Mark R. Nehler

Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia

OBJECTIVE To develop a set of suggested objective performance goals (OPG) for evaluating new catheter-based treatments in critical limb ischemia (CLI), based on evidence from historical controls. METHODS Randomized, controlled trials of surgical, endovascular, and pharmacologic/biologic treatments for CLI were reviewed according to specified criteria regarding study population and data quality. Line-item data were obtained for selected studies from the sponsor/funding agency. A set of specific outcome measures was defined in accordance with the treatment goals for the CLI population. Risk factors were examined for their influence on key endpoints, and models of stratification based on specific clinical and anatomic variables developed. Sample size estimates were made for single-arm trial designs based on comparison to the suggested OPG. RESULTS Bypass with autogenous vein was considered the established standard, and data compiled from three individual randomized, controlled trials (N = 838) was analyzed. The primary efficacy endpoint was defined as perioperative (30-day) death or any major adverse limb event (amputation or major reintervention) occurring within one year. Results of open surgery controls demonstrated freedom from the primary endpoint in 76.9% (95% confidence interval [CI] 74.0%-79.9%) of patients at one year, with amputation-free survival (AFS) of 76.5% (95% CI 73.7%-79.5). An additional 3% non-inferiority margin was suggested in generating OPG for catheter-based therapies. Defined clinical (age > 80 years and tissue loss) and anatomic (infra-popliteal anatomy or lack of good quality saphenous vein) risk subgroups provided significantly different point estimates and OPG threshold values. CONCLUSIONS For new catheter-based therapies in CLI, OPGs offer a feasible approach for pre-market evaluation using non-randomized trial designs. Such studies should incorporate risk stratification in design and reporting as the CLI population is heterogeneous with respect to baseline variables and expected outcomes. Guidelines for CLI trial design to address consistency in study cohorts, methods of assessment, and endpoint definitions are provided.

Functional outcome in a contemporary series of major lower extremity amputations

PURPOSE We undertook this study to document the functional natural history of patients undergoing major amputation in an academic vascular surgery and rehabilitation medicine practice. METHODS A retrospective review was conducted of consecutive patients undergoing major lower extremity amputation and rehabilitation in a university and Department of Veterans Affairs hospital. Main outcome variables included operative mortality, follow-up, survival, median time to incision healing, secondary operative procedures for wound management, and conversion from below-knee amputation (BKA) to above-knee amputation (AKA). For surviving patients, quality of life was determined by degree of ambulation, eg, outdoors, indoors only, or no ambulation; use of a prosthesis; and independence, eg, community housing or nursing facility. RESULTS From August 1997 through March 2002, 154 patients (130 men; median age, 62 years) underwent 172 major amputations, 78 AKA and 94 BKA, because of either critical limb ischemia (87%) or diabetic neuropathy (13%). Thirty-day operative mortality was 10%. Mean follow-up was 14 months. Healing at 100 and 200 days, as determined with the Kaplan-Meier method, was 55% and 83%, respectively, for BKA, and 76% and 85%, respectively, for AKA. Twenty-three BKA and 16 AKA required additional operative revision, and 18 BKA ultimately were converted to AKA. Survival was 78% at 1 year and 55% at 3 years. Function in surviving patients at 10 and 17 months, respectively, was as follows: 21% and 29% of patients ambulated outdoors, 28% and 25% ambulated indoors only, and 51% and 46% of patients were nonambulatory; 32% and 42% of patients used prosthetic limbs; and 17% and 8% of patients who lived in the community before amputation required care in a nursing facility. CONCLUSIONS We were surprised to find that vascular patients in a contemporary setting who require major lower extremity amputation and rehabilitation often remain independent despite infrequent prosthesis use and outdoor ambulation. Although any hope for postoperative ambulation in this population requires salvaging the knee joint, because of the morbidity incurred in both wound healing and rehabilitation efforts, aggressive effort should be reserved for selected patients at good risk. Ability to predict ambulation after BKA in the vascular population is poor.

