Chapter I: Definitions, epidemiology, clinical presentation and prognosis

The concept of chronic critical limb ischaemia (CLI) emerged late in the history of peripheral arterial occlusive disease (PAOD). The historical background and changing definitions of CLI over the last decades are important to know in order to understand why epidemiologic data are so difficult to compare between articles and over time. The prevalence of CLI is probably very high and largely underestimated, and significant differences exist between population studies and clinical series. The extremely high costs associated with management of these patients make CLI a real public health issue for the future. In the era of emerging vascular surgery in the 1950s, the initial classification of PAOD by Fontaine, with stages III and IV corresponding to CLI, was based only on clinical symptoms. Later, with increasing access to non-invasive haemodynamic measurements (ankle pressure, toe pressure), the need to prove a causal relationship between PAOD and clinical findings suggestive of CLI became a real concern, and the Rutherford classification published in 1986 included objective haemodynamic criteria. The first consensus document on CLI was published in 1991 and included clinical criteria associated with ankle and toe pressure and transcutaneous oxygen pressure (TcPO(2)) cut-off levels <50 mmHg, <30 mmHg and <10 mmHg respectively). This rigorous definition reflects an arterial insufficiency that is so severe as to cause microcirculatory changes and compromise tissue integrity, with a high rate of major amputation and mortality. The TASC I consensus document published in 2000 used less severe pressure cut-offs (≤ 50-70 mmHg, ≤ 30-50 mmHg and ≤ 30-50 mmHg respectively). The thresholds for toe pressure and especially TcPO(2) (which will be also included in TASC II consensus document) are however just below the lower limit of normality. It is therefore easy to infer that patients qualifying as CLI based on TASC criteria can suffer from far less severe disease than those qualifying as CLI in the initial 1991 consensus document. Furthermore, inclusion criteria of many recent interventional studies have even shifted further from the efforts of definition standardisation with objective criteria, by including patients as CLI based merely on Fontaine classification (stage III and IV) without haemodynamic criteria. The differences in the natural history of patients with CLI, including prognosis of the limb and the patient, are thus difficult to compare between studies in this context. Overall, CLI as defined by clinical and haemodynamic criteria remains a severe condition with poor prognosis, high medical costs and a major impact in terms of public health and patients' loss of functional capacity. The major progresses in best medical therapy of arterial disease and revascularisation procedures will certainly improve the outcome of CLI patients. In the future, an effort to apply a standardised definition with clinical and objective haemodynamic criteria will be needed to better demonstrate and compare the advances in management of these patients.

Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples

Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Observational data, ecological studies and models suggest that sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART).

Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples

Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Observational data, ecological studies and models suggest that sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART).

Initial clinical experience with the 4-F self-expanding XPERT stent system for infrapopliteal treatment of patients with severe claudication and critical limb ischemia

PURPOSE: To evaluate the primary success and short-term patency associated with a new 4-F sheath-compatible self-expanding nitinol stent after failed conventional angioplasty of distal popliteal and infrapopliteal lesions in severe lifestyle-limiting claudication (LLC) and chronic critical limb ischemia (CLI). MATERIALS AND METHODS: Between May 2003 and July 2005, 35 patients with Rutherford category 3-5 disease (16 patients with CLI, 19 patients with LLC) underwent percutaneous transluminal angioplasty (PTA) and stent implantation. Indications for stent placement were residual stenosis, flow-limiting dissections, or elastic recoil after PTA. Before and after the intervention and during the 6-month follow-up, clinical investigation, color-flow and duplex Doppler ultrasonography, and digital subtraction angiography were performed. Technical success, primary patency at 6 months, clinical improvement as defined by Rutherford with clinical and hemodynamic measures, and complications were evaluated. RESULTS: A total of 22 patients underwent distal popliteal artery stent placement and 13 underwent tibioperoneal artery stent placement. Stent implantation was successfully performed in all patients. After stent placement, the primary cumulative patency rate for the study group at 6 months was 82%. The mean resting ankle-brachial index at baseline was 0.50 +/- 0.16 and significantly increased to 0.90 +/- 0.17 at 12-24 hours after intervention and 0.82 +/- 0.24 at latest follow-up (P < .001 for both). The sustained clinical improvement rate was 80% at the 6-month follow-up. The 6-month limb salvage rate regarding major amputation was 100%. The rate of major complications was 17%. CONCLUSIONS: Infrapopliteal application of the new nitinol stent is a safe, feasible, and effective method with good short-term patency rate in the treatment of severe LLC and chronic CLI.

