A comparison of programmable and nonprogrammable compression devices for treatment of lymphoedema using an administrative health outcomes dataset.

BACKGROUND: Patients with lymphoedema experience lifelong swelling and recurrent cellulitis despite use of complete decongestive therapy. Pneumatic compression devices (PCDs), including nonprogrammable and programmable devices that meet individual patient needs, support long-term self-care in the home. OBJECTIVES: Patients with either a nonprogrammable device (NP-PCD) or a dynamic pressure programmable device [P-PCD; Flexitouch® (Tactile Medical, Minneapolis, MN, U.S.A.)] were evaluated to compare associated clinical and health utilization outcomes pre-/postdevice acquisition. METHODS: Retrospective analysis of deidentified administrative claims from 2007 through 2013 of a large U.S. insurer. Outcome variables included rates of lymphoedema-related cellulitis, manual therapy use, outpatient services and inpatient hospitalizations. Multivariate regression analysis was performed to (i) compare outcomes for the 12 months pre- and postdevice acquisition and (ii) compare these two device types for their treatment-associated benefits. RESULTS: The sample consisted of 1013 NP-PCD and 718 P-PCD recipients. Compared with the NP-PCD group, P-PCD patients' baseline cellulitis rate was higher, whereas their postdevice cellulitis rate was lower. In the cancer cohort, the NP-PCD group had a 53% reduction in episodes of cellulitis (from 17·9% to 8·5%), compared with a greater 79% reduction in the P-PCD group (from 23·7% to 5·0%) (P < 0·001). In the noncancer cohort, the P-PCD group also experienced a larger 76% decline (from 31·0% to 7·4%) vs. 54% decline (from 22·9% to 10·6%) in cellulitis rates (P = 0·003). Outpatient service use reduced in both device groups, with greater reductions observed in the P-PCD group. Both device groups experienced reductions in manual therapy use. Inpatient hospitalizations were largely stable with reductions observed only in the noncancer cohort of the P-PCD group. CONCLUSIONS: P-PCD receipt was associated with superior lymphoedema-related health outcomes and reductions in cellulitis.

Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia.

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Characterizing axillary web syndrome: ultrasonographic efficacy.

The aim of this study was to determine if ultrasound could successfully characterize axillary web syndrome (AWS) and clarify the pathophysiologic basis of AWS as a vascular or lymphatic abnormality, or an abnormal tissue structure. This prospective study evaluated women who developed AWS following breast cancer surgery. Using an 18 MHz ultrasound transducer, images were taken of the AWS cord and compared to mirror images on the contralateral side. A blinded radiologist assessed the ultrasound characteristics of and structural changes in the skin and subcutaneous tissue and formulated an opinion as to the side in which AWS was located. Seventeen subjects participated in the study. No structure or abnormality consistent with AWS could be identified by ultrasound. There were no statistical differences between the ipsilateral and contralateral side in skin thickness; subcutaneous reflector thickness, number or disorganization; or subcutaneous tissue echodensity (p>0.05). The radiologist correctly identified the side with AWS in 12 of 17 subjects (=0.41). A distinct ultrasonographic structure or abnormality could not be identified in subjects with AWS using 18 MHz ultrasound. The inability to identify a specific structure excludes the possibility that AWS is associated with vein thrombosis or a fascial abnormality, and supports the theory that AWS may be pathology that is not visible with 18 MHz ultrasound, such as microlymphatic stasis or binding of fibrin or other proteins in the interstitial space.

Pneumatic compression device treatment of lower extremity lymphedema elicits improved limb volume and patient-reported outcomes.

