Introduction
Atrial fibrillation (AF) is the most commonly diagnosed and treated
arrhythmia in clinical practice with substantial and increasing health
burden. In the United States, 2.7 to 6.1 million individuals are
currently suffered, and its prevalence is estimated to be more than 8
million people by the year 2050 1, 2. Stroke is the
most feared complication of AF, and oral anticoagulation could help
prevent most cases of stroke 3. Non-vitamin K
antagonist oral anticoagulants (NOACs) now have become an alternative to
vitamin K antagonists for preventing stroke in AF patients4. Rivaroxaban, one of the most used NOACs, was
approved for stroke prevention in AF patients based on the pivotal
randomized controlled clinical trial (RCT) of ROCKET AF5, which demonstrated the efficacy of rivaroxaban in
reducing AF-related stroke risk. RCTs are conducted on highly selective
populations and are managed in tightly controlled settings. Therefore,
RCTs are considered as the gold standard for assessing treatment
efficacy and the results are of highest reliability.
Nevertheless, RCTs, such as
ROCKET
AF, usually exclude certain patient groups, for example, AF patients
with
CHADS2 score of 0 to 1 5, which
account for about 40% of the whole AF population in the real-world
setting 6, 7. It is well known that AF patients with
different stroke risk estimated by CHADS2 score might
receive different benefits from anticoagulation therapy8. Such rigorous exclusions could inevitably limit the
generalizability of evidence from trials, failing to be reflective of
treatment benefits and risks in all patient populations actually treated
in the real practice. Therefore, uncertainty exists when physicians
making anticoagulation decisions of rivaroxaban for patients who have
been excluded from ROCKET AF.
Non-RCTs using routine electronic healthcare databases, such as
insurance claims data or registry data, are available for large and
diverse patient populations, which could complete the RCTs by capturing
rare adverse events and long-term outcomes, as well as provide outcome
estimates of treatment effectiveness in broad patient populations.
However, the results of observational studies often differ from those of
RCTs, which might mainly result from the differences in patient
characteristics, drug adherence, and outcome measurement across studies
that differ in design 9.
XANTUS,
a prospective, single-arm, observational study described the use of
rivaroxaban in a broad unselected AF patient population6. ROCKET AF and XANTUS exhibited different baseline
characteristics. Lower value of CHADS2 score was
observed in patients of XANTUS, and the proportion of patients with
prior stroke, heart failure, hypertension, or diabetes mellitus was also
lower in XANTUS than that in ROCKET AF, which might lead to the outcome
discrepancy between these two studies 10.
Moreover, effectiveness and safety of rivaroxaban in AF patients are
also varied among different observational studies. The incidence of
stroke/systemic embolism (SE) was observed to be 0.8 event per 100
patient-years in XANTUS 6, while different rates were
detected as 1.9 and 4.6 per 100 patient-years in other two observational
studies 7, 11, respectively (Table S1). Such
significant variations within observational studies might result from
the difference in study design, data source, definition of outcomes,
length of observation, analysis methods, et al.12.
Accordingly, although real-world studies could support and extend RCT
findings to large patient populations, the results could be suspect.
In order to obtain sustained results of rivaroxaban in the use of
anticoagulation for AF patients, it is desirable to make the results of
ROCKET AF and the real-world studies to mutually complete each other. To
our knowledge, generalizing the baseline characteristics of RCT
population to match those of real-world patients could facilitate
generation of evidence for effectiveness and safety of treatments in
excluded populations, thus providing more relevant evidence for
decision-makers 9. In this study, we propose a
discrete event simulation (DES) to predict the counterfactual outcomes
of ROCKET AF that would have it been conducted in broader observational
study populations.
Methods