	The Netherlands	Pooled patient-level data from the PADI and JUVENTAS trials (2006-unknown)	CLI patients undergoing one of the PADI or JUVENTAS interventions	Analysis of pooled RCT data	Time Point: Mort. (DM-/DM+) 6 months: 8.0%/12.8% 1 year: 17.9%/19.2% 2 years: 25.6%/32.0% 3 years: 31.3%/38.1% 4 years: 36.1%/43.0% 5 years: 48.0%/55.7%
Baubeta Fridh (2017)^Citation76	Sweden	Swedish National Quality Register for Vascular Surgery (Swedvasc) (2008–2013)	CLI patients who had a revascularization treatment	Observational cohort study	Time Point: Mortality 6 months: 13.5% 1 year: 20.5% 2 years: 31.7% 3 years: 41.4%
Freisinger (2017)^Citation32	Germany	German health insurer data (2009–2011)	Hospitalized CLI patients with tissue loss	ICD-10 diagnosis and German procedure (OPS) codes to identify cases and procedures	4-Year (Rutherford 5) Without diabetes: 50% With diabetes: 50% 4-Year (Rutherford 6) Without diabetes: 63% With diabetes: 60%
Melillo (2016)^Citation78	Italy	University hospital (Years not stated; 5–15 year follow-up)	CLI patients consecutively admitted to medical or surgical wards	Retrospective case-control study	Time Point: Mortality 1 year: 15% 2 years: 24% 5 years: 43%
van Haelst (2018)^Citation79	The Netherlands	Hospital Discharge Register; Population Register; Cause of Death Register (1998–2010)	CLI patients not admitted in prior 3 years	ICD-9 and ICD-10 codes used to identify CLI cases	Time Point: Mort. (Male/Female) 1 yr (1998–2004): 25.9%/27.3% 1 yr (2005–2010): 24.5%/23.9% 5 yrs (1998–2004): 59.5%/60.3% 5 yrs (2005–2010): 57.9%/57.1%
Mustapha (2018)^Citation20	United States	Medicare fee-for-service Parts A and B (2011–2015)	Adult US Medicare population	ICD-9 and CPT codes used to identify CLI cases	1-Year Rest pain: 16.2% Ulcer: 23.9% Gangrene: 33.2% 4-Year Rest pain: 40.1% Ulcer: 55.0% Gangrene: 68.5%

Notes: ^aPublication dates listed; data used in the individual studies may be considerably older; ^bWith (22%) and without (18%) one study with substantially longer follow-up; 1-year mortality based on the median follow-up of the included studies being 1 year.

Abbreviations: Amp, amputation; CLI, critical limb ischemia; CPT, Current Procedural Terminology^®; DM, diabetes mellitus; ICD-9/10, International Classification of Diseases 9th/10th Revision; JUVENTAS, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation; OPS, Operationen und Prozedurenschlüssel [German procedure classification]; OXVASC, Oxford Vascular Study; PADI, Percutaneous Transluminal Balloon Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia; RCT, randomized clinical trial; yr(S), year(S).

Table 5 Commonly used generic and disease-specific quality of life instruments in CLI studies

QOL instrument	Abbreviation	Domains	Scoring
Short-Form 36 or RAND Short-Form 36	SF-36 or RAND-36	36 items assessing 8 health-related concepts including physical functioning, bodily pain, general health, vitality, social functioning, mental health, and emotional well-being. The measure also yields psychometrically-based physical and mental health summary scores.	0 to 100
Short-Form 6 Dimension	SF-6D	The SF-6D health index is designed for calculating Quality Adjusted Life Years (QALYs), which are used to estimate the cost-effectiveness of health interventions.	0 to 1
EuroQol-5D (Utility Measure) EuroQol-Visual Analog Scale	EQ-5D EQ-VAS	A descriptive system of 5 dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Visual analog scale from 0 to 100.	EQ-5D Items: 0–1 VAS: 0–100
Nottingham Health Profile	NHP	38 statements addressing 6 health-related concepts including energy, pain, emotional reaction, sleep, social isolation, and physical mobility.	0–100
FLeQKI [German]	FLeQKI [German]	35 items addressing 7 domains including comorbidity, physical pain, physical functioning, physical state, social functioning, mental health, and therapy-induced limitations.
Vascular Quality of Life Questionnaire	VascuQOL-25 VascuQOL-6	25 questions assessing 5 domains including pain, symptoms, activities, social well-being, and emotional well-being. 6 items assessing the same 5 domains listed above.	1–7 6–24
Walking Impairment Questionnaire	WIQ	16 questions assessing 4 domains including symptoms, distance, speed, and climbing.	0–100
World Health Organization Quality of Life Assessment Instrument	WHOQOL-100 WHOQOL-BREF	100 questions assessing physical health, psychological health, social relationships, and environment. 26 questions assessing 4 domains including physical health, psychological health, social relationships, and environment.	0–100 0–100