OBJECTIVES: Examine the effectiveness of an advanced pneumatic compression device (APCD) in reducing limb volume (LV), and to evaluate clinician and patient-reported outcomes. DESIGN: Device registry study. MATERIALS AND METHODS: Data were collected prospectively for 196 lower extremity lymphedema patients prescribed an APCD. Baseline and post-treatment LVs were calculated and clinical outcomes (skin changes, pain, and function) were assessed. Patient-reported outcomes and satisfaction utilizing a pre- and post-treatment survey were also evaluated. RESULTS: 90% of APCD-treated patients experienced a significant reduction in LV with 35% enjoying a reduction >10%. Mean LV reduction was 1,150 mL or 8% (p < .0001). Greater baseline LV and BMI were strong predictors of LV reduction (p < .0001). Clinician assessment indicated that the majority of patients experienced improvement in skin fibrosis and function. Patient-reported outcomes showed a significant increase in ability to control lymphedema through APCD treatment, with an increase in function and a reduction in the interference of pain. 66% were "very satisfied" with the APCD treatment. CONCLUSION: APCD use is associated with consistent reductions in LV, with favorable patient-reported outcomes. Results demonstrate that reduction in LV and pain, combined with functional improvement and patient satisfaction can be achieved, providing tangible benefit for lower extremity patients.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease.

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study.

We aimed to evaluate in a phase I dose-escalation study, the safety of intramuscular injections of a novel non-viral plasmid DNA expressing two isoforms of human hepatocyte growth factor (HGF) (VM202) in patients with critical limb ischemia (CLI). In total, 12 patients with CLI and unsuitable for revascularization were consecutively assigned to increasing doses (2 to 16 mg) of VM202 administered into the ischemic calf muscle at days 1 and 15. Patients were evaluated for safety and tolerability, changes in ankle- and toe brachial index (ABI and TBI), and pain severity score using a visual analog scale (VAS) throughout a 12-month follow-up period. Median age was 72 years and 53% of the patients were male. VM202 was safe and well tolerated with no death during the 12-month follow-up. Median ABI and TBI significantly increased from 0.35 to 0.52 (P=0.005) and from 0.15 to 0.24 (P=0.01) at 12 months follow-up. Median VAS decreased from 57.5 to 16.0 mm at 6 months follow-up (P=0.03). In this first human clinical trial, VM202, which expresses two isoforms of human HGF, appear to be safe and well tolerated with encouraging clinical results and thus supports the performance of a phase II randomized controlled trial.

The next 10 years in the management of peripheral artery disease: perspectives from the 'PAD 2009' Conference.

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease.

OBJECTIVES: Poor blood pressure (BP) control is common amongst patients with symptomatic atherothrombotic disease. It is unclear whether BP control and management differ across atherothrombotic disease subtypes. METHODS: We analysed the baseline data of 44,984 patients with documented coronary artery disease (CAD) only (n = 30,414), cerebrovascular disease (CVD) only (n = 11,359) and peripheral arterial disease (PAD) only (n = 3211) from the international REduction of Atherothrombosis for Continued Health Registry and investigated the impact of atherothrombotic disease subtype on BP control and use of antihypertensive drugs. RESULTS: The proportion of patients with BP controlled (<140/90 mmHg) was higher in CAD (58.1%) than in CVD (44.8%) or PAD (38.9%) patients (P < 0.001). Amongst patients with treated hypertension, CAD patients were more likely to have BP controlled than were CVD patients [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.59-1.75] or PAD (OR = 2.30; 95% CI = 2.10-2.52). These differences were smaller in women than in men and decreased with age. Amongst treated patients, CAD patients were more likely to receive > or =3-drug combination therapies than were CVD (OR = 1.73; 95% CI = 1.64-1.83) or PAD (OR = 1.64; 95% CI = 1.49-1.80) patients. Adjustment for age, gender, waist obesity, diabetes, education level and world region did not alter the results. CONCLUSIONS: Coronary artery disease patients are more likely than CVD or PAD patients to have BP controlled and to receive antihypertensive drugs, particularly combination therapies. Promotion of more effective BP control through combination antihypertensive therapies could improve secondary prevention and therefore prevent complications in CVD and PAD patients.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Albuminuria and peripheral arterial disease: results from the multi-ethnic study of atherosclerosis (MESA).

