Rivaroxaban

2,528 views

Published on

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,528
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Rivaroxaban

  1. 1. ROCKET-AFRivaroxaban versus Warfarin inNonvalvular Atrial Fibrillationby Theodore Graphos
  2. 2. Objective The primary objective of this study is to demonstrate that the efficacy of rivaroxaban, a direct FXa inhibitor, is non-inferior to that of dose-adjusted warfarin for the prevention of thromboembolic events in subjects with non-valvular atrial fibrillation as measured by the composite of stroke and non-central nervous system (non-CNS) systemic embolism.
  3. 3. Article JOURNAL New England Journal of Medicine ▪ Peer-reviewed AUTHORS ▪ Physicians (mostly cardiologists) ▪ No statistician listed FUNDING ▪ Johnson & Johnson Pharmaceutical Research and Development ▪ Bayer HealthCare
  4. 4. Background A-fib MEDSCAPE  Atrial fibrillation (AF) is a relatively common cardiac arrhythmia that can have adverse consequences related to: 1) A reduction in cardiac output (symptoms) 2) Atrial and atrial appendage thrombus formation (stroke and peripheral embolization). In addition, affected patients may be at increased risk for mortality.
  5. 5. Background Stroke Risk Non-valvular a-fib • 2- to 7-fold increased risk of stroke Valvular a-fib • 17-fold increased risk of stroke
  6. 6. Competitors Dabigatran Rivaroxaban Apixaban Edoxaban Stroke prevention RELY ARISTOTLEA-Fib RELY-ABLE ROCKET-AF AVERROES <> Rivaroxaban is currently Treatment RECOVER EINSTEIN-DVT FDA approved for VTE AMPLIFY HOKUSAI RECOVER-2 & EINSTEIN-PE prophylaxis after major Long-term secondary prophylaxis REMEDY EINSTEIN- AMPLIFY-EXT HOKUSAI orthopedic surgery Extension RESONATE Prophylaxis in acute medical illnessVTE <> MAGELLAN ADOPT <> The only other new anticoagulant approved Prophylaxis after REMODEL (Knee) major orthopedic REMOBILIZE (Knee) for a-fib is dabigatran surgery RECORD (1-4) NCT00097357 <> RENOVATE (Hip) RENOVATE 2 (Hip) Secondary prevention ATLAS ACS TIMI 46 ENGAGE AF-ACS REDEEM APPRAISE-2 NCT00809965 TIMI 48
  7. 7. Design & Oversight ROCKET-AF Executive Committee • Study design • Oversight Duke Clinical Research Institute • Coordinated the trial • Primary data analysis • Independent of the sponsor Protocol was approved by IRBs at participating sites
  8. 8. Structure Multi-center  1178 sites, 45 countries Randomized Double-blind Double-dummy Event-driven  405 adjudicated endpoint events reached followed by study closure activities
  9. 9. Subjects Inclusion criteria Subjects meet all of the following: Non-valvular atrial fibrillation – “Subjects with atrial fibrillation and valvular disease (either mitral stenosis or prosthetic valve) are excluded even though they have a clear indication for anticoagulant therapy since the previous placebo controlled trials of warfarin therapy did not include these subjects.” – A-fib with a concomitant valve disorder is associated with a much higher risk of thromboembolism Moderate-to-high risk of stroke – Hx of stroke, TIA, or non-CNS systemic embolism - OR - CHADS2 score of 2 or more – >90% were required to have a previous thromboembolism or CHADS2 score of 3 or more
  10. 10. SubjectsExclusion criteria Cardiac-Related Conditions Hemorrhage Risk-Related Criteria Excluded mostly due to significantly Excluded mostly due to increased risk higher risk of thromboembolism of clinically significant bleeding  Hemodynamically significant mitral valve stenosis  Active internal bleeding  Prosthetic heart valve (annuloplasty with or without  History of or condition associated with increased prosthetic ring, commissurotomy and/or valvuloplasty bleeding risk including, but not limited to: are permitted) – Major surgical procedure or trauma within 30 days  Planned cardioversion (electrical or pharmacological) before the randomization visit  Transient atrial fibrillation caused by a reversible – Clinically significant gastrointestinal bleeding disorder (e.g., thyrotoxicosis, PE, recent surgery, MI) within 6 months before the randomization visit  Known presence of atrial myxoma or left ventricular – History of intracranial, intraocular, spinal, or thrombus atraumatic intra-articular bleeding  Active endocarditis – Chronic hemorrhagic disorder – Known intracranial neoplasm, arteriovenous malformation, or aneurysm  Planned invasive procedure with potential for uncontrolled bleeding, including major surgery  Platelet count <90,000/μL at the screening visit  Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg
  11. 11. SubjectsExclusion criteria Concomitant Conditions and Therapies Excluded due to addition of confounding variables  Severe, disabling stroke (modified Rankin score of 4 to  Anticipated need for chronic treatment with a non- 5, inclusive) within 3 months or any stroke within 14 steroidal anti-inflammatory drug days before the randomization visit  Systemic treatment with a strong inhibitor of cytochrome  Transient ischemic attack within 3 days before the P450 3A4, such as ketoconazole or protease inhibitors, within 4 days before randomization, or planned treatment randomization visit during the time period of the study  Indication for anticoagulant therapy for a condition  Treatment with a strong inducer of cytochrome P450 3A4, other than atrial fibrillation (e.g., VTE) such as rifampin/rifampicin, within 4 days before  Treatment with: randomization, or planned treatment during the time period of the study ▫ Aspirin >100 mg daily  Anemia (hemoglobin <10 g/dL) at the screening visit ▫ Aspirin in combination with thienopyridines  Pregnancy or breast-feeding within 5 days before randomization  Any other contraindication to warfarin ▫ Intravenous antiplatelets within 5 days before randomization  Known HIV infection at time of screening  Calculated CLCR <30 mL/min at the screening visit (refer ▫ Fibrinolytics within 10 days before randomization to Attachment 4 for calculating CLCR) ▫ Note: Aspirin ≤100 mg monotherapy is allowed  Known significant liver disease (e.g., acute clinical and thienopyridine monotherapy is allowed. hepatitis, chronic active hepatitis, cirrhosis), or ALT >3x the ULN Additional exclusion criteria common to most trials (past drug abuse, hypersensitivity, conflicts of interest, etc.)
  12. 12. SubjectsExclusion criteria Concomitant Conditions and Therapies Excluded due to addition of confounding variables  Severe, disabling strokeTreatment with:4 to  (modified Rankin score of  Anticipated need for chronic treatment with a non- 5, inclusive) within 3 months or any stroke within 14 steroidal anti-inflammatory drug • Aspirin >100 mg daily days before the randomization visit  Systemic treatment with a strong inhibitor of cytochrome Transient ischemic attack within 3 days before the P450 3A4, such as ketoconazole or protease inhibitors,  randomization visit • Aspirin in combination with thienopyridines within 4 days before randomization, or planned treatment during the time period of the study  Indication for anticoagulant therapy for5 days before within a condition randomization  Treatment with a strong inducer of cytochrome P450 3A4, other than atrial fibrillation (e.g., VTE) such as rifampin/rifampicin, within 4 days before • Intravenous antiplatelets within 5 daysplanned treatment during the time randomization, or before  Treatment with: ▫ Aspirin >100 mg daily randomization period of the study  Anemia (hemoglobin <10 g/dL) at the screening visit ▫ Aspirin in combination with thienopyridines within • Fibrinolytics 10 days before breast-feeding  Pregnancy or within 5 days before randomization randomization  Any other contraindication to warfarin ▫ Intravenous antiplatelets within 5 days before  Known HIV infection at time of screening randomization Note: Aspirin ≤100 mg monotherapy is<30 mL/min at the screening visit (refer  Calculated CLCR allowed ▫ Fibrinolytics within 10 days before randomization and thienopyridine monotherapy is 4 for calculating CLCR) to Attachment allowed. ▫ Note: Aspirin ≤100 mg monotherapy is allowed  Known significant liver disease (e.g., acute clinical and thienopyridine monotherapy is allowed. hepatitis, chronic active hepatitis, cirrhosis), or ALT >3x the ULN Additional exclusion criteria common to most trials (past drug abuse, hypersensitivity, conflicts of interest, etc.)
  13. 13. SubjectsRandomization  Central computerized randomization  1:1 ratio  Stratified, based on – Country – Prior VKA use (> 6 week) – Prior stroke, TIA, or non-CNS systemic embolism Written informed consent was obtained for all subjects
