Long-term cost-effectiveness analysis of endovascular versus open repair for abdominal aortic aneurysm based on four randomized clinical trials.

BACKGROUND: A number of published economic evaluations of elective endovascular aneurysm repair (EVAR) versus open repair for abdominal aortic aneurysm (AAA) have come to differing conclusions about whether EVAR is cost-effective. This paper reviews the current evidence base and presents up-to-date cost-effectiveness analyses in the light of results of four randomized clinical trials: EVAR-1, DREAM, OVER and ACE. METHODS: Markov models were used to estimate lifetime costs from a UK perspective and quality-adjusted life-years (QALYs) based on the results of each of the four trials. The outcomes included in the model were: procedure costs, surveillance costs, reintervention costs, health-related quality of life, aneurysm-related mortality and other-cause mortality. Alternative scenarios about complications, reinterventions and deaths beyond the trial were explored. RESULTS: Models based on the results of the EVAR-1, DREAM or ACE trials did not find EVAR to be cost-effective at thresholds used in the UK (up to £30,000 per QALY). EVAR seemed cost-effective according to models based on the OVER trial. These results seemed robust to alternative model scenarios about events beyond the trial intervals. CONCLUSION: These analyses did not find that EVAR is cost-effective compared with open repair in the long term in trials conducted in European centres. EVAR did appear to be cost-effective based on the OVER trial, conducted in the USA. Caution must be exercised when transferring the results of economic evaluations from one country to another.

Vitamin D and cardiovascular disease.

Vitamin D plays a classical hormonal role in skeletal health by regulating calcium and phosphorus metabolism. Vitamin D metabolites also have physiological functions in nonskeletal tissues, where local synthesis influences regulatory pathways via paracrine and autocrine mechanisms. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D, binds to the vitamin D receptor that regulates numerous genes involved in fundamental processes of potential relevance to cardiovascular disease, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, and cell adhesion. Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin-angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations.

The UK EndoVascular Aneurysm Repair (EVAR) trials: randomised trials of EVAR versus standard therapy.

OBJECTIVE: To assess the efficacy of endovascular aneurysm repair (EVAR) against standard alternative management in patients with large abdominal aortic aneurysm (AAA). DESIGN: Two national, multicentre randomised trials - EVAR trials 1 and 2. SETTING: Patients were recruited from 38 out of 41 eligible UK hospitals. PARTICIPANTS: Men and women aged at least 60 years, with an AAA measuring at least 5.5 cm on a computerised tomography scan that was regarded as anatomically suitable for EVAR, were assessed for fitness for open repair. Patients considered fit were randomised to EVAR or open repair in EVAR trial 1 and patients considered unfit were randomised to EVAR or no intervention in EVAR trial 2. INTERVENTIONS: EVAR, open repair or no intervention. MAIN OUTCOME MEASURES: The primary outcome was mortality (operative, all-cause and AAA related). Patients were flagged at the UK Office for National Statistics with centrally coded death certificates assessed by an Endpoints Committee. Power calculations based upon mortality indicated that 900 and 280 patients were required for EVAR trials 1 and 2, respectively. Secondary outcomes were graft-related complications and reinterventions, adverse events, renal function, health-related quality of life and costs. Cost-effectiveness analyses were performed for both trials. RESULTS: Recruitment occurred between 1 September 1999 and 31 August 2004, with targets exceeded in both trials: 1252 randomised into EVAR trial 1 (626 to EVAR) and 404 randomised into EVAR trial 2 (197 to EVAR). Follow-up closed in December 2009 with very little loss to follow-up (1%). In EVAR trial 1, 30-day operative mortalities were 1.8% and 4.3% in the EVAR and open-repair groups, respectively: adjusted odds ratio 0.39 [95% confidence interval (CI) 0.18 to 0.87], p = 0.02. During a total of 6904 person-years of follow-up, 524 deaths occurred (76 AAA related). Overall, there was no significant difference between the groups in terms of all-cause mortality: adjusted hazard ratio (HR) 1.03 (95% CI 0.86 to 1.23), p = 0.72. The EVAR group did demonstrate an early advantage in terms of AAA-related mortality, which was sustained for the first few years, but lost by the end of the study, primarily due to fatal endograft ruptures: adjusted HR 0.92 (95% CI 0.57 to 1.49), p = 0.73. The EVAR procedure was more expensive than open repair (mean difference £1177) and not found to be cost-effective, but the model was sensitive to alternative assumptions. In EVAR trial 2, during a total of 1413 person-years of follow-up, a total of 305 deaths occurred (78 AAA related). The 30-day operative mortality was 7.3% in the EVAR group. However, this group later demonstrated a significant advantage in terms of AAA-related mortality, but this became apparent only after 4 years: overall adjusted HR 0.53 (95% CI 0.32 to 0.89), p = 0.02. Sadly, this advantage did not result in any benefit in terms of all-cause mortality: adjusted HR 0.99 (95% CI 0.78 to 1.27), p = 0.97. Overall, EVAR was more expensive than no intervention (mean difference £10,222) and not found to be cost-effective. CONCLUSIONS: EVAR offers a clear operative mortality benefit over open repair in patients fit for both procedures, but this early benefit is not translated into a long-term survival advantage. Among patients unfit for open repair, EVAR is associated with a significant long-term reduction in AAA-related mortality but this does not appear to influence all-cause mortality. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 55703451. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 9. See the HTA programme website for further project information.

Enzymic characteristics of fat globule membranes from bovine colostrum and bovine milk.