Notes: Data from Alabi 2017,⁴ Lawall 2012,¹¹ Monaro 2016,¹² Steunenberg 2016,¹⁵ Wohlgemuth 2007.⁸⁰

Abbreviations: QOL, quality of life; CLI, critical limb ischemia.

Table 6 Baseline SF-36/RAND-36 quality of life scores (0–100) for patients with CLI

Publication	Instrument	PF	RP	BP	GH	VT	SF	RE	MH	PCS	MCS	CLI Population	Procedure(s)
Burt (2010)^Citation38	SF-36	–	–	–	–	–	–	–	–	31.1	57.6	100%	Autologous peripheral blood cell implantation
Deutschmann (2007)^Citation39	SF-36	24.8	5.6	13.9	50^a	28.1	70^a	28.5	46^a	–	–	52%	Percutaneous transluminal angioplasty
Engelhardt^b (2008)^Citation40	SF-36	25	12	21	56	41	50	38	56			100%	Infrageniculate bypass surgery
Forbes (2010)^Citation41	SF-36 SF-36	22.7 23.0	10.3 13.1	30.4 32.0	49.1 48.0	34.2 36.3	40.6 44.2	31.5 36.3	58.9 60.1			100%^c 100%^c	Angioplasty Bypass surgery
Keeling (2008)^Citation42	SF-36	35.6	16.7	39.3	60.4	44.4	71.8	55.6	75.5	–	–	44%	Percutaneous transluminal angioplasty
Kumar (2011)^Citation43	RAND-36	20.9	21.1	31.7	28.9	21.8	28.6	23.5	–	–	–	100%	Various revascularization procedures
Landry (2014)^Citation44	SF-36	30	4	25	49	42	47	57	69	–	–	100%	Lower extremity bypass surgery
Peeters Weem^d (2016)^Citation45	SF-36	33	38	45	38	48	41	45	47	35	49	100%^d	Autologous bone marrow cell therapy
Shigematsu (2010)^Citation46	SF-36	24.4 22.9	28.7 2.1	32.1 30.1	38.4 36.8	43.1 45.0	50.5 45.8	30.9 11.1	50.6 59.0			100%	Hepatocyte growth factor plasmid No treatment
Sprengers (2010)^Citation14	SF-36	28	34.4	32.9	39.7	44.8	36.9	39.5	42.6	30.8	45.9	100%	Bone marrow cell therapy
van Hattum^e (2011)^Citation47	RAND-36	49	38	59	55	55	65	56	68	37	48	28%	Bypass surgery
Wohlgemuth (2008)^Citation48	SF-36	40.7	26.9	17.6	29.3	55.6	70.2	51.9	62.3			70%	Bypass surgery
Maglinte (2012)^Citation49	SF-36	50.7	49.5	50.6	50.1	53.7	51.4	51.4	54.3	49.2	53.8	-	US population norms

Notes: ^aBaseline SF-36 scores estimated from figure #3 in Deutschmann 2007;³⁹ bA weighted average of the baseline SF-36 scores for the three patient subgroups (Non-Diabetes, Diabetes, and Secondary Amputation) from Table #3 in Engelhardt 2008;⁴⁰ cCLI population defined as “severe lower limb ischemia” in the Forbes 2010⁴¹ study (BASIL trial); ^dFor the purpose of this analysis, the CLI patient population from the Peeters Weem 2016⁴⁵ study was defined as patients with “no option severe limb ischemia”; baseline SF-36 scores estimated from figure #2 in Peeters Weem 2016;⁴⁵ eFor the purposes of this analysis, the SF-36 scores presented in the table earlier are from Table II in the van Hattum 2011⁴⁷ study for the Bypass and Oral Anticoagulants or Aspirin (BOA) Study group.

