Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phosphorylation test. Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide, with PPIs frequently associated to prevent gastrointestinal bleeding. The clinical impact of these results remains uncertain but merits further investigation.
IMPORTANCE The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain.OBJECTIVES To 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.DESIGN, SETTING, AND PARTICIPANTS Randomized, 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.INTERVENTIONS Warfarin or placebo for 18 months. MAIN OUTCOMES AND MEASURESThe 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.RESULTS After 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; P = .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.CONCLUSIONS AND RELEVANCE Among 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.
Objective-Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. Methods and Results-We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17-estradiol orally (nϭ63) or 50 g 17-estradiol transdermally per day (nϭ68), both associated with 100 mg progesterone daily or placebo (nϭ65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (Pϭ0.006) and transdermal ERT (PϽ0.001), but there was no significant effect of transdermal ERT compared with placebo (Pϭ0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1ϩ2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Conclusions-Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration. Key Words: hormone replacement therapy Ⅲ APC resistance Ⅲ blood coagulation Ⅲ randomized trial Ⅲ factor V S everal observational studies [1][2][3][4][5][6][7] found that oral estrogen replacement therapy (ERT) was associated with a 2-fold increased risk of venous thromboembolism (VTE). This finding was confirmed in 2 randomized clinical trials. 8,9 Furthermore, consistent data provided evidence that oral ERT resulted in coagulation activation. 10 -14 However, studies investigating the effect of transdermal estrogen on the thrombotic process are scarce. 3,15 Activated protein C (APC) resistance has recently emerged as a risk factor for venous thrombosis. 16,17 In most cases, this defect is related to the presence of the R506Q mutation in factor V (FV) Leiden. 18 However, an APC-resistant phenotype detected in the absence of FV Leiden is also an independent risk factor for venous thrombosis. 19 Observational studies 20 -22 and 1 randomized trial 23 showed that oral ERT could induce an acquired APC resistance. Little is known about the effect of transdermal ERT on APC resistance. Therefore, we conducted a randomized, placebocontrolled trial that investigated the effect of both oral and transdermal estrogen/progesterone regimens on the anticoagulant response to APC and on coagulation activation. Methods Study Design and SettingThis study was a randomized, double-blind, placebo-controlled, parallel-group trial that took place at the Hôpital de la Cavale Blanche, Brest, France, between September 1999 and August 2001. Participants were followed up by regular visits, at randomization (baseline), and after 6 months. A medical revi...
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