Small is beautiful: why profundaplasty should not be forgotten

BACKGROUND: Surgical profundaplasty (SP)is used mainly as an adjunct to endovascular management of peripheral vascular disease (PAD) today. Results from earlier series of profundaplasty alone have been controversial, especially regarding its hemodynamic effect. The question is: Can profundaplasty alone still be useful? Our aim was to evaluate its role in the modern management of vascular patients. METHODS: This was a retrospective outcome study. A consecutive series of 97 patients (106 legs) from January 2000 through December 2003 were included. In 55 (52%) legs, the superficial femoral artery was occluded. These patients were included in the current analysis. Of these patients 14 (25%) were female. Mean age was 71 ((11) years. Nineteen (35%) were diabetic. The indication for operation was claudication in 29 (53%), critical leg ischemia (CLI) in 26 (47%), either with rest pain in 17 (31%), or ulcer/gangrene in 9 (16%). Endarterectomy with patch angioplasty with bovine pericardium was performed in all cases. Mean follow-up was 33 ( 14 months. Mean preoperative ankle brachial index (ABI) was 0.6. Sustained clinical efficacy was defined as upward shift of 1 or greater on the Rutherford scale without repeat target limb revascularization (TLR) or amputation. Mortality, morbidity, need for TLR, or amputation were separate endpoints. RESULTS: Postoperatively, ABI was significantly improved (mean = 0.7), in 24 (44%) by more than 0.15. At three years, cumulative clinical success rate was 80%. Overall, patients with claudication had a better outcome than those with CLI (p = 0.04). Two (4%) major amputations and 2 (4%) minor ones were performed, all in patients with CLI. None of the 9 (16%) ulcers healed. CONCLUSION: Profundaplasty is still a valuable option for patients with femoral PAD and claudication without tissue loss. It is a straightforward procedure that combines good efficacy with low complication rates. Further endovascular treatment may be facilitated. It is not useful for patients with the combination of critical ischemia and tissue loss.

Successful lower extremity angioplasty improves brachial artery flow-mediated dilation in patients with peripheral arterial disease

INTRODUCTION: Peripheral arterial disease (PAD) is associated with systemic impaired flow-mediated dilation (FMD) and increased risk for cardiovascular events. Decreased FMD may be caused by a decrease in arterial shear stress due to claudication and inflammation due to muscle ischemia and reperfusion. We assumed that endovascular revascularization of lower limb arterial obstructions ameliorates FMD and lowers inflammation through improvement of peripheral perfusion. METHODS: The study was a prospective, open, randomized, controlled, single-center follow-up evaluation assessing the effect of endovascular revascularization on brachial artery reactivity (FMD) measured by ultrasound, white blood cell (WBC) count, high-sensitive C-reactive protein (hs-CRP), and fibrinogen. We investigated 33 patients (23 men) with chronic and stable PAD (Rutherford 2 to 3) due to femoropopliteal obstruction. Variables were assessed at baseline and after 4 weeks in 17 patients (group A) who underwent endovascular revascularization and best medical treatment, and in 16 patients (group B) who received best medical treatment only. RESULTS: FMD did not differ between group A and B (4.96% +/- 1.86% vs 4.60% +/- 2.95%; P = .87) at baseline. It significantly improved after revascularization in group A (6.44% +/- 2.88%; P = .02) compared with group B at 4 weeks of follow-up (4.53% +/- 3.17%; P = .92), where it remained unchanged. The baseline ankle-brachial index (ABI) was similar for group A and B (0.63 +/- 0.15 vs 0.66 +/- 0.10; P = .36). At 4 weeks of follow-up, ABI was significantly increased in group A (1.05 +/- 0.15; P = .0004) but remained unchanged in group B (0.62 +/- 0.1). WBC counts of the two groups were comparable at baseline (group A: 7.6 +/- 2.26 x 10(6)/mL and group B: 7.8 +/- 2.02 x 10(6)/mL, P = .81). In group A, the leukocyte count significantly decreased after angioplasty from 7.6 +/- 2.26 to 6.89 +/- 1.35 x 10(6)/mL (P = .03). For group B, WBC count did not differ significantly compared with baseline (7.76 +/- 2.64 x 10(6)/mL; P = .94). No effects were observed on hs-CRP or fibrinogen from endovascular therapy. CONCLUSION: Endovascular revascularization with reestablishment of peripheral arterial perfusion improves FMD and reduces WBC count in patients with claudication. Revascularization may therefore have clinical implications beyond relief of symptoms, for example, reducing oxidative stress caused by repeated muscle ischemia or increased shear stress due to improved ambulatory activity.

