Jes Sanddal Lindholt

Screening for abdominal aortic aneurysms: single centre randomised controlled trial

Abstract Objective To determine whether screening Danish men aged 65 or more for abdominal aortic aneurysms reduces mortality. Design Single centre randomised controlled trial. Setting All five hospitals in Viborg County, Denmark. Participants All 12 639 men born during 1921-33 and living in Viborg County. In 1994 we included men born 1921-9 (64-73 years). We also included men who became 65 during 1995-8. Interventions Men were randomised to the intervention group (screening by abdominal ultrasonography) or control group. Participants with an abdominal aortic aneurysm > 5 cm were referred for surgical evaluation, and those with smaller aneurysms were offered annual scans. Outcome measures Specific mortality due to abdominal aortic aneurysm, overall mortality, and number of planned and emergency operations for abdominal aortic aneurysms. Results 4860 of 6333 men were screened (attendance rate 76.6%). 191 (4.0% of those screened) had abdominal aortic aneurysms. The mean follow-up time was 52 months. The screened group underwent 75% (95% confidence interval 51% to 91%) fewer emergency operations than the control group. Deaths due to abdominal aortic aneurysms occurred in nine patients in the screened group and 27 in the control group. The number needed to screen to save one life was 352. Specific mortality was significantly reduced by 67% (29% to 84%). Mortality due to non-abdominal aortic aneurysms was non-significantly reduced by 8%. The benefits of screening may increase with time. Conclusion Mass screening for abdominal aortic aneurysms in Danish men aged 65 or more reduces mortality.

Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans

Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus–circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications.

Critical Role of Mast Cell Chymase in Mouse Abdominal Aortic Aneurysm Formation

Background— Mast cell chymase may participate in the pathogenesis of human abdominal aortic aneurysm (AAA), yet a direct contribution of this serine protease to AAA formation remains unknown. Methods and Results— Human AAA lesions had high numbers of chymase-immunoreactive mast cells. Serum chymase level correlated with AAA growth rate (P=0.009) in a prospective clinical study. In experimental AAA produced by aortic elastase perfusion in wild-type (WT) mice or those deficient in the chymase ortholog mouse mast cell protease-4 (mMCP-4) or deficient in mMCP-5 (Mcpt4−/−, Mcpt5−/−), Mcpt4−/− but not Mcpt5−/− had reduced AAA formation 14 days after elastase perfusion. Even 8 weeks after perfusion, aortic expansion in Mcpt4−/− mice fell by 50% compared with that of the WT mice (P=0.0003). AAA lesions in Mcpt4−/− mice had fewer inflammatory cells and less apoptosis, angiogenesis, and elastin fragmentation than those of WT mice. Although KitW-sh/W-sh mice had protection from AAA formation, reconstitution with mast cells from WT mice, but not those from Mcpt4−/− mice, partially restored the AAA phenotype. Mechanistic studies suggested that mMCP-4 regulates expression and activation of cysteine protease cathepsins, elastin degradation, angiogenesis, and vascular cell apoptosis. Conclusions— High chymase-positive mast cell content in human AAA lesions, greatly reduced AAA formation in Mcpt4−/− mice, and significant correlation of serum chymase levels with human AAA expansion rate suggests participation of mast cell chymase in the progression of human and mouse AAA.

Long-term benefit and cost-effectiveness analysis of screening for abdominal aortic aneurysms from a randomized controlled trial

The aim was to estimate long‐term mortality benefits and cost‐effectiveness of screening for abdominal aortic aneurysm (AAA) in men aged 64–73 years.

Screening for Abdominal Aortic Aneurysm Reduces Overall Mortality in Men: A Meta-analysis of the Mid- and Long-term Effects of Screening for Abdominal Aortic Aneurysms

BACKGROUND Four randomised controlled trials of screening older men for abdominal aortic aneurysms (AAA) have been completed. A meta-analysis was performed to examine the pooled effects of screening on both mid- and long-term AAA-related and total mortality, and operations for AAA. METHODS Pooled mid-term (3(1/2)-5 years) and long term (7-15 years) effects were calculated as odds-ratios (ORs) with 95% confidence intervals in fixed effect models. Long-term data from the West Australian trial were limited to all-caurse deaths. Heterogeneity between the studies was assessed by the chi(2)-test. In cases of heterogeneity, random effect models were used. RESULTS The pooled mid-term analysis showed the offer of screening caused a significant reduction in AAA related mortality (OR=0.56, 95% C.I. 0.44,0.72), and emergency operations (OR=0.55, 95% C.I.: 0.39; 0.76), while the number of elective operations increased significantly (OR=3.27, 95% C.I.: 2.14; 5.00). Overall mortality was reduced, but not significantly (OR=0.94, 95% C.I.: 0.86; 1.02). The long-term results also showed a significant reduction in AAA-related mortality (OR=0.47, 95% C.I.: 0.25; 0.90), overall mortality (OR=0.94, 95% C.I.: 0.92; 0.97) and emergency operations (OR=0.48, 95% C.I.: 0.28; 0.83), while the number of elective operations increased significantly (OR=2.81, 95% C.I.: 2.40; 3.30). CONCLUSION Population screening for AAA reduces AAA-related and overall mortality, however local differences may exits which could influence cost effectiveness of screening.

