Silvy Laporte

Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism: A Randomized Clinical Trial

IMPORTANCEnAlthough retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear.nnnOBJECTIVEnTo evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; nu2009=u2009200) or anticoagulation alone with no filter implantation (control group; nu2009=u2009199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers.nnnINTERVENTIONSnFull-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement.nnnMAIN OUTCOMES AND MEASURESnPrimary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications.nnnRESULTSnIn the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; Pu2009=u2009.50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients.nnnCONCLUSIONS AND RELEVANCEnAmong hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00457158.

Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta‐analysis

Summary.u2002 Background:u2003The benefit‐to‐risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low‐molecular‐weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated. Objectives:u2003We performed a meta‐analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments. Patients and methods:u2003An exhaustive literature search, both manual and computer‐assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures. Results:u2003VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) =u200a0.56, 95% confidence interval (CI) 0.37, 0.84, Pu2003<u20030.01] and clinical PE (651 patients, RR =u200a0.23, 95% CI 0.09, 0.59, Pu2003<u20030.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RRu200a=u200a2.91, 95% CI 1.09, 7.75, Pu2003=u20030.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR =u200a0.46, 95% CI 0.25, 0.82, Pu2003=u20030.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR =u200a1.51, 95% CI 1.27, 1.79, Pu2003<u20030.001; and 6131 patients, RR =u200a1.51, 95% CI 1.04, 2.17, Pu2003=u20030.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant. Conclusions:u2003In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.

Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial

IMPORTANCEnThe optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain.nnnOBJECTIVESnTo determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6-month nonrandomized treatment period on a vitamin K antagonist.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers.nnnINTERVENTIONSnWarfarin or placebo for 18 months.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months.nnnRESULTSnAfter randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; Pu2009=u2009.001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups.nnnCONCLUSIONS AND RELEVANCEnAmong patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00740883.

Ximelagatran and melagatran vs. low-molecular-weight heparin in major orthopedic surgery: relationship between efficacy and safety and timing of initial administration.

Ximelagatran, a new orally administered antithrombotic, is a prodrug of the subcutaneous form melagatran acting through direct inhibition of thrombin. To date, six clinical studies have compared melagatran/ximelagatran with lowmolecular-weight heparins (LMWH) in short-term prophylaxis (6–12 days) [1–6]. The results of these studies have shown conflicting data concerning the benefit–risk ratio of ximelagatran. However, various therapeutic schedules were used in these studies in terms of dose and timing of administration of melagatran/ximelagatran or LMWH. Thus, as has already been suggested for LMWH [7,8] or fondaparinux [9], the timing of the first administration may affect the efficacy or safety of melagatran/ximelagatran. With this in mind, we studied, using the techniques of meta-analysis and metaregression, the benefit–risk ratio of the different regimen of melagatran/ximelagatran in preventing postoperative venous thromboembolic events in major orthopedic surgery according to the timing of the initial administration of this novel antithrombotic. The selected studies for the meta-analysis were randomized studies comparing ximelagatran 24 mg b.i.d. whether or not preceded by subcutaneous melagatran with LMWH for preventing deep venous thrombosis (DVT) after total hip replacement (THR), or total knee replacement (TKR). The efficacy end points were total DVT (asymptomatic or symptomatic) and proximal DVT and were detected by mandatory venography at the end of treatment period or earlier if clinically suspected. Safety end points were severe bleeding and transfusion (allogeneic or autologous blood). All events were adjudicated by an independent adjudication committee and limited to the study period (maximum 12 days). The metaanalysis was performed using the logarithm of the relative risk (RR). The RR results are presented with 95% confidence intervals (CI). The effect of the timing of melagatran/ximelagatran initiation on its benefit–risk ratio was first evaluated by performing an analysis on the two groups of studies investigating, respectively, preoperatively administered melagatran/ ximelagatran vs. LMWH, and postoperatively administered melagatran/ximelagatran vs. LMWH. The effect of timing was also evaluated by a fixed-effect meta-regression analysis of study-specific risk ratios bymeans of weighted linear regression [10]. The time used in the meta-regression was the mean time to first dose given to patients (observed in the study) or, if this was not mentioned in the article, the average time of the first administration according to the protocol. Six studies with a total of 8450 patients were included in the meta-analysis. The summary of each study is presented in Table 1. We first performed an analysis on the two groups of studies investigating, respectively, preoperatively administered melagatran/ximelagatran and postoperatively administered melagatran/ximelagatran. Preoperative administration seemed to be more effective than postoperative administration as regards the effect on total DVT (preoperative melagatran/ximelagatran RR 1⁄4 0.68 (95% CI, 0.51–0.89) vs. postoperative melagatran/ ximelagatran RR 1⁄4 1.14 (95% CI, 0.77–1.69); heterogeneity test between subgroups, P 1⁄4 0.03) as well as proximal DVT [preoperative melagatran/ximelagatran RR 1⁄4 0.37 (0.25– 0.55), vs. postoperative melagatran/ximelagatran RR 1⁄4 1.28 (0.59–2.77); heterogeneity test between subgroups, P < 0.01]. Conversely, preoperative administration seemed to increase the proportion of patients requiring a transfusion [preoperative melagatran/ximelagatran RR 1⁄4 1.08 (1.04–1.14) vs. postoperative melagatran/ximelagatran RR 1⁄4 0.95 (0.90–0.99); heterogeneity test between subgroups, P < 0.01], and also of severe bleeding [preoperative melagatran/ximelagatran RR 1⁄4 2.51 (1.60–3.92) vs. postoperative melagatran/ximelagatran RR 1⁄4 0.85 (0.52–1.40); heterogeneity test between subgroups, P < 0.01]. Correspondence: Paul Zufferey, EA3065 Groupe de Recherche sur la Thrombose, Unité de Pharmacologie Clinique, CHU Saint-Etienne Bellevue, 42055 Saint-Etienne cedex 2, France. Tel.: +33 4 77 12 07 16; fax: +33 4 77 12 78 20; e-mail: paul.zufferey@ chu-st-etienne.fr

Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta-analysis of 5 randomized trials in non-cancer and cancer patients☆

PURPOSEnDue to its specific pharmacokinetic profile, tinzaparin, a low-molecular-weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding.nnnMATERIALS AND METHODSnA systematic literature search identified randomized studies on long-term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed-effect model in the overall population and cancer population.nnnRESULTSnFive randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients.nnnCONCLUSIONSnTinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE.

Functional hypoparathyroidism in postmenopausal women with fragility fracture

INTRODUCTIONnSecondary hyperparathyroidism sometimes is lacking despite authentic vitamin D insufficiency (VDI) and the concept of functional hypoparathyroidism with a protective role on bone status has been proposed. Therefore, we tested the hypothesis that its prevalence was very low in a population of women with a peripheral fragility fracture.nnnMETHODSnWe conducted our study in postmenopausal women, admitted for such a fracture in our Fracture Liaison Service. All had bone mineral density (BMD), biochemical assessment and a medical visit.nnnRESULTSnTwo hundred and thirty seven women (72.9±11.6-year-old) were included and 90.4% had VDI (25[OH]D≤30 ng/mL). Yet, 87.9% of the latter had normal PTH levels less or equal to 64 ng/L. In this population with VDI (n=214), we found no PTH plateau level related to 25(OH)D. Since a recent study reported an increase in the risk of fracture only when 25(OH)D was below 15 ng/mL, we then used this value as a new threshold. We observed a significant difference in hip BMD between patients with 25(OH)D either less or equal to or greater than 15 ng/mL. However, 81.2% of the formers were still with normal PTH with no difference in BMD whether PTH level was above or within normal range.nnnCONCLUSIONnIn a population of postmenopausal women with a fragility fracture, we found that 25(OH)D less or equal to 15 ng/mL was associated with significantly lower hip BMD. Even using this low threshold, we found a high prevalence of functional hypoparathyroidism and it was not associated with any difference in hip or spine BMD. Overall, our results do not support the hypothesis of a protective effect of this biological profile.

Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: A meta-analysis of observational studies

Graphical abstract Figure. No caption available. &NA; Selective serotonin reuptake inhibitors (SSRIs) have been reported to be potentially associated with an increased risk of bleeding. A meta‐analysis of observational studies was conducted to quantify this risk. Case‐control and cohort studies investigating bleeding risk under SSRI therapy were retrieved by searching the Medline, Pascal, Google Scholar and Scopus databases. Case‐control studies were included if they reported bleeding incidents with and without the use of SSRIs and cohort studies were included if they reported the rate of bleeds among SSRI users and non‐users. The main outcome was severe bleeding, whatever the site. Only data concerning SSRI belonging to the ATC class N06AB were used. For both case‐control and cohort studies, we recorded the adjusted effect estimates and their 95% confidence intervals (CI). Pooled adjusted odds ratio (OR) estimates were computed for case‐control and cohort studies using an inverse‐variance model. Meta‐analysis of the adjusted ORs of 42 observational studies showed a significant association between SSRI use and the risk of bleeding [OR 1.41 (95% CI 1.27–1.57), random effect model, p < 0.0001]. The association was found for the 31 case‐control studies (1,255,073 patients), with an increased risk of 41% of bleeding [OR 1.41 (95% CI 1.25–1.60)], as well as for the 11 cohort studies including 187,956 patients [OR 1.36 (95% CI 1.12–1.64)]. Subgroup analyses showed that the association remained constant whatever the characteristics of studies. This meta‐analysis shows an increased risk of bleeding of at least 36% (from 12% to 64%) based on the high‐level of observational studies with SSRIs use.

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism. Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6u2005months who were randomised to receive an additional 18u2005months of warfarin or placebo and followed up for 2u2005years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6u2005months of anticoagulation). During a median follow-up of 41u2005months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33–9.99) for age 50–65u2005years, 4.70 (95% CI 1.78–12.40) for age >65u2005years, 2.06 (95% CI 1.14–3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6u2005months and 2.38 (95% CI 1.15–4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6u2005months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence. After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6u2005months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence. Residual pulmonary embolism is an independent predictor for recurrence after unprovoked pulmonary embolism http://ow.ly/jf0X30fQQGf

Lived experience of having a child with stroke: A qualitative study

OBJECTIVEnTo assess the lived experience of parents whose child has suffered a stroke.nnnMETHODSnA qualitative study model was chosen, comprising in-depth interviews with parents separately or altogether. A semi-structured interview guide was used. Interviews were audio-recorded, transcribed verbatim and analysed using constant comparison and content analysis. Participant checking was performed. Thirteen families of children aged 1 month to 17 years, having suffered ischaemic or haemorrhagic arterial stroke within one to five years, were recruited. Interviews were conducted within home setting.nnnRESULTSnAfter fourteen interviews, data saturation was met and six main narrative themes were identified, underlining a common path of stroke lived experience: brutality of diagnosis, lack of information regarding disease condition, feeling of abandonment after discharge from hospital, focus on functional recovery, late awareness of cognitive disorders, and need for psychological support and family adaptation.nnnCONCLUSIONnThis is the first qualitative study reporting lived experience of childhood stroke caregivers. In line with other qualitative studies exploring the feelings of parents coping with severe neurological conditions of childhood, our results advocate the need for evaluation of family centred health interventions.

PK evaluation of fondaparinux sodium for the treatment of thrombosis

Introduction: Fondaparinux sodium (pentasaccharide) was the first of a new class of antithrombotic agents developed for the prevention and treatment of venous thromboembolism (VTE), blocking thrombin generation by selectively inhibiting factor Xa. Areas covered: This review focuses on the currently available information evaluating the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of fondaparinux in the prevention and treatment of VTE and treatment of acute coronary syndromes (ACS). Expert opinion: Fondaparinux is an alternative to low-molecular-weight heparins (LMWH) for thromboprophylaxis in various clinical settings (major orthopedic surgery of the lower limbs, major abdominal surgery, immobilized medical patients at high risk of VTE), as well as for the treatment of VTE (deep venous thrombosis, pulmonary embolism). It is currently challenged, in the context of both surgical thromboprophylaxis and acute VTE treatment, by the new oral anticoagulants. Fondaparinux remains the sole drug validated in patients with isolated superficial vein thrombosis of the lower limbs, and at prophylactic doses is a good alternative to LMWH at anticoagulant doses for patients with ACS, especially those ineligible for percutaneous coronary intervention.