Prostanoids for Critical Limb Ischemia: A Clinical Review and Consideration of Current Guideline Recommendations.

For many years, the only pharmacological option for patients with critical limb ischemia (CLI) unsuitable for revascularization has been prostanoids; however, some recent guidelines have become very restrictive regarding their use. We review the available evidence on the use of prostanoids and analyze the guideline positions as well as the possible reasons for changes over time. In most placebo-controlled trials and meta-analyses, prostanoids showed a significant effect in improving rest pain, promoting ulcer healing and reducing major amputations. Results for iloprost were especially consistent. Different prostanoid drugs have different evidence of efficacy, thus using a generic term "prostanoids" is misleading. Unfortunately, the available evidence is often of low quality and probably not sufficient to support an extensive use of prostanoids in all patients, and further high-quality randomized trials are needed. Consequently, some recent guidelines do not recommend treatment with prostanoids in this setting. However, in our opinion, pending definitive evidence, patients with CLI who have a viable limb in whom revascularization is unfeasible or has a poor chance of success, without alternative to amputation, may benefit from treatment with iloprost, balancing harms and benefits in each case.

Noninvasive Transcutaneous Monitoring in Long-Term Follow-Up of Patients With Thromboangiitis Obliterans Treated With Intravenous Iloprost.

We evaluated the effectiveness of intravenous iloprost (IVI) in outpatients with thromboangiitis obliterans (TAO) and lower limb noninvasive transcutaneous monitoring (TCM) at follow-up (FU). Ten consecutive patients with TAO underwent IVI therapy. Transcutaneous oxygen (TcPo 2) and carbon dioxide (TcPco 2) determination and laser Doppler flowmetry (LDF) were performed before and after IVI at 3, 6, and 12 months of FU. Clinical response was positive in 7 patients, whereas 3 nonresponders underwent a second IVI cycle with 1 showing a late positive clinical response. After 12 months of FU, all patients were alive without amputations. Supine and dependent TcP2 levels significantly improved (P < .005). Hallux LDF values showed significant change with the maximal hyperemic test at 44°C (P < .005). Forefoot maximal hyperemic test at 44°C LDF (P < .005) and improved venous arterial reflex (P < .05) showed statistically significant time evolution. We demonstrated some degree of IVI effectiveness and evaluated TCM in patients with TAO.

The prostacyclin analogue iloprost increases circulating endothelial progenitor cells in patients with critical limb ischemia.

Patients with critical limb ischemia (CLI) have low levels of endothelial progenitor cells (EPC). Iloprost has been demonstrated to stimulate vascular endothelial growth factor (VEGF) and promote angiogenesis. We investigated the effects of iloprost on EPC levels in vivo in CLI patients. Twenty-three patients with stage III and IV CLI were treated with iloprost for four weeks, improving clinical and instrumental parameters. Mononuclear cells isolated from peripheral blood were cultured to obtain "early" EPC, evaluated counting adherent cells with double positivity for acetylated low-density lipoprotein uptake and Ulex Europaeus lectin at flow cytometry. These cells also co-expressed the monocyte markers CD14 and CD45. Iloprost increased EPC number in the whole patient population: pre-treatment median: 13,812/ml; range: 1,263-83,648/ml; post-treatment median: 23,739/ml; range: 3,385-99,251/ml; p = 0.035, irrespective of age, sex, disease stage or atherosclerosis risk factors. In conclusion, iloprost increases EPC number in peripheral blood in vivo. Such an effect may have therapeutic relevance.

Women and peripheral arterial disease: same disease, different issues.

OBJECTIVES: Atherosclerosis is a multifactorial disease and, thus, its clinical manifestations are likely to present gender-specific differences with respect to their development, course, symptom complexes and prognosis. The present study aimed to examine sex differences in peripheral arterial disease (PAD) and its clinical correlates. METHODS: PAD severity, quality of life (assessed by ST-22), cardiovascular risk factors, inflammatory profile and comorbidity were assessed in 163 men and 68 women who were consecutively diagnosed with PAD at three Italian University vascular centres. RESULTS: Compared to men, women showed a higher prevalence of critical limb ischemia (P = 0.018), but had a less impaired quality of life (assessed by ST-22), and were less likely to have a history of lower extremity revascularization. Furthermore, women tended to be older (P = 0.058), and more likely to present hypercholesterolemia (P = 0.053), diabetes mellitus (P = 0.001), body mass index > or = 30 kg/m2 (P = 0.003) and metabolic syndrome (P = 0.001). Conversely, C-reactive protein plasma levels were similar in the two groups. No gender-specific difference was observed in cardiovascular comorbidity; however, the condition showing the strongest association with coronary artery disease was diabetes mellitus in women (odds ratio = 4.96, P = 0.021), and smoking in men (odds ratio = 2.66, P = 0.008). CONCLUSION: In PAD, there are several sex differences in baseline characteristics, especially with respect to the weight and significance of cardiovascular risk factors. Knowledge of these differences may help achieve optimal gender-specific cardiovascular risk prevention.

Transcutaneous oxygen and carbon dioxide levels with iloprost administration in diabetic critical limb ischemia.

