The objective was to assess adverse outcomes in relation to the simplified Pulmonary Embolism Severity Index (PESI) score in patients treated with rivaroxaban or standard therapy in the phase III EINSTEIN PE study and to evaluate the utility of the simplified PESI score to identify low-risk pulmonary embolism (PE) patients.
A post hoc analysis of EINSTEIN PE data was performed to assess the efficacy and safety of rivaroxaban in patients with a range of simplified PESI scores. Recurrent venous thromboembolism, fatal PE, all-cause mortality, and major bleeding were stratified by simplified PESI scores of 0, 1, or ≥2 and according to treatment period at 7, 14, 30, and 90 days and at the end of the full intended treatment period.
Simplified PESI scores could be calculated in 4,831 of the 4,832 randomized patients; of those, 53.6, 36.7, and 9.7% had PESI scores of 0, 1, and ≥2, respectively. Among patients with simplified PESI scores of 0 or 1, fatal PE, all-cause mortality, and other adverse outcomes were uncommon within the first 7, 14, and 30 days. Patients with simplified PESI scores of ≥2 had more frequent adverse outcomes. Major bleeding was lower in the rivaroxaban group, particularly in those with simplified PESI scores of 1 or ≥2.
The findings support using risk stratification with the simplified PESI score to identify low-risk patients with PE.
The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.
We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5–2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.
Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4–23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.
The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.
Clinicaltrials.gov: NCT01516840 and NCT01516814.
Electronic supplementary material
The online version of this article (doi:10.1186/s12959-015-0035-3) contains supplementary material, which is available to authorized users.
Deep vein thrombosis; Japan; Pulmonary embolism; Randomized trial; Rivaroxaban; Unfractionated heparin; Venous thromboembolism; Warfarin
Statins may reduce the risk of first and recurrent venous thromboembolism (VTE). No data are available on their potential benefit in patients treated with the oral anticoagulant rivaroxaban.
The EINSTEIN DVT/PE and EINSTEIN Extension studies compared rivaroxaban with standard of care (n=8280) and placebo (n=1188), respectively. The incidences of recurrent VTE and major bleeding per 100 patient-years for exposure (or not) to statins were calculated. A Cox proportional hazards model was constructed, stratified by index event and intended treatment duration, with statin use as a time-dependent variable, for each treatment group (rivaroxaban vs enoxaparin/vitamin K antagonist or placebo) and adjusted for relevant variables.
In EINSTEIN DVT/PE, 1509 (18.3%) patients used statins during the at-risk period, and 6731 (81.7%) did not. Overall, 2.6 recurrent VTEs occurred per 100 patient-years with statin use compared with 3.8 per 100 patient-years without statins (adjusted hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.46–1.25). HRs for recurrent VTE were similar for concomitant use of rivaroxaban-statin and enoxaparin/VKA-statin. Major bleeding events occurred in 3.0 per 100 patient-years with statin use compared with 2.3 per 100 patient-years without statins (adjusted HR 0.77; 95% CI 0.46–1.29). Due to adjustments in the Cox regression model, the direction of this HR is in contrast to the crude comparison. In EINSTEIN Extension, no recurrent VTEs occurred with statin use in the rivaroxaban group compared with 1.6 per 100 patient-years without statins. In the placebo group, 12.2 recurrent VTEs occurred per 100 patient-years with statin use compared with 13.2 per 100 patient-years without (adjusted HR 0.81; 95% CI 0.35–1.86).
The effect of statins in this secondary analysis of the EINSTEIN VTE treatment program is consistent with other studies that suggest a reduced risk of recurrent VTE, but conclusive evidence of this benefit is lacking. Statins are simple to use, inexpensive, very safe and do not cause bleeding. Therefore, the potential effect on reducing recurrent VTE, which is in the range of that of acetylsalicylic acid, deserves evaluation in a large randomized trial.
Trial registration number
ClinicalTrials.gov: EINSTEIN PE, NCT00439777; EINSTEIN DVT, NCT00440193; EINSTEIN Extension, NCT00439725.
Anticoagulant therapy; Rivaroxaban; Statins; Venous thromboembolism
Patients with renal impairment receiving classical anticoagulation for venous thromboembolism (VTE) are at increased risk of bleeding and possibly pulmonary embolism. We examined the efficacy and safety of oral rivaroxaban in patients with VTE with and without renal impairment.