Abbreviations: BP, Bodily Pain; CLI, critical limb ischemia; GH, General Health; MCS, Mental Component Summary; MH, Mental Health; PCS, Physical Component Summary; PF, Physical Functioning; RAND-36, 36-item Short-Form Health Survey; RE, Role Emotional; RP, Role Physical; SF, Social Functioning; SF-36, 36-item Short-Form Health Survey; VT, Vitality.

Table 7 Baseline EuroQol-5D utility scores and VAS scores for patients with CLI

Publication	Instrument	Baseline score	CLI population	Procedures
EuroQol-5D
Egberg (2010)^Citation52	EQ-5D	0.54	15%	Percutaneous transluminal angioplasty
Forbes (2010)^Citation41	EQ-5D EQ-5D SF-6D SF-6D	0.26 0.28 0.53 0.54	100%^a 100%^a 100%^a 100%^a	Angioplasty Bypass surgery Angioplasty Bypass surgery
Pisa (2012)^Citation35	EQ-5D	0.56	100%	NA
van Hattum (2011)^Citation47	EQ-5D	0.68	28%	Bypass surgery
Szende (2014)^Citation54	EQ-5D	0.825	–	US population norm
VAS
Bague (2017)^Citation50	VAS for EQ-5D	65.8	13%	Endovascular
Brother (2015)^Citation51	VAS	45.6	100%	Open surgery or endovascular treatment
Forbes (2010)^Citation41	VAS for EQ-5D VAS for EQ-5D	53 55	100%^a 100%^a	Angioplasty Bypass surgery
Klepanec (2012)^Citation53	VAS for EQ-5D	51	100%	Intramuscular delivery of autologous bone marrow cells
Pisa (2012)^Citation35	VAS for EQ-5D	56	100%	NA
van Hattum (2011)^Citation47	VAS for EQ-5D	66	28%	Bypass surgery
Szende (2014)^Citation54	VAS for EQ-5D	80	–	US population norm

Note: ^aCLI population defined as “severe lower limb ischemia” for Forbes 2010⁴¹ (BASIL trial).

Abbreviations: CLI, critical limb ischemia; EQ-5D, EuroQol-5 Dimension; NA, not applicable; SF-6D, Short-Form Six-Dimension; VAS, visual analog scale.

Table 8 Index CLI hospitalization costs

Publication	Country/region	Data source (years)	Currency	Population details	Methods	Total cost
Reinecke (2015)^Citation26	Germany	German health insurer data (2009–2011)	Euro	Hospitalized CLI patients	ICD-10 dx and German procedure (OPS) codes to identify cases and procedures	Mean Cost 2011: €5,316 (Rutherford 4) 2011: €6,021 (Rutherford 5) 2011: €8,461 (Rutherford 6)
Agarwal (2016)^Citation22	United States	Nationwide Inpatient Sample (2003–2011)	2015 USD	Hospitalized CLI patients	ICD-9 diagnosis and procedure codes used to identify cases and procedures	Mean Cost 2003: ~$23,000 2007: ~$23,000 2011: ~$23,000
Dua (2016)^Citation63	United States	Nationwide Inpatient Sample (2001–2011)	2015 USD	Elective admissions to treat CLI	ICD-9 diagnosis and procedure codes used to identify cases and procedures	Median Cost 2001: $12,568 2004: $15,588 2007: $17,964 2011: $20,587
Freisinger (2017)^Citation32	Germany	German health insurer data (2009–2011)	Euro	Hospitalized CLI patients with tissue loss	ICD-10 dx and German procedure (OPS) codes to identify cases and procedures	Mean Cost Rutherford 5 2011: €5,975 (with DM) 2011: €6,058 (without DM) Rutherford 6 2011: €8,860 (with DM) 2011: €8,080 (without DM)
Martinez (2018)^Citation64	United States	Nationwide Readmissions Database (2013–2014)	USD	CLI patients undergoing revascularization procedures	ICD-9 diagnosis and procedure codes used to identify cases and procedures	Mean Cost Index admission: $29,148 Readmission: $17,681

Abbreviations: CLI, critical limb ischemia; DM, diabetes mellitus; ICD-9/10, International Classification of Diseases 9th/10th Revision; OPS, Operationen und Prozedurenschlüssel [German procedure classification]; USD, US dollar.

Figure S1 CLI amputation rates.

Abbreviations: CLI, critical limb ischemia; OXVASC, Oxford Vascular Study.

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