Warfarin is an established treatment for prevention of ischaemic stroke in patients with atrial fibrillation, but the value of this agent relative to aspirin in unclear. In the first Stroke Prevention in Atrial Fibrillation (SPAF-I) study, direct comparison of warfarin with aspirin was limited by the small number of thromboembolic events. SPAF-II aims to address this issue and also to assess the differential effects of the two treatments according to age. We compared warfarin (prothrombin time ratio 1.3-1.8, international normalised ratio 2.0-4.5) with aspirin 325 mg daily for prevention of ischaemic stroke and systemic embolism (primary events) in two parallel randomised trials involving 715 patients aged 75 years or less and 385 patients older than 75; we sought reductions in the absolute rate of primary events by warfarin compared with aspirin of 2% per year and 4% per year, respectively. In the younger patients, warfarin decreased the absolute rate of primary events by 0.7% per year (95% CI-0.4 to 1.7). The primary event rate per year was 1.3% with warfarin and 1.9% with aspirin (relative risk [RR] 0.67, p = 0.24). The absolute rate of primary events in low-risk younger patients (without hypertension, recent heart failure, or previous thromboembolism) on aspirin was 0.5% per year (95% CI 0.1 to 1.9). Among older patients, warfarin decreased the absolute rate of primary events by 1.2% per year (95% CI-1.7 to 4.1). The primary event rate per year was 3.6% with warfarin and 4.8% with aspirin (RR 0.73, p = 0.39). In this older group, the rate of all stroke with residual deficit (ischaemic or haemorrhagic) was 4.3% per year with aspirin and 4.6% per year with warfarin (RR 1.1). Warfarin may be more effective than aspirin for prevention of ischaemic stroke in patients with atrial fibrillation, but the absolute reduction in stroke rate by warfarin is small. Younger patients without risk factors had a low rate of stroke when treated with aspirin. In older patients the rate of stroke (ischaemic and haemorrhagic) was substantial, irrespective of which agent was given. Patient age and the inherent risk of thromboembolism should be considered in the choice of antithrombotic prophylaxis for patients with atrial fibrillation.

Haemopoietic growth factors are accepted as accelerating haemopoietic recovery after bone-marrow grafting, yet no large randomised trials have been published that convincingly show benefit. Lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) was given to 315 patients after bone-marrow transplantation in a prospective randomised placebo-controlled multicentre trial. 1 day after bone-marrow infusion, 163 patients received lenograstim 5 micrograms/kg per day by 30-min infusion, and 152 patients received placebo daily for 28 days or until neutrophil recovery. 137 patients had lymphoma, 35 myeloma, 85 acute lymphoblastic leukaemia, and 58 a solid tumour. Patients were stratified by age and by type of bone-marrow transplantation (BMT). Neutrophil recovery to above 10(9)/L for 3 consecutive days was seen earlier in lenograstim-treated patients (16 vs 27 days, p < 0.001). Time to neutrophil recovery above 0.5 x 10(9)/L was reduced (14 vs 20 days, p < 0.001). The difference was significant both in autograft (20 vs 14 days, p < 0.001) and allograft (20 vs 14 days, p < 0.01) patients, in children (20 vs 13 days, p < 0.001), and adults. Lenograstim-treated patients had fewer days of infection, and of antibiotic administration, and also spent less time in hospital. However, clinical and microbiological sepsis was similar in both groups. There was no significant toxicity ascribed to lenograstim. Survival was the same at days 100 and 365. In patients undergoing autologous or allogeneic BMT for neoplastic disease, lenograstim significantly reduced duration of neutropenia and led to earlier hospital discharge.

Pre-eclampsia is a common and serious complication of pregnancy that affects both mother and child. Review of previous small trials of antiplatelet therapy, particularly low-dose aspirin, suggested reductions of about three-quarters in the incidence of pre-eclampsia and some avoidance of intrauterine growth retardation (IUGR), but larger trials have not confirmed these results. In our multicentre study 9364 women were randomly assigned 60 mg aspirin daily or matching placebo. 74% were entered for prophylaxis of pre-eclampsia, 12% for prophylaxis of IUGR, 12% for treatment of pre-eclampsia, and 3% for treatment of IUGR. Overall, the use of aspirin was associated with a reduction of only 12% in the incidence of proteinuric pre-eclampsia, which was not significant. Nor was there any significant effect on the incidence of IUGR or of stillbirth and neonatal death. Aspirin did, however, significantly reduce the likelihood of preterm delivery (19.7% aspirin vs 22.2% control; absolute reduction of 2.5 [SD 0.9] per 100 women treated; 2p = 0.003). There was a significant trend (p = 0.004) towards progressively greater reductions in proteinuric pre-eclampsia the more preterm the delivery. Aspirin was not associated with a significant increase in placental haemorrhages or in bleeding during preparation for epidural anaesthesia, but there was a slight increase in use of blood transfusion after delivery. Low-dose aspirin was generally safe for the fetus and newborn infant, with no evidence of an increased likelihood of bleeding. Our findings do not support routine prophylactic or therapeutic administration of antiplatelet therapy in pregnancy to all women at increased risk of pre-eclampsia or IUGR. Low-dose aspirin may be justified in women judged to be especially liable to early-onset pre-eclampsia severe enough to need very preterm delivery. In such women it seems appropriate to start low-dose aspirin prophylactically early in the second trimester.