Prespecified subgroup analysis of the EINSTEIN DVT and EINSTEIN PE studies comparing fixed-dose rivaroxaban with enoxaparin/a vitamin K antagonist (VKA), performed in 8246 patients enrolled from 2007 to 2011 in 314 hospitals.
Outcomes were recurrent VTE and major or clinically relevant nonmajor bleeding in patients with normal renal function (n = 5569; 67.3%) or mild (n = 2037; 24.6%), moderate (n = 636; 7.7%), or severe (n = 21; 0.3%) renal impairment. Rates of recurrent VTE were 1.8%, 2.8%, 3.3%, and 4.8% in patients with normal renal function and mild, moderate, and severe renal impairment, respectively (ptrend = 0.001). Hazard ratios for recurrent VTE were similar between treatment groups across renal function categories (pinteraction = 0.72). Major bleeding in rivaroxaban recipients occurred in 0.8%, 1.4%, 0.9%, and 0%, respectively (ptrend = 0.50). Respective rates in enoxaparin/VKA recipients were 1.0%, 3.0%, 3.9%, and 9.1% (ptrend < 0.001). Rivaroxaban–enoxaparin/VKA hazard ratios were 0.79 (95% confidence interval [CI] 0.46–1.36) for normal renal function, 0.44 (95% CI 0.24–0.84) for mild renal impairment, and 0.23 (95% CI 0.06–0.81) for moderate renal impairment (pinteraction = 0.034).
Patients with symptomatic VTE and renal impairment are at increased risk of recurrent VTE. Renal impairment increased the risk of major bleeding in enoxaparin/VKA-treated patients but not in rivaroxaban-treated patients.
NCT00440193 and NCT00439777.
Anticoagulants; Bleeding; Renal insufficiency; Rivaroxaban; Venous thromboembolism
Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.
We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects.
No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p = 0.625). A burning sensation, erythema, itching and dryness were most frequently reported.
This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement.
The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients.
A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding.
The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36–3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31–1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy.
In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world.
Trial registration number
EINSTEIN PE, ClinicalTrials.gov
NCT00439777; EINSTEIN DVT, ClinicalTrials.gov
Rivaroxaban; Deep vein thrombosis; Pulmonary embolism; Venous thromboembolism; Vitamin K antagonist; Randomized trial
Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.
A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75.
A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66–1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37–0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy.
The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups.
EINSTEIN-PE: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.
Rivaroxaban; Standard therapy; Venous thromboembolism; Randomized controlled trials
Direct oral anticoagulants that target a single coagulation factor have been developed as an alternative to standard therapies with heparin and/or vitamin K antagonists. The purpose of this study was to derive non-inferiority margins suitable for randomised clinical studies designed to evaluate these agents for the treatment of venous thromboembolism (VTE).
We performed a systematic review to derive non-inferiority margins suitable for use in studies evaluating direct oral anticoagulants for the treatment of VTE. A PubMed search identified publications that evaluated current standard treatment versus placebo, ‘no treatment’ or ‘less intensive treatment’ in patients with symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Publications were eligible if they had a randomised study design, included patients with symptomatic DVT and/or PE, used objective diagnostic methods to document the index event and reported objectively confirmed symptomatic recurrent VTE.
Fourteen publications were included in the analysis. Recurrent VTE occurred in 25 (1.5%) out of 1715 patients who received current standard of care and in 157 (9.2%) out of 1711 patients who received placebo, ‘no treatment’ or ‘less intensive treatment’, for an odds ratio of 0.18 (95% confidence interval, 0.14−0.25; test for heterogeneity, p=0.87). In order to preserve 50% or 75% of the established treatment effect using a linear scale, the corresponding thresholds for non-inferiority equalled 2.50 and 1.75, respectively.
This systematic review and statistical approach determined non-inferiority margins suitable for use in studies of direct oral anticoagulants for the treatment of DVT and/or PE.
Non-inferiority margin; Oral anticoagulants; Venous thromboembolism
This review aims to give an overview of available published evidence concerning the association between physical activity and asthma in children, adolescents and adults.
We included all original articles in which both physical activity and asthma were assessed in case-control, cross-sectional or longitudinal (cohort) studies. Excluded were studies concerning physical fitness, studies in athletes, therapeutic or rehabilitation intervention studies such as physical training or exercise in asthma patients. Methodological quality of the included articles was assessed according to the Newcastle-Ottawa Scale (NOS).
