A Randomised Controlled Trial of Consent Procedures for the Use of Residual Tissues for Medical Research: Preferences of and Implications for Patients, Research and Clinical Practice.

BACKGROUND: Despite much debate, there is little evidence on consequences of consent procedures for residual tissue use. Here, we investigated these consequences for the availability of residual tissue for medical research, clinical practice, and patient informedness. METHODS: We conducted a randomised clinical trial with three arms in six hospitals. Participants, patients from whom tissue had been removed for diagnosis or treatment, were randomised to one of three arms: informed consent, an opt-out procedure with active information provision (opt-out plus), and an opt-out procedure without active information provision. Participants received a questionnaire six weeks post-intervention; a subsample of respondents was interviewed. Health care providers completed a pre- and post-intervention questionnaire. We assessed percentage of residual tissue samples available for medical research, and patient and health care provider satisfaction and preference. Health care providers and outcome assessors could not be blinded. RESULTS: We randomised 1,319 patients, 440 in the informed consent, 434 in the opt-out plus, and 445 in the opt-out arm; respectively 60.7%, 100%, and 99.8% of patients' tissue samples could be used for medical research. Of the questionnaire respondents (N = 224, 207, and 214 in the informed consent, opt-out plus, and opt-out arms), 71%, 69%, and 31%, respectively, indicated being (very) well informed. By questionnaire, the majority (53%) indicated a preference for informed consent, whereas by interview, most indicated a preference for opt-out plus (37%). Health care providers (N = 35) were more likely to be (very) satisfied with opt-out plus than with informed consent (p = 0.002) or opt-out (p = 0.039); the majority (66%) preferred opt-out plus. CONCLUSION: We conclude that opt-out with information (opt-out plus) is the best choice to balance the consequences for medical research, patients, and clinical practice, and is therefore the most optimal consent procedure for residual tissue use in Dutch hospitals. TRIAL REGISTRATION: Dutch Trial Register NTR2982.

Screening for aneurysm of the abdominal aorta: prevalence in patients with stroke or TIA.

BACKGROUND AND PURPOSE: Population screening for aneurysms of the abdominal aorta (AAA) is still not implemented in any country, despite proven benefit both in decreased mortality and in cost effectiveness. Detecting a subpopulation with higher prevalence of AAA may alter this situation. METHODS: Between 2002 and 2005, all patients with a stroke or transient ischaemic attack (TIA) admitted to the department of Neurology of a community-based hospital were classified according to the Toast criteria and enrolled in a prospective study to assess the diameter of the abdominal aorta. The diameter was assessed by ultrasonography. A written questionnaire and blood tests were used to assess risk factors. RESULTS: The prevalence of AAA amongst the 499 screened patients in the study was 5.8% [95% confidence interval (CI) 5.6-6.0%]. Of the risk factors or Toast criteria, only male gender and age over 59 years correlated significantly with AAA. In the subgroup of 235 men aged over 59 years, the prevalence of AAA was 11.1% (95% CI 10.4-11.8%). CONCLUSION: The prevalence of AAA in men over 59 years of age presenting with a stroke or TIA is nearly twofold increased (11.1%) compared with all patients. Therefore, screening for AAA in this subgroup of patients seems beneficial. However, further studies are needed to confirm this finding and to explore the clinical benefit and cost effectiveness.

Effect of homocysteine-lowering treatment with folic acid plus vitamin B on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial.

