1. Journal Club Jad Skaf 11/12/2009 Dabigatran Vs. Warfarin in Patients with Atrial Fibrillation

3. BACKGROUND Warfarin Substantial risk of major bleedings (approximately 1.2% per year) Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 2001; 119:194S–206S.

4. Dietary intake of vitamin K; hepatic dysfunction; changes in the gut flora; patient compliance; and alcohol intake. Even within the controlled setting of a clinical trial, it has not been possible to stay within the therapeutic window more than 50% of the time. Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84:469–481. - Vitamin K epoxide reductase complex subunit 1 (VKORC1). - Cytochrome P450 2C9 (CYP2C9) In summary, therapy with VKAs is complex, potentially dangerous, and unpleasant, and this has resulted in considerable difficulty in convincing physicians and patients to adhere to current practice guidelines, with a resulting undertreatment in a considerable proportion of patients at risk. Frykman V, Beerman B, Ryden L, Rosenqvist M. Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications. Eur Heart J 2001; 22:1954–1959. 40%

5. Hence the Search for Newer Anticoagulants to decrease Cardio-vascular Events esp. in patients with AF CLOPIDOGREL -Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events ACTIVE-W trial -ACTIVE-A trial, comparing clopidogrel and aspirin with aspirin alone in patients with contraindication to warfarin

6. VKA inhibit the synthesis of factors II, VII, IX, and X Indirect via antithrombin: Fondaparinux Indirect via antithrombin: UFH, LMWH Direct Xa inhibition: Rivaroxaban, Apixaban Direct Thrombin Inhibition: Hirudin Bivalirudin Argatroban Dabigatran

7. Dabigatran Etexilate (PRADAXA) Direct, competitive inhibitor of thrombin. Bioavailability - 6.5%, 80% of the given dose is excreted by the kidneys Half-life - 12 to 17 hrs Does not require regular monitoring -Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation PETRO Study Am J Cardiol 2007;100:1419-26. -Dabigatran etexilate versus enoxaparin for prevention of VTE after total hip replacement Lancet 2007;370:

8. Question ? Is Dabigatran non-inferior to Warfarin for preventing stroke or other systemic Embolism in patients with AF ?

9. Non Inferiority Trials (NIT) Indications: - Clinical trials are increasingly being required to show benefits on clinical end-points rather than surrogate end- points - The incremental benefits of newer treatments are getting smaller Trials to show that the new treatment has an effect similar to that of the standard, rather than outright superiority. ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic)-2 GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-III COBALT (Continuous Infusion Versus Double-Bolus Administration of Alteplase)

10. NIT Weaknesses Assay Sensitivity - A trial that successfully demonstrates superiority has simultaneously demonstrated assay sensitivity. However, a noninferiority trial that successfully finds the effects of the treatments to be similar has demonstrated no such thing. - A well-executed clinical trial that correctly demonstrates the treatments to be similar can not be distinguished, on the basis of the data alone, from a poorly executed trial that fails to find a true difference. - Therefore, a noninferiority trial must rely on an assumption of assay sensitivity on the basis of information external to the trial, such as the quality control procedures or the reputation of the investigator. Poor Compliance with the study medication Poor diagnostic criteria Excessive variability of measuremen ts Biased end- point assessment.

11. NIT Weaknesses Assay Sensitivity Analysis of noninferiority trials Blinding Specifying the noninferiority margin -Specify the equivalence margin on the basis of a clinical notion of a minimally important effect. -The equivalence margin is often chosen with reference to the effect of the active control in historical placebo controlled trials. ITT alternative?

12. CONCLUSION - NIT There are inherent problems with NIT that make their results clearly less credible than those of a placebo- controlled trial. However, it is not always possible to include a placebo treatment for ethical reasons, and there will always be a need for clinical trials to test new treatments that are either no more effective than the standard (but which may offer some other advantage, such as better safety or more convenient dosing) or offer such a small increase in efficacy that the size of a superiority trial would be prohibitive. Be aware of the issues and account for them appropriately.

13. Journal club questions What is the question? Why does it matter? How does it fit with what already is known? What does it add to literature? Study design, methods and findings. How generalisable is the data=Validity? Strengths and weaknesses Can the information change the current practice? How can you imply the findings into your practice?

14. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) A phase 3, multicenter, prospective, open-label, randomized trial with blinded evaluation of all outcomes (PROBE design), designed to compare two fixed doses Of dabigatran, each administered in a blinded manner, With open-label use of warfarin in patients who had Atrial fibrillation and were at increased risk for stroke.

15. INCLUSION Criteria 1.) AF.There is ECG documented AF on the day of screening or randomization.The patient has had a symptomatic episode of paroxysmal or persistent AF documented by 12-lead ECG within 6 m before randomization.There is documentation of symptomatic or asymptomatic paroxysmal or persistent AF on 2 separate occasions, at least 1 day apart, one of which is within 6 m before randomization. In this case, AF may be documented by 12 lead ECG, rhythm strip, pacemaker/ICD electrogram, or Holter ECG..The duration of AF should be at least 30 s..Electrograms (not marker channels or mode switch episodes) from pacemakers and defibrillators can be used to document only 1 episode of paroxysmal or persistent AF2.) 2.) In addition to documented AF, patients must have one of the following: a. History of previous Stroke, TIA, or systemic embolism b. EF <40% documented by echocardiogram, radionuclide or contrast angiogram in the last 6 m c. Symptomatic heart failure, New York Heart Association class 2 or higher in the last 6 m d. Age ≥75 y e. Age ≥65 y and one of the following: i) Diabetes mellitus on treatment ii) Documented CAD iii) HTN requiring medical treatment 3.) Age >18 y at entry 4.) Written, informed consent

16. EXCLUSION Criteria Severe heart-valve disorder. Stroke within 14 days or severe stroke within 6 months before screening. A condition that increased the risk of hemorrhage. Creatinine Cl < 30 ml/min. Active liver disease. Pregnancy.

