(rivaroxaban)
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XARELTO® (rivaroxaban)
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Real-World Evidence of XARELTO - Graham Study
Last Updated: 09/05/2024
Summary
- Randomized controlled trials (RCTs) represent the highest level of rigor and evidence as compared to real-world studies, which could have certain biases that may not be controlled for with statistical techniques. It is important to consider study methodology strengths and weakness when interpreting real-world studies.1
, 2 - The majority of published real-world data demonstrates a consistent balance relative to the safety and efficacy of XARELTO when used in clinical practice.1,2
Methods: Patients were identified with any inpatient or outpatient diagnoses of atrial fibrillation or atrial flutter based on ICD-9 coding. An inverse probability of treatment weighting was used to adjust for potential confounding due to baseline imbalances in study co-variates, while preserving sample size. Patients were followed from the day after entry and continued until disenrollment from Medicare, a gap in anticoagulant days of supply exceeding 3 days, a prescription fill for a different anticoagulant, kidney transplantation or initiation of dialysis, or admission to a skilled nursing facility, nursing home, or hospice care.
Outcomes: Primary outcomes were thromboembolic stroke, ICH, major extracranial bleeding (including gastrointestinal [GI] bleeding), and mortality. Outcomes were defined using previously validated algorithms based on ICD-9 diagnosis codes. Major extracranial bleeding was defined as a fatal bleeding event, a hospitalized bleeding event requiring transfusion, or hospitalization with hemorrhage into an extracranial critical site. This definition differed from that in ROCKET-AF due to the lack of data to document a decrease in hemoglobin concentration of at least 2 g/dL or the number of units transfused. The only data collected on mortality was the date, not the cause of death.
Results:
- A total of 52,240 dabigatran and 66,651 XARELTO patients contributed to 15,524 and 20,199 person-years of on-treatment follow-up (mean duration, 108 and 111 days, respectively), respectively.
- There were 306 thromboembolic strokes, 176 ICH events, 1209 major extracranial bleeding events (of which 1018 [84.2%] were GI), and 846 deaths.
- Primary outcome results comparing XARELTO to dabigatran are presented in Table: Primary Outcome Results for XARELTO vs Dabigatran.
| Crude (unadjusted) incidence rate per 1000 person-years (no. of events) | | |||
|---|---|---|---|---|
| XARELTO | Dabigatran | Adjusted HR (95% CI) | P-value | |
| Thromboembolic Stroke | 7.7 (156) | 9.7 (150) | 0.81 (0.65 – 1.01) | 0.07 |
| ICH | 5.8 (118) | 3.7 (58) | 1.65 (1.20-2.26) | 0.002 |
| Major extracranial bleeding | 39.4 (796) | 26.6 (413) | 1.48 (1.32-1.67) | <0.001 |
| GI | 32.5 (656) | 23.3 (362) | 1.40 (1.23-1.59) | <0.001 |
| Mortality | 24.7 (500) | 22.2 (346) | 1.15 (1.00-1.32) | 0.051 |
| Abbreviations: CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial hemorrhage; no., number. | ||||
- For the mortality endpoint, XARELTO risk was significantly increased in patients >75 years and in those with a CHADS2 score >2.
- The secondary analysis found no differences over time for any of the study outcomes, except thromboembolic stroke, for which XARELTO risk was decreased during the first 90 days of use, but not thereafter (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55-0.93 vs HR: 1.14; 95% CI: 0.74-1.75; P-value for interaction=0.07).
The primary limitations of the study include the following:
- The mean duration of on-treatment follow-up was less than 4 months, thereby reducing sample size at longer durations of use. At 4 months, approximately 30% of XARELTO and 25% of dabigatran patients were still in the study.
- There is no reporting of laboratory (serum creatinine) values, which are required to determine if prescribing was consistent with the labeling. In this study, patients taking a lower dose of the study drug were excluded. It is possible that a higher proportion of XARELTO-treated patients with renal impairment were treated off-label with the standard dose because of the broader creatinine clearance range guiding XARELTO dosing. If this occurred, a greater anticoagulant effect with XARELTO might be observed.
- The study was restricted to patients ≥65 years of age, and treatment effects may be different in a younger patient population.