BACKGROUND: A high plasma homocysteine concentration is an independent risk factor for large and possibly small vessel disease. We investigated the effects of homocysteine-lowering treatment with folic acid plus vitamin B(6) on markers of cerebrovascular atherosclerosis and cerebral microangiopathy. MATERIALS AND METHODS: Using 158 healthy siblings (mean age 46.0 +/- 7.6 years) of patients with premature atherosclerotic disease, we performed a randomized, placebo-controlled trial using 5 mg of folic acid plus 250 mg of vitamin B(6) daily (n = 78) or placebo medication (n = 80). Participants were followed for 2 years with magnetic resonance angiography (MRA) (carotid stenosis; carotid and/or vertebral elongation) and magnetic resonance imaging (MRI) (white matter abnormalities; cerebral atrophy). RESULTS: Seventeen (10.8%) subjects refused MRA/MRI owing to claustrophobia and were excluded. From the remaining 141 participants, 68 received vitamin and 73 received placebo medication [42 (61.8%) and 48 (65.8%) had postmethionine hyperhomocysteinaemia, respectively]. Twenty-four participants (15.2%; 10 in the treatment and 14 in the placebo group) did not complete both years of the trial. Vitamin treatment was associated with an increase in plasma folate (13-fold vs. placebo; P < 0.001) and vitamin B(6) (8.8-fold; P < 0.001). Fasting and postmethionine total homocysteine concentrations decreased 38.7% (95% CI, 27.4-50.0) and 29.1% (95% CI, 19.2-39.0) vs. placebo (all P < 0.001). During follow up six individuals in the vitamin-treated and 11 in the placebo-treated group deteriorated in their outcome measurements. Vitamin treatment, as compared with placebo, was associated with nonsignificantly improved outcomes on both MRA and MRI outcome measurements (odds ratio 0.48; 95% CI 0.17-1.41; P = 0.18 and 0.48; CI 0.14-1.60; P = 0.23, respectively). CONCLUSIONS: These results could indicate a possible favourable effect of homocysteine-lowering treatment on cerebrovascular atherosclerosis and cerebral microangiopathy among healthy siblings of patients with premature atherosclerotic disease, but larger trials are required to establish this with certainty.

Homocysteine-lowering treatment with folic acid plus vitamin B6 lowers urinary albumin excretion but not plasma markers of endothelial function or C-reactive protein: further analysis of secondary end-points of a randomized clinical trial.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for atherosclerosis and is thought to induce its effects through causing endothelial dysfunction. We studied the effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on urinary and plasma markers of endothelial function, and on plasma C-reactive protein, a marker of chronic inflammation. DESIGN: We performed a placebo-controlled 2-year trial among 158 healthy siblings of patients with premature atherosclerotic disease to determine the effect of daily folic acid (5 mg) plus vitamin B6 (250 mg) treatment as compared with placebo medication (n = 80) on markers of endothelial function (urinary albumin-to-creatinine ratio and plasma concentrations of soluble E-selectin, soluble vascular cell adhesion molecule-1, von Willebrand factor, tissue-type plasminogen activator and plasminogen activator inhibitor-1) and inflammation (C-reactive protein). Outcome variables were assessed at baseline and after 1 and 2 years of treatment. RESULTS: Fasting homocysteine concentrations ( micromol L-1) at baseline and after treatment were 14.7 +/- 8.2 and 7.4 +/- 1.9 in the vitamin and 14.7 +/- 8.8 and 12.0 +/- 5.4 for the placebo group, respectively. Vitamin treatment was associated with a decreased urinary albumin-to-creatinine ratio at follow up [regression coefficient (beta) -0.20 mg mmol-1 (CI: -0.43-0.03); P = 0.09]. After adjustment for age, sex, baseline concentrations of postmethionine total homocysteine plus the baseline albumin-to-creatinine ratio, the beta was -0.23 mg mmol-1 (CI: -0.43 to -0.02; P = 0.03), which amounts to a decrease of approximately 20%. There was no apparent effect of vitamin treatment on the other markers. CONCLUSIONS: Homocysteine-lowering vitamin treatment in healthy siblings of patients with premature atherosclerotic disease is associated with a decreased urinary albumin-to-creatinine ratio, but not with other markers of endothelial dysfunction, or in plasma C-reactive protein. The clinical significance of these findings remains to be determined.

Continuing expansion of internal iliac artery aneurysms after surgical exclusion of the inflow. A report of two cases.

Two patients with continuing expansion of an internal iliac artery aneurysm following earlier repair of an aortoiliac aneurysm are described. At the primary operation, inflow to small internal iliac aneurysms had been interrupted by simple proximal ligation only. During follow-up, however, increasing diameter of the by CT-angiography completely thrombosed internal iliac aneurysms required re-operation. The observation of continuing growth of thrombosed internal iliac artery aneurysms following proximal ligation emphasises the danger of persistent collateral circulation and supports the concept of endotension in the absence of endoleak following endovascular AAA repair.

Decreased smooth muscle cell/extracellular matrix ratio of media of femoral artery in patients with atherosclerosis and hyperhomocysteinemia.