Contemporary management of isolated iliac aneurysms

OBJECTIVE Because isolated common iliac artery aneurysms are infrequent, are difficult to detect and treat, and have traditionally been associated with high operative mortality rates in reported series, we analyzed the outcomes of operative repair of 31 isolated common iliac artery aneurysms in 21 patients to ascertain morbidity and mortality rates with contemporary techniques of repair. METHODS A retrospective review study was conducted in a university teaching hospital and a Department of Veterans Affairs Medical Center. Perioperative mortality and operative morbidity rates were examined in 17 men and four women with isolated common iliac artery aneurysms between 1984 and 1997. Ages ranged from 38 to 87 years (mean 69 +/- 8 years). Slightly more than half of the cases were symptomatic, with abdominal pain, neurologic, claudicative, genitourinary, or hemodynamic symptoms. One aneurysm had ruptured and one was infected. There was one iliac artery-iliac vein fistula. All aneurysms involved the common iliac artery. Coexistent unilateral or bilateral external iliac aneurysms were present in four patients; there were three accompanying internal iliac aneurysms. Overall, 52% of patients had unilateral aneurysms and 48% had bilateral aneurysms. Aneurysms ranged in maximal diameter from 2.5 to 12 cm (mean 5.6 +/- 2 cm). No patients were unavailable for follow-up, which averaged 5.5 years. RESULTS Nineteen patients underwent direct operative repair of isolated iliac aneurysms. One patient had placement of an endoluminal covered stent graft; another patient at high risk had percutaneous placement of coils within the aneurysm to occlude it in conjunction with a femorofemoral bypass graft. Patients with bilateral aneurysms underwent aortoiliac or aortofemoral interposition grafts, whereas unilateral aneurysms were managed with local interposition grafts. There were no deaths in the perioperative period. Only one elective operation (5%) resulted in a significant complication, compartment syndrome requiring fasciotomy. The patient treated with the covered stent required femorofemoral bypass when the stent occluded 1 week after the operation. The patient treated with coil occlusion of a large common iliac aneurysm died 2 years later when the aneurysm ruptured. CONCLUSIONS Isolated iliac artery aneurysms can be managed with much lower mortality and morbidity rates than aneurysm previously been reported by using a systematic operative approach. Percutaneous techniques may be less durable and effective than direct surgical repair.

Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population

BACKGROUND Critical limb ischemia (CLI) represents the most severe clinical manifestation of peripheral arterial disease (PAD) and is the major cause of ischemic amputation in the United States. Risk factors and the associated incidence and prevalence of CLI have not been well described in the general population. This study describes the risk factors for PAD progression to CLI and estimates the annual incidence and prevalence of CLI in a representative United States patient cohort. METHODS This was a retrospective cohort analysis of adults with commercial, Medicare supplemental, or Medicaid health insurance who had at least one PAD or CLI health care claim from January 1, 2003, through December 31, 2008, and 12 months of continuous coverage. Two subgroups of CLI presentation were identified: primary CLI (patients without any prior PAD or subsequent PAD diagnostic code >30 days after CLI diagnostic code) and secondary CLI (patients with prior PAD or subsequent PAD diagnostic codes ≤30 days of a CLI diagnostic code). Patterns of presentation, annual incidence, and prevalence of CLI were stratified by health care plan. Risk factors for progression to CLI were compared by presentation type. RESULTS From 2003 to 2008, the mean annual incidence of PAD was 2.35% (95% confidence interval [CI], 2.34%-2.36%) and the incidence of CLI was 0.35% (95% CI, 0.34%-0.35%) of the eligible study population, with primary and secondary presentations occurring at similar rates. The mean annualized prevalence of PAD was 10.69% (95% CI, 10.67%10.70%) and the mean annualized prevalence of CLI was 1.33% (95% CI, 1.32%-1.34%) of the eligible study population, and two-thirds of the cases presented as secondary CLI. CLI developed in 11.08% (95% CI, 11.30%-11.13%) of patients with PAD. A multivariable model demonstrated that diabetes, heart failure, stroke, and renal failure were stronger predictors of primary rather than secondary CLI presentation. CONCLUSIONS These data establish new national estimates of the incidence and prevalence of CLI and define key risk factors that contribute to primary or secondary presentations of CLI within a very large contemporary insured population cohort in the United States.

Functional outcomes and quality of life in peripheral arterial disease: current status

This review examines current evidence for baseline functional impairment and changes with therapy in patients with peripheral arterial disease (PAD) - ranging from patients without claudication or critical limb ischemia (CLI) but other exertional leg symptoms (erroneously referred to as asymptomatic in the Fontaine classifi cation system), to patients with claudication and those with CLI. The review points out that the status of functional outcomes research is markedly different in focus and development in the different levels of disease severity - paradoxically less studied in the more severe CLI population than in patients with claudication, for example.

