dr. Hengki Wijaya * dr. Djoko Heri Hermanto, SpPD-KHOM ** JOURNAL READING *Resident of Internal Medicine, Faculty of Medicine, Brawijaya University, Saiful Anwar Hospital **Supervisor of Internal Medicine, Faculty of Medicine, Brawijaya University, Saiful Anwar Hospital The Hokusai-VTE Investigators
International Journal of Rheumatic Diseases 2012; 15: 6268 1 INTRODUCTION 2 Venous thromboembolism is the 3rd most common cardiovascular disease after myocardial infarction and stroke.
The standard treatment consists of LMWH followed by vitamin K antagonists.
A number of studies have established that new oral anticoagulants with or without initial heparin therapy are effective alternatives.
Edoxaban is a direct inhibitor of activated factor X with a rapid onset of action. It is administered orally once daily and has proven antithrombotic efficacy.
GOAL Broadening applicability to real-world practice and encouraging the enrollment of all patients, including those with extensive disease, by specifying that treatment should be initiated with the proven, global standard of parenteral heparin. 3 MATERIALS AND METHODS (1) 4 Study Oversight Randomized, double-blind trial Comparation between: Enoxaparin followed by edoxaban with heparin followed by warfarin Patients -Inclusion criteria: 1. 18 years or older 2. Acute, symptomatic DVT involving the popliteal, femoral, or iliac veins or acute, symptomatic PE (with / without DVT). -Exclusion criteria: 1. Contraindications to heparin or warfarin 2. Receiving treatment for more than 48 hours of heparin 3. Receiving more than one dose of a vitamin K antagonist 4. Having cancer for which long-term treatment with LMWH 5. Another indication for warfarin therapy, continued to receive treatment with aspirin at a dose of more than 100 mg daily or dual antiplatelet 6. Cr Cl <30 ml /minute
MATERIALS AND METHODS (2) 5 Initial therapy with open-label enoxaparin for at least 5 days. Edoxaban or warfarin was administered in a double- blind, double-dummy fashion. Edoxaban (or placebo) Started after discontinuation of initial heparin. 60 mg orally once daily, or 30 mg once daily in patients with a Cr Cl of 30 - 50 ml /minute or body weight of 60 kg or less or receiving concomitant with potent P-glycoprotein inhibitors. Warfarin (or placebo) Started concurrently with the study regimen of heparin, with adjustment of the dose to maintain INR between 2.0 and 3.0. All measurements were performed by means of a point-of-care device that provided an actual INR value for patients receiving warfarin and a sham INR value for patients receiving edoxaban. INR measurements were required to be performed at least monthly. Edoxaban or warfarin was to be continued for at least 3 months and for a maximum of 12 months.
6 MATERIALS AND METHODS (3) MATERIALS AND METHODS (4) 7 Outcome Measures The primary efficacy outcome the incidence of adjudicated symptomatic recurrent VTE, which was defined as a composite of DVT or nonfatal /fatal PE. Death was adjudicated as related to VTE, other cardiovascular disease, bleeding, or other causes. PE was considered to be the cause of death if there was objective documentation that a pulmonary embolism caused the death or if the death could not be attributed to a documented cause and pulmonary embolism could not be ruled out. Secondary efficacy outcomes included the primary efficacy outcome combined with either death from cardiovascular causes or death from any cause. The principal safety outcome was the incidence of adjudicated clinically relevant bleeding, which was defined as a composite of major or clinically relevant nonmajor bleeding. MATERIALS AND METHODS (4) 8 Surveillance and Follow-up Patients underwent assessment on days 5 through 12, 30, and 60 after randomization and monthly or every 3 months after discontinuing the study drug. All patients were to be contacted at month 12. Patients were instructed to report symptoms suggestive of recurrent VTE or bleeding.
Statistical Analysis The study was designed as an event-driven trial to test the hypothesis that edoxaban would be noninferior to warfarin RANDOMIZATION & FOLLOW UP 9 From January 2010 through October 2012, a total of 8292 patients were enrolled at 439 centers in 37 countries RESULTS(1)
10 RESULTS(2) 11 RESULTS(3) 12 RESULTS (4) 13 DISCUSSION(1) Patients with VTE, treatment with heparin followed by oral edoxaban once daily, as compared with standard therapy, was noninferior with respect to efficacy superior with respect to bleeding. fewer fatal and intracranial bleeds in the edoxaban group between-group difference with respect to major bleeding did not reach statistical significance. 14 DISCUSSION(2) The design of the Hokusai-VTE study, as compared with a design calling for on treatment analyses only, allowed for a better understanding of the outcomes that may be expected in clinical practice. In the on-treatment analysis, we observed low rates of recurrence that were similar to those seen in contemporary studies. The use of the traditional sequence of a heparin lead-in followed by an oral agent may be considered a limitation of the Hokusai-VTE study. 15 DISCUSSION(3) Halving of the daily dose of edoxaban to 30 mg maintained efficacy with significantly less bleeding than that observed in the warfarin group. 16 CONCLUSIONS The Hokusai-VTE study showed that in a broad spectrum of patients with VTE, including those with severe PE, edoxaban administered once daily after initial heparin was noninferior to standard therapy with warfarin after initial heparin, with significantly less bleeding. 17 18 DOES THIS STUDY ADDRESS A CLEAR QUESTION? 19 V V V V ARE THE RESULTS OF THIS SINGLE TRIAL VALID? V V V V V V V THIS JOURNAL IS VALID WHAT WERE THE RESULTS? 20 EER= 35% CER= 65% ARR= 30% RRR= 46% NNT= 3 patient ARR to population= 29,68% - 30,32% NNT to population= 3 CAN I APPLY THESE VALID, IMPORTANT RESULTS TO MY PATIENT? V V V V THIS JOURNAL IS APPLICABLE THANK YOU 21