Drug Therapy for Improving Walking Distance in Intermittent Claudication: A Systematic Review and Meta-analysis of Robust Randomised Controlled Studies

OBJECTIVES To evaluate the efficacy of pharmacological interventions in improving walking capacity and health-related quality of life for people with intermittent claudication. DATASOURCES: We searched Medline, EMBASE, Cochrane library and relevant websites for studies published from the start of the databases to February 2009. In addition, reference lists were manually searched. REVIEW METHODS Based upon a power calculation, only robust (n>56), peer-reviewed, double-blinded, randomised and placebo-controlled trials were included. The main outcomes evaluated were maximal walking distance (MWD) and pain-free walking distance on a treadmill. Random models were used in the statistical analysis, and chi-square test were used to test for heterogeneity. RESULTS Among 220 trials, only 43 trials fulfilled the quality criteria. Treatment periods, follow-up and treadmill protocols varied substantially. Vasodilator agents and phosphodiesterase inhibitors show robust significant results compared to placebo, but the improvements in MWD are modest. The highest benefit was caused by lipid-lowering agents, which in mean gained above 160 m in MWD, while the other agents only improved MWD about 50 m. CONCLUSION Several drugs have shown to improve MWD, but with limited benefits. Statins seem to be the most efficient drug at the moment.

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.

OBJECTIVES The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. METHODS The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). RESULTS LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). CONCLUSIONS LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

Low-Dose Aspirin May Prevent Growth and Later Surgical Repair of Medium-Sized Abdominal Aortic Aneurysms

Experimental data suggest that aspirin-induced platelet inhibition may retard growth of abdominal aortic aneurysms. In this article, whether low-dose aspirin use is associated with reduced aneurysm progression and subsequent need for surgery is examined. In this observational cohort study within a screening trial, 148 patients with small aneurysms (maximum diameter 30-48 mm) annually are followed. Patients were referred for surgery when the aneurysmal diameter exceeded 50 mm. Median follow-up time was 6.6 years. Among patients whose abdominal aortic aneurysms were initially 40 to 49 mm in size, the abdominal aortic aneurysm expansion rate for low-dose aspirin users compared with nonusers was 2.92 mm/y versus 5.18 mm/y (difference 2.27 mm/y, 95% CI, 0.42-4.11). No difference in expansion rates and risk ratios for operative repair was found for patients with abdominal aortic aneurysms <40 mm. For medium-sized abdominal aortic aneurysms, low-dose aspirin may prevent abdominal aortic aneurysm growth and need for subsequent repair, but residual confounding cannot be excluded.

Natural history of abdominal aortic aneurysm with and without coexisting chronic obstructive pulmonary disease

PURPOSE To study the relation between abdominal aortic aneurysms and chronical obstructive pulmonary disease (COPD), in particular the suggested common elastin degradation caused by elastase and smoking. METHODS A cross-sectional population study and a prospective cohort study of small abdominal aortic aneurysms was performed in a community setting. All previous diagnoses recorded in a hospital computer database were received for 4404 men 65 to 73 years of age who had been invited to a population screening for abdominal aortic aneurysm. One hundred forty-one men had AAA (4.2%). They were asked to participate in an interview, a clinical examination, and collection of blood sample. Men with an abdominal aortic aneurysm 3 to 5 cm in diameter were offered annual ultrasound scans to check for expansion. RESULTS Among patients with COPD 7.7% had abdominal aortic aneurysms (crude odds ratio=2.05). The adjusted odds ratio, however, was only 1.59 after adjustment for coexisting diseases associated with abdominal aortic aneurysm (P=.13). The mean annual expansion was 2.74 mm per year among patients with COPD, 2.72 among patients without COPD, and 4.7 mm among patients who used oral steroids compared with 2.6 among patients who did not use steroids (P < .05). Concentration of serum elastin peptide and plasma elastase-alpha1-antitrypsin complexes correlated negatively with forced expiratory volume in the first second (FEV1) among patients with COPD. However, multivariate regression analysis showed that concentration of serum elastin peptide, therapy with beta-agonists, and FEV1 correlated positively with degree of expansion but that concentration of plasma elastase-alpha1-antitrypsin complexes and serum alpha1-antitrypsin did not influence expansion, suggesting that elastase plays an important role in the pathogenesis of COPD but not of abdominal aortic aneurysm. CONCLUSION The high prevalence of abdominal aortic aneurysm among patients with COPD is more likely to be caused by medication and coexisting diseases rather than a common pathway of pathogenesis.

Development and validation of QoL5 for clinical databases. A short, global and generic questionnaire based on an integrated theory of the quality of life

OBJECTIVE To develop and validate a short, global, and generic quality of life (QoL) questionnaire for clinical databases. The construct validity and item weighting of existing questionnaires are increasingly questioned. DESIGN Cross-sectional population study. SUBJECT 2460 Danes aged 18-88 years, randomly selected through the Danish Central Person Registry. INTERVENTIONS Ten questions covering the spectrum of the integrative theory of QoL together with the Nottingham Health Profile (NHP), Sickness Impact Profile (SIP), and self-estimated QoL questionnaire were sent by mail. A test-retest study of 50 people was conducted after one month. MAIN OUTCOME MEASURES Construct and criterion validity, reliability, and sensitivity. RESULTS QoL5 correlations with SIP, NHP, Self-estimated QoL were 0.37, 0.52, and 0.76, respectively, and increased among those who were unwell. Cronbachs alpha was 0.69. All correlations in Siegels test were over 0.6, and the test-retest correlation was 0.82. Only 12 respondents in each group will be needed to detect a difference of 10% in the QoL score between two groups. CONCLUSIONS QoL5 is a valid global and generic QoL measurement. Despite the use of only five questions, internal consistency and sensitivity were acceptable. So a relevant and practical outcome measurement is available for clinical databases.