Critical Limb Ischemia: An Overview of the Epidemiologic and Clinical Implications

Friday, 09/03/10 | 18884 reads

Fahad G. Bitar, MD and Lawrence A. Garcia, MD


Peripheral arterial disease (PAD) represents a continuum of arterial obstructive syndromes that for the lower extremity ranges from the asymptomatic to limb loss. The overall prevalence of PAD has been estimated to be as high as 20% of the general population. However, the overall prevalence of critical limb ischemia (CLI) is sparse in the general population, whereas the progression of arterial obstructive disease to CLI is highly variable in the published literature. CLI represents the ultimate progression of arterial obstructive disease that may culminate in limb loss. In this manuscript we discuss the prevalence of CLI in the general population and further evaluate the likelihood of progression to a state of CLI from non-critical disease states in the lower extremities.



Peripheral arterial disease (PAD) represents a continuum of disease entities that range from asymptomatic PAD, stable symptomatic intermittent claudication, critical limb ischemia (CLI), acute limb ischemia and amputation. CLI is defined as PAD causing resting lower-extremity pain or having threatened or frank tissue loss,1,2 and is classified as Rutherford-Becker Class 4–6 or Fontaine Class III and IV.2 CLI is a disabling disease and represents the end of the spectrum of PAD prior to tissue and limb loss. Other definitions for CLI have been suggested to include absolute pressures of ankle pressure 10 Here we review the epidemiologic and clinical syndrome of CLI and its progression from non-limb-threatening PAD.

Prevalence of CLI

The prevalence of CLI in the general population is scarce and difficult to assess, while the incidence of progression of PAD to CLI is widely variable in the published literature. The largest published population study, known as the HUNT 2 study, involved a questionnaire completed by 20,291 Norwegian men and women (9,640 men and 10,651 women) in Nord-Trondelag County between 1995 and 1997 and included all residents between ages 20–69 years.8 CLI was defined as a toe, foot or ankle ulcer that failed to heal or a persistent pain in the forefoot in the supine position that improves with standing. The prevalence of CLI in this population was 0.24% (0.26% for men and 0.24% for women). The age-adjusted prevalence of CLI increased with age (0.14% in those aged 40–49 years, 0.26% in those aged 50–59 years, and 0.39% for those aged 60–69 years). Smoking conferred a 2.3 times increased risk of CLI compared to subjects who never smoked, while diabetes mellitus conferred a 4.4 times increased risk of developing CLI compared to the general population. Subjects with older age, angina pectoris, elevated total cholesterol, elevated serum triglyceride and higher body mass index were independently associated with an increased risk of developing CLI compared with the general population. The prevalence of CLI was estimated to be 2,500 per million inhabitants. This prevalence, however, may be higher in the elderly population (age > 70 years). The prevalence of CLI in this population might have been confounded by including ulcers with non-atherosclerosis etiology such as venous ulcers which can cause pain and take a long time to heal.

In another European cross-sectional study, 5,080 Swedish subjects between the ages of 60 and 90 years were examined and completed questionnaires to determine the prevalence of PAD and CLI.9 PAD was defined as an ankle-brachial index (ABI) 60 years of age with CLI (based on a definition of ankle pressure

In another large population study, the Heinz Nixdrof Recall study,11 PAD was considered present if the ABI was

Claudicant Limb and the Incidence of Progression to CLI

Progression to CLI from intermittent claudication is difficult to determine, though several previous studies have evaluated this. In the Edinburgh Artery Study,3 1,592 randomly selected patients were followed for 5 years. The incidence of intermittent claudication (IC) was 4.5% in the general population. Of the patients with IC, 1.4% developed a leg ulcer over the next 5 years. Another 8.2% of the IC patients underwent surgical reconstruction. Combining both the surgical (assuming that surgery is indicated for tissue loss and resting pain) and leg ulcer patients, a total of 9.6% of IC patients will potentially progress to CLI over the next 5 years.