Continuous positive airway pressure (CPAP) is the treatment of choice for the sleep apnoea/hypopnoea syndrome (SAHS); it is usually given with the aim of improving daytime cognitive function, mood, and sleepiness. However, its efficacy has not been validated by controlled trials. We have carried out a randomised, placebo-controlled, crossover study of objective daytime sleepiness, symptoms, cognitive function, and mood in a consecutive series of 32 SAHS patients with a median apnoea plus hypopnoea frequency of 28 (range 7-129) per hour slept. Patients were treated with 4 weeks each of CPAP and an oral placebo, which they were told might improve upper airway muscle function during sleep. Assessments on the last day of each treatment included a multiple sleep latency test and tests of symptom scores, mood profiles, and cognitive performance. The patients had significantly less daytime sleepiness on CPAP than during the placebo period (mean sleep latency 7.2 [SE 0.7] vs 6.1 [0.7] min, p = 0.03). There were also improvements with CPAP in symptom ratings (2.1 [0.2] vs 4.3 [0.3], p < 0.001), mood (p < 0.05 for several measures), and cognitive performance, which showed improved vigilance (obstacles hit in Steer Clear "driving" test 76 [5] vs 81 [6], p < 0.01), mental flexibility (trail-making B time 66 [5] vs 75 [5] s, p < 0.05), and attention (p < 0.05). Objectively monitored CPAP use averaged only 3.4 (0.4) hours per night, but this study provides evidence of improved cognitive performance even at this low level of CPAP compliance.

Pressure sores are a problem, especially in elderly patients. Our study was designed to determine the effectiveness in pressure-sore prevention of a new interface-pressure decreasing mattress. In a prospective randomised controlled clinical trial we tested the Comfortex DeCube mattress (Comfortex, Winona, USA) against our standard hospital mattress in 44 patients with femoral-neck fracture and concomitant high pressure-sore risk score. In addition both groups were treated according to the Dutch consensus protocol for the prevention of pressure sores. On admission and 1 and 2 weeks after admission, pressure sores were graded. The two groups were similar in patient characteristics and pressure-sore risk factors. At 1 week, 25% of the patients nursed on the DeCube mattress and 64% of the patients nursed on the standard mattress had clinically relevant pressure sores (grade 2 or more). At 2 weeks the figures were 24% and 68%, respectively. The maximum score over the several body regions of the pressure-sore grading, measured on a 5-point sale, was significantly different in favour of the DeCube mattress at 1 week (p = 0.0043) and 2 weeks (p = 0.0067) postoperatively. We show that the occurrence of pressure sores and their severity can be significantly reduced when patients at risk are nursed on an interface-pressure decreasing mattress.

Warm heart surgery--37 degrees C cardioplegia with systemic normothermia--has been introduced as an alternative to conventional hypothermic cardiac surgery. A randomised trial comparing warm (W) and cold (C) methods was done in 1732 patients undergoing isolated coronary bypass surgery in three adult cardiac surgery centres at the University of Toronto, Canada. Allocation to W (860 patients) or C (872) was stratified by urgent versus elective operations and by surgeon. There were no striking baseline differences in patients' demographics, angiographic findings, or operative procedures. All but 4.2% of patients initially received antegrade cardioplegia; a further 2.1% switched to retrograde delivery intra-operatively. Crossovers to C occurred in 7.7% of cases either due to difficulty in sustaining cardiac arrest or due to coronary flooding. Analysis, however, was on an intention-to-treat basis. The 30-day all-cause mortality was 2.5% in C patients and 1.4% in the W group (p 0.12). There was no difference in non-fatal Q-wave infarction rates (W 10.1%, C 11.1%), but enzymatic infarction by serial creatine kinase MB fraction (CK-MB) measurements was reduced (W 12.3% vs C 17.3%, p < 0.001) as was the mean area under the CK-MB curve. Postoperative low-output syndrome was less frequent in W patients (6.1% vs 9.3%, p 0.01). There were no differences in the rates of stroke, reoperation for bleeding or tamponade, or sternal rewiring/debridement for dehiscence or infection. Warm heart surgery is a safe and effective alternative to conventional hypothermic techniques for patients undergoing coronary bypass surgery.