A literature search was performed until June 2011 and resulted in 6,951 publications derived from PubMed and 1,978 publications from EMBASE. In total, 39 studies met the inclusion criteria: 5 longitudinal studies (total number of subjects n = 85,117) with physical activity at baseline as exposure, and asthma incidence as outcome. Thirty-four cross-sectional studies (n = 661,222) were included. Pooling of the longitudinal studies showed that subjects with higher physical activity levels had lower incidence of asthma (odds ratio 0.88 (95% CI: 0.77–1.01)). When restricting pooling to the 4 prospective studies with moderate to good study quality (defined as NOS≥5) the pooled odds ratio only changed slightly (0.87 (95% CI: 0.77–0.99)). In the cross-sectional studies, due to large clinical variability and heterogeneity, further statistical analysis was not possible.
The available evidence indicates that physical activity is a possible protective factor against asthma development. The heterogeneity suggests that possible relevant effects remain hidden in critical age periods, sex differences, or extremes of levels of physical activity (e.g. sedentary). Future longitudinal studies should address these issues.
The percentage of time within the target INR range 2.0 to 3.0 (TTR) in patients treated with vitamin K antagonists varies considerably among efficacy-studies of novel anticoagulants. In order to properly asses the quality of anticoagulant control in upcoming cost-effectiveness studies and real life registries this systematic review reports a benchmark of TTR for different treatment durations in patients with venous thromboembolism and discusses ways to calculate TTR.
Medline and Embase were searched for studies published between January 1990 and May 2012. Randomized controlled trials and cohort studies reporting the TTR in patients with objectively confirmed venous thromboembolism treated with vitamin K antagonists (VKA) were eligible. Duplicate reports, studies only reporting INR during initial treatment or with VKA treatment less than 3 months were excluded. Three authors assessed trials for inclusion and extracted data independently. Discrepancies were resolved by discussion between the reviewers. A meta-analysis was performed by calculating a weighted mean, based on the number of participants in each included study, for each time-period in which the TTR was measured since the confirmation of the diagnosis of VTE.
Forty studies were included (26064 patients). The weighted means of TTR were 54.0% in the first month since the start of treatment, 55.6% in months 1 to 3, 60.0% in months 2 to 3, 60.0% in the months1 to 6+ and 75.2% in months 4 to 12+. Five studies reported TTR in classes. The INR in these studies was ≥67% of time in therapeutic range in 72.0% of the patients.
Reported quality of VKA treatment is highly dependent on the time-period since the start of treatment, with TTR ranging from approximately 56% in studies including the 1st month to 75% in studies excluding the first 3 months.
To investigate the natural history of carotid atherosclerosis in patients who experienced a TIA or ischemic stroke.
Patients and Methods
Ninety-two TIA/stroke patients (57 men, mean age 67.7±9.8 years) with ipsilateral <70% carotid stenosis underwent multisequence MRI of the plaque ipsilateral to the symptomatic side at baseline and after one year. For each plaque, several parameters were assessed at both time points.
Carotid lumen, wall and total vessel ( = carotid lumen and wall) volume did not significantly change. Forty-four patients had a plaque with a lipid-rich necrotic core (LRNC) at baseline, of which 34 also had a LRNC after one year. In three patients a LRNC appeared after one year. Thirty patients had a plaque with a thin and/or ruptured fibrous cap (FC) at both time points. In seven patients, FC status changed from thin and/or ruptured into thick and intact. In three patients, FC status changed from thick and intact into thin and/or ruptured. Twenty patients had intraplaque hemorrhage (IPH) at both time points. In four patients, IPH disappeared, whereas in three patients, new IPH appeared at follow-up.
In TIA/stroke patients, carotid plaque morphology does not significantly change over a one-year period. IPH and FC status change in a minority of patients.
Screening with ankle-brachial index (ABI) measurement could be clinically relevant to avoid cardiovascular events in subjects with asymptomatic atherosclerosis. To assess the practical impact of guidelines regarding the use of ABI as a screening tool in general practice, the corresponding number needed to screen, including the required time investment, and the feasibility of ABI performance, was assessed.
An observational study was performed in the setting of 955 general practices in the Netherlands. Overall, 13,038 subjects of ≥55 years presenting with symptoms of intermittent claudication and/or presenting with ≥ one vascular risk factor were included. Several guidelines recommend the ABI as an additional measurement in selected populations for risk assessment for cardiovascular morbidity.
Screening of the overall population of ≥50 years results in ≈862 subjects per general practice who should be screened, resulting in a time-requirement of approximately 6 weeks of full time work. Using an existing clinical prediction model, 247 patients per general practice should be screened for PAD by ABI measurement.
