Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism.

Preliminary data and clinical experience have suggested an increased risk of abnormal uterine bleeding (AUB) in women of reproductive age treated with anticoagulants, but solid data are lacking. The TEAM-VTE study was an international multicenter prospective cohort study in women aged 18 to 50 years diagnosed with acute venous thromboembolism (VTE). Menstrual blood loss was measured by pictorial blood loss assessment charts at baseline for the last menstrual cycle before VTE diagnosis and prospectively for each cycle during 3 to 6 months of follow-up. AUB was defined as an increased score on the pictorial blood loss assessment chart (>100 or >150) or self-reported AUB. AUB-related quality of life (QoL) was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire. The study was terminated early because of slow recruitment attributable to the COVID-19 pandemic. Of the 98 women, 65 (66%) met at least one of the 3 definitions of AUB during follow-up (95% confidence interval [CI], 57%-75%). AUB occurred in 60% of women (36 of 60) without AUB before VTE diagnosis (new-onset AUB; 95% CI, 47%-71%). Overall, QoL decreased over time, with a mean Menstrual Bleeding Questionnaire score increase of 5.1 points (95% CI, 2.2-7.9), but this decrease in QoL was observed only among women with new-onset AUB. To conclude, 2 of every 3 women who start anticoagulation for acute VTE experience AUB, with a considerable negative impact on QoL. These findings should be a call to action to increase awareness and provide evidence-based strategies to prevent and treat AUB in this setting. This was an academic study registered at www.clinicaltrials.gov as #NCT04748393; no funding was received.

Value of TENS for relief of chronic low back pain with or without radicular pain.

OBJECTIVES: To evaluate the efficacy of transcutaneous electrical neurostimulation (TENS) in patients with chronic low back pain (LBP). DESIGN: Prospective, randomized, multicentre, single-blind study. SETTING: Twenty-one French pain centres. PARTICIPANTS: Two hundred thirty-six consecutive adult patients consulting for chronic LBP, with or without radicular pain (mean age ± standard deviation: 53 ± 13 years; range: 28-86 years). INTERVENTION: Patients were randomly assigned to receive either active (n = 117) or sham (n = 119) TENS in four 1-h daily treatment sessions for 3 months. MAIN OUTCOME MEASURES: The primary outcome measured was improvement of functional status at 6 weeks (Roland-Morris Disability Questionnaire). Secondary outcome measures were improvement of functional status at 3 months, pain relief (weekly visual analogue scale assessments), positive functional repercussions of pain levels on quality of life, a diminution of the use of analgesic and anti-inflammatory medication, satisfaction with the overall treatment strategy and compliance. RESULTS: Functional status did not differ between the groups, whether at 6 weeks or 3 months (p = 0.351 at 6 weeks). A significant improvement between the first and last visual analogue scale assessments was observed in patients with either lumbar pain alone or lumbar and radicular pain treated with active TENS. Other outcome measures did not differ significantly between the two groups. CONCLUSION: There was no functional benefit of TENS in the treatment of patients with chronic LBP.

Older people included in a venous thrombo-embolism clinical trial: a patients' viewpoint.

BACKGROUND AND OBJECTIVES: despite the numerous publications debating ethical rules of clinical research, older patients' opinions are rarely taken into account. We report on the feelings and memories related by older patients included in a randomised controlled trial. DESIGN AND SETTINGS: a closed-questionnaire was submitted to patients, aged >65 years, who had been included in the randomised trial "PREPIC". PREPIC was a multicentre open trial performed in France, that included 400 patients over 42 months. The aim of PREPIC was to evaluate the benefits and risks of prophylactic filter placement in patients with proximal deep-vein thrombosis who were considered to be at risk for pulmonary embolism. RESULTS: 104 patients (mean age: 74 years) were interviewed. At the time the trial was proposed to them, 45% of patients felt surprised or shocked and 30% feared incurring additional risks. While 85% of patients did not remember the trial methods (including the randomisation), most older patients (77%) not only judged that they received clear medical information but also well remembered (95%) the aim of the study and the treatment they received (67%). Finally, most older patients not only did not regret their participation (91%), but would also recommend their close relations to participate in a clinical trial (62%). CONCLUSIONS: this study demonstrates that medical scientific information can be understood and remembered by older people.

