Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Direct oral anticoagulants in the treatment of acute venous thromboembolism in patients with obesity: A systematic review with meta-analysis.

BACKGROUND: Direct oral anticoagulants' (DOAC) pharmacokinetics are affected by obesity. Their efficacy and safety in obesity (BMI≥30 kg/m2) and morbid obesity (BMI≥40 kg/m2) are still unclear in the treatment of venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy/safety of DOAC versus vitamin K antagonist (VKA)/low molecular weight heparin (LMWH) for the treatment of VTE in patients with obesity and morbid obesity. The primary efficacy/safety outcomes were VTE recurrence and major bleeding (MB). Clinically relevant non-MB and mortality were also evaluated. METHODS: A systematic literature search (MEDLINE, EMBASE, CENTRAL, Web of Science) identified studies evaluating DOAC in the treatment of VTE in patients with obesity and reporting one of the outcomes. Relative risks (RR) and 95 % confidence intervals (CI) were estimated using the Mantel-Haenszel method. RESULTS: We included 21 studies (50,360pts) of which 16,150 patients had a BMI≥30 kg/m2 and 6443 patients had a BMI≥40 kg/m2. VTE recurrence was similar with DOAC compared to VKA/LMWH in patients with obesity (RR 1.03;95 %CI 0.93-1.15;p = 0.55) and morbid obesity (RR 1.06;95 %CI 0.94-1.19;p = 0.35). DOAC were also associated with a reduction in MB (RR 0.57;95 %CI 0.34-0.94;p = 0.03 and RR 0.71;95 %CI 0.50-1.00;p = 0.05 in patients with obesity and morbid obesity, respectively). Subgroup analyses comparing randomized controlled trials to observational studies showed consistent results. No difference was observed in regards of clinically relevant non-MB and mortality. CONCLUSION: There is no signal for differences in VTE recurrence in patients with obesity and morbid obesity treated with DOAC compared to VKA/LMWH, while DOAC likely reduce the risk of MB compared to VKA/LMWH.

DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis.

Low molecular weight heparins (LMWH) are the standard of care for the treatment of cancer-associated venous thromboembolism (CA-VTE). We performed a systematic review and meta-analysis to compare the effects of direct oral anticoagulants (DOAC) versus LMWH for the treatment of CA-VTE. The primary efficacy and safety outcomes were VTE recurrence and major bleeding (MB). The secondary outcomes were clinically relevant non-MB (CRNMB), all-cause mortality and the net clinical benefit. We searched MEDLINE, EMBASE, CENTRAL and Web of Science (inception-December 2019) and abstracts of relevant conferences (2000-2019) to identify randomized controlled trials comparing DOAC and LMWH for the treatment of CA-VTE. Relative risks (RR) and 95% confidence intervals were estimated (Mantel-Haenszel method, random-effects models). A non-inferiority analysis with a margin of 1.3 for the upper boundary of the RR was conducted for the primary outcomes. From 637 references, we included four publications which encompass three trials (1756 patients). Compared to LMWH, DOAC were associated with a trend for decreased VTE recurrence (RR 0.51; 95%CI 0.25-1.03; p = 0.06; I2 = 51%), whereas MB (RR 1.64; 95%CI 1.00-2.69; p = 0.05; I2 = 0%) and CRNMB (RR 1.83; 95%CI 1.04-3.20; p = 0.03; I2 = 50%) were significantly more frequent with DOAC. Conversely, all-cause mortality (RR 1.06; 95%CI 0.83-1.35; p = 0.64; I2 = 36%) and net clinical benefit (RR 0.74; 95%CI 0.38-1.42; p = 0.36; I2 = 65%) were comparable. DOAC were non-inferior to LMWH in preventing CA-VTE recurrence, but were associated with an increased risk of MB and CRNMB. Further studies are required to confirm these results and inform on the risk/benefit ratio for specific populations.

Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysis of the management outcome studies.