Screening the entire population of ≥50 years will in our opinion not be feasible in general practice. A more rationale and efficient approach might be screening of subsets of the population of ≥55 years based on a clinical prediction model.
To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness.
RESEARCH DESIGN AND METHODS
We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6–12.5) years.
During the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03–1.66) and HR = 1.27 (1.00–1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness.
Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.
To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs).
RESEARCH DESIGN AND METHODS
We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6–12.5).
The incidence of fatal and nonfatal CVD and all-cause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13–3.21) and 2.12 (1.26–3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91–2.77) for fatal and nonfatal CVD events and to 1.90 (1.09–3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036).
Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association.
Selective decontamination of the digestive tract (SDD) has been shown to decrease the infection rate and mortality in intensive care units (ICUs); Lactobacillus plantarum 299/299v plus fibre (LAB) has been used for infection prevention and does not harbour the potential disadvantages of antibiotics. The objective was to assess whether LAB is not inferior to SDD in infection prevention.
Two hundred fifty-four consecutive ICU patients with expected mechanical ventilation ≥48 h and/or expected ICU stay ≥72 h were assigned to receive SDD: four times daily an oral paste (polymyxin E, gentamicin, amphotericin B), enteral solution (same antibiotics), intravenous cefotaxime (first 4 days) or LAB: two times daily L. plantarum 299/299v with rose-hip.
The primary endpoint was infection rate. A difference <12% between both groups indicated non-inferiority of LAB. The trial was prematurely stopped after a study reporting increased mortality in critically ill pancreatitis patients receiving probiotics. No significant difference in infection rate [31% in the LAB group, 24% in the SDD group (OR 1.68, 95% CI 0.91–3.08; p = 0.10)] was found. ICU mortality was 26% and not significantly different between the LAB and SDD groups. Gram-positive cocci and Pseudomonas aeruginosa were significantly more frequently isolated from surveillance cultures in the SDD group compared to the LAB group (for sputum: 18 vs. 10% and 33 vs. 14%). Significantly more Enterobacteriaceae were found in the LAB group (23 vs. 50%). No increase in antibiotic resistance was found during and after SDD or LAB use.
The trial could not demonstrate the non-inferiority of LAB compared with SDD in infection prevention. Results suggest no increased ICU mortality risk in the LAB group.
Antibiotics; Critical care; Lactobacillus; Nosocomial infections; Survival
The reference standard for diagnosing peripheral arterial disease in primary care is the ankle brachial index (ABI). Various methods to measure ankle and brachial blood pressures and to calculate the index are described.
To compare the ABI measurements performed in primary care with those performed in the vascular laboratory. Furthermore, an inventory was made of methods used to determine the ABI in primary care.
Design of study
Primary care practice and outpatient clinic.
Consecutive patients suspected of peripheral arterial disease based on ABI assessment in primary care practices were included. The ABI measurements were repeated in the vascular laboratory. Referring GPs were interviewed about method of measurement and calculation of the index. From each patient the leg with the lower ABI was used for analysis.
Ninety-nine patients of 45 primary care practices with a mean ABI of 0.80 (standard deviation [SD] = 0.27) were included. The mean ABI as measured in the vascular laboratory was 0.82 (SD = 0.26). A Bland–Altman plot demonstrated great variability between ABI measurements in primary care practice and the vascular laboratory. Both method of blood pressure measurements and method of calculating the ABI differed greatly between primary care practices.
This study demonstrates that the ABI is often not correctly determined in primary care practice. This phenomenon seems to be due to inaccurate methods for both blood pressure measurements and calculation of the index. A guideline for determining the ABI with a hand-held Doppler, and a training programme seem necessary.
diagnosis; Doppler effect; intermittent claudication; peripheral vascular diseases; ultrasonography
Disease severity and functional impairment in patients with intermittent claudication is usually quantified by the measurement of pain-free walking distance (intermittent claudication distance, ICD) and maximal walking distance (absolute claudication distance, ACD). However, the distance at which a patient would prefer to stop because of claudication pain seems a definition that is more correspondent with the actual daily life walking distance. We conducted a study in which the distance a patient prefers to stop was defined as the functional claudication distance (FCD), and estimated the reliability and validity of this measurement.
