Stroke Prevention with the Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin in Patients with Non-Valvu

1. Stroke Prevention with the Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin in Patients with Non-Valvular Atrial Fibrillation (SPORTIF III): Randomized Controlled Trial Lisa Tang, MD Journal Club Presentation August 19, 2004

2. Clinical Question: Is ximelagatran as effective as warfarin in preventing stroke for patients with non-valvular atrial fibrillation?

3. Goal of the Study: To determine the safety and antithrombotic efficacy of ximelagatran as an alternative to warfarin for prevention of thromboembolism in patients with atrial fibrillation

4. Atrial Fibrillation Most frequent sustained cardiac rhythm disturbance, occurring in approximately 1% of patients aged < 50 years and up to 10% of those >80 years [1] Major cause of systemic thromboembolic events A powerful independent risk factor for ischemic stroke Incidence of stroke: increased 5 fold in patients with AF to approximately 5% per year for primary events and 12% per year for recurrent events, compared to patients without AF.

5. Ximelagatran (Exanta, AstraZeneca)An Oral Direct Thrombin Inhibitor

6. Mechanism of Ximelagatran: Ximelagatran is bioconverted to melagatran. Active form: melagatran, a direct inhibitor of soluble and fibrin-bound thrombin Target: thrombin which cleaves fibrinogen to form fibrin and activates platelets and several other coagulation factors.Ximelagatran is bioconverted to melagatran. Active form: melagatran, a direct inhibitor of soluble and fibrin-bound thrombin Target: thrombin which cleaves fibrinogen to form fibrin and activates platelets and several other coagulation factors.

7. Advantages of Ximelagatran: Rapid onset of action Stable pharmacokinetics independent of the hepatic P450 enzyme system No known clinically significant food or drug interactions Unaffected by bodyweight, age, sex, or ethnic origins Rapid onset of action Stable pharmacokinetics independent of the hepatic P450 enzyme system No known clinically significant food or drug interactions Unaffected by bodyweight, age, sex, or ethnic origins

8. Warfarin: Blocks the Vitamin-K dependent clotting factors: II (prothrombin), VII, IX, and X, produced by the liver.

9. Disadvantages of Warfarin: A risk of major hemorrhage: approximately 1.2% per year [1] Narrow therapeutic margin requiring frequent coagulation monitoring to ensure appropriate dosing. Interactions with numerous drugs and foods

10. Study Design: Randomized controlled trial Compared fixed doses of ximelagatran: 36 mg BID without coagulation monitoring with warfarin dosed to maintain an INR between 2.0-3.0 based on blood test monitoring at maximum intervals of 4 weeks. Long term Phase III study Open label, parallel group

11. Study Design –cont: Blinded event assessment by central committees which also monitored patient safety. Manufacturer sponsored Treatment allocation was balanced according to aspirin therapy at entry, previous stroke or TIA and country using an adaptive algorithm. Treatment was randomized using a masked, interactive voice response system.

12. Study Design –cont: An aggregate of 80 primary events. 90% power to exclude a difference in the rate of primary events greater than 2% per year

13. Study Design –cont: A minimum of 12 months of follow-up per patient, where patients are seen at 1, 4, and 6 weeks, and then at 2,3,4,5,6,8,10, and 12 months, and every 3 months thereafter for detection of stroke or systemic embolism (primary events), TIA, acute MI, or bleeding complications. Mean length of follow-up: 17.4 months

14. Study Participants: The study began in August 2000 with enrollment ending in September 2001. Patients with atrial fibrillation from hospitals, doctor’s offices, and health-care clinics at 259 sites in 23 countries in Europe, Australia, New Zealand, and Asia. A total of 3407 patients Study participants on ximelagatran: n= 1704 Study participants on warfarin: n= 1703

15. Inclusion Criteria: Patients with non-valvular atrial fibrillation and at least 1 additional stroke risk factor: Hypertension, Age older than 75 years Previous stroke, transient ischemic attack or systemic embolism Left ventricular dysfunction (left ventricular ejection fraction less than 40% or symptomatic congestive heart failure) Age older than 65 years with coronary artery disease or diabetes mellitus.

16. Exclusion Criteria: Recent stroke within the previous 30 days Transient ischemic attack within 3 days Acute coronary syndrome Conditions associated with increased risk of bleeding Endocarditis Planned major surgery or cardioversion Drug addiction, or alcohol abuse Renal insufficiency (calculated creatinine clearance <30 mL/min)

17. Demographics and Clinical Characteristics of Patients:

18. Demographics and Clinical Characteristics of Patients –cont: Predominantly white men (mean age 70 years) Duration of AF: 1 year or more in 2679 (79%) patients Persistent dysrhythmia: 3123 (92%) patients. A history of stroke or TIA: 822 (24%) patients Hypertension: 2459 (72%) Left ventricular dysfunction: 1158 (34%) 2345 (69%) of patients had more than one additional risk factor for thromboembolism.

19. Outcome Measures: Primary Outcome: The combined endpoint of stroke (ischemic or hemorrhagic) or systemic embolic event

20. Outcome Measures: Secondary Outcomes: The combined endpoint of death, stroke, systemic embolism, and/or myocardial infarction The combined endpoint of ischemic stroke, transient ischemic attack, and/or systemic embolism. Bleeding Treatment discontinuation

21. Outcome Measures –cont: The primary endpoints were assessed via intention to treat. Local study-affiliated neurologists or stroke specialists who were masked to treatment assessed main outcomes. An independent, masked, Central Event Adjudication Committee then reviewed these reports.