Fat globule membranes have been isolated from bovine colostrum and bovine milk by the dispersion of the fat in sucrose solutions at 4 degrees C and fractionation by centrifugation through discontinuous sucrose gradients. The morphology and enzymic characteristics of the separated fractions were examined. Fractions comprising a large proportion of the total extracted membrane were thus obtained having high levels of the Golgi marker enzymes UDP-galactose N-acetylglucosamine beta-4-galactosyltransferase and thiamine pyrophosphatase. A membrane-derived form of the galactosyltransferase has been solubilized from fat and purified to homogeneity. This enzyme is larger in molecular weight than previously studied soluble galactosyltransferases, but resembles in size the galactosyltransferase of lactating mammary Golgi membranes. In contrast, when fat globule membranes were prepared by traditional procedures, which involved washing the fat at higher temperatures, before extraction, galactosyltransferase was not present in the membranes, having been released into supernatant fractions, When the enzyme released by this procedure was partially purified and examined by gel filtration, it was found to be of a degraded form resembling in size the soluble galactosyltransferase of milk. The release is therefore attributed to the action of proteolytic enzymes. Our observations contrast with previous biochemical studies which suggested that Golgi membranes do not contribute to the milk fat globule membrane. They are, however, consistent with electron microscope studies of the fat secretion process, which indicate that secretory vesicle membranes, derived from the Golgi apparatus, may provide a large proportion of the fat globule membrane.

Affinity labeling of bovine colostrum galactosyltransferase with a uridine 5'-diphosphate derivative.

The dialdehyde produced by the periodate cleavage of the ribose moiety of uridine 5'-diphosphate (UDP) has been used as an affinity label for the UDP-galactose/UDP binding site of galactosyltransferase from bovine colostrum. This derivative causes progressive inactivation of galactosyltransferase at a rate dependent on its concentration, and under certain conditions is a competitive inhibitor with respect to UDP-galactose. The substrate UDP-galactose protects the enzyme from inactivation. The inactivation is also dependent on Mn2+ concentration in a range that implies that the binding of Mn2+ at site I is a prerequisite for the binding of the UDP derivative. The inactivation can be progressively reversed by nitrogenous bases, or stabilized by KBH4 reduction, which is consistent with the hypothesis that a Schiff base has formed with a lysine residue. Galactosyltransferase was inactivated with a [3H]UDP derivative and the predominant labeled peptide, from thermolysin digestion, isolated and characterized as: Ser-Gly-Lys-UDP.

Metal ion activation of galactosyltransferase.

Galactosyltransferase, which functions as the catalytic component of lactose synthase and in the glycosylation of glycoproteins, has been previously reported to have an absolute dependence on Mn2+ for activity, with a Kd for Mn2+ (10(-3) M) 2 to 3 orders of magnitude greater than the physiological range of Mn2+ concentrations (v 10(-6) M). Reinvestigation of the metal ion dependence of this enzyme has shown that Zn2+, Cd2+, Fe2+, Co2+, and Pr3+ also produce activation, although with lower activities at saturation than that attained with Mn2+. Velocity against metal ion concentration curves for all metals, including Mn2+, are sigmoid, suggesting the presence of two or more activating metal binding sites on the enzyme. The presence of two sites is confirmed by studies using both Mn2+ and Ca2+. While galactosyltransferase is inactive in the presence of Ca2+ alone, at low concentrations of Mn2+ (10(-5) M), enzyme activity is stimulated by Ca2+. A more detailed investigation by steady state kinetics has revealed that there is a tight binding site for Mn2+ (site I: Kd of 2 X 10(-6) M) from which Ca2+ is excluded, and a site at which Ca2+ can replace Mn2+ (site II: Kd for Ca2+ of 1.76 X 10(-3) M), to which metal binding has a specific synergistic effect on UDP-galactose binding, possibly as a result of the formation of an enzyme-Ca2+-UDP-galactose bridge complex. The site I Mn2+, site II Ca2+-activated enzyme has a maximum velocity similar to that of the Mn2+-activated enzyme, and is the enzyme form that must act in lactose synthesis in vivo. A trypsin-degraded form of galactose transferase (galactosyltransferase-T) (Powell, J.T., and Brew, K. (1974) Eur. J. Biochem. 48, 217-228) appears to lack site I and is activated by Ca2+ in the absence of Mn2+.

On the interaction of alpha-lactalbumin and galactosyltransferase during lactose synthesis.

The regulatory effect of alpha-lactalbumin in the lactose synthase system has been ascribed to its reversible association with a complex of galactosyltransferase with Mn2+ and UDP-galactose, prior to the binding of monosaccharides; the resulting complex has a higher affinity for various monosaccharides. Two steps in the postulated catalytic cycle have been investigated; UDP-galactose binding to enzyme-Mn2+ by equilibrium dialysis and alpha-lactalbumin binding to enzyme-Mn2+-UDP-galactose by sedimentation velocity and kinetics. There is a single binding site for UDP-galactose on the enzyme-Mn2+ complex, and the dissociation constant for UDP-galactose from enzyme-Mn2+-UDP-galactose was found to be 72 muM at 37 degrees. The formation of a complex between galactosyltransferase and alpha-lactalbumin in the presence of Mn2+ and UDP-galactose was observed as an increase in sedimentation coefficient of enzyme activity So20,w from 3.25 +/- 0.03 in the absence of alpha-lactalbumin to 4.22 +/- 0.03 at saturating concentrations of alpha-lactalbumin, a value closely similar to that of a cross-linked 1:1 complex of the proteins under the same conditions (4.35 +/- 0.03). No interaction was observed in the absence of substrates or with UDP-galactose and EDTA. From the ultracentrifuge data and steady state kinetics, dissociation constants for alpha-lactalbumin from the enzyme-Mn2+-UDP-galactose-alpha-lactalbumin complex were determined at several temperatures and salt concentrations. These showed good internal agreement. The free energy change delta G degrees for the association of the two proteins is calculated, and the results are discussed in relation to the nature of the interaction.