The aim of this study was to determine whether the morphology of the muscular femoral artery in patients with atherosclerosis and hyperhomocysteinemia differs from that of atherosclerotic vessels from patients with normal homocysteine levels. Whole-vessel biopsies of the superficial femoral artery were taken from patients with symptomatic atherosclerotic disease with and without hyperhomocysteinemia and from patients without atherosclerosis from traumatic amputations. The morphology of these specimens was studied qualitatively by light and electron microscopy and quantitatively by light microscopy in combination with a video overlay system. Atherosclerotic lesions in patients with hyperhomocysteinemia were morphologically similar to those in patients with normal homocysteine levels, except for a significantly decreased smooth muscle cell/extracellular matrix ratio of the media in hyperhomocysteinemic patients (P=0.02 versus normohomocysteinemic atherosclerotic group and P=0.001 versus group without a history of cardiovascular disease). Hyperhomocysteinemia is associated with a significant decrease of the smooth muscle cell/extracellular matrix ratio of the media of muscular femoral arteries without significant changes in medial thickness. Further investigations should concentrate on the cause of this newly discovered phenomenon and its impact on vascular compliance.

Percutaneous duplex-guided thrombin injection for treatment of iatrogenic femoral artery pseudoaneurysms.

OBJECTIVES: to evaluate the feasibility of treatment of post-catheterisation pseudoaneurysms with duplex-guided thrombin injection. TECHNIQUE: the technique of duplex-guided injection of thrombin in post-catheterisation pseudoaneurysms of the femoral artery is described and illustrated. RESULTS: between December 1998 and October 1999, eight post-catheterisation pseudoaneurysms of the femoral artery were successfully thrombosed with thrombin injection. One patient developed a new pseudoaneurysm within 6 hours and this was also successfully treated with thrombin. Follow-up duplex-scanning at 3 months revealed no recurrences. No other adverse events occurred. CONCLUSIONS: this initial experience suggests that duplex-guided thrombin injection in the treatment of post-catheterisation pseudo-aneurysms is feasible and safe.

Normohomocysteinaemia and vitamin-treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature atherothrombotic cerebrovascular disease. A prospective cohort study.

BACKGROUND: Mild hyperhomocysteinaemia (HHC) is associated with an increased risk of premature atherothrombotic cerebrovascular disease. We investigated the clinical efficacy with regard to the incidence of cardiovascular events of treatment of mild HHC with vitamin B(6) plus folic acid. METHODS: We studied 224 consecutive patients with clinically manifest atherothrombotic cerebrovascular disease with onset before the age of 56. Follow-up was obtained in 203 (90.6%) patients. At baseline, 52 (25.6%) were hyperhomocysteinaemic after methionine loading and started treatment with vitamin B(6) (250 mg) plus folic acid (5 mg); 151 (74.4%) were normohomocysteinaemic (reference group). RESULTS: During follow-up (median 57 months), 31 (20.5%) of the normo- and 11 (21.2%) of the hyperhomocysteinaemic patients had a new cardiovascular event. The crude incidence rate per person-year for any cardiovascular event was similar in both groups (0.043 [CI, 0.029-0.057] in the normo- vs. 0.045 [CI, 0.021-0. 069] in the hyperhomocysteinaemic group). Multivariate Cox-regression analyses showed that hypertension and cholesterol levels were associated with an increased risk of new cardiovascular events in the total group [relative risk [RR] (yes vs. no), 7.4 (3. 4-16.0) and RR (per 1 mmol/l), 1.9 (CI, 1.4-2.7)]. The adjusted RR for new cardiovascular events in the hyper- as compared to the normohomocysteinaemic patients was 0.96 (CI, 0.48-1.92). CONCLUSION: These data are consistent with a protective effect of treatment with vitamin B(6) plus folic acid in patients with premature atherothrombotic cerebrovascular disease and post-methionine HHC.

[Radiation-induced arterial disease]. / Door bestraling geïnduceerd arterieel vaatlijden.