17. Dabigatran 110 mg BIDDabigatran 150 mg BID Warfarin 1,3,5 mg 18113 1ary outcome: stroke or systemic embolism 1ary safety outcome: major hemorrhage 2ary outcomes: stroke, systemic embolism, death (2005-2007) 6015 6076 6022 2 Years Age 71.4±8.6 Men 64.3 % CHADS2 score 32.6 Long Term VKA 50.1 % Age 71.5±8.8 Men 63.2 % CHADS2 score 32.2 Long Term VKA 50.2 % Age 71.6±8.6 Men 63.3 % CHADS2 score 30.9 Long Term VKA 48.6 %

19. INR INR measured at least monthly. The time that the INR was within the therapeutic range was calculated with the use of the method of Rosendaal et al. These data were reported back to the participating centers with advice for optimal INR control. Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted. 14d1m3mQ3m / 1 st yearQ4m / 2 nd year

20. Statistical Analysis The primary efficacy variable is the time to the first occurrence of Stroke (including hemorrhagic) or systemic embolism using the Cox Proportional hazard model. The null hypothesis: Hazard ratio of dabigatran vs warfarin is larger than or equal to the specified noninferiority margin δ = 1.46

21. This noninferiority margin was derived from a Meta Analysis of trials of vitamin K antagonists as compared with control therapy in patients with atrial fibrillation, with the margin defined according to the upper bound of the 95% confidence interval for the relative risk of the primary outcome in the control group versus the warfarin group. 95% Cox regression was used to calculate relative risks, confidence intervals, and P values. Chi square testing was used to compare rates of medication discontinuation and adverse events.

22. Dabigatran 110 mg BIDDabigatran 150 mg BID Warfarin 1,3,5 mg 18113(2005-2007) 6015 6076 6022 20.7 % 21.2 % 16.6% Stroke: 182 (1.53 % / yr) Hgic Stroke: 0.12% Stroke: 169 (1.99 % / yr) Hgic Stroke: 0.38% Stroke: 134 (1.11 % / yr) Hgic Stroke: 0.10%

23. In Stroke or systemic embolism prevention: The 150-mg dose of dabigatran was also superior to warfarin (relative risk, 0.66; 95% confidence interval [CI], 0.53 to 0.82; P<0.001), but the 110-mg dose was not (relative risk, 0.91; 95% CI, 0.74 to 1.11; P = 0.34).

25. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group

29. CONCLUSION Both dabigatran doses were non-inferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. In addition, the 150-mg dose of dabigatran was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg dose was superior to warfarin with respect to major bleeding.

30. Weaknesses of Re-Ly Declared a delta of 1.46 (relative risk) as the margin of non- inferiority! Translated this says that a 46% difference in the rate of stroke or arterial clot is clinically non-significant! This choice was justified on the basis of trials comparing warfarin to PLACEBO as analyzed in a 10-year-old meta-analysis*. It is obvious that an ex-post difference between a therapy and placebo in superiority trials does not apply to non-inferiority trials of two active agents. P. Petersen, G. Boysen and J. Godtfredsen et al., Placebo-controlled, randomised trial of warfarin and ASA for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study, Lancet 1 (1989), pp. 175–179. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators, The effect of low-dose warfarin on the risk of stroke in nonrheumatic atrial fibrillation, N Engl J Med 323 (1990), pp. 1505–1511. Stroke Prevention in Atrial Fibrillation Investigators, Stroke prevention in atrial fibrillation study. Final results, Circulation 84 (1991), pp. 527–539. European Atrial Fibrillation Trial Study Group, Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke, Lancet 342 (1993), pp. 1255–1262.

31. This just means that the RR point estimate for 110 mg versus warfarin is statistically significantly different from a RR of 1.46 It does NOT mean that the comparison between the two drugs on stroke and arterial clot is highly clinically significant, but misleadingly suggests so. P-value for non- inferiority ??? This creates an artificial and exaggerated impression of the difference between these two agents.

32. But here again, the 95% CI is narrower than the margin of non- inferiority, and had the results gone the other direction, as in Scenarios 3 and 4, (in favor of warfarin), we would have still claimed non-inferiority, even though warfarin would have been statistically significantly "better than" dabigatran! So it is unfair to claim superiority on the basis of a statistically significant result favoring dabigatran

33. This is the problem that is likely to crop up when you make your margin of non-inferiority excessively wide, which you will do if you wish to stack the deck in favor of your therapy.

34. Imagine the reverse. If dabigatran was the existing agent for prevention of stroke in A-fib, and warfarin was the new kid on the block. If the makers of warfarin had designed this trial AND GOTTEN THE EXACT SAME DATA, they would have said (look at the left of the figure and the dashed red line there) that warfarin is non-inferior to the 110 mg dose of dabigatran, but that it was not non-inferior to the 150 mg dose of dabigatran. They would NOT have claimed that dabigatran was superior to warfarin, nor that warfarin was inferior to dabigatran, because the 95% CI of the difference between warfarin and dabigatran 150 mg crosses the pre-specified margin of non-inferiority. And to claim superiority of dabigatran, the 95% CI of the difference would have to fall all the way to the left of the dashed red line on the left. (See Piaggio, JAMA, 2006.)

35. Does that make any sense ?