Cerebellar cleft: a form of prenatal cerebellar disruption

In contrast to malformations, cerebellar disruptions have attracted little interest in the literature. We draw attention for the first time to the hypothesis that cerebellar clefts are residual changes following a prenatal cerebellar insult, and represent disruptions. We reviewed the clinical records and MR findings of six patients with a cerebellar cleft, two of whom also had prenatal MRI at 24 weeks of gestation. The clefts were located in the left cerebellar hemisphere in five cases, in the right in one patient. Other typical findings included disorderly alignment of the cerebellar folia and fissures, irregular gray/white matter junction, and abnormal arborization of the white matter in all patients. The cerebellar cleft extended into the fourth ventricle in three cases, and in two children cystic cortical lesions were seen. Supratentorial schizencephaly was found in two patients. In two patients there was a documented fetal cerebellar hemorrhage at 24 weeks of gestation. We conclude that cerebellar clefts are residual changes resulting from a prenatal cerebellar insult and consequently represent disruptions rather than primary malformations. The supratentorial findings are also in agreement with an acquired lesion. The outcome in these children was variable, mainly depending of the presence of supratentorial lesions.

Bailout revascularization of chronic femoral artery occlusions with the new outback catheter following failed conventional endovascular intervention

PURPOSE: To report the application of a true lumen re-entry device in the bailout treatment of chronic total occlusions (CTO) of the superficial femoral artery (SFA) after failed angioplasty. METHODS: Nineteen patients (12 men; mean age 81 years, range 61-97) with 20 SFA CTOs and Rutherford category 2 to 5 ischemia were prospectively evaluated. All CTOs had unsuccessful recanalization using conventional techniques and were subsequently treated with the Outback LTD catheter. Follow-up at 3, 6, and 12 months included ankle/toe pressure measurement and pulse volume recordings. Endpoints were revascularization rate, target lesion revascularization, and limb salvage. RESULTS: Revascularization was achieved in 95% of the cases. There were 2 (10%) periprocedural complications unrelated to the re-entry device, which were resolved by endovascular or surgical treatment. The target lesion revascularization rate was 10%, with the 2 events occurring at 3 and 6 months, respectively, in patients with Rutherford category 4-5 ischemia. There was one below-the-knee amputation in the patient with failed revascularization. CONCLUSION: The acute failure of endovascular treatment of SFA CTOs is most often due to an inability to re-enter the true lumen after the occlusion is crossed in a subintimal plane. Bailout revascularization with the Outback LTD catheter is highly successful and shows a low device-related complication rate. This needle- and fluoroscopic-based re-entry device increases the endovascular success rate and is therefore expanding the minimally invasive treatment options for surgically unfit patients.

Incidence and clinical implications of stent fractures of the Xpert self-expanding nitinol stent in infrainguinal arteries

BACKGROUND: Different stents in infrainguinal arteries have recently been associated with stent fractures and unfavorable clinical outcome, although data is limited regarding fractures of the Xpert selfexpanding nitinol stent. Thus, purpose of the present investigation was to evaluate its incidence and clinical implications in lower limb arteries. PATIENTS AND METHODS: Fifty-three consecutive patients (53 limbs) with peripheral arterial disease underwent secondary Xpert stent implantation due to suboptimal primary balloon angioplasty (PTA). Median age was 76 years. Stent fractures were evaluated by plain X-ray at median follow-up of 16 months. Stent patency was assessed by duplex ultrasound and sustained clinical improvement was defined as improvement of the ABI of > or = 0.10 together with improvement of at least one Rutherford class above the baseline finding throughout follow-up. RESULTS: Median length of femoropopliteal and infrapopliteal lesion was 3.0 and 2.3 cm, respectively. Sixtyfive stents were implanted in 43 limbs with femoropopliteal and 10 stents in 10 limbs with infrapopliteal lesion, respectively. Stent fractures occurred in 3 of 43 limbs (7.0%) of patients with femoropopliteal lesion with stent-based fracture rate of 4.6%. All fractured stents showed multiple struts fractures and occurred in the distal and middle superficial femoral artery. No stent fracture was observed in infrapopliteal lesions. The fractured stents were not associated with any clinical deterioration. Sustained clinical improvement was 71.0% and 54.6% for femoropopliteal and infrapopliteal lesions, respectively. Stent patency assessed by duplex was 65.2 and 63.9% for femoropopliteal and infrapopliteal lesions, respectively. CONCLUSIONS: Fractures of the Xpert stent were seldom and not associated with unfavorable clinical outcome at midterm follow-up.

Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples

BACKGROUND Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART). OBJECTIVES To determine if ART use in an HIV-infected member of an HIV-discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples. SEARCH METHODS We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. SELECTION CRITERIA Randomised controlled trials (RCT), cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 3,833 references and examined 87 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS One RCT and nine observational studies were included in the review. These ten studies identified 2,112 episodes of HIV transmission, 1,016 among treated couples and 1,096 among untreated couples. The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]. All index partners in this study had CD4 cell counts at baseline of 350-550 cells/µL. Similarly, the summary rate ratio for the nine observational studies was 0.58 [95% CI 0.35, 0.96], with substantial heterogeneity (I(2)=64%). After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.36 [95% CI 0.17, 0.75] with substantial heterogeneity (I(2)=62%). We also performed subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had ≥350 CD4 cells/µL, we estimated a rate ratio of 0.12 [95% CI 0.01, 1.99]. In this subgroup, there were 247 transmissions in untreated couples and 30 in treated couples. AUTHORS' CONCLUSIONS ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed.Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered.

Clinically-driven need for secondary interventions after endovascular revascularization of tibial arteries in patients with critical limb ischemia

PURPOSE To assess the need for clinically-driven secondary revascularization in critical limb ischemia (CLI) patients subsequent to tibial angioplasty during a 2-year follow-up. METHODS Between 2008 and 2010, a total of 128 consecutive CLI patients (80 men; mean age 76.5±9.8 years) underwent tibial angioplasty in 139 limbs. Rutherford categories, ankle-brachial index measurements, and lower limb oscillometries were prospectively assessed. All patients were followed at 3, 6, 12 months, and annually thereafter. Rates of death, primary and secondary sustained clinical improvement, target lesion (TLR) and target extremity revascularization (TER), as well as major amputation, were analyzed retrospectively. Primary clinical improvement was defined as improvement in Rutherford category to a level of intermittent claudication without unplanned amputation or TLR. RESULTS All-cause mortality was 8.6%, 14.8%, 22.9%, and 29.1% at 3, 6, 12, and 24 months. At the same intervals, rates of primary sustained clinical improvement were 74.5%, 53.0%, 42.7%, and 37.1%; for secondary improvement, the rates were 89.1%, 76.0%, 68.4%, and 65.0%. Clinically-driven TLR rates were 14.6%, 29.1%, 41.6%, 46.2%; the rates for TER were 3.0%, 13.6%, 17.2%, and 27.6% in corresponding intervals, while the rates of major amputation were 1.5%, 5.5%, 10.1%, and 10.1%. CONCLUSION Clinically-driven TLR is frequently required to maintain favorable functional clinical outcomes in CLI patients following tibial angioplasty. Dedicated technologies addressing tibial arterial restenosis warrant further academic scrutiny.

IN.PACT Amphirion paclitaxel eluting balloon versus standard percutaneous transluminal angioplasty for infrapopliteal revascularization of critical limb ischemia: rationale and protocol for an ongoing randomized controlled trial

BACKGROUND The effectiveness and durability of endovascular revascularization therapies for chronic critical limb ischemia (CLI) are challenged by the extensive burden of infrapopliteal arterial disease and lesion-related characteristics (e.g., severe calcification, chronic total occlusions), which frequently result in poor clinical outcomes. While infrapopliteal vessel patency directly affects pain relief and wound healing, sustained patency and extravascular care both contribute to the ultimate "patient-centric" outcomes of functional limb preservation, mobility and quality of life (QoL). METHODS/DESIGN IN.PACT DEEP is a 2:1 randomized controlled trial designed to assess the efficacy and safety of infrapopliteal arterial revascularization between the IN.PACT Amphirion™ paclitaxel drug-eluting balloon (IA-DEB) and standard balloon angioplasty (PTA) in patients with Rutherford Class 4-5-6 CLI. DISCUSSION This multicenter trial has enrolled 358 patients at 13 European centers with independent angiographic core lab adjudication of the primary efficacy endpoint of target lesion late luminal loss (LLL) and clinically driven target lesion revascularization (TLR) in major amputation-free surviving patients through 12-months. An independent wound core lab will evaluate all ischemic wounds to assess the extent of healing and time to healing at 1, 6, and 12 months. A QoL questionnaire including a pain scale will assess changes from baseline scores through 12 months. A Clinical Events Committee and Data Safety Monitoring Board will adjudicate the composite primary safety endpoints of all-cause death, major amputation, and clinically driven TLR at 6 months and other trial endpoints and supervise patient safety throughout the study. All patients will be followed for 5 years. A literature review is presented of the current status of endovascular treatment of CLI with drug-eluting balloon and standard PTA. The rationale and design of the IN.PACT DEEP Trial are discussed. IN.PACT DEEP is a milestone, prospective, randomized, robust, independent core lab-adjudicated CLI trial that will evaluate the role of a new infrapopliteal revascularization technology, the IA-DEB, compared to PTA. It will assess the overall impact on infrapopliteal artery patency, limb salvage, wound healing, pain control, QoL, and patient mobility. The 1-year results of the adjudicated co-primary and secondary endpoints will be available in 2014. TRIAL REGISTRATION NCT00941733