Diagnosis of pulmonary embolism in patients with proximal deep vein thrombosis: specificity of symptoms and perfusion defects at baseline and during anticoagulant therapy.

To determine the specificity of pulmonary embolism (PE) symptoms and lung scan perfusion defects in patients with deep vein thrombosis (DVT), we analyzed data on 400 patients with phlebography-proven proximal DVT included in a prospective trial. As the incidence of PE during anticoagulant therapy was the main outcome measure of the trial, all patients underwent lung scanning and/or pulmonary angiography within 48 h of inclusion, and then whenever PE was suspected. Angiography was recommended in patients with nondiagnostic lung scan. At baseline, the presence or absence of PE could be ascertained in 350 patients (87.5%), and 197 (56%) had PE. Sensitivity and specificity of symptoms for PE were 74 and 67%, respectively. Among 37 patients with symptoms and nondiagnostic lung scan, only 8 (22%) had PE at angiography. During anticoagulant therapy (3 mo), there were 29 events suspicious for PE, mostly (53%) within 2 wk of inclusion. Repeated perfusion studies with comparison to baseline tests excluded PE in 21 cases. Cumulated 3-mo risks of suspected and confirmed on-treatment PE were 6.8% (95% CI, 5.4- 8.2%) and 2.0% (95% CI, 0.6-3.4%) respectively. Even in patients with known proximal DVT, PE symptoms are unspecific and careful imaging studies are needed for diagnosis, both at baseline and during anticoagulant therapy.

Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery.

BACKGROUND: Low molecular weight heparins (LMWHs) have become routine thromboprophylaxis in general surgery. However, their actual clinical effect, its magnitude relative to that of unfractionated heparin (UFH), and the optimal dose are still debated. METHODS: A meta-analysis was performed of all available randomized trials in general surgery comparing LMWH with placebo or no treatment, or with UFH. RESULTS: Comparison versus placebo or no treatment confirmed that the significant reduction in asymptomatic deep vein thrombosis (DVT) obtained with LMWH (n = 513; relative risk (RR) 0.28 (95 per cent confidence interval 0.14-0.54)) was associated with a significant reduction in clinical pulmonary embolism (n = 5456; RR 0.25 (0.08-0.79)) and clinical venous thromboembolism (VTE) (n = 4890; RR 0.29 (0.11-0.73)), and a trend towards a reduction in overall mortality rate. Comparison versus UFH showed a trend in favour of LMWH, with a significant reduction in clinical VTE (P = 0.049), a trend also found for cancer surgery. LMWH at doses below 3400 anti-Xa units seemed to be as effective as, and safer than, UFH, while higher doses yielded slightly superior efficacy but increased haemorrhagic risk, including that of major haemorrhage. CONCLUSION: Asymptomatic DVT may be regarded as a reliable surrogate endpoint for clinical outcome in studies investigating thromboprophylaxis in general surgery. LMWH seems to be as effective and safe as UFH. Determination of the optimal dose regimen of LMWH for this indication requires further investigation.

Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials.

BACKGROUND: The prevention of venous thromboembolic disease is less studied in medical patients than in surgery. METHODS: We performed a meta-analysis of randomised trials studying prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in internal medicine, excluding acute myocardial infarction or ischaemic stroke. Deep-vein thrombosis (DVT) systematically detected at the end of the treatment period, clinical pulmonary embolism (PE), death and major bleeding were recorded. RESULTS: Seven trials comparing a prophylactic heparin treatment to a control (15,095 patients) were selected. A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions = 56% and 58% respectively, p <0.001 in both cases), without significant difference in the incidence of major bleedings or deaths. Nine trials comparing LMWH to UFH (4,669 patients) were also included. No significant effect was observed on either DVT, clinical PE or mortality. However LMWH reduced by 52% the risk of major haemorrhage (p = 0.049). CONCLUSIONS: This meta-analysis, based on the pooling of data available for several heparins, shows that heparins are beneficial in the prevention of venous thromboembolism in internal medicine.

Pharmacokinetic and pharmacodynamic variations of acenocoumarol orally administrated either once or twice daily in patients with deep venous thrombosis.

