Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of ...venous thromboembolism.
We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism.
During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval CI, 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events.
In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council Australia and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).
The purpose of this study was to evaluate serum HE4 as a biomarker to detect recurrent disease during follow-up of patients with endometrial adenocarcinoma (EAC).
We performed a retrospective ...analysis of 98 EAC patients treated at Innsbruck Medical University, between 1999 and 2009. Twenty-six patients developed recurrent disease. Median follow-up was 5 years. Serum HE4 and CA125 levels were analyzed using the ARCHITECT assay (Abbott, Wiesbaden, Germany) pre-operatively (baseline), post-operative (interval) and after histological confirmation of recurrent disease or when patients returned for clinical review with no evidence of recurrent disease (recurrence/final)). Receiver operator curves (ROC), Spearman rank correlation coefficient, chi-squared and Mann-Whitney tests were used for statistical analysis.
HE4 levels decreased after initial treatment (p = 0.001) and increased again at recurrence (p = 0.002). HE4 was elevated (>70 pmol/L) in 21 of 26 (81%) and CA125 was elevated (>35 U/ml) in 12 of 26 (46%) patients at recurrence. In endometrioid histology (n = 69) serum HE4 measured during follow up (Area under the curve (AUC) = 0.87, 95%CI 0.79-0.95) was a better indicator of recurrence than CA125 (AUC = 0.67, 95%CI 0.52-0.83). A HE4 level of 70 pmol/L was associated with a sensitivity of 84%, a specificity of 74% and a negative predictive value of 93% when assessing for recurrent endometrioid EAC.
This is a preliminary description of HE4 serum levels measured during routine follow up of EAC patients. Serum HE4 measured during clinical follow-up may identify recurrent disease particularly in patients with endometrioid histology. Further prospective validation of HE4 is warranted.
Advanced prehospital interventions for severe brain injury remains controversial. No previous randomised trial has been conducted to evaluate additional physician intervention compared with paramedic ...only care.
Participants in this prospective, randomised controlled trial were adult patients with blunt trauma with either a scene GCS score <9 (original definition), or GCS<13 and an Abbreviated Injury Scale score for the head region ≥3 (modified definition). Patients were randomised to either standard ground paramedic treatment or standard treatment plus a physician arriving by helicopter. Patients were evaluated by 30-day mortality and 6-month Glasgow Outcome Scale (GOS) scores. Due to high non-compliance rates, both intention-to-treat and as-treated analyses were preplanned.
375 patients met the original definition, of which 197 was allocated to physician care. Differences in the 6-month GOS scores were not significant on intention-to-treat analysis (OR 1.11, 95% CI 0.74 to 1.66, p=0.62) nor was the 30-day mortality (OR 0.91, 95% CI 0.60 to 1.38, p=0.66). As-treated analysis showed a 16% reduction in 30-day mortality in those receiving additional physician care; 60/195 (29%) versus 81/180 (45%), p<0.01, Number needed to treat =6. 338 patients met the modified definition, of which 182 were allocated to physician care. The 6-month GOS scores were not significantly different on intention-to-treat analysis (OR 1.14, 95% CI 0.73 to 1.75, p=0.56) nor was the 30-day mortality (OR 1.05, 95% CI 0.66 to 1.66, p=0.84). As-treated analyses were also not significantly different.
This trial suggests a potential mortality reduction in patients with blunt trauma with GCS<9 receiving additional physician care (original definition only). Confirmatory studies which also address non-compliance issues are needed.
NCT00112398.
Aims/hypothesis
In the double-blind placebo-controlled Fenofibrate Intervention and Event Lowering in Diabetes trial (
n
= 9,795), fenofibrate reduced major cardiovascular events in type 2 diabetes. ...Sex-related differences in fenofibrate response could be clinically relevant and were pre-specified analyses.
Methods
Women (
n
= 3,657) and men (
n
= 6,138) with type 2 diabetes not using statins were assigned fenofibrate (200 mg/day) or placebo for 5 years. Effects on lipoproteins and total cardiovascular events were evaluated by sex.