Arterial occlusive disease developed after radiation therapy in three patients: a woman aged 56 had a sensation of heaviness in her right arm and bluish-black discolorations of fingers 3 years after radiation therapy for breast carcinoma, and two men aged 46 and 45 years had intermittent claudication 23 and 14 years, respectively, after radiation therapy for testicle malignancy. After creation of a bypass, the symptoms subsided. Radiation-induced arterial disease is a rare complication after radiotherapy and usually presents after a latent period of several years. Arterial lesions induced by radiotherapy may be distinguished from atherosclerotic lesions by their atypical localization, limited to the irradiated sites, and occurrence at an earlier age. Symptoms may be masked by pain, limitation of motion, nerve root damage and lymphoedema and may therefore not always be recognized. Indications for treatment are identical to those for atherosclerotic occlusive disease, but due to increased risk of restenosis, rethrombosis and graft infection, percutaneous transluminal angioplasty (with or without stent), endarterectomy or venous bypass surgery should be preferred to prosthetic bypass material.

Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial.

BACKGROUND: A high plasma homocysteine concentration is associated with increased risk of atherothrombotic disease. We investigated the effects of homocysteine-lowering treatment (folic acid plus vitamin B6) on markers of subclinical atherosclerosis among healthy siblings of patients with premature atherothrombotic disease. METHODS: We did a randomised, placebo-controlled trial among 158 healthy siblings of 167 patients with premature atherothrombotic disease. 80 were assigned placebo and 78 were assigned 5 mg folic acid and 250 mg vitamin B6 daily for 2 years. The primary endpoint was the development or progression of subclinical atherosclerosis as estimated from exercise electrocardiography, the ankle-brachial pressure index, and carotid and femoral ultrasonography. FINDINGS: Ten participants in the treatment group, and 14 in the placebo group dropped out. Vitamin treatment, compared with placebo, was associated with a decrease in fasting homocysteine concentration (from 14.7 to 7.4 micromol/L vs from 14.7 to 12.0 micromol/L), and in postmethionine homocysteine concentration (from 64.9 to 34.9 micromol/L vs from 64.8 to 50.3 micromol/L). It was also associated with a decreased rate of abnormal exercise electrocardiography tests (odds ratio 0.40 [0.17-0.93]; p=0.035). There was no apparent effect of vitamin treatment on ankle-brachial pressure indices (0.87 [0.56-1.33]), or on carotid and peripheral-arterial outcome variables (1.02 [0.26-4.05] and 0.86 [0.47-1.59], respectively). INTERPRETATION: Homocysteine-lowering treatment with folic acid plus vitamin B6 in healthy siblings of patients with premature atherothrombotic disease is associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events.

Is semi-closed endarterectomy of the superficial femoral artery combined with a short venous bypass in case of insufficient venous material an acceptable alternative for limb-threatening ischemia?

BACKGROUND: The aim of this study was to analyse the results of infragenual arterial revascularisation using semiclosed endarterectomy of the superficial femoral artery combined with a short venous bypass in patients with critical leg ischemia and insufficient venous material for a straightforward femorocrural reconstruction. METHODS: From December 1990 through December 1998 thirty patients were studied (22 males and 8 females; mean age 65 years, range 31-92 years). The mean follow-up was 26 months (range 1-96 months). Cumulative primary patency and limb salvage rates were calculated according to life-table analysis. RESULTS: The cumulative primary patency was 60.3% at 1 year and 48.4% at 3 years. The limb salvage rate was 68.6% at 1 and at 3 years. CONCLUSIONS: In patients with limb-threatening ischemia and lack of venous material for a straightforward venous femorocrural bypass, semi-closed endarterectomy of the superficial femoral artery combined with a short popliteo-crural bypass provides a good alternative.

Is organ ischaemia a determinant of the outcome of operations for suprarenal aortic aneurysms?

OBJECTIVE: To find out if morbidity and mortality after thoracoabdominal approaches for suprarenal aortic aneurysms are related to the duration of organ ischaemia. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 72 operations for suprarenal aortic aneurysms. MAIN OUTCOME MEASURES: Duration of organ ischaemia, morbidity and mortality. RESULTS: There were 72 patients with 3 group A (Crawford type III), 10 group B (Crawford type IV), 37 group C (supracoeliac), and 22 group D (suprarenal) aneurysms. Median duration of ischaemia was 57 minutes for both the spinal cord and the mesenteric arteries, and 59 and 63 minutes for the right and left renal arteries, respectively. There were 52 major complications in 33 patients. Mesenteric ischaemia of longer than 60 minutes was associated with a significant higher complication rate (21/32, 66% compared with 13/40, 33%, p = 0.01). Spinal cord ischaemia of longer than 60 minutes was not associated with a significantly increased incidence of paraplegia (2/40 compared with 6/32, p = 0.13). CONCLUSIONS: We conclude that with surgery for suprarenal aneurysms a significant higher complication rate is noted with increased duration of mesenteric ischaemia.