Essentials Computed tomographic pulmonary angiography (CTPA) is used to exclude pulmonary embolism. This meta-analysis explores the occurrence of venous thromboembolic events (VTE) after a CTPA. Occurrence of VTE after a negative CTPA is ˜8% in study subgroups with a prevalence of PE ≥ 40%. CTPA may be insufficient to safely rule out VTE as a stand-alone diagnostic test for this subgroup. SUMMARY: Background Outcome studies have reported the safety of computed tomographic pulmonary angiography (CTPA) as a stand-alone imaging technique to rule out pulmonary embolism (PE). Whether this can be applied to all clinical probabilities remains controversial. Objectives We performed a meta-analysis to determine the proportion of patients with venous thromboembolic events (VTE) despite a negative CTPA according to pretest PE prevalence. Methods We searched MEDLINE, EMBASE and the Cochrane Library (January 1990 to May 2017) for outcome studies recruiting patients with suspected PE using CTPA as a diagnostic strategy. The primary outcome was the cumulative occurrence of VTE at 3 months following a negative CTPA. Results Twenty-two different studies were identified. VTE was confirmed in 2.4% of patients (95% CI, 1.3-3.8%) either at the time of the index event or in the 3 months follow-up. Subgroup analyses suggested that the cumulative occurrence of VTE was related to pretest prevalence of PE, as VTE occurred in 1.8% (95% CI, 0.5-3.7%), 1.4% (95% CI, 0.7-2.3%), 1.0% (95% CI, 0.5-1.8%) and 8.1% (95% CI, 3.5-14.5%) of subgroups of patients with a PE prevalence < 20%, 20-29%, 30-39% and ≥ 40%, respectively. This was further confirmed using meta-regression analysis. Conclusions The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.

Identity crisis in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) shares many hallmarks with cancer. Cancer cells acquire their hallmarks by a pathological Darwinian evolution process built on the so-called cancer cell "identity crisis." Here we demonstrate that PAH shares the most striking features of the cancer identity crisis: the ectopic expression of normally silent tissue-specific genes.

Tiotropium improves walking endurance in COPD.

The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 µg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean±sd between-group difference of 128±141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity.

Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis.

BACKGROUND: The role of biomarkers such as B-type natriuretic peptides (BNP and NT-proBNP) and troponins in risk stratification of acute pulmonary embolism (APE) is still debated. A meta-analysis was performed to assess the association between raised natriuretic peptide levels, alone or in conjunction with troponins, and all-cause and APE-related mortality, serious adverse events and echographic right ventricular dysfunction. METHODS: MEDLINE and EMBASE databases were searched and conference abstracts were hand searched up to February 2008. Studies were included if a 2x2 table could be constructed based on natriuretic peptide results and at least one of the outcomes. RESULTS: Twenty-three studies were included (1127 patients). Raised natriuretic peptide levels were significantly associated with all-cause mortality (odds ratio (OR) 6.2; 95% confidence interval (CI) 3.0 to 12.7), APE-related mortality (OR 5.0; 95% CI 2.2 to 11.5) and serious adverse events (OR 6.7; 95% CI 3.9 to 11.6), with homogeneity across studies. Among patients with raised natriuretic peptide levels, increased serum troponins were associated with a further increase in the risk of adverse outcomes. Analysis of the accuracy of natriuretic peptides in detecting right ventricular dysfunction was limited by heterogeneity across studies. BNP appeared to have better sensitivity and specificity than NT-proBNP in detecting right ventricular dysfunction. CONCLUSIONS: Raised levels of B-type natriuretic peptides identified a subset of patients with APE at higher risk of adverse outcomes. Among patients with raised natriuretic peptide levels, increased troponins were found to be an independent prognostic marker. The results of this meta-analysis may have important clinical implications in the management of APE.

Changes in exercise haemodynamics during treatment in pulmonary arterial hypertension.