Results
Baseline total, LDL-, HDL- and non-HDL cholesterol and apolipoproteins A-I and B differed between sexes, and these and triacylglycerol levels improved with fenofibrate in both sexes (all
p
< 0.001). Fenofibrate reduced total, LDL- and non-HDL cholesterol and apolipoprotein B more in women (all
p
< 0.001), independent of menopausal status and statin uptake. Adjusted for covariates, fenofibrate reduced total cardiovascular outcomes (cardiovascular death, fatal and non-fatal stroke and carotid and coronary revascularisation) by 30% in women (95% CI 8%, 46%;
p
= 0.008) and 13% in men (95% CI −1%, 24%;
p
= 0.07) with no treatment-by-sex interaction (
p >
0.1). In patients with high triacylglycerol levels and low HDL-cholesterol, fenofibrate reduced total cardiovascular outcomes by 30% (95% CI −7%, 54%) in women and 24% (95% CI 2%, 42%) in men, with no treatment-by-sex interaction (
p >
0.1).
Conclusions/interpretation
Fenofibrate improved the lipoprotein profile more in women than men. Cardiovascular event reductions with fenofibrate were consistently similar in women and men, both overall and among those with low HDL-cholesterol and high triacylglycerol levels. These data provide reassurance about fenofibrate efficacy in women and men. Both sexes with type 2 diabetes should be considered for fenofibrate therapy for cardioprotection.
Abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability ...of the Na+ channel blocker and membrane stabiliser flecainide in ALS.
A double-blind, placebo-controlled, randomised clinical trial of flecainide (200mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period.
Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 95% CI 0.49 to 0.98; Placebo 0.81 0.49 to 2.12 P=0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 0.01 to 0.11; Placebo 0.14 0.09 to 0.19, P=0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: −15±12%; Placebo −59±12%; P=0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo.
This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.
•To determine safety and neuroprotective potential, a double-blind, placebo-controlled, randomised trial of the Na+ channel blocking agent flecainide was conducted in ALS.•Flecainide was well tolerated, with no serious adverse events.•Although there was some evidence that flecainide stabilised peripheral axonal membrane function, the study was not powered to provide evidence of benefit on functional decline.
Changes in nerve excitability function occur in patients with amyotrophic lateral sclerosis (ALS). We conducted a double-blind, placebo-controlled, randomised clinical trial to examine the impact of a membrane/nerve stabilizer (flecainide) in ALS patients. Although there was some evidence that flecainide stabilised peripheral axonal membrane function in ALS, the study was not powered to find evidence that flecainide benefited patient function.
Abstract Aims The Warfarin Self-Management Anticoagulation Research Trial (Warfarin SMART) was designed to determine whether patients self-managing warfarin (PSM) using the CoaguChek device and a ...dosing algorithm developed for the trial could keep the INR (International Normalised Ratio) test in target range at least as often as patients managed by usual care by the family doctor or hospital clinic. Methods and results 310 patients were randomly assigned to PSM or usual care. The PSM group was trained to perform home INR testing and warfarin dosing using a validated ColourChart algorithm. The primary endpoint was the proportion of times over 12 months that a monthly, blinded “outcome INR test”, measured in a central laboratory, was outside the patient's target therapeutic range. The rate of out-of-range outcome INRs was lower in PSM, and non-inferior to the usual care group (PSM: 36% vs. usual care: 41%, P < 0.001 for non-inferiority; P = 0.08 for superiority in closed-loop testing). The deviations from the patient's midpoint of target INR range ( P = 0.02) and number of extreme INRs ( P = 0.03) were significantly less in the PSM group than the usual-care group. There was no significant difference between groups in rates of bleeding or thrombotic adverse events. Conclusion Patient self-management performed at least as well as usual care in maintaining the INR within the target range, without any safety concerns. This treatment modality for the long-term use of warfarin has the potential to change current local and international practice.
It has been suggested that prehospital care teams that can provide advanced prehospital interventions may decrease the transit time through the ED to CT scan and subsequent surgery. This study is an ...exploratory analysis of data from the Head Injury Retrieval Trial (HIRT) examining the relationship between prehospital team type and time intervals during the prehospital and ED phases of management.
Three prehospital care models were compared; road paramedics, and two physician staffed Helicopter Emergency Medical Services (HEMS) - HIRT HEMS and the Greater Sydney Area (GSA) HEMS. Data on prehospital and ED time intervals for patients who were randomised into the HIRT were extracted from the trial database. Additionally, data on interventions at the scene and in the ED, plus prehospital entrapment rate was also extracted. Subgroups of patients that were not trapped or who were intubated at the scene were also specifically examined.