Reconstruction of the supra-aortic trunks.

OBJECTIVE: To review our 10-year experience of reconstruction of the supra-aortic trunks. DESIGN: Retrospective study. SETTING: Teaching hospital, The Netherlands. SUBJECTS: 47 patients who required reconstruction of the supra-aortic trunks for stenotic or occlusive disease between April 1987 and May 1997. INTERVENTIONS: Right-sided bifurcation graft through a sternotomy (n = 25), left-sided thoracotomy (n = 1), and extra-anatomic bypass (n = 21). MAIN OUTCOME MEASURES: Morbidity, mortality, and long term patency. RESULTS: 3 patients died (6%); 7 (15%) developed major complications (leak from the brachiocephalic stump, n = 2, and acute occlusion of the bypass graft, n = 5) all of which were successfully treated by immediate reoperation; and 9 (19%) developed minor complications, all of which resolved within 3 months. The median follow up was 36 months (range 1-108), and the 3-year patency rate was 80%. No patient died during the follow up period, but a further 3 were lost to follow up. The remaining 41 were all assessed by duplex scanning or angiography, and 3 required further operation for recurrent symptoms; 33 remained completely free of symptoms. CONCLUSION: Symptomatic stenotic or occlusive lesions of the supra-aortic trunks can be treated with acceptable morbidity and mortality, giving long term benefit to patients.

Dobutamine-atropine stress echocardiography and clinical data for predicting late cardiac events in patients with suspected coronary artery disease.

PURPOSE: To compare the relative value of clinical variables with dobutamine-atropine stress echocardiography to predict cardiac events during long-term follow-up. Dobutamine stress echocardiography is increasingly used for the detection of coronary artery disease, but little is known of its prognostic value. PATIENTS AND METHODS: A total of 430 patients (310 men; mean age 61 years, range 22 to 90) were enrolled in the study. Patients were referred for chest pain complaints and were unable to perform an adequate exercise stress test. All patients underwent dobutamine-atropine stress test (incremental dobutamine infusion: 10 to 40 micrograms/kg/minute, continued with atropine 0.25 to 1 mg intravenously if necessary to achieve 85% of the age predicted maximal heart rate, without symptoms or signs of ischemia) and clinical cardiac evaluation. Follow-up was 17 +/- 5 months, with a minimum of 6 months; 3 patients were lost to follow-up. Cardiac events were defined as cardiac death, nonfatal myocardial infarction, and coronary revascularization. RESULTS: Seventy-nine cardiac events occurred in 76 patients: cardiac death (n = 11), nonfatal myocardial infarction (n = 18), and coronary revascularization (n = 50). By multivariate regression analysis, the prognostic value of the stress test in addition to common clinical variables was assessed. (1) Cardiac death was predicted by age greater than 70 years (odds ratio 5.6, 1.5 to 20) or new wall motion abnormalities in a study that is normal at rest (odds ratio 4.1, 1.1 to 15). (2) Death or myocardial infarction was predicted by a history of myocardial infarction (odds ratio 4.8, 1.8 to 13) or age greater than 70 years (odds ratio 2.3, 1.1 to 5.4), and the stress test outcome provided no additional information. (3) If all events were combined, only stress test results were prognostic: new wall motion abnormalities in a study that is normal at rest (odds ratio 3.1, 1.9 to 5.1), wall motion abnormalities at rest (wall motion score at rest > or = 1.12) (odds ratio 2.5, 1.4 to 4.0), or any new wall motion abnormalities during stress (odds ratio 2.0, 1.4 to 3.8). The positive predictive value of any new wall motion abnormality during stress for all late cardiac events was 25% (95% confidence interval [CI] 19 to 31) with a negative predictive value of 87% (95% CI 83 to 91). CONCLUSION: In a large cohort of unselected patients with chest pain syndromes, new wall motion abnormalities induced by dobutamine provide additional information for late cardiac events, independent of clinical variables.