Randomised trials have shown that duodenal ulcers treated by H2 blockers heal faster if Helicobacter pylori is eradicated concurrently. It remains unknown whether eradication of H pylori without suppression of acid-secretion, is sufficient to allow healing. 153 patients with H pylori infection and duodenal ulcer were randomised to receive either a 1-week course of bismuth subcitrate, tetracycline, and metronidazole (76), or omeprazole for 4 weeks with the same three-drug regimen for the first week (77). Endoscopy and antral biopsies were done at entry and 4 weeks after treatment. 132 patients were suitable for analysis. Duodenal ulcers healed in 60 (92%; 95% CI 86-100%) patients taking bismuth, tetracycline, and metronidazole compared with 63 (95%; 88-100%) taking omeprazole in addition to the three other drugs. H pylori was eradicated in 61 (94%; 88-100%) who received only three drugs compared with 66 (98%; 96-100%) who received omeprazole as well. Symptoms were reduced more effectively during the first week in patients who received omeprazole (p = 0.003). We conclude that a 1-week regimen of bismuth, tetracycline, and metronidazole for patients with H pylori and duodenal ulcer eradicates the organism and heals the ulcer in most patients. Concurrent administration of omeprazole reduces ulcer pain more rapidly but has no effect on ulcer healing.

The use of long-term oral anticoagulant treatment after myocardial infarction remains controversial because of conflicting findings on mortality in previous trials and the increased risk of bleeding associated with anticoagulants. We have carried out a randomised, placebo-controlled, double-blind, multicentre trial in 3404 hospital survivors of myocardial infarction. Eligible patients were randomly assigned to anticoagulant (nicoumalone or phenprocoumon) or placebo treatment within 6 weeks of discharge. The target prothrombin time was 2.8-4.8 international normalised ratio. During mean follow-up of 37 (range 6-76) months there were 170 deaths among 1700 anticoagulant-treated patients and 189 in 1704 placebo-treated patients (hazard ratio 0.90 [95% CI 0.73-1.11]). Anticoagulant treatment led to significant reductions by comparison with placebo treatment in recurrent myocardial infarction (114 vs 242 patients; hazard ratio 0.47 [0.38-0.59]) and cerebrovascular events (37 vs 62; 0.60 [0.40-0.90]). Major bleeding complications were seen in 73 patients who received anticoagulants and 19 who received placebo. We conclude that long-term oral anticoagulant treatment after myocardial infarction in low-risk patients has a limited effect on mortality but achieves substantial benefit by reducing the risk of cerebrovascular events and recurrent myocardial infarction.

Adjuvant systemic treatment for resectable breast cancer changes the natural history of the disease but provides only a small and delayed effect on survival. Evaluation of the types of first relapse avoided by available treatments may explain why effects on mortality are small and appear late during follow-up. In randomised clinical trials done by the International Breast Cancer Study Group (IBCSG) between 1978 and 1985, 2108 patients with node-positive disease received more-effective treatments (6 or more cycles of cyclophosphamide, methotrexate, fluorouracil and prednisone; with or without tamoxifen, or tamoxifen and prednisone alone), and 722 patients received less-effective treatments (no treatment or a single cycle of chemotherapy). 3 main categories of first site of relapse were defined and evaluated by cumulative incidence analysis: local or regional, and distant soft tissue, bone, and viscera. The more-effective treatments reduced the cumulative incidence of first relapse in local or regional and distant soft tissue sites at 10 years from 36% to 18% (p = 0.0001); first relapse in bone and viscera was not altered by the more-effective treatments. These results were similar for premenopausal and postmenopausal women, and for patients with oestrogen-receptor-positive or oestrogen-receptor-negative tumours. Adjuvant systemic treatments in current use improve patient outcome mainly by reducing the incidence of first local or regional and distant soft-tissue relapses, while first recurrences in bone or viscera are influenced much less. More intensive treatments at present being tested in clinical trials might affect bone and visceral relapses and have a greater and earlier influence on survival.

Patients with a short bowel malabsorb dietary nutrients with loss of calories and weight. Malabsorbed carbohydrates are fermented by colonic bacteria to short-chain fatty acids, which are absorbed and supply energy. The maximum energy-consumption capacities in patients with short bowel were individually measured on 40:40% carbohydrate:fat diets. 8 patients with colon in continuity and 6 patients with jejunostomies were placed on isocaloric 60:20% or 20:60% carbohydrate:fat diets and faecal excretions of calories, carbohydrates, fat, nitrogen, and fluids were compared. The high-carbohydrate low-fat diet reduced faecal loss of energy by 2.0 MJ/day compared to the low-carbohydrate high-fat diet in patients with colon in continuity, and absorption of energy increased from 49 to 69% (p < 0.001). Faecal excretions of carbohydrates were low and not influenced by the change in carbohydrate intakes (26 g/day and 28 g/day, respectively) whereas faecal fat (46 g/day and 106 g/day) was highly dependent on dietary intakes and accounted for differences in faecal loss of energy. In contrast, patients with jejunostomies excreted equal amounts of calories on the high-carbohydrate diet (4.8 MJ/day) and the high-fat diet (5.9 MJ/day; p = 0.08); and the percentage of calories absorbed was not different (55% and 48%, respectively; p = 0.21). Furthermore, in patients without colon the excretions of carbohydrates (80 g/day and 42 g/day on high-carbohydrate and low-carbohydrate diets, respectively) and fat (69 g/day and 35 g/day on high-fat and low-fat diets, respectively) were proportional to the amounts ingested. The large intestine is important in the digestion of carbohydrates and hence in the salvage of calories in patients with short bowel and severe malabsorption.

