❶Lungenembolie Development Mechanism|Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism — NEJM|Lungenembolie Development Mechanism Publikationen: CCB| Lungenembolie Development Mechanism|Original Article. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. Deborah M. Siegal, M.D., John T. Curnutte, M.D., Ph.D., Stuart J. Connolly, M.D.|Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism|Dr. med. Stefano Bordignon]
N Engl J Med ; The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. Full Text of Background In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days interquartile range, 8 to 11we compared oral dabigatran, administered at a dose of mg twice daily, Lungenembolie Development Mechanism warfarin that was dose-adjusted to achieve an international normalized ratio of 2.
The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests.
Full Text of Methods A total of 30 of the patients randomly assigned to receive dabigatran 2. The hazard ratio with dabigatran was 1. Major bleeding episodes occurred in 20 patients assigned to dabigatran 1. The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9. Full Text of Results For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.
Full Text of Discussion Venous thromboembolism affects 1 to 2 adults per annually and is the third most common cause of vascular death after myocardial infarction and stroke. Dabigatran etexilate hereafter termed dabigatran is an orally available, potent, direct inhibitor of thrombin.
It is rapidly converted by ubiquitous esterases to the active drug, is administered in fixed doses without the need for coagulation monitoring, is excreted by the kidney, and has a half-life of 12 to 17 hours. In Lungenembolie Development Mechanism RE-COVER study, a double-blind, double-dummy, randomized trial, we compared 6 months of treatment with dabigatran, at a fixed dose of mg twice daily, with Lungenembolie Development Mechanism warfarin therapy, after initial parenteral anticoagulation.
The study was funded, designed, and conducted, and the data analyzed, by Boehringer Ingelheim in conjunction with the steering committee, whose members vouch for the accuracy Lungenembolie Development Mechanism completeness of the data and the analyses in this report.
The members of the steering committee wrote the manuscript and made the decision to submit it for publication. Patients were recruited from clinical centers in 29 countries. Patients 18 years of Lungenembolie Development Mechanism or older who had acute, symptomatic, objectively verified proximal deep-vein thrombosis of the legs or pulmonary embolism and for whom 6 months of anticoagulant therapy was considered to be an appropriate treatment were potentially eligible.
There were no weight restrictions. All patients provided written informed consent, and the institutional review board at each participating clinical center approved the study. Before randomization, the diagnosis of venous thromboembolism was established with the use of compression ultrasonography or venography of leg veins and ventilation—perfusion lung scanning, angiography, or spiral computed tomography of pulmonary arteries.
Additional baseline examination of the initially nonexamined Lungenembolie Development Mechanism or legs with the use of compression ultrasonography and, in case of symptomatic deep-vein thrombosis, examination of the learn more here arteries with the use of perfusion lung scanning or spiral computed tomography were required to be performed within 72 hours after randomization.
We used a computer-generated randomization scheme with variable block sizes, stratified according to presentation pulmonary embolism or deep-vein thrombosis without symptomatic pulmonary embolism and the presence or absence of active cancer. Staff members at the clinical centers called an interactive voice-response system that randomly assigned subjects to one of the supplied medication kits.
The treatment-group check this out was concealed from all the investigators and their staff at the coordinating Lungenembolie Development Mechanism and the clinical centers and Kräuter Krampf jeder Drink the clinical monitors.
Patients were assigned in a 1: Initial treatment with an approved parenteral anticoagulant generally unfractionated heparin administered intravenously or low-molecular-weight heparin administered subcutaneously was usually started before random assignment.
Warfarin or a placebo that looked identical to warfarin was generally started on the day of random assignment and was adjusted to achieve an INR of 2. Administration of dabigatran or a placebo that looked identical to dabigatran was initiated, and the parenteral anticoagulant was check this out, once the parenteral anticoagulant had been given for at least 5 days and the true or sham INR was recorded as 2.
The first dose of dabigatran was given within 2 hours before the time that the Behandlung von Krampfadern ohne Ärzte dose of initial parenteral therapy would have been due or at the time of discontinuation of intravenous unfractionated heparin. Patients were assessed at 7 days and then monthly until 6 months and were told to contact their study site immediately if symptoms developed that were source of venous thromboembolism or bleeding.
An additional follow-up visit was scheduled for 30 days after completion of the study, unless the patient had discontinued the study drug before 6 months, had started open-label anticoagulant therapy, or had been enrolled in another trial. Symptoms suggestive of recurrent venous thromboembolism were Lungenembolie Development Mechanism with the use of the same diagnostic methods that had been used Lungenembolie Development Mechanism the initial diagnosis.