One of the largest published studies on the natural history of claudicant legs4 by Acquino and colleagues followed up 1,244 patients with IC over an average of 45 months. The mean ABI was 0.52 and the population was entirely male. The authors estimated the rate of developing an ischemic ulcer at 23% over 10 years, while the rate of developing ischemic rest pain was 30%. Therefore, combining both patients with resting pain and ulcers (assuming that patients did not develop both) led to an annual rate of 5.3% of claudicant legs progressing to CLI.

In two separate papers5,6 from surgical referral centers, the risk of a claudicant patient developing CLI was highest in the first year after referral and ranged from 7.5–21%. The risk of developing subsequent CLI was lower, at 2.2% and 9.1%, respectively. The incidence of overall CLI in one of the observed populations6 was high, at 44%, at a mean follow up of 4.1 years. Rosenbloom and colleague7 followed 195 patients who had claudication and a positive stress test for an average of 8 years; they noted that the rate of IC progression to CLI was 24% at 5 years and 41% at 8 years. Thus, for the claudicant limb, the risk of progression to CLI ranges from 1.4–5.3% per year, with the highest rate progressing to CLI being in the first year of presentation for rest pain and ranging from 7.5–21%.

The wide variation of the incidence of CLI and the progression of IC to CLI could be partially explained by the differences in the population demographics (Table 1), which include the definition of CLI, gender, the presence of diabetes, smoking cessation, risk factor modification, baseline ABI and inclusion criteria in the study. It also depends on the pattern of referral to the surgical centers. More advanced IC cases are expected to be seen in surgical centers, therefore yielding a higher rate of progression to CLI. It is also possible that the referring physicians may observe the claudicant patient and hold off on referral until the patient develops a worsening IC, in which the risk of progressing to CLI might be higher than stable IC. It is also possible that patients with PAD were asymptomatic and were either not diagnosed with PAD or not referred to a specialized center due to the absence of symptoms, and were therefore not followed up, or CLI was their initial presentation to the specialized center.

Predictors of IC/PAD progression to CLI

The initial ABI at the time of a patient’s presentation is the most consistent predictor of progression to CLI (Table 2).4–7 Naschitz and colleagues noted that an ABI 0.7 progressed to CLI. A decrease of > 0.15 in ABI also conferred a 1.9-fold increased risk of progression to CLI.6 Other predictors included the presence of diabetes mellitus,4 ankle systolic blood pressure (SBP) 7 Ironically, there was an inverse relationship between the % decrease in ABI after exercise and the progression of IC to CLI.7


The natural history of PAD is known to be a slow progression of symptoms over time, but within this overall pattern there is considerable variation. The time course for CLI remains variable, as noted above. However, the onset of rest pain clearly differentiates this process from other arterial obstructive diseases. Furthermore, atherosclerosis, like coronary artery disease, is the most common cause of symptomatic obstruction in the peripheral arterial tree. We further know and understand that atherosclerosis is primarily a systemic and local inflammatory process leading to the obstructive disease process.

Peripheral atherosclerosis has an identical risk factor profile associated with it, as does coronary artery disease. These typical risk factors have been identified for peripheral arterial occlusive disease, which include age, gender, diabetes, tobacco abuse and others such as hypertension and hyperlipidemia. The most important independent risk factors remain age and gender as non-modifiable factors increasing the risk of peripheral arterial disease two- to three-fold, whereas smoking is the most important modifiable risk factor and increases the risk of PAD three-fold. Diabetes, likewise, plays a role in the development and progression of PAD.


The overall consequences of PAD, and specifically CLI, are immense in terms of costs, patient lives lost and overall morbidity. Understanding the process of CLI and its socioeconomic impact and likelihood of progression to limb loss is paramount to effectively treat and rescue limbs for this very challenging patient subset.


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From the Divisions of Cardiology and Vascular Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts.

The authors report no conflicts of interest regarding the content herein.

Address for correspondence: Lawrence A. Garcia, MD, FACC, FAHA, St. Elizabeth’s Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135. E-mail:

Special Focus: CLI

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