A total of 3125 incidents were randomised in the trial yielding 505 cases with significant injury that were treated by road paramedics, 302 patients treated by the HIRT HEMS and 45 patients treated by GSA HEMS. The total time from emergency call to CT scan was non-significantly faster in the HIRT HEMS group compared with road paramedics (medians of 1.9 hours vs. 2.1 hours P = 0.43) but the rate of prehospital intubation was 41% higher in the HIRT HEMS group (46.4% vs. 5.3% P < 0.001). Most time intervals for the GSA HEMS were significantly longer with a regression analysis indicating that GSA HEMS scene times were 13 (95% CI, 7-18) minutes longer than the HIRT HEMS independent of injury severity, entrapment or interventions performed on scene.
This study suggests that well-rehearsed and efficient interventions carried out on-scene, by a highly trained physician and paramedic team can allow earlier critical care treatment of severely injured patients without increasing the time elapsed between injury and hospital-based intervention. There is also indication that role specialisation improves time intervals in physician staffed HEMS which should be confirmed with purpose designed trials.
Objectives This study sought to assess whether baseline and change in contemporary sensitive troponin I (TnI) levels predicts coronary heart disease (CHD) death and myocardial infarction (MI), and to ...determine the effects of pravastatin on TnI levels. Background The role of troponins in predicting long-term outcomes in patients with stable CHD is not clearly defined. Methods The LIPID (Long-Term Intervention With Pravastatin in Ischaemic Disease) study randomized patients with cholesterol levels of 155 to 271 mg/dl 3 to 36 months after MI or unstable angina to placebo or pravastatin 40 mg per day. TnI levels were measured at baseline and after 1 year in 7,863 patients. Median follow-up was 6 years. Change in TnI was defined as moving up or down 1 tertile or ≥50% change. Results Baseline TnI tertiles were <0.006 ng/ml, 0.006 to <0.018 ng/ml, and ≥0.018 ng/ml. TnI levels were related to CHD death and MI after adjustment for 23 risk factors and treatment (≥0.018 ng/ml vs. <0.006 ng/ml hazard ratio HR: 1.64; 95% CI: 1.41 to 1.90; p < 0.001). TnI levels increased in 23.0%, were unchanged in 51.3%, and decreased in 25.7% of patients. Pravastatin decreased TnI levels by 0.003 ng/ml versus placebo (p = 0.002). In landmark analyses, increases in TnI levels were associated with increased numbers of CHD death and MI (HR: 1.31; 95% CI: 1.06 to 1.62) and decreases with decreased risk (HR: 0.90; 95% CI: 0.74 to 1.09; overall p = 0.01). Data were similar with 50% change criteria. Net reclassification improvement by adding TnI to the baseline model for CHD death and MI was 4.8% (p = 0.01). Conclusions Baseline TnI levels and change at 1 year are independent predictors of CHD death and MI. TnI levels are strong predictors of risk, and change modifies risk.
Preeclampsia is associated with fetal growth restriction and low birth weights. Neurotrophins, which mediate neuronal growth and development, are also increased in the placenta and cord blood in ...preeclampsia. Hence, the aim of this study was to determine whether fetal head growth is altered in preeclampsia, adjusting for growth restriction and other confounding variables.
This research included a retrospective cohort study, looking at fetal head circumference at birth, plus a case-control study examining fetal head circumference at mid-gestation. The head circumference at birth analysis consisted of 14,607 pregnancies (preeclampsia = 382, control = 14,225), delivered between July 2006 and June 2012 at Nepean Hospital, Australia. Head circumference at birth, in addition to other maternal and fetal variables, was sourced from the Nepean Obstetric Database. The head circumference at mid-gestation study consisted of 756 pregnancies (preeclampsia = 248, control = 508), delivered within the same data collection period at Nepean Hospital. Head circumference at mid-gestation was retrieved from an earlier ultrasound scan. Exclusion criteria included >1 fetus, illegal drug use, alcohol consumption, and chronic or gestational hypertension. Generalized linear models were used to analyze fetal head circumference in preeclampsia versus controls, adjusting for confounding variables.
Head circumference increased at a greater rate in preeclampsia versus controls, adjusted for gestation, fetal gender, birth weight and length, smoking, maternal BMI, and growth restriction. At mid-gestation, there was no difference in head circumference between preeclampsia and controls.
For the first time, this research has suggested increased fetal head growth in preeclampsia, adjusted for confounders. This finding may be explained by altered fetal exposure to neurotrophins in preeclampsia. The long-term neurodevelopmental consequences of preeclampsia remain unclear.
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