In this clinical validity study we included patients with intermittent claudication, following a supervised exercise therapy program. The first study part consisted of two standardised treadmill tests. During each test ICD, FCD and ACD were determined. Primary endpoint was the reliability as represented by the calculated intra-class correlation coefficients. In the second study part patients performed a standardised treadmill test and filled out the Rand-36 questionnaire. Spearman's rho was calculated to assess validity.
The intra-class correlation coefficients of ICD, FCD and ACD were 0.940, 0.959, and 0.975 respectively. FCD correlated significantly with five out of nine domains, namely physical function (rho = 0.571), physical role (rho = 0.532), vitality (rho = 0.416), pain (rho = 0.416) and health change (rho = 0.414).
FCD is a reliable and valid measurement for determining functional capacity in trained patients with intermittent claudication. Furthermore it seems that FCD better reflects the actual functional impairment. In future studies, FCD could be used alongside ICD and ACD.
The side effects and burden of anticoagulant treatments may contribute to poor compliance and consequently to treatment failure. A specific questionnaire is necessary to assess patients' needs and their perceptions of anticoagulant treatment.
A conceptual model of expectation and satisfaction with anticoagulant treatment was designed by an advisory board and used to guide patient (n = 31) and clinician (n = 17) interviews in French, US English and Dutch. Patients had either atrial fibrillation (AF), deep venous thrombosis (DVT), or pulmonary embolism (PE). Following interviews, three PACT-Q language versions were developed simultaneously and further pilot-tested by 19 patients. Linguistic validations were performed for additional language versions.
Initial concepts were developed to cover three areas of interest: 'Treatment', 'Disease and Complications' and 'Information about disease and anticoagulant treatment'. After clinician and patient interviews, concepts were further refined into four domains and 17 concepts; test versions of the PACT-Q were then created simultaneously in three languages, each containing 27 items grouped into four domains: "Treatment Expectations" (7 items), "Convenience" (11 items), "Burden of Disease and Treatment" (2 items) and "Anticoagulant Treatment Satisfaction" (7 items). No item was deleted or added after pilot testing as patients found the PACT-Q easy to understand and appropriate in length in all languages. The PACT-Q was divided into two parts: the first part to measure the expectations and the second to measure the convenience, burden and treatment satisfaction, for evaluation prior to and after anticoagulant treatment, respectively. Eleven additional language versions were linguistically validated.
The PACT-Q has been rigorously developed and linguistically validated. It is available in 14 languages for use with thromboembolic patients, including AF, PE and DVT patients. Its validation and psychometric properties have been tested and are presented in a separate manuscript.
The ankle brachial index (ABI) is a well-established tool for screening and diagnosis of peripheral arterial disease (PAD). In this study we assessed the validity of ABI determination using a pocket Doppler device compared with automatic vascular laboratory measurement in patients suspected of PAD.
Consecutive patients with symptoms of PAD referred for ABI measurement between December 2006 and August 2007 were included. Resting ABI was determined with a pocket Doppler, followed by ABI measurement with automatic vascular laboratory equipment, performed by an experienced vascular technician. The leg with the lowest ABI was used for analysis.
From 99 patients the mean resting ABI was 0.80 measured with the pocket Doppler and 0.85 measured with vascular laboratory equipment. A Bland-Altman plot demonstrated great correspondence between the two methods. The mean difference between the two methods was 0.05 (P < .001). Multivariate linear regression analysis showed no dependency of the difference on either the average measured ABI or affected or unaffected leg.
Since the small, albeit statistically significant, difference between the two methods is not clinically relevant, our study demonstrates that ABI measurements with pocket Doppler and vascular laboratory equipment yield comparable results and can replace each other. Results support the use of the pocket Doppler for screening of PAD, allowing initiation of cardiovascular risk factor management in primary care, provided that the equipment operator is experienced.
If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index.
To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease.
Design of study
An observational study.
General practice in The Netherlands.
This observational study included patients of ≥55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease.
Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category.
This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.
ankle brachial index; atheroscelerosis; clinical decision rule; Edinburgh Claudication Questionnaire; intermittent claudication; peripheral vascular disease
Understanding the pathogenesis of malaria in pregnancy and its consequences for both the mother and the baby is fundamental for improving malaria control in pregnant women.
The study aimed to investigate the role of ABO blood groups on pregnancy outcomes in an area of unstable malaria transmission in eastern Sudan.
A total of 293 women delivering in New Half teaching hospital, eastern Sudan during the period October 2006–March 2007 have been analyzed. ABO blood groups were determined and placental histopathology examinations for malaria were performed. Birth and placental weight were recorded and maternal haemoglobin was measured.