| RCT | Real-World Studies | |||||
|---|---|---|---|---|---|---|
| ROCKET AF4 | XANTUS5 | US DoD PMSS6 | RELIEF-Germany7 | REVISIT-US8 | Graham et al3 | |
| Study Design | Prospective, randomized, controlled, comparative (international, including US) | Prospective, observational, noninterventional (international, ex-US)) | Retrospective, EMR database analysis (US) | Retrospective, EMR database analysis (German) | Retrospective, comparative, claims database analysis (US) | Retrospective, comparative, claims database analysis (US) |
| Data Source | Not applicable | Observational, noninterventional cohort study in real-world clinical practice | US Department of Defense EMR | German Primary Care Physician EMR database (IMS Disease Analyzer) | US Truven MarketScan claims database | US Medicare database |
| Primary Endpoint | Efficacy: composite of stroke and nonCNS systemic embolism; safety: composite of major and clinically relevant nonmajor bleeding events | Safety: AEs, which included major bleeding, all-cause death, and any other AEs and serious AEs; thromboembolic events were recorded as AEs | Major bleeding | Time to composite of ischemic stroke, TIA, ICH, MI, nontraumatic ICH | Combination of ischemic stroke or ICH; these endpoints were also evaluated separately | Efficacy: thromboembolic stroke; safety: ICH, major extracranial bleeding events, major GI bleeding, death |
| Definition of Endpoints | Stroke defined as sudden focal neurological deficit of presumed cerebrovascular etiology that persisted beyond 24 hours and not due to another identifiable cause. Systemic embolism defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of another likely mechanism. Major bleeding defined was defined as clinically overt bleeding associated with death, transfusion ≥2 units, hemoglobin decrease ≥2 units, or involvement at a critical site | ISTH definition of major bleeding: bleeding associated with death, transfusion, hemoglobin decrease ≥2 g/dL, occurred at a critical site, or as associated with an intervention. A verified algorithm was used to search the database for all bleeding AEs and AEs, and all events were adjudicated by a Central adjudication Committee | Major bleeding defined via validated Cunningham algorithm, which identifies bleeding-related hospitalizations from a primary discharge diagnosis | ICD-10 diagnostic codes | Occurrence of endpoints determined by presence of ICD-9-CM code, as recommended by the US FDA “Mini-Sentinel” postmarketing surveillance system | Outcomes defined using validated algorithms based on ICD-9 diagnosis codes. Major extracranial bleeding defined as fatal bleeding, hospitalized bleeding requiring transfusion, hospitalization with bleeding into an extracranial critical bleeding site. Death was ascertained by linkage to Social Security files, which provide the date, but not cause of death |
| Number of XARELTO Patients | 7131 | 6784 | 27,467 | 1039 | 11,411 | 66,651 |
| Duration - Observation Period | 590 days (median exposure); 770 days (follow-up) | 1 year | 15 months | 1 year | - | 4 months |
| CHA2DS2 Score (Mean) | 3.48 | 2.0 | 2.2 (no major bleed); 3.0 (major bleed) | 1.7 | 1.92 | - |
| Results | ||||||
| Ischemic Stroke (Events Per 100 pt-yrs) | 1.34 | 0.5* | - | 0.69 | 0.54 | 0.77 |
| ICH (Events Per 100 pt-yrs) | 0.5 | 0.4 | 0.1* | 0.1 | 0.49 | 0.58 |
| Major Bleeding (Events Per 100 pt-yrs) | 3.6 | 2.1 | 2.9 | - | - | 3.94 |
| Major GI Bleeding (Events Per 100 pt-yrs) | 2.0 | 0.9 | 1.5* | - | - | 3.25 |
| Death (All-Cause; Events Per 100 pt-yrs) | 1.9 | 1.9 | - | - | - | 2.47 |
| Limitations | Not applicable | - Single-arm study (no control arm) - Selection bias - Due to observational design, interference with patient management, such as reinforcement of lab and other investigations, was not allowed, leading to large number of patients with unknown CrCl values - Outcomes per XARELTO dose were not adjusted for baseline risk factors | - This is retrospective study using data points originally collected for EMR and claims purposes, rather than research - Records capture drug dispensing information rather than drug administration, and connecting use of XARELTO to bleeding events only establishes temporal association rather than a causal relationship - Major bleeding definition is not an exact match with the pivotal clinical study (ROCKET AF), and major bleeding was not adjudicated | - Only a small number of primary events seen - Claims analysis may contain coding inaccuracies/missing data that can result in biases and residual confounding variables - Excluded patients on doses of XARELTO not consistent with product labelling | - Administrative claims databases have little, if any, data on vitals and laboratory results, and therefore, it was not possible to determine whether XARELTO prescribing was consistent with labelling or the duration of time warfarin users spent in the therapeutic INR range of 2.0‐3.0 - While propensity‐score matching generated cohorts that were comparable in key characteristics, only those variables measured in MarketScan could be matched upon and residual confounding cannot be excluded. MarketScan has a substantial lag in time to data availability. As a result, upon securing these data and performing analysis in early 2016, MarketScan data was only available through October 2014 | - Short observation period of 4 months - Since lab data (eg, CrCl to assess kidney function) was not available, unable to verify if dosing was consistent with labelling (ie, dosing adjustment for renal impairment) - Population restricted to age >65 years |
| Abbreviations: AEs, adverse events; CNS, central nervous system; CrCl, creatinine clearance; DoD, Department of Defense; EMR, electronic medical record; GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Hemostasis; MI, myocardial infarction; PMSS, postmarketing safety surveillance study; RCT, randomized controlled trial; TIA, transient ischemic attack; US, United States. †These studies are funded by Janssen Scientific Affairs, LLC, and Bayer Healthcare. * | ||||||
References
| 1 | De Lusignan S, Crawford L, Munro N. Creating and using real-world evidence to answer questions about clinical effectiveness. J Innov Health Inform. 2015;22(3):368-373. |
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