Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Analysis from the ROCKET AF trial (Rivaroxaban once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Journal of the American College of Cardiology 2013;61:651-58.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/23391196
| Methods | Study design: Post-hoc analysis of a non-inferiority randomized controlled study with a parallel-design
Number of groups: Two group |
| Participants | Number of participants: 14143 randomized for treatment in the original study, 5882 completed without discontinuation so were included for this posthoc analysis
· Rivaroxaban deprescribing group: 3040 participants · Warfarin continued therapy group: 2842 participants Age: Median 73 years Sex: 5590 female, 8553 male Participants with dementia: No Inclusion criteria: · Age ≥18 years · Persistent or paroxysmal atrial fibrillation documented on ≥2 episodes · Risk of future stroke: o History of stroke/TIA or systemic embolism, or o ≥2 of the following: § Congestive heart failure or left ventricular ejection fraction ≤35% § Hypertension (systolic blood pressure ≥180 mmHg or diastolic Blood pressure ≥100 mmHg) § Age ≥75 years § Diabetes mellitus Exclusion criteria: (see ROCKET-AF paper for inclusion/exclusion criteria) · Cardiovascular-related conditions o Prosthetic heart valve o Planned cardioversion o Atrial fibrillation secondary to reversible disorders (i.e., thyrotoxicosis) o Known presence of atrial myxoma or left ventricular thrombus o Active endocarditis o Hemodynamically significant mitral stenosis · Hemorrhage risk-related criteria o Active internal bleeding o History of, or condition associated with, increased bleeding risk, including major surgical procedure or trauma within 30 days before randomization o Clinically significant gastrointestinal bleeding within six months before randomization o History of intracranial, intraocular, spinal, or atraumatic intraarticular bleeding o Chronic hemorrhagic disorder o Known intracranial neoplasm, arteriovenous malformation, or an aneurysm o Planned invasive procedure with potential for uncontrolled bleeding, including major surgery · Concomitant conditions and therapies o Any stroke within 14 days before randomization o Transient Ischemic Attack within three days before randomization o Indication for anticoagulant therapy for a condition other than Atrial fibrillation (e.g., VTE) o Treatment with § Acetylsalicylic acid 100 mg daily § Acetylsalicylic acid in combination with thienopyridines within five days before randomization § Intravenous antiplatelets within five days before randomization § Fibrinolytics within 10 days before randomization § Anticipated need for long-term treatment with a non-steroidal anti-inflammatory drug § Systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within four days before randomization, or planned treatment during the period of the study § Treatment with a strong inducer of cytochrome P450 3A4, such as rifampicin, phenytoin, phenobarbital, or carbamazepine, within four days before randomization, or planned treatment during the period of the study Country: International Setting: Community – 1,100 sites across 45 countries |
| Interventions | Medicine: Rivaroxaban
Withdrawal schedule: Not described Comparator: At the end of the study, participants underwent blinded transition from rivaroxaban or warfarin to open-label therapy, most commonly warfarin Note: warfarin group were not deprescribed, rather switched from blinded to open therapy |
| Outcomes | Stroke
Non-central nervous system embolism Myocardial infarction Vascular death Major Bleeding |
| Dates | Dates: December 2006 to September 2010
Duration: Three to 30 days for deprescribing posthocanalysis |
| Funding sources | ROCKET-AF study was sponsored by Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, and Bayer HealthCare AG, Leverkusen, Germany. |
| Notes | This study includes non-adherence and deprescribing. However, the end of study data is the deprescribing data and can be separated from non-adherence and drug holidays. This means the end of study parameters may be biased toward warfarin because it switches from blinded to open administration. |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | Low risk | Randomization was performed with the use of a central 24-hour, computerized, automated voice-response system |
| Allocation concealment (selection bias) | Low risk | The randomized allocation was performed centrally. |
| Blinding of participants and personnel (performance bias) | High risk | The deprescribing group participants were in a randomized,double-blind trial, so the participants were blinded during that study. However, the deprescribing phase was not blinded, and the outcome assessors and personnel were aware of allocation during the deprescribing phase of the study. |
| Blinding of outcome assessment (detection bias) | High risk | As above |
| Incomplete outcome data (attrition bias) | Unclear risk | There appears to have been a clear protocol followed for the randomized,double-blind placebo-controlled study, but not for this posthocanalysis. Insufficient reporting of attrition in this part of the study |
| Selective reporting (reporting bias) | Low risk | The primary efficacy end-point was the composite of all stroke (both ischemic and hemorrhagic) and systemic embolism. The principal safety end-point was the composite of major and non-major clinically-relevantbleeding events. Both were reported. |
| Other bias | High risk | The results may reflect differences in the effectivehalf-life of the two drugs. Other medical therapy is not analyzed, and it may be significant
The study consisted of two arms, one transitioning from blinded warfarin to open warfarin and the other transitioning from blinded rivaroxaban to open warfarin. It is unclear if the greater number of incidences for rivaroxaban is related to this, but there would appear to be reasonable doubt. The therapeutic INR is relevant before withdrawal for the warfarin group, and after transitioning to warfarin for both groups: · “For the ROCKET-AF study, the warfarin group had a therapeutic INR 55% of the time. It is not stated in this paper how many of the people in either group were at therapeutic INR levels and how long it took them to reach therapeutic levels after ceasing blinded therapy. · “As previously noted, more than 60% of warfarin-treated patients completing the study had a therapeutic INR (2.0 to 3.0) at the first protocol-allowed check at 3 days, whereas less than 50% of rivaroxaban-treated patients transitioning to open-label vitamin K antagonist therapy had a therapeutic INR (2.0 to 3.0) at 30 days.” “”The study was supported by grants from Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, and Bayer HealthCare AG, Leverkusen, Germany.””” |
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