ROCKET AF (2011): Rivaroxaban vs Warfarin in Atrial Fibrillation

/, Atrial Fibrillation, Cardiology, Haematology, Haemostasis and Thrombosis, Novel Oral Anticoagulants/ROCKET AF (2011): Rivaroxaban vs Warfarin in Atrial Fibrillation

ROCKET AF (2011): Rivaroxaban vs Warfarin in Atrial Fibrillation

Clinical question: in patients with atrial fibrillation, is rivaroxaban non-inferior to warfarin for the prevention of stroke or systemic embolism?

Study design: multi-centre, randomized, double-blind, double-dummy, event-driven trial

Inclusion criteria:

  • Age ≥ 18
  • Non-valvular atrial fibrillation documented on ECG
  • History of stroke, TIA or systemic embolism, or ≥ 2 of the following (i.e. CHADS2 ≥ 2) :
    • Hypertension
    • Heart failure and / or EF ≤ 35%
    • Age ≥ 75
    • Diabetes mellitus

Exclusion criteria:

  • Valvular heart disease, including infective endocarditis and prosthetic heart valves
  • Planned for cardioversion
  • Transient AF provoked by reversible underlying condition (thyrotoxicosis, PE, MI etc)
  • Patients with atrial myxoma or LV thrombus
  • Increased risk of bleeding, including but not limited to:
    • Bleeding diathesis
    • Major surgery within the last 30 days
    • Gastrointestinal haemorrhage within the last 6 months
    • Previous intracranial, spinal, retroperitoneal or spontaneous intraarticular bleeding
    • Sustained uncontrolled hypertension (≥180/100)
  • Planned invasive or major surgery
  • Platelet count < 90 x 109 or anaemia Hb < 10
  • Severe, disabling stroke within 3 months, or any stroke within 14 days
  • Any other indication for anticoagulation besides AF
  • On DAPT or aspirin > 100mg/day (single antiplatelet use allowed)
  • Treatment with strong inhibitors / inducers of cytochrome P450 enzymes
  • Creatinine clearance < 30 ml/min
  • Significant liver disease
  • Known HIV infection
  • Contraindication to warfarin

Intervention:

  • Patients randomized to two groups
  • Rivaroxaban 20mg OM or 15mg OM if CrCl 30 – 49 ml/min with sham INR
  • Warfarin, target INR 2 – 3

Patient characteristics:

  • 14267 patients enrolled between June 2009 and May 2010
  • Mean age 83
  • 40% female
  • Means CHADS2 score 3.48 in rivaroxaban group, 3.46 in warfarin group (no difference)

Outcomes and results:

  • Primary outcomes:
    • Composite of stroke, systemic embolism
      • Per-protocol analysis: rivaroxaban (1.7%/yr) not inferior to warfarin (2.2%/yr), Hazard ratio 0.79, 95% CI 0.66 – 0.96 (p < 0.001 for non-inferiority)
      • Intention-to-treat analysis: rivaroxaban (2.1%/yr) not inferior to warfarin (2.4%/yr), HR0.88, 95% CI 0.74 – 1.03 (p < 0.001 for non-inferiority, p = 0.12 for superiority)
    • Composite of major and non-major, clinically-relevant bleeding events
      • No difference between rivaroxaban (14.9%/yr) and warfarin (14.5%/yr), p = 0.44
      • Rate of intracranial haemorrhage significantly lower with rivaroxaban (0.5%/yr) compared to warfarin (0.7%/yr), p = 0.02
      • Rate of gastrointestinal haemorrhage significantly higher with rivaroxaban (3.2%) compared with warfarin (2.2%), p < 0.001
    • Secondary outcomes:
      • No difference in composite of stroke, systemic embolism or death from cardiovascular causes
      • No difference in rate of myocardial infarction (0.9%/yr for rivaroxaban, 1.1%/yr for warfarin)

Limitations:

  • Device used to measure INR was a point-of-care device (Alere INRatio Monitor System). This device was recalled by the US FDA in December 2014 because INR values from certain patients (those with abnormal haematocrit, conditions causing raised fibrinogen, bleeding or unusual bruising) were lower than laboratory plasma-measured values. This may confound the high bleeding risk seen in the warfarin group with a “therapeutic” INR.
    • Post-hoc analysis of data conducted for the ROCKET AF committee suggests that this limitation had no effect on the primary efficacy and safety outcomes of the trial (Patel MR, Hellkamp MS, Fox KA. Point-of-care warfarin monitoring in the ROCKET AF trial. N Engl J Med. 2016;374:785-788
  • There is a difference between the intention-to-treat analysis and the per-protocol analysis for the primary outcome measure. Both showed that rivaroxaban was non-inferior to warfarin, however, the per-protocol analysis also demonstrated that rivaroxaban was superior to rivaroxaban. Whether or not rivaroxaban is truly superior to warfarin will require further investigation.
  • There were significantly fewer patients with a CHADS2 score of 6 in the rivaroxaban group compared to the warfarin group, which may confound the study findings of non-inferiority of rivaroxaban (these are the patients at highest risk of thromboembolic events)
  • Rates of gastrointestinal haemorrhage associated with either anticoagulant may be even high than reported, given patients with GI bleeding within the last 6 months were excluded from the study
  • In the warfarin group, INR values were, on average, therapeutic 55% of the time, which may influence primary outcome measures. This value is lower than values of approximately 65%, which have been achieved in other studies.

Conclusions:

  • Rivaroxaban is non-inferior to warfarin in the prevention of stroke or systemic embolism in patients with atrial fibrillation
  • There is no significant difference between rivaroxaban and warfarin with respect to the rates of major or clinically-significant non-major bleeding
  • Rivaroxaban is associated with higher rates of gastrointestinal haemorrhage but lower rates of intracranial haemorrhage compared with warfarin

Reference: Patel  MR, Mahaffey  KW, Garg  J, Pan  G, Singer  DE, Hacke  W, Breithardt  G, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365(10):883-91.

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