Stent placement vs. balloon angioplasty for popliteal artery treatment: two-year results of a prospective, multicenter, randomized trial.

PURPOSE To investigate the 2-year technical and clinical results of primary nitinol stent placement in comparison with percutaneous transluminal angioplasty (PTA) in the treatment of de novo lesions of the popliteal artery. METHODS The ETAP study (Endovascular Treatment of Atherosclerotic Popliteal Artery Lesions: balloon angioplasty vs. primary stenting; www.ClinicalTrials.gov identifier NCT00712309) is a prospective, randomized trial that enrolled 246 patients (158 men; mean age 72 years) who were randomly assigned to receive a nitinol stent (n=119) or PTA (n=127) for lesions averaging 42.3 mm in length. The results of the primary study endpoint were published. Secondary outcome measures and endpoints included primary patency (freedom from duplex-detected target lesion restenosis), target lesion revascularization (TLR), secondary patency, changes in ankle-brachial index and Rutherford class, and event-free survival (freedom from target limb amputation, TLR, myocardial infarction, and death). RESULTS In total, 183 patients (89 stent and 94 PTA) were available for the 2-year analysis. The primary patency rate was significantly higher in the stent group (64.2%) than in the PTA group (31.3%, p=0.0001). TLR rates were 22.4% and 59.5%, respectively (p=0.0001). When provisional stent placement in the PTA arm was not considered as TLR and loss in patency, the differences prevailed between the study groups but were not significant (64.2% vs. 56.1% for primary patency, respectively; p=0.44). A significant improvement in ABI and Rutherford category was observed at 2 years in both groups. CONCLUSION In treatment of obstructive popliteal artery lesions, provisional stenting reveals equivalent patency in comparison to primary stenting. However, the 2-year results of this trial suggest the possibility of a shift toward higher patency rates in favor of primary stenting.

An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia.

OBJECTIVE Recent small single-center data indicate that the current hemodynamic parameters used to diagnose critical limb ischemia are insensitive. We investigated the validity of the societal guidelines-recommended hemodynamic parameters against core laboratory-adjudicated angiographic data from the multicenter IN.PACT DEEP (RandomIzed AmPhirion DEEP DEB vs StAndard PTA for the treatment of below the knee Critical limb ischemia) Trial. METHODS Of the 358 patients in the IN.PACT DEEP Trial to assess drug-eluting balloon vs standard balloon angioplasty for infrapopliteal disease, 237 had isolated infrapopliteal disease with an available ankle-brachial index (ABI), and only 40 of the latter had available toe pressure measurements. The associations between ABI, ankle pressure, and toe pressure with tibial runoff, Rutherford category, and plantar arch were examined according to the cutoff points recommended by the societal guidelines. Abnormal tibial runoff was defined as severely stenotic (≥70%) or occluded and scored as one-, two-, or three-vessel disease. A stenotic or occluded plantar arch was considered abnormal. RESULTS Only 14 of 237 patients (6%) had an ABI <0.4. Abnormal ankle pressure, defined as <50 mm Hg if Rutherford category 4 and <70 mm Hg if Rutherford category 5 or 6, was found only in 37 patients (16%). Abnormal toe pressure, defined as <30 mm Hg if Rutherford category 4 and <50 mm Hg if Rutherford category 5 or 6, was found in 24 of 40 patients (60%) with available measurements. Importantly, 29% of these 24 patients had an ABI within normal reference ranges. A univariate multinomial logistic regression found no association between the above hemodynamic parameters and the number of diseased infrapopliteal vessels. However, there was a significant paradoxic association where patients with Rutherford category 6 had higher ABI and ankle pressure than those with Rutherford category 5. Similarly, there was no association between ABI and pedal arch patency. CONCLUSIONS The current recommended hemodynamic parameters fail to identify a significant portion of patients with lower extremity ulcers and angiographically proven severe disease. Toe pressure has better sensitivity and should be considered in all patients with critical limb ischemia.