Surgical treatment of threatened reversed infrainguinal vein grafts

PURPOSE Current information concerning the results of surgical revision of threatened infrainguinal vein grafts is largely limited to in situ conduits. Infrainguinal grafts may be threatened by intrinsic graft lesions or significant stenosis in the adjacent inflow or outflow arteries. To assess the results of operative revision of infrainguinal reversed vein grafts, we reviewed our experience with surgical revision of threatened infrainguinal reversed vein grafts identified through a program of postoperative clinical and vascular laboratory graft surveillance. METHODS All patients who underwent surgical revision of a threatened but patent infrainguinal reversed vein graft from January 1987 through April 1993 were identified through review of our vascular registry. Data were analyzed for type of vein used, date of original reversed vein graft, clinical and vascular laboratory findings leading to reversed vein graft revision, results of preoperative angiography, patient risk factors, operative techniques and complications, and long-term assisted primary graft patency and limb salvage. RESULTS Ninety-six patients with 100 infrainguinal reversed vein grafts (69) femoral-popliteal, 31 femoral-tibial) underwent 117 surgical vein graft revisions or inflow procedures during the study period. Eighty-one percent of the original reversed vein grafts consisted of a single segment of greater saphenous vein. All revised grafts had at least a 50% stenosis in the graft itself or the proximal or distal artery. A single revision was performed in 85 grafts, two revisions in 13 grafts, and three revisions in two grafts. There were nine (8%) isolated inflow procedures, eight (7%) vein patch angioplasties, 62 (53%) interposition vein grafts, and 29 (25%) vein graft extensions to a new distal anastomotic site. The remaining nine (8%) procedures consisted of combinations of the above. Median time to primary graft revision after initial graft implantation was 15 months (range 2 days to 316 months). Mean time to secondary revision after primary revision was 21 months. Operative mortality was 0.9%. Cumulative assisted primary patency of the original grafts revised for stenotic lesions was 99%, 96%, and 92% at 1, 3, and 5 years, respectively. Limb salvage was 99%, 97%, and 97% at 1, 3, and 5 years, respectively. CONCLUSIONS Although surgical revision of reversed vein graft requires much use of alternative vein sources, these procedures can be performed with minimum mortality and provide excellent assisted primary graft patency and limb salvage.

Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol

This study aims to evaluate the reliability of repeated graded workload treadmill testing (G-test; 2 mph; 0% grade, increasing 2% every 2 min) and to compare the reliability of a constant workload treadmill protocol (C-test; 2 mph; 12% grade) versus the graded workload treadmill protocol in patients with intermittent claudication, studied longitudinally. A clinical trial investigating an orally stable prostacycline derivative that included 330 patients with intermittent claudication was performed. The trial employed three active treatment groups and one placebo group. Because there were no significant inter-group differences at baseline or after treatment, data from all groups were pooled for the evaluation of treadmill test reliability. Treadmill data were obtained from a 2-week run-in phase where three G-tests were performed, as well as from the beginning and the end of a 3-month double-blind phase where a G-test and a C-test were performed in random order. Treadmill test reliability was described through test process-related and between-subject variances and also using variance-derived parameters such as the reliability coefficient (RC) and the relative precision (RP). A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance. Estimates of variance were described for both the maximal or absolute claudication distance (ACD) and the initial claudication distance (ICD) with each treadmill test. Reliability estimates are reported for the total study sample and for patients with baseline claudication distances <300 feet and .300 feet (approximately <100 m; .100 m), as measured with the C-test. The cut-off value was empirically chosen to separate severely diseased from mild to moderately diseased claudicants. Theoretical considerations suggest that reliability measures may differ in these subgroups. With repeated testing during the run-in phase for the measure of ACD, the G-test had an RC of 0.952 and an RP of 21.9%. With the comparison of both test protocols in the entire study population for the measurement of ACD, the G-test had an RC of 0.902 and an RP of 31.3%, while the C-test had an RC of 0.876 and an RP of 35.2%. The results for ICD on the G-test were an RC of 0.809 and an RP of 43.7%, while the C-test had an RC of 0.737 and an RP of 51.3%. The reliability of the ACD measurement for RC and RP was numerically superior to those for the ICD for both protocols. In patients with a baseline ACD <300 feet, the RC for ACD on the G-test was 0.827 and the RP was 41.4%. In contrast, on the C-test the RC decreased to 0.250 and the RP increased to 86.6%. These changes in RC and RP were due to a marked decrease in the between-subject variance, demonstrating the inability of the C-test to separate appropriately the different claudication distances in populations with highly limited baseline claudication distances. During a run-in phase, the G-test has excellent test characteristics. During the longitudinal phase of a trial, the reliability of G-tests and C-tests are comparable in the entire study population. However, in patients with low claudication distances, the G-test should be given preference over the C-test.