Improvement in exercise capacity may not be associated with significant changes in resting pulmonary haemodynamics. The present prospective study documented the relationships between improvement in 6-min walking distance (6MWD) and changes in resting and exercise pulmonary haemodynamics after treatment in patients with idiopathic pulmonary arterial hypertension (IPAH). A total of 42 IPAH patients underwent supine submaximal exercise haemodynamic assessments at baseline and after 5+/-2 months of therapy. The 6MWD, the corresponding chronotropic response (peak minus resting heart rate), and resting and exercise haemodynamic variables were analysed. The isoflow was defined as the lowest of the pre- and post-treatment peak cardiac index (CI). The extrapolated isoflow mean pulmonary artery pressure ((pa)) was used to characterise changes in (pa)-CI regression lines following treatment. Patients were given bosentan (n = 28), epoprostenol (n = 12) or both. The 6MWD increased significantly, from 399+/-88 to 442+/-86 m. On univariate analysis, changes in 6MWD correlated with changes in isoflow (pa), chronotropic response, resting haemodynamics (CI, pulmonary vascular resistance and mixed venous oxygen saturation) and exercise haemodynamics (peak CI). On multivariate analysis, only changes in isoflow (pa) and chronotropic response were independently associated with changes in 6MWD. Improvement in exercise tolerance with chronic therapy is independently related to improvement in pulmonary haemodynamics measured in exercise but not in resting conditions.

Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) exhibit a limited increase in stroke volume on exercise, and the heart rate (HR) increases may reflect the main mechanism that allows cardiac output to increase. The current prospective study documented the contribution of HR to the 6-min walking distance (6MWD) in idiopathic (IPAH) and nonidiopathic PAH. Eighty-three patients (46 IPAH and 37 nonidiopathic PAH) underwent haemodynamic evaluation and a 6MWD test. Chronotropic response (peak walking HR minus resting HR) and peripheral oxygen saturation were monitored. Fifty-seven patients were also assessed after 5+/-2 months of treatment (bosentan n = 38, epoprostenol n = 14, bosentan-epoprostenol n = 3, iloprost n = 2). Before treatment, the 6MWD was related to numerous demographic, haemodynamic and walking test characteristics. Stepwise regression analysis indicated that the only factors significantly associated with the 6MWD were stroke volume and chronotropic response in both IPAH and nonidiopathic PAH patients. Following treatment, changes in 6MWD were significantly related to changes in chronotropic response in both IPAH and nonidiopathic PAH. In conclusion, baseline stroke volume and chronotropic response were independently associated with the 6-min walking distance in pulmonary arterial hypertension. The lack of chronotropic response may reflect the loss in normal physiological reserve in more unwell patients.

[Diagnosis and classification of pulmonary arterial hypertension]. / Diagnostic et classification des hypertensions artérielles pulmonaires.

The clinical classification of types of pulmonary hypertension has made it possible to better standardize the approach to the diagnosis and treatment of patients, to perform clinical studies among homogeneous patients, and to discover common laboratory abnormalities that may serve as markers or help elucidate mechanisms of disease. Pulmonary arterial hypertension groups together different diseases that affect the small-caliber pulmonary arteries and lead to a progressive increase in pulmonary arterial resistance and right heart failure. A specific diagnosis of pulmonary arterial hypertension is generally based on a detailed and methodical clinical evaluation. Pulmonary biopsy is rarely indicated. Work-up in a center specialized in the management of this disease is frequently appropriate when the cause of the hypertension is not clear or when a specific treatment is envisaged.

Detection of elevated glutathione in meningiomas by quantitative in vivo 1H MRS.