The literature suggests that variations in anticoagulant effect occur when acenocoumarol is administrated in a daily dose. We assessed the anticoagulant effects of acenocoumarol with INR, factors VII and X and protein C in 12 randomly selected hospitalised patients with deep-vein thrombosis, six of them receiving a daily dose of acenocoumarol, the other six receiving twice daily doses. When the drug effect had been at a steady-state for at least 72 h, five blood samples were drawn per patient over a period of 24 h. No nycthemeral significant variations were noted for INR, factor X and protein C in the two groups (P > 0.10). Nycthemeral significant variation in factor VII when acenocoumarol was administered once daily was noted (P = 0.02), but the clinical relevance of factor VII variation at steady-state is uncertain. In spite of the short pharmacokinetic half-life of acenocoumarol, a stable nycthemeral pharmacodynamic activity was observed after once daily administration; twice-daily administration of acenocoumarol does not appear to be justified.

Early versus delayed introduction of oral vitamin K antagonists in combination with low-molecular-weight heparin in the treatment of deep vein thrombosis. a randomized clinical trial. The ANTENOX Study Group.

OBJECTIVE: To compare oral anticoagulant treatment (fluindione) started on either the 1st or the 10th day of a low-molecular-weight heparin (enoxaparin) treatment for deep vein thrombosis confirmed by venography. DESIGN: An open, multicenter, randomized study in two parallel treatment groups. INTERVENTIONS: All patients received enoxaparin, 1 mg/kg s.c. twice daily, and oral fluindione, 20 mg once daily, either beginning on day 1 or on day 10 of the enoxaparin treatment. Enoxaparin was discontinued once the international normalized ratio under fluindione was stable between 2.0 and 3.0 over 2 days. Fluindione treatment was maintained during a 3-month follow-up period. OUTCOME MEASUREMENTS: Specific examinations (venography and/or V/Q lung scanning and/or angiography) were performed only in the event of a clinically suspected recurrence of venous thromboembolism during the 3-month follow-up period. All cases were blindly assessed by an independent Reading Committee. RESULTS: A clinically suspected venous thromboembolism was confirmed by objective tests in 1 of 223 patients (group of delayed introduction of fluindione; n = 111). Equivalence was demonstrated between the two treatment schedules (p < 0.0001) for a maximal difference of 10% (90% confidence interval: -2.42 to 0.58). The mean duration of hospitalization was significantly reduced (p = 0.0001) in the group with early introduction of fluindione. The incidence of hemorrhage was comparable between the two treatment groups. CONCLUSION: Early and delayed introduction of oral anticoagulant treatment in association with subcutaneous enoxaparin in patients with deep vein thrombosis was shown to be equivalent in preventing the recurrence of venous thromboembolism. In patients with early introduction of oral anticoagulant, hospitalization was significantly reduced.

Dosing time optimizes sustained-release ketoprofen treatment of osteoarthritis.

A double-blind randomized parallel-group trial was undertaken to evaluate the influence of the dosing time of sustained-release ketoprofen (SRK) on its acceptability and efficacy. The SRK was prescribed for 2 weeks (200 mg once a day) to 117 outpatients with osteoarthritis of the knee and/or hip. One group received SRK in the morning (at 8 a.m.) and the other group in the evening (at 8 p.m.). The principal aim of the trial concerned the acceptability, whereas efficacy was its secondary aim. The principal trial criterion was defined as the number of spontaneous recordings of adverse effects. Results showed clearly that the acceptability of SRK in the SRK morning group was worse than that in the evening group (39% of patients with one or more adverse effects in the SRK morning group versus 19% in the evening group; p = 0.019). It is important to stress the difference concerning the number of adverse effects (48 for SRK morning group versus 23 for SRK evening group; p = 0.0234). The analgesic efficacy seemed to be similar, but one criterion was statistically significant: The duration of analgesic efficacy was more important for the SRK evening group than for the morning group (9.37 and 5.47 h, respectively; p = 0.001). To increase its acceptability, evening administration of SRK seems to be preferred over morning administration in osteoarthritis. However, other trials of the same type, assessing other antiinflammatory agents, are necessary before a general extrapolation of such results can be undertaken.