Homocysteinemia as a Risk Factor for Atherosclerosis: A Review

Elevation in plasma homocysteine has been widely studied as an independent risk factor for atherosclerosis. Animal laboratory models have demonstrated rapid onset vascular lesions with homocysteine infusion. A large body of data indicates a consistent relationship between plasma homocysteine and symptomatic atherosclerotic disease involving the coronary, peripheral, and cerebral circulations. Elevated plasma homocysteine can be predictably normalized with oral folate in most patients. Despite the wealth of published clinical data on this topic, it is unknown if normalization of plasma homocysteine in patients with symptomatic atherosclerosis will prevent or arrest the disease process.

Assessment of functional status and quality of life in claudication.

BACKGROUND Treadmill walking is commonly used to evaluate walking impairment and efficacy of treatment for intermittent claudication (IC) in clinical and research settings. Although this is an important measure, it does not provide information about how patients perceive the effects of their treatments on more global measures of health-related quality of life (HRQOL). METHODS PubMed/Medline was searched to find publications about the most commonly used questionnaires to assess functional status and/or general and disease-specific HRQOL in patients with peripheral artery disease (PAD) who experience IC. Inclusion criteria for questionnaires were based on existence of a body of literature in symptomatic PAD. RESULTS Six general questionnaires and seven disease-specific questionnaires are included, with details about the number of domains covered and how each tool is scored. The Medical Outcomes Study Short Form 36-item questionnaire and Walking Impairment Questionnaire are currently the most used general and disease-specific questionnaires at baseline and after treatment for IC, respectively. CONCLUSIONS The use of tools that assess functional status and HRQOL has importance in both the clinical and research areas to assess treatment efficacy from the patients perspective. Therefore, assessing HRQOL in addition to treadmill-measured walking ability provides insight as to the effects of treatments on patient outcomes and may help guide therapy.

Patterns of artery disease in 450 patients undergoing revascularization for critical limb ischemia: Implications for clinical trial design

OBJECTIVE The pattern and distribution of arterial occlusions and stenoses in patients with critical limb ischemia presenting at two academic medical centers was described. METHODS From January 1998 to December 2006, 450 consecutive critical limb ischemia patients who underwent arteriography and infrainguinal revascularization at the University of Colorado Health Sciences Center or Southern Illinois University were retrospectively evaluated. Demographics, clinical morbidities, and Fontaine stage were recorded. The arterial tree was categorized into three groups: the aorta and iliac arteries (A-I); the common femoral, superficial femoral, and profunda femoral arteries (Fem); and the popliteal and tibial arteries (Pop-Tib). Arterial segments within groups were categorized as subcritical stenoses (patent or <50% stenoses), critical stenoses (single or multiple >50% stenoses), or occluded (segmental occlusions of any length). Patients with diabetes mellitus, end-stage renal disease, and Fontaine stage (III vs IV) were analyzed for differing disease patterns according to their chart history. RESULTS Occlusive disease was present in 5% in all arterial segments (A-I + Fem + Pop-Tib), in 1% in the A-I + Fem group, in 2% in the A-I + Pop-Tib group, in 3% in A-I group, in 4% in the Fem group, in 30% in the Fem + Pop-Tib group, and in 55% in the Pop-Tib group. Descriptive comparisons among subgroups demonstrated a 61% to 69% prevalence of popliteal and tibial occlusive patterns in patients with diabetes mellitus, end-stage renal disease, and Fontaine stage IV. Furthermore, 65% of patients with Pop-Tib occlusions had associated critical stenoses in the proximal arterial groups. CONCLUSION More than half of critical limb ischemia patients undergoing infrainguinal revascularization have arterial occlusions in the popliteal or tibial arterial segments, or both, with associated critical stenoses in the femoral arterial segments, which is even greater in the subgroups with diabetes mellitus, end-stage renal disease, and Fontaine stage IV. Knowledge of such occlusive patterns is important for the development of novel infrainguinal endovascular and angiogenesis therapies for critical limb ischemia.