Glutathione has major roles in removing free radicals and toxins from normal tissues, but its presence in tumor cells hinders the effectiveness of many anticancer therapies. Analysis of short echo time brain tumor (1)H spectra at 1.5 T using a linear combination of metabolite spectra (LCModel) suggested a significant contribution of glutathione to meningioma spectra. By in vivo MRS (TE = 30 ms, TR = 2020 ms), reduced glutathione was found to be significantly elevated in meningiomas (3.3 +/- 1.5 mM, Mann Whitney, P < 0.005) compared to normal white matter (1.2 +/- 0.15 mM) and low-grade gliomas (1.0 +/- 0.26 mM), in agreement with published histofluorescence studies of tumor biopsies. Glx concentrations were also found to be elevated in meningiomas compared to astrocytomas or normal white matter, indicative of metabolic differences. The ability to noninvasively quantify reduced glutathione in vivo may aid selection of treatment therapies and also provide an indication of tumor aggressiveness.

Automatic quantitation of localized in vivo 1H spectra with LCModel.

The LCModel method analyzes an in vivo spectrum as a Linear Combination of Model in vitro spectra from individual metabolite solutions. Complete model spectra, rather than individual resonances, are used in order to incorporate maximum prior information into the analysis. A nearly model-free constrained regularization method automatically accounts for the baseline and lineshape in vivo without imposing a restrictive parameterized form on them. LCModel is automatic (non-interactive) with no subjective input. Approximately maximum-likelihood estimates of the metabolite concentrations and their uncertainties (Cramér-Rao lower bounds) are obtained. LCModel analyses of spectra from users with fields from 1.5 to 9.4 T and a wide range of sequences, particularly with short TE, are used here to illustrate the capabilities and limitations of LCModel and proton MRS.

Toward an in vivo neurochemical profile: quantification of 18 metabolites in short-echo-time (1)H NMR spectra of the rat brain.

Localized in vivo (1)H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T(1) than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-microL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in (1)H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, gamma-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

Water diffusion in rat brain in vivo as detected at very large b values is multicompartmental.

The diffusion-weighted signal attenuation of water in rat brain was measured with pulsed-field gradient nuclear magnetic resonance methods in a single voxel under in vivo and global ischemic conditions. The diffusion-attenuated water signal was observed in vivo at b values of 300 ms/microm2 (strength of diffusion weighting) and diffusion times up to 400 ms. A series of constant diffusion time (CT) experiments with varied gradient directions and diffusion times revealed a multiexponential decay with apparent diffusion coefficients (ADC) covering two orders of magnitude from 1 to 0.01 microm2/ms. In a four-exponential fit, the observed changes during global ischemia could be fully explained by changes in the relative volume fractions only with unchanged ADCs. An anisotropy of the ADC, detected at small b values, was not observed for the ADC at large b values, but for the concomitant volume fractions. An inverse Laplace Transform of the CT curves, performed with CONTIN, resulted in continuously distributed diffusion coefficients, for which the term 'diffusogram' is proposed. This approach was more appropriate than a discrete exponential model with four to six components, being related to the morphology of brain tissue and its cell size distribution. On the basis of an analytical, quantitative model, it is suggested that the measured ADC at small b values reflects mainly properties of the restricting boundaries, i.e. the relative volume fractions and the extracellular tortuosity, while the intrinsic intracellular diffusion constant and the exchange time are predicted to have minor influence.

Effect of cyclosporine A on cytochrome P-450-mediated drug metabolism in the partially hepatectomized rat.