22. Results: Data were collected on all study participants who enrolled in the study except for 10 patients who never took the study drug. Slightly more patients taking warfarin completed the study on assigned treatment (86% vs. 82% taking ximelagatran).

23. Results -cont:

24. Primary Events: In the group treated with warfarin: 56 patients during 2440 patient-years (yearly rate: 2.3%) vs. in the group treated with ximelagatran: 40 patients during 2446 patient-years (yearly rate: 1.6%) had primary events. The difference was not significant. Absolute risk reduction: 0.7% [95% CI –0.1 to 1.4], p=0.10 Relative risk reduction: 29% [95% CI –6.5 to 52]

25. Results: There was no statistically significant difference in the rate of secondary events between ximelagatran and warfarin with the exception of rates of bleeding. By intention to treat, all-cause mortality was 79 patients in the warfarin group (3.2% per year) and 78 patients (3.2% per year) in the ximelagatran group.

26. Secondary Events:

27. Adverse Effects: Elevated serum transaminases: three times the upper limit of normal was more common with ximelagatran (6% of patients, n = 107) vs. warfarin (1% of patients, n=14). 57 patients assigned to ximelagatran (3.4%) had elevated serum transaminases five times the upper limit of normal. 48 patients assigned to ximelgatran discontinued the study treatment due to elevated transaminases.

28. Strengths of This Study: Largest randomized trial of anticoagulation in atrial fibrillation to date Masked event assessment by local study-affiliated neurologists and an independent, masked, Central Event Adjudication Committee Follow-up completed for 96% of the study participants

29. Limitations of This Study: Open label treatment The safety and efficacy of ximelagatran in patients with impaired renal function is not addressed. The mechanism of elevated transaminases in patients taking ximelagatran is unknown. Initial LFT monitoring in the first 6 months is recommended although the frequency of liver function monitoring remains yet to be determined.

30. Limitations of This Study -cont: Safety of ximelagatran in patients with AF that are not represented in the SPORTIF III remains yet to be determined. Thus, ximelagatran should only be used in selected populations with AF. The use of aspirin varied between the ximelagatran group (13%) and the warfarin group (10%) with p=0.010. The potential for confounding by aspirin was not addressed.

31. Conclusions: Ximelagatran is non-inferior to warfarin in preventing stroke for patients with non-valvular atrial fibrillation. It does not require monitoring of INR. It is associated with elevated transaminases and fewer bleeding complication.

32. Other Studies that Investigated the Use of Ximelagatran: SPORTIF V, with double-blind treatment allocation involving 3922 patients at 409 North American sites. A Phase III trial similar to SPORTIF III, except for treatment blinding. In the group treated with warfarin: 51 patients (yearly rate: 1.6%) vs. in the group treated with ximelagatran: 37 patients (yearly rate: 1.2%) had the primary events. The difference was not significant with p=0.13. Combined analysis of both studies is planned.

33. Other Studies that Investigated the Use of Ximelagatran -cont: A recent clinical trial comparing ximelagatran and low molecular weight heparin in the prevention of venous thromboembolism after total knee arthroplasty Use of ximelagatran plus aspirin vs. aspirin alone in secondary prophylaxis after myocardial infarction in the study, ESTEEM

34. Discussion: Will the results of this study change your practice? What more information would you need before incorporating it to your practice? If the results of this study are confirmed by SPORTIF V, will you switch your patient who is doing well on warfarin to ximelagatran? Would you only make the changes in certain patient populations?

35. Bibliography: Halperin JL, Ximelagatran Compared with Warfarin for Prevention of Thromboembolism in Patients with Non-Valvular Atrial Fibrillation: Rationales, Objectives, and Design of A Pair of Clinical Studies and Baseline Patient Characteristics (SPORTIF III and V) American Heart Journal, 2003 Sept; 146(3): pg 431-438 Executive Steering Committee, Stroke Prevention with the Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin in Patients with Non-Valvular Atrial Fibrillation (SPORTIF III): Randomized Controlled Trial, Lancet 2003 Nov; (362): pg 1691-1698 Verheugt, Freek, Ximelagatran or Warfarin in Atrial Fibrillation, Lancet 2004 Feb; (363) pg 734-735 Verheugt, Freek, Can We Pull the Plug on Warfarin in Atrial Fibrillation, Lancet 2003 Nov; (362): pg 1686-1687 Francis, Charles, Ximelagatran: a New Anticoagulant; Best Practice & Research Clinical Hematology, 2004, Vol 17, No 1 pg 139-152 McCullough et al, Ximelagatran: A Novel Oral Direct Thrombin Inhibitor for Long Term Anticoagulation, Reviews in Cardiovascular Medicine, 2004, Vol 5 No 2, pg 99-103 Boos, Christopher J and More, Ranjit S, Review: Anticoagulation for Non-Valvular Atrial Fibrillation-Towards a New Beginning with Ximelagatran, Current Controlled Trials in Cardiovascular Medicine 2004, 5:3

36. Acknowledgements: David Thom, MD, PhD Julie Haugen, MLIS