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Brass E.P.,University of California at Los Angeles | Cooper L.T.,Mayo Medical School | Hanson P.,CPC Clinical Research | Hiatt W.R.,CPC Clinical Research | Hiatt W.R.,Aurora University
Journal of Vascular Surgery

Background: Patients with claudication secondary to peripheral artery disease have a substantial impairment in walking capacity. This study evaluated factors suspected to be correlated with treadmill walking performance in an effort to gain insights into the pathophysiology of the impairment. Methods: A multivariate model was developed to define the associations between clinical and laboratory biomarkers with treadmill peak walking time (PWT) in patients enrolled in three clinical trials. The model was initially developed in a cohort of 385 patients from one trial using 23 candidate-independent variables and then tested in the combined data from the other two trials (351 patients). Results: The final model was built from 14 variables that met the predefined univariate criteria of P <.15. Main effects remaining in the model were age, resting ankle-brachial index, smoking status, hypertension, statin use, country (United States vs non-United States countries), and high-sensitivity C-reactive protein. The model was highly statistically significant (P <.0001) but explained only a limited portion of the population heterogeneity (r2 = 0.173). The main effects plus interaction terms had an r2 = 0.2178. The main effects model was tested in an independent cohort of 351 patients from two other clinical trials in peripheral arterial disease that did not include high-sensitivity C-reactive protein. The model successfully fit the data set, based on prospectively defined root mean squared error and was statistically significant (P =.0005) but had lower overall explanatory power than in the index cohort (r2 = 0.0687). Conclusions: As expected, age and ankle-brachial index contributed to exercise limitation among patients with PAD. The association of C-reactive protein, hypertension, and smoking with PWT is consistent with a role for inflammation or oxidative stress in determining treadmill walking performance. In contrast to previous reports from smaller and more homogenous populations, clinical attributes and biomarkers explain only a small portion of PWT heterogeneity. © 2013 by the Society for Vascular Surgery. Source

Belch J.,Institute of Cardiovascular Research | Hiatt W.R.,Aurora University | Hiatt W.R.,CPC Clinical Research | Baumgartner I.,University of Bern | And 3 more authors.
The Lancet

Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival. In this phase 3 trial (EFC6145/TAMARIS), 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries. All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria (ankle pressure <70 mm Hg or a toe pressure <50 mm Hg, or both, or a transcutaneous oxygen pressure <30 mm Hg on the treated leg). Patients were randomly assigned to either NV1FGF at 0·2 mg/mL or matching placebo (visually identical) in a 1:1 ratio. Randomisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country. Investigators, patients, and study teams were masked to treatment. Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1, 15, 29, and 43. The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00566657. 259 patients were assigned to NV1FGF and 266 to placebo. All 525 patients were analysed. The mean age was 70 years (range 50-92), 365 (70) were men, 280 (53) had diabetes, and 248 (47) had a history of coronary artery disease. The primary endpoint or components of the primary did not differ between treatment groups, with major amputation or death in 86 patients (33) in the placebo group, and 96 (36) in the active group (hazard ratio 1·11, 95 CI 0·83-1·49; p=0·48). No significant safety issues were recorded. TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death in patients with critical limb ischaemia. Thus, this group of patients remains a major therapeutic challenge for the clinician. Sanofi-Aventis, Paris, France. © 2011 Elsevier Ltd. Source

Taylor R.R.,University of Colorado at Denver | Hoffman K.L.,University of Colorado at Denver | Schniedewind B.,University of Colorado at Denver | Clavijo C.,University of Colorado at Denver | And 3 more authors.
Journal of Pharmaceutical and Biomedical Analysis

Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples.We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6. μm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction.The range of reliable response in plasma and CSF was 3.05-20,000ng/ml (r2>0.99) and 27.4-20,000ng/ml (r2>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen.DBS are a valid matrix for acetaminophen pharmacokinetic studies. © 2013 Elsevier B.V. Source

Nehler M.R.,University of Colorado at Denver | Duval S.,University of Minnesota | Diao L.,CPC Clinical Research | Annex B.H.,University of Virginia | And 4 more authors.
Journal of Vascular Surgery

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. Copyright © 2014 by the Society for Vascular Surgery. Source

Yeung E.,U.S. National Institutes of Health | Krantz M.J.,Denver Health Medical Center | Krantz M.J.,Aurora University | Krantz M.J.,CPC Clinical Research | And 5 more authors.
Annals of Noninvasive Electrocardiology

Background Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) are associated with persistent symptoms and ventricular dysfunction. Approved medical therapies have undesirable side effects and proarrhythmic liability. Ranolazine is a novel antianginal that preferentially blocks the late sodium current. This current is enhanced among patients with cardiomyopathy; a promising target population for ranolazine. The utility of ranolazine, however, for ventricular arrhythmia suppression has not been well characterized. Objectives We sought to determine the effectiveness of ranolazine for suppression of ventricular ectopy, particularly in the setting of ventricular dysfunction where enhanced efficacy might be expected. Methods We retrospectively evaluated eight patients (six with >10% PVC burden and two with incessant VT) treated with ranolazine. Arrhythmia frequency was evaluated by continuous monitoring before and after ranolazine initiation and the correlation between ventricular function and reduction in PVC burden was assessed. Results Among six patients with PVCs, ranolazine resulted in a median decrease in PVC burden of 60.2% (P = 0.06). In two cases of apparent PVC-induced cardiomyopathy, normalization of ventricular function was observed. A significant, inverse correlation between baseline ejection fraction and percentage reduction in PVCs was observed (rho = -0.89, P = 0.02). In two patients treated for incessant VT despite Class III antiarrhythmic therapy, ranolazine eliminated VT and prevented recurrent defibrillator therapy. Conclusions Although not approved for this indication, ranolazine appears effective for symptomatic ventricular arrhythmias. The reduction in PVC burden was greatest among individuals with reduced ventricular function, perhaps due to enhanced late sodium current associated with cardiomyopathy. A confirmatory prospective trial seems warranted. © 2014 Wiley Periodicals, Inc. Source

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