Iloprost, a prostacyclin analogue, is a treatment option for surgically unsuitable diabetic chronic critical limb ischemia (CLI), although its outcome is difficult to be anticipated clinically. Whether transcutaneous (tc) oxygen tension (PO2) predicts the response to iloprost in diabetic CLI is unclear at this point and, in that same context, the prognostic role of tc carbon dioxide tension (PCO2), another ischemia-sensitive parameter, is unknown. Supine and dependent tcPO2 and tcPCO2 were measured at baseline and after 4 weeks of iloprost treatment in 31 limbs of 26 type-2 diabetic angiopathies with CLI not amenable to surgery. Success was defined as pain relief and significant reduction of analgesics. Clinical outcome was stratified by baseline tcPO2 and tcPCO2 tertiles, and likelihood ratios (LR) quantified the increase from pretest chances given a certain result. Iloprost succeeded in 16 (52%) and failed in 15 limbs (48%) and post-treatment tcPO2 followed a parallel course. Failures increased by ascending baseline tcPCO2 and descending tcPO2 tertiles; successes behaved specularly. Predictions of failure based on elevated tcPCO2 (>53 mm Hg) were more efficient than relying on depressed tcPO2 (LR 10.7 vs 3.6); success was almost certain when tcPO2 was >23 mm Hg (LR = 17.8). Dependent determinations were less useful than supine measurements for prognostic use. Elevated tcPCO2 predicted failure efficiently and high tcPO2 was a useful prognostic tool for success of iloprost, suggesting that their combined use may allow better prognostic stratification and improve the therapeutic approach to diabetic CLI.

[Medical therapy in critical lower limb ischemia when immediate revascularization is not feasible]. / La terapia medica dell'ischemia critica degli arti inferiori non immediatamente rivascolarizzabile.

Revascularization by either bypass surgery or endovascular recanalization is considered the first-choice treatment in patients with critical limb ischemia (CLI). Only conservative options are left in CLI patients in whom successful revascularization strategies are not possible: in these patients, at present, prostanoids (iloprost and prostaglandin [PGE1]) represent the pharmacological treatment of choice. Iloprost resulted more effective than PGE1, in a 6 month follow-up, in both limb savage and in prevention of cardiovascolar death, either in diabetic or non diabetic patients with unreconstructable CLI. In our experience, in patients who have responded to a first cycle of therapy (early responders), performed for at least 2-3 weeks, cyclic annual further treatments with iloprost are usually able to stabilize arterial disease, with a regression to Fontaine II stage and, in absence of further arterial complications, with complete limb preservation for an unlimited period of time. In non-responder patients, who are not urgently supposed to undergo amputation, a second cycle of iloprost carried out within few months from the first one, is able to increase the percentage of responders to prostanoids (late responders). Vice versa, in non-responders to repeat prostanoid cycles, it is useful to verify the outcomes of further attempts at saving, the symptomatic limb by surgical or endovascular re-timing, spinal cord stimulation, gene or stem cell therapy. Our recent better outcomes are related to earlier microvascular diagnosis and to earlier, repeat, pharmacological treatments with iloprost. Transcutaneous oxygen and carbon dioxide monitoring improves the possibility of an earlier diagnosis of microvascular damages and categorizes CLI patients in responders and non-responders after prostanoid treatments.

[Major and minor amputation rates and lower critical limb ischemia: the epidemiological data of western Tuscany]. / Tassi di amputazione maggiore e minore ed ischemia critica degli arti inferiori: dati epidemiologici dalla Toscana occidentale.

BACKGROUND: The aim of this study was to evaluate the incidence of major amputations and critical limb ischemia in an unselected population of western Tuscany. METHODS: Out of an overall 1234000 people living in Pisa and surroundings (western Tuscany), a total amount of 306 patients underwent 319 different major/minor amputations during the year 2002 in private and public hospitals, both in Tuscany and in other regions. RESULTS: 84.6% (n = 270) of the amputations were atherosclerotic, while 15.4% (n = 49) were non-atherosclerotic. The patients with unreconstructable critical limb ischemia, who underwent amputations at the symptomatic limbs, had a minor amputation rate (at toes or forefoot) of 46.7%, while the major amputation rate (over the ankle) was 53.3%. The 144 major amputations were performed in 76.4% (n = 110) of the cases above the knee and in the remaining 23.6% (n = 34) of cases below the knee. Early hospital mortality rates of the amputees for ischemic causes were 7.6% in patients who underwent major amputations, and 0.8% in cases with minor amputations, respectively. Overall, in western Tuscany, the incidence of the major amputation rate per million inhabitants was 117 cases per year, with a total of 468 new cases of reconstructable and unreconstructable critical limb ischemia per year (this number was calculated multiplying by 4 the number of major amputations). CONCLUSIONS: On the basis of our real epidemiological data, the theoretical major amputation rates per year were 408 in Tuscany and 6652 in Italy, respectively. The extrapolation of our results showed that the overall critical limb ischemia incidence consists of 1638 cases in Tuscany and of 26676 patients in Italy, respectively.