Bleeding Lungenembolie Development Mechanism defined as major if it was clinically Lungenembolie Development Mechanism and if it was associated with a fall in the hemoglobin level of at least 20 g per liter, resulted in the need for transfusion of 2 or more units of red cells, involved a critical site, or was fatal. Other adverse events, results of liver-function tests and other laboratory measures, occurrence of acute coronary syndromes, and adherence quantified by Lungenembolie Development Mechanism von Varizen Laser were routinely assessed.
All suspected outcome events and deaths were classified by central adjudication committees, whose members were unaware of the treatment assignments. The trial was designed to determine whether 6 months of dabigatran therapy was as effective as 6 months of warfarin therapy i. A sample size of patients, with in each group, and an expected total of 46 events satisfied these requirements. No formal interim analyses were planned or performed. The data and safety monitoring board monitored safety and efficacy end points.
The primary analysis for efficacy was a comparison between the groups lіkar Varizen the time to the first occurrence of the composite end point of symptomatic venous thromboembolism or death associated with venous thromboembolism in the 6 months after random assignment, as assessed by the hazard ratio calculated with the use of the Cox model and the difference in risk calculated with Lungenembolie Development Mechanism use of Kaplan—Meier estimates.
Both summary statistics were adjusted for the initial presentation i. If noninferiority was established by both criteria, testing for superiority of dabigatran was to Lungenembolie Development Mechanism performed. We analyzed efficacy according to a modified intention-to-treat principle, since patients who did not receive any Конечно Laserbehandlung von Varizen Bratsk Пожалуйста drug were excluded from all analyses, as was Lungenembolie Development Mechanism in the protocol.
The 6-day period after the last intake of the study drug was not included source the analysis if patients started open-label anticoagulant therapy or if they were enrolled in the RE-MEDY study ClinicalTrials. All safety analyses and secondary efficacy analyses were predefined. From April through Novembera total of patients were Lungenembolie Development Mechanism assigned to a study group; Seven patients in the dabigatran group and 18 in the warfarin group did not receive any Lungenembolie Development Mechanism medication 4 did not meet the inclusion criteria for venous thromboembolism, 11 met the exclusion criteria, 5 withdrew consent, 4 never took the study drug, and 1 had another reason.
A total of patients in the dabigatran group and in the warfarin group were included in the analysis of efficacy. One patient who was assigned to receive dabigatran mistakenly received warfarin during the entire study; this patient did not have any outcome event and was included as part of the warfarin group in the safety analysis. There were no significant differences between the groups Lungenembolie Development Mechanism baseline characteristics Table 1 Table 1 Characteristics of the Patients and Treatments.
Parenteral anticoagulation was given for a mean of 10 days in both treatment groups. The details of the treatment given are shown click here Table 1. The Lungenembolie Development Mechanism number of INR values obtained in the warfarin group over the course of 6 months Lungenembolie Development Mechanism The study drug was stopped before 6 months von Thrombophlebitis, nehmen patients The observation time for the assessment of efficacy was shorter Lungenembolie Development Mechanism 6 months in patients 7.
Although it was intended that all patients who stopped the study drug owing to an adverse event or who were considered to show nonadherence would complete 6 months of follow-up, this did not always occur.
After completion of 6 months in this trial, patients in the dabigatran http://mdtw.de/wunden-an-den-beinen-wenn-die-diabetes-behandlung.php and patients in the warfarin group gave additional informed consent and were randomly assigned a second time to receive treatment with dabigatran or warfarin as extended secondary prophylaxis, as Lungenembolie Development Mechanism of the double-blind RE-MEDY study.
The investigators suspected that recurrent venous thromboembolism had occurred or that a death had been related to recurrent venous thromboembolism in patients in the dabigatran group and patients in the warfarin group. After central adjudication, the primary Lungenembolie Development Mechanism for efficacy was confirmed in 30 patients in the dabigatran group 2. The difference in risk was 0. The results for the components of Lungenembolie Development Mechanism primary end point are shown in Table 2 Table 2 Efficacy and Bleeding Outcomes.
There was no significant difference in efficacy in predefined subgroups see the Supplementary Appendix. Since noninferiority was established, we tested for superiority and found that it was not reached. A total of 20 patients in the dabigatran group 1. The Lungenembolie Development Mechanism ratio with dabigatran for major bleeding at 6 months was 0.
The sites of major bleeding events in the dabigatran group were gastrointestinal nine eventsurogenital fiveintraarticular oneintramuscular oneor click the following article sixand the sites in the warfarin group were urogenital six eventsgastrointestinal fiveintraarticular fourintracranial three Lungenembolie Development Mechanism, intramuscular threeor other four ; some patients had bleeding at more than one site.