114 (39.7%), 61 (22.1%) and 118 (38.2%) women were primiparae, secundiparae and multiparae, respectively. The ABO blood group distribution was 82(A), 59 (B), 24 (AB) and 128 (O). Placental histopathology showed acute placental malaria infections in 6 (2%), chronic infections in 6 (2%), 82 (28.0%) of the placentae showed past infection and 199 (68.0%) showed no infection. There was no association between the age (OR = 1.02, 95% CI = 0.45–2.2; P = 0.9), parity (OR = 0.6, 95% CI = 0.3–1.2; P = 0.1) and placental malaria infections. In all parity blood group O was associated with a higher risk of past (OR = 1.9, 95% CI = 1.1–3.2; P = 0.01) placental malaria infection. This was also true when primiparae were considered separately (OR = 2.6, 95% CI = 1.05–6.5, P = 0.03).
Among women with all placental infections/past placental infection, the mean haemoglobin was higher in women with the blood group O, but the mean birth weight, foeto-placental weight ratio was not different between these groups and the non-O group.
These results indicate that women of eastern Sudan are at risk for placental malaria infection irrespective to their age or parity. Those women with blood group O were at higher risk of past placental malaria infection.
Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism.
Design Double blind randomised placebo controlled trial.
Setting 35 centres in eight countries.
Participants 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days.
Interventions 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days.
Outcome measure The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month.
Results 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died.
Conclusion Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.
Poor compliance with antihypertensive medication is assumed to be an important reason for unsatisfactory control of blood pressure. Poor compliance is difficult to detect. Each method of measuring compliance has its own strengths and weaknesses.
The aim of the present study was to compare patient compliance with antihypertensive drugs as measured by two methods, electronic monitoring versus refill compliance.
161 patients with a diagnosis of hypertension for at least a year prior to inclusion, and inadequate blood pressure control (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 95 mmHg) despite the use of antihypertensive drugs, were included. Patients' pharmacy records from 12 months prior to inclusion were obtained. Refill compliance was calculated as the number of days for which the pills were prescribed divided by the total number of days in this period. After inclusion compliance was measured with an electronic monitor that records time and date of each opening of the pillbox. Agreement between both compliance measures was calculated using Spearman's correlation coefficient and Cohen's kappa coefficient.
There was very little agreement between the two measures. Whereas refill compliance showed a large range of values, compliance as measured by electronic monitoring was high in almost all patients with estimates between 90% and 100%. Cohen's kappa coefficient was 0.005.
While electronic monitoring is often considered to be the gold standard for compliance measurements, our results suggest that a short-term electronic monitoring period with the patient being aware of electronic monitoring is probably insufficient to obtain valid compliance data. We conclude that there is a strong need for more studies that explore the effect of electronic monitoring on patient's compliance.
Objective To validate the use of the Wells clinical decision rule combined with a point of care D-dimer test to safely exclude pulmonary embolism in primary care.
Design Prospective cohort study.
Setting Primary care across three different regions of the Netherlands (Amsterdam, Maastricht, and Utrecht).
Participants 598 adults with suspected pulmonary embolism in primary care.
Interventions Doctors scored patients according to the seven variables of the Wells rule and carried out a qualitative point of care D-dimer test. All patients were referred to secondary care and diagnosed according to local protocols. Pulmonary embolism was confirmed or refuted on the basis of a composite reference standard, including spiral computed tomography and three months’ follow-up.
Main outcome measures Diagnostic accuracy (sensitivity and specificity), proportion of patients at low risk (efficiency), number of missed patients with pulmonary embolism in low risk category (false negative rate), and the presence of symptomatic venous thromboembolism, based on the composite reference standard, including events during the follow-up period of three months.
Results Pulmonary embolism was present in 73 patients (prevalence 12.2%). On the basis of a threshold Wells score of ≤4 and a negative qualitative D-dimer test result, 272 of 598 patients were classified as low risk (efficiency 45.5%). Four cases of pulmonary embolism were observed in these 272 patients (false negative rate 1.5%, 95% confidence interval 0.4% to 3.7%). The sensitivity and specificity of this combined diagnostic approach was 94.5% (86.6% to 98.5%) and 51.0% (46.7% to 55.4%), respectively.
Conclusion A Wells score of ≤4 combined with a negative qualitative D-dimer test result can safely and efficiently exclude pulmonary embolism in primary care.