BACKGROUND: The association of albuminuria with cardiovascular disease (CVD) is increasingly recognized, but its association with peripheral arterial disease (PAD) is not well characterized in subjects with or without diabetes. METHODS: Using data from the Multi-Ethnic Study of Atherosclerosis, a cohort free of clinical vascular disease, we analyzed the cross-sectional association between albuminuria and PAD in diabetic and nondiabetic subjects. A spot urine albumin-creatinine ratio (ACR) was used to define albuminuria in two ways: presence or absence of albuminuria and the degree of albuminuria (no albuminuria defined as urine ACR<17 mg/g for men and <25mg/g for women, microalbuminuria as urine ACR 17 to 249 mg/g for men and 25 to 334 mg/g for women, and macroalbuminuria as urine ACR> or =250 mg/g for men and > or =355 mg/g for women). PAD was defined by ankle-brachial index (ABI)<0.9. RESULTS: Among the 6760 subjects, aged 45-84 years, 326 (4.8%) had prevalent PAD. Eight hundred and thirteen (12.0%) subjects had microalbuminuria and 100 (1.5%) had macroalbuminuria. Among diabetic subjects, those with albuminuria (micro- and macroalbuminuria combined) were 1.90 times more likely to have PAD (95% CI: 1.19-3.04) than those with no albuminuria. After adjusting for CVD risk factors, the odds ratio modestly attenuated to 1.65 (95% CI: 1.00-2.74). For nondiabetic subjects, there were no statistically significant associations observed in the univariable and multivariable analyses. The degree of albuminuria was not associated with PAD in either diabetic or nondiabetic subjects. CONCLUSIONS: The presence, but not magnitude of albuminuria, is an important risk factor for PAD in diabetic but not in nondiabetic subjects.

The Minnesota Regional Peripheral Arterial Disease Screening Program: toward a definition of community standards of care.

The Minnesota Regional Peripheral Arterial Disease Screening Program was designed to define the efficacy of community PAD detection efforts, to assess the disease-specific and health-related morbidity, to assess PAD awareness rates, and to determine the magnitude of atherosclerosis disease risk factors and the intensity of their management. The target population was recruited via mass media efforts directed at individuals over 50 years of age and those with leg pain with ambulation. Screening sessions included assessments of the ankle-brachial index, blood pressure, fasting lipid profile, and use of validated tools to detect symptomatic claudication (by the Modified WHO-Edinburgh Claudication Questionnaire), walking impairment (Walking Impairment Questionnaire - WIQ), quality of life (MOS SF-36), PAD awareness, and the intensity of PAD medical therapeutic interventions. PAD was defined as any ankle-brachial index < or =0.85 or a history of lower extremity revascularization. The program evaluated 347 individuals and identified 92 subjects with PAD and 255 subjects without PAD, yielding a detection rate of 26.5%. Individuals with PAD were older, tended to have higher blood pressures, and had a significant walking impairment and an impaired health-related quality of life compared with the non-PAD subjects. Current rates of tobacco use were low. Lipid-lowering, estrogen replacement, anti-platelet, and antihypertensive medications and exercise therapies were underutilized in the PAD cohort. Peripheral arterial disease awareness was low in these community-identified patients. This Program demonstrated that individuals with PAD can be efficiently identified within the community, but that current standards of medical care are low. These data can assist in the future development of PAD awareness, education, and treatment programs.

Peripheral arterial disease detection, awareness, and treatment in primary care.

CONTEXT: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice. OBJECTIVE: To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics. DESIGN AND SETTING: The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999. PATIENTS: A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease. MAIN OUTCOME MEASURES: Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis. RESULTS: PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups. CONCLUSIONS: Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.

Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.

PURPOSE: We tested the hypothesis that propionyl-L-carnitine would improve peak walking time in patients with claudication. Secondary aims of the study were to evaluate the effects of propionyl-L-carnitine on claudication onset time, functional status, and safety. SUBJECTS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 155 patients with disabling claudication from the United States (n = 72) or Russia (n = 83) received either placebo or propionyl-L-carnitine (2g/day orally) for 6 months. Subjects were evaluated at baseline and 3 and 6 months after randomization with a graded treadmill protocol at a constant speed of 2 miles per hour, beginning at 0% grade, with increments in the grade of 2% every 2 minutes until maximal symptoms of claudication forced cessation of exercise. Questionnaires were used to determine changes in functional status. RESULTS: At baseline, peak walking time was 331 +/- 171 seconds in the placebo group and 331 +/- 187 seconds in the propionyl-L-carnitine group. After 6 months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 +/- 222 seconds (a 54% increase) as compared with an improvement of 75 +/- 191 seconds (a 25% increase) for those on placebo (P <0.001). Similar improvements were observed for claudication onset time. Propionyl-L-carnitine treatment significantly improved walking distance and walking speed (by the Walking Impairment Questionnaire), and enhanced physical role functioning, reduced bodily pain, and resulted in a better health transition score (by the Medical Outcome Study SF-36 Questionnaire). The incidence of adverse events and study discontinuations were similar in the two treatment groups. CONCLUSIONS: Propionyl-L-carnitine safely improved treadmill exercise performance and enhanced functional status in patients with claudication.

Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery.

BACKGROUND: After coronary artery bypass surgery, patients have a high cumulative rate of graft closure and recurrent ischemic events. We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin, the accepted standard, in these patients. METHODS AND RESULTS: The event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization were determined for the 1480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin in a trial of 19 185 patients. The event rate per year of vascular death, myocardial infarction, stroke, or rehospitalization was 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (P:=0.001). A risk reduction was also seen in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients on clopidogrel versus aspirin (P:=0.030). In a multivariate model incorporating baseline clinical characteristics, clopidogrel therapy was independently associated with a decrease in vascular death, myocardial infarction, stroke, or rehospitalization in patients with a history of cardiac surgery, with a 31.2% relative risk reduction (95% CI, 15.8 to 43.8; P:=0.0003). Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) population, multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit (P:=0.015). CONCLUSION: Compared with aspirin, clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery, along with a decreased risk of bleeding.

Proteinuria in a placebo-controlled study of basic fibroblast growth factor for intermittent claudication.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 microg/kg for 6 sequential weeks (total dose 12 microg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

PAD awareness, risk, and treatment: new resources for survival--the USA PARTNERS program.

Peripheral arterial disease (PAD) is a very common manifestation of atherosclerosis and is associated with a high risk of cardiovascular morbidity and mortality. Despite the magnitude of the problem, PAD is often under-recognized in clinical practice until its limb manifestations are severe or heart attack or stroke supervene. The PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) program, recently completed in the USA, had five aims: (1) creation of a method for detection of PAD in primary care practice; (2) assessment of the awareness of the PAD diagnosis in both patients and physicians; (3) assessment of the magnitude of the atherosclerotic risk factor burden and intensity of treatment of atherosclerotic risk factors in PAD patients; (4) assessment of the disease-specific and general quality of life of PAD patients in their communities; and (5) provision of an educational intervention to foster improved community-prescribed medical interventions for patients with PAD. Lack of public and physician interest in PAD contrasts with the high prevalence and poor medical prognosis of PAD. The intention of PARTNERS was to create a community-based program to measure current rates of PAD awareness, physician recognition and treatment intensity. Data obtained will form the basis of future clinical investigations to improve clinical care for PAD patients in the USA.

Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators.

BACKGROUND: Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system. We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding. METHODS AND RESULTS: The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized, blinded, multicenter, trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infarction or symptomatic peripheral arterial disease. Without any double-counting of events, the number of rehospitalizations for ischemic events (defined as angina, transient ischemic attack, or limb ischemia) or bleeding events was determined for the entire cohort. There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin (1502 vs 1673; P =.010) over an average of 1.6 years of treatment. This reduction in rehospitalization was consistent across individual outcomes of angina, transient ischemic attack, limb ischemia, and bleeding. Compared with aspirin, clopidogrel also resulted in a 7.9% relative risk reduction in a combined end point of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (15.1% to 13.7% at 1 year; P =.011). Adjusting for baseline prognostic variables, clopidogrel therapy was an independent predictor for reduction of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (P =.009). CONCLUSIONS: Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin. This meaningful end point tracks well with other, more traditional measures of outcome and has incremental value beyond such end points.

Are atopic individuals genetically predisposed to produce a specific protease profile in antigen processing?

Genetic factors play a major role in the development of allergic diseases such as asthma and atopic dermatitis. Since allergic response involves immune processes such as antigen-processing and -presentation, it is conceivable that the genes involved in the regulation of these processes may be crucial in determining an individual's susceptibility to allergic diseases. In this paper, it is proposed that proteases, used in antigen-processing, are involved in the genetic predisposition to allergic diseases.