INR values were not obtained when bleeding occurred, in order to avoid unblinding of the treatment assignment. A total of 71 patients in the dabigatran group 5. The relative risk of bleeding with dabigatran as compared with warfarin was similar among the subgroups data not shown.
The only type of bleeding that showed a Lungenembolie Development Mechanism to higher incidence in the dabigatran group von Krampfadern Minsk Preis gastrointestinal hemorrhage Lungenembolie Development Mechanism 2. There were patients in Lungenembolie Development Mechanism dabigatran group 9.
The number of patients who died, had an acute coronary syndrome, or had an elevation Lungenembolie Development Mechanism the alanine aminotransferase level or the aspartate aminotransferase level exceeding three times the upper limit of normal while taking the study drug did not differ significantly between the treatment groups Table 3 Table 3 Adverse Events during the Double-Dummy Phase and during the Total Period of Treatment.
A combination of an alanine aminotransferase level exceeding three times the upper limit of normal and bilirubin exceeding twice the upper limit of normal was seen in two patients in the Lungenembolie Development Mechanism group of whom one had pancreatic cancer and the other had cholangitis and four patients in the warfarin group of whom three had pancreatic cancer and one had uterine cancer with liver metastases.
There were no significant differences between the two treatment groups in the frequency of any adverse events Table 3 except for dyspepsia 2. In this large, double-blind trial involving patients with acute venous thromboembolism, Lungenembolie Development Mechanism compared 6 months of treatment with dabigatran, administered at a dose of mg twice daily, with warfarin therapy, after initial continue reading with parenteral anticoagulation.
We showed that dabigatran is noninferior to warfarin when Lungenembolie Development Mechanism is dose-adjusted to achieve and maintain an INR in the range of 2. Behandlung von Krampfadern HLS Korporalen thromboembolism or related deaths occurred in 30 patients in the dabigatran group as compared with 27 patients in the warfarin group.
Dabigatran is an Lungenembolie Development Mechanism anticoagulant agent because direct thrombin inhibitors suppress thrombus growth by inhibiting both fibrin-bound and free thrombin, which converts fibrinogen to fibrin.
The rates Lungenembolie Development Mechanism bleeding with dabigatran were similar to or lower than those with warfarin. There were 20 major bleeding events in the dabigatran group as compared with 24 in the warfarin group, and there were fewer episodes of nonmajor bleeding with dabigatran than with warfarin. These findings are consistent with data on bleeding from the Randomized Evaluation of Long-Term Anticoagulation Therapy trial RE-LY; NCT8 in which open-label dabigatran and warfarin therapies Lungenembolie Development Mechanism compared in patients with atrial fibrillation.
In the RE-LY trial, major bleeding and intracranial Lungenembolie Development Mechanism were less frequent among patients receiving dabigatran at a dose of Lungenembolie Development Mechanism twice daily than among those receiving warfarin, and in Lungenembolie Development Mechanism the RE-LY trial and the current study, the incidence of nonmajor bleeding was reduced with dabigatran.
Clinically relevant nonmajor bleeding is an important factor to consider, since its management is time-consuming and costly 16 and since bleeding is the most important reason for the perception of click health and quality of life among patients treated with warfarin. In trials of the only previously available oral direct Lungenembolie Development Mechanism inhibitor, ximelagatran, noninferiority with respect to warfarin was achieved in the treatment of recurrent venous thromboembolism, and rates of visit web page bleeding were similar in both treatment groups.
The mechanism for increased dyspepsia among patients receiving dabigatran therapy is currently unknown. None of the other adverse events differed significantly between the treatments. Therefore, additional studies should be performed that involve patients whose here characteristics differ markedly from this population. A limitation of the study is that the first dose of dabigatran, which has a rapid onset of effect, was given only after initial parenteral anticoagulation therapy had been administered for a median of 9 days continue reading range, 8 to Thus, there are no data to support the use of dabigatran monotherapy for acute venous thromboembolism.
We chose to treat patients in the dabigatran group with initial parenteral anticoagulation, because treatment of acute venous thromboembolism with ximelagatran see more appeared to be associated please click for source a higher early rate of recurrent venous thromboembolism than did treatment with enoxaparin and warfarin.
Our trial Lungenembolie Development Mechanism data to support dabigatran as a fixed-dose oral treatment for acute deep-vein thrombosis and pulmonary embolism. For Lungenembolie Development Mechanism and health care providers, dabigatran is a far more convenient drug than warfarin because it has no known interactions with foods and minimal interactions with other drugs and therefore does Lungenembolie Development Mechanism require routine blood-coagulation testing.
Kearon, consulting fees from Boehringer Ingelheim; Dr.