Despite its hepatotoxic potential, cyclosporine A (CsA) has been reported to positively influence compensatory liver growth. To probe the physiological consequences of CsA on the recovery of liver function, studies were initiated in the 2/3 partially hepatectomized (PHx) rat, taking the recovery of cytochromes P-450-dependent drug metabolism as primary outcome. CsA was administered at a dose of 3. 33 mg/kg/day for 10 days. Drug metabolism was evaluated by the recovery of 14CO2 after administration of isotopically labeled model drugs and by studying the expression of the P-450 transcripts involved in their biotransformation before and 24 to 96 h after PHx. Before PHx, neither the steady-state mRNA nor the in vivo disposition of caffeine (CYP1A2), erythromycin (CYP3A2 and 3A1), or aminopyrine (CYP2B1 and 2C11) were influenced by CsA. Studies 24 h after PHx revealed a 29 to 39% reduction in the elimination of [14C]aminopyrine and [14C]erythromycin, which was unaffected by CsA. Their metabolism at 48 to 96 h after PHx also remained unaffected by CsA. By contrast, postPHx, [14C]caffeine elimination decreased to a level closely proportional to the loss in liver mass. In addition, CsA accelerated the recovery and/or prevented the decrease of caffeine elimination 24 h after PHx but not at later time points, indicating an early, but unsustained, beneficial effect of CsA on the recovery of CYP1A2-mediated activities. These data show that at the critical time of greatest loss in liver mass, CsA has only a selective influence on the biotransformation of cytochrome P-450 protein-dependent activities and that its effect on the regeneration process does not translate into an overall accelerated recovery of the hepatic drug-metabolizing function.

Physician based surveillance system for occupational respiratory diseases: the experience of PROPULSE, Québec, Canada.

OBJECTIVE: To evaluate the feasibility of implementing a physician based surveillance system of occupational respiratory diseases (PROPULSE) in Québec with regard to physician participation rate, characteristics of reported cases, and comparison with official statistics from the Workers' Compensation Board (WCB). METHODS: All chest physicians and allergists in Québec were asked to report suspected new cases of occupational respiratory diseases, on a monthly basis, between October 1992 and September 1993. For each case, personal information was collected and the physician's opinion on whether the condition was related to work was categorised as highly likely, likely, and unlikely. RESULTS: Of the 161 physicians initially approached, 68% participated. Physicians rated 48% of suspected cases as highly likely, 29% as likely, and 20% as unlikely. The most often reported diagnosis was asthma (63%), followed by diseases related to asbestos (16%). Silicosis was less frequent (5%) but it was reported for six workers under 40 of whom five were involved in sandblasting activities. The high proportion of cases of asthma probably reflects the increasing importance of this disease but may also reflect the different patterns of reporting among physicians with different expertise. The distribution of cases by diagnostic category is quite different between the PROPULSE system and that of the WCB (annual mean number of compensated cases during a four year period). Asthma and allergic alveolitis are more frequent in PROPULSE, reactive airways dysfunction syndrome are about the same in both systems, and other diseases are more frequent among compensated cases. The most frequent sensitising agents reported for asthma were the same in both systems (isocyanates, flour, and wood dust). 15% of the PROPULSE cases were not covered by the WCB, and therefore would not be found in the board's official statistics. CONCLUSIONS: A physician based reporting procedure can be implemented as part of a surveillance system to supplement data from other sources and thus provide a better understanding of the occurrence of occupational respiratory diseases.

Conformational analysis of galanin using end to end distance distribution observed by Förster resonance energy transfer.

The structural dynamics of the flexible neuropeptide galanin in solution were studied by Förster resonance energy transfer measurements at different temperatures by time-resolved fluorescence spectroscopy to determine its conformational heterogeneity. Endogenous tryptophan at position 2 acted as the fluorescent donor and the non fluorescent acceptor dinitrophenyl or the fluorescent acceptor dansyl were selectively attached to lysine 25 in porcine galanin. The coexistence of different structures of the neuropeptide galanin in trifluoroethanol solution was revealed by the model independent analysis of the distribution of relaxation times from the time-resolved resonance energy transfer data. Multiple conformational states are reflected by distinct end-to-end distance populations. The conformations differ in mean donor-acceptor distance by about 15, and are consistent with the extended and folded backbone conformations of two alpha-helical regions separated by a flexible hinge. The effect that the labelling of galanin has on binding to the receptor was also evaluated. DNP-galanin showed the same high affinity to galanin receptors as unlabelled galanin, whereas DNS-galanin had significantly reduced affinity.