† These authors contributed equally.
Academic Editor: Brian Tomlinson
The populations included in the randomized controlled clinical trials and observational studies were different. The effectiveness and safety of rivaroxaban for stroke prevention in patients with atrial fibrillation (AF) varied among studies. This study aimed to estimate the real-world outcomes of rivaroxaban in patients with AF accurately. A discrete event simulation (DES) was used to predict the counterfactual results of the ROCKET AF study. The hypothetical cohorts of patients were generated using Monte Carlo simulation according to the baseline covariate distributions that matched the marginal distribution of covariates reported in the ROCKET AF and three observational studies. The DES model structure was constructed based on a priori knowledge about disease progression and possible outcomes of patients with AF. The DES model accurately replicated the overall results of the ROCKET AF study. Both predicted stroke/systematic embolism (SE) and major bleeding rates were lower in the three observational studies than in the simulated ROCKET AF study. The risk difference of stroke/SE and major bleeding was not significant among the predicted outcomes of the three observational studies. Although some differences existed in the absolute rates of stroke/SE and major bleeding between observed and simulated studies, the results confirmed that rivaroxaban was noninferior to warfarin for the prevention of stroke/systematic embolism with no significance in the risk of major bleeding in large AF populations, which was similar to the results of ROCKET AF.
Atrial fibrillation (AF) is the most commonly diagnosed and treated arrhythmia in clinical practice, with an increasing health burden. In the United States, 2.7 to 6.1 million individuals are currently suffering from AF, and it is estimated to be prevalent in more than 8 million people by the year 2050 [1, 2]. Stroke is the most feared complication of AF, which is usually prevented by oral anticoagulation [3]. Non-vitamin K antagonist oral anticoagulants (NOACs) have become an alternative to vitamin K antagonists for preventing stroke in patients with AF [4]. Rivaroxaban, one of the most commonly used NOACs, was approved for stroke prevention in patients with AF based on the pivotal randomized controlled clinical trial (RCT), namely ROCKET AF study [5]. This trial demonstrated the efficacy and safety 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 have the highest reliability.
Nevertheless, RCTs, such as the ROCKET AF
study, usually exclude certain patient groups; for example, AF patients
with a CHADS
Real-world observational studies using routine electronic healthcare databases,
such as insurance claims data or registry data, are available for large and
diverse patient populations, and could be used to capture 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]. The
XANTUS study, a real-world, prospective, observational cohort study described the
use of rivaroxaban in a broad unselected AF patient population [6]. In both
ROCKET AF and XANTUS studies, patients exhibited different baseline
characteristics. In the XANTUS study, a lower CHADS
Moreover, the effectiveness and safety of rivaroxaban in patients with AF also varied among different observational studies. The incidence of stroke/systematic embolism (SE) was observed to be 0.8 event per 100 patient-year in the XANTUS study [6], whereas different rates (1.9 and 4.6 per 100 patient-year) were observed in two other observational studies [7, 11] (Supplementary Table 1). Such significant variations in observational studies might result from differences in study design, data source, definition of outcomes, length of observation, analysis methods, etc. [12]. Although real-world studies could support and extend RCT findings to larger patient populations, the results could be biased.
To obtain generalizable results on the use of rivaroxaban in patients with AF, it is desirable to make the results of the ROCKET AF study and real-world studies complement each other. To the best of our knowledge, generalizing the baseline characteristics of the RCT population to match those of real-world patients could facilitate the generation of evidence for effectiveness and safety of treatments in excluded populations, thus providing more relevant evidence for decision-makers [9]. It is worth noting that discrete event simulation (DES) is a method that can mimic the disease pathways and outcomes over time according to a function of treatment and patient-level covariates [13]. Using DES, we could generalize the results to real-world patients with a different distribution of characteristics from the RCT population. Previous studies [14, 15] have used DES to estimate the percentage of patients with atherosclerotic cardiovascular disease who would require lipid-lowering therapy (LLT) intensification in real practice and evaluate the impact of LLT intensification on cardiovascular events. In this study, we proposed a DES to predict the counterfactual outcomes of ROCKET AF that would have been conducted in larger observational study populations.
The ROCKET AF was selected as a case of RCT
that evaluated the efficacy and safety of rivaroxaban versus warfarin in patients
with AF. XANTUS, a prospective observational study, was chosen to investigate
whether the results regarding the effectiveness and safety of rivaroxaban
obtained in the ROCKET AF study could translate into real-world clinical
practice. Two other retrospective observational studies (Laliberté, 2014 [7]
and Amin, 2017 [11]) were used to assess the effectiveness and safety of
rivaroxaban versus warfarin in routine care. Patient baseline characteristics of
the four studies were collected, including age, sex, previous thromboembolic
events (stroke, SE), transient ischaemic attack (TIA), myocardial infarction
(MI), heart failure (HF), hypertension, diabetes mellitus (DM), and CHADS
A DES model was developed and reprogrammed in Python (version
3.7, The Python Software Foundation, USA). The hypothetical cohorts of patients
were generated according to the baseline covariate distributions that matched the
marginal distribution of covariates reported in the ROCKET AF, XANTUS, and two
other observational studies (Laliberté, 2014 [7] and Amin, 2017 [11]), using
Monte Carlo simulation by random sampling. Random sampling continued until 7000
patients were simulated for each treatment group, and this was similar to the
sample size of the ROCKET AF study. Fig. 1 presents the DES model structure built
based on a priori knowledge about disease progression and possible
outcomes of patients with