  14. 14. SubjectsDemographics No statistically significant differences in patient characteristics between treatment arms (though this was not explicitly stated) P<0.05 for all characteristics
  15. 15. SubjectsDemographics No statistically significant differences in patient characteristics between treatment arms (though this was not explicitly stated) P<0.05 for all medications
  16. 16. InterventionTreatment Arms Rivaroxaban Warfarin 20 mg daily Dose-adjusted to (or 15 mg daily in CrCl of 30 to 49 target INR between 2.0 and 3.0 ml/min) Why 20 mg? Why warfarin? • 20 mg dose is based on dose- • Chosen as comparator because ranging Phase II study warfarin is indicated for the • Lowest studied dose study population based on the CHEST guidelines  Compliance was assessed by periodic pill counts
  17. 17. InterventionBlinding Patients were given "Rivaroxaban" and "Warfarin" together, but one was a placebo • Specially-designed point-of-care INR device • Sham INR values for rivaroxaban patients • Validated algorithm produced values based on the distribution if values in warfarin-treated patients similar to those in the study population
  18. 18. Outcomes Primary SAFETY 1) Stroke + Systemic embolism Secondary 2) Stroke + Systemic embolism + Vascular death EFFICACY 3) Stroke + Systemic embolism + Vascular death + Myocardial infarction 4) Individual components of the composite endpoints Primary 1) Major and nonmajor clinically relevant bleeding
  19. 19. StatisticsPower analysis • 363 events for 95% power • Increased by 10% to 405 (more robust) • Assumed warfarin treatment group event rate of 2.3% per year • Assumed annual dropout rate of 15% • Estimated to need 14,000 subjects to reach 405 events
  20. 20. ResultsPrimary Efficacy A RESULT: Non-inferior to warfarin
  21. 21. ResultsPrimary Efficacy B RESULT: Superior to warfarin
  22. 22. ResultsPrimary Efficacy C RESULT: Not superior to warfarin
  23. 23. Analysis Criticism from FDA reviewers regarding events occurring after discontinuation of rivaroxaban More events occurred when patients on rivaroxaban switched to warfarin than in patients already on warfarin Probably due to difficulty achieving therapeutic INR (patients already on warfarin were already therapeutic)
  24. 24. ResultsSafety RESULT: No statistical difference
  25. 25. Rivaroxaban better Warfarin better ResultsSafety
  26. 26. ResultsSafety P<0.001 Rivaroxaban worse All others - no statistically significant difference
  27. 27. ResultsSecondary Efficacy B Safety, as treated population 1) Composite of stroke, systemic embolism, and vascular death ▫ Superior to warfarin 2) Composite of stroke, systemic embolism, vascular death, and myocardial infarction ▫ Superior to warfarin 3) Hemorrhagic stroke and non- CNS embolism events were statistically different in favor of rivaroxaban, but the event counts were very small and the clinical significance is minor
  28. 28. ResultsSubgroups Authors report “both safety and efficacy [were] consistent across all prespecified subgroups.” However… Statistically significant differences were recorded for a few patient characteristics. Results tended towards superior efficicay of rivaroxaban but with increased risk of bleeding Clinical significance is minimal
  29. 29. Analysis • Large population • Randomization was nearly perfect • Primary efficacy endpoints were analyzed using multiple population sets Strengths • Warfarin within therapeutic goal only 55% of the time Weaknesses • Could not determine if investigators tested whether or not blinding was maintained • Thienopyridine usage not reported
  30. 30. Analysis The top 25% of centers that appropriately maintained warfarin within goal still resulted in a hazard ratio that favored rivaroxaban
  31. 31. Conclusions Author’s conclusions Rivaroxaban was noninferior to warfarin in the prevention of subsequent stroke or systemic embolism. There were no significant differences in rates of major and clinically relevant nonmajor bleeding between the two study groups, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. My conclusions I agree with the author’s conclusion. Note that rivaroxaban had a higher incidence of GI bleeding. If approved, rivaroxaban would be a good alternative to warfarin for busy patients that can reliably take medication and in patients in which warfarin’s multitude of drug interactions makes it difficult to manage.

×