Donor-specific bone marrow infusion after organ grafting can induce tolerance in animals. In this randomised controlled study we show it has no benefit in patients undergoing liver transplantation. Of 25 patients, 9 received bone marrow 5 days after a 10 day course of antithymocyte globulin. Immunosuppression was maintained with cyclosporin only. An average of 3.0 rejection episodes per patient was seen in the bone marrow group compared to 3.1 in the controls. Chimerism was not found in peripheral blood or bone marrow of recipients using erythrocyte antigen markers, PCR for donor class II DNA or Y-probe in-situ hybridisation in one female recipient of male liver and bone marrow.

Nicotine-replacement therapy (NRT) by gum, transdermal patch, intranasal spray, or inhalation is expensive but how effective is it? We have done a meta-analysis of controlled trials to see how effects on abstinence rates are influenced by the clinical setting, the level of nicotine dependency, the dosage of NRT, and the intensity of additional advice and support offered. Published or unpublished randomised controlled trials of NRT that have assessed abstinence at least 6 months after the start of NRT were identified and 53 trials (42 gum, 9 patch, 1 intranasal spray, 1 inhaler), with data from 17,703 subjects, were included in the analyses. Use of NRT increased the odds ratio (OR) of abstinence to 1.71 (95% confidence interval 1.56-1.87) compared with those allocated to the control interventions. The ORs for the different forms of NRT were 1.61 for gum, 2.07 for transdermal patch, 2.92 for nasal spray, and 3.05 for inhaled nicotine. These odds were non-significantly higher in subjects with higher levels of nicotine dependence but they were largely independent of the intensity of additional support provided or the setting in which NRT was offered. We conclude that the currently available forms of NRT are effective therapies to aid smoking cessation.

Although laparoscopic cholecystectomy has rapidly become routine practice in the UK, there has been no rigorous comparison of it with open cholecystectomy. In our trial, 302 patients were randomised to laparoscopic or minilaparotomy cholecystectomy. Recovery after surgery was assessed by length of hospital stay, outpatient review at 10 days and 4 weeks, and patient questionnaires 1, 4, and 12 weeks after surgery. The mean operation time was 14 min shorter for minilaparotomy, while median post-operative hospital stay was 2 days shorter after laparoscopic cholecystectomy. The hospital costs were about 400 pounds greater for the laparoscopic procedure. Laparoscopic patients returned to work in the home sooner; at 1 week, they had better physical and social functioning, were less limited by physical problems, and had less pain and depression. At 4 weeks, only physical functioning and depression scores were better in the laparoscopic group, and by 3 months there were no differences. Laparoscopic patients were more satisfied with the appearance of their scars. The incidence of complications after both procedures was 20%. Compared to minilaparotomy cholecystectomy, laparoscopic cholecystectomy results in shorter hospital stay, less postoperative dysfunction, and quicker return to normal activities, but is more costly.

Severe hypoglycaemia with brain dysfunction limits intensified therapy in patients with insulin-dependent diabetes mellitus, despite evidence that such therapy reduces the risk of chronic complications of the disease. We have investigated the effect of infusing lactate (a potential non-glucose fuel for brain metabolism) on protective, symptomatic neurohumoral responses and on brain function during hypoglycaemia in seven healthy men. Elevation of lactate (within a physiological range) substantially diminished catecholamines, growth hormone, cortisol, and symptomatic responses to hypoglycaemia and lowered the glucose level at which these responses began. Glucagon responses were unaffected. Lactate was also associated with a significant lowering of the glucose level at which brain function deteriorated, suggesting that brain function was protected during the hypoglycaemia. The defect in counter-regulation is similar to that seen in hypoglycaemia-prone diabetic patients. Initiation of the protective responses to hypoglycaemia (except glucagon) can be delayed by supporting metabolism with an alternative metabolic fuel. Cerebral cortical dysfunction of severe hypoglycaemia is also delayed. Our demonstration that higher brain function can be protected during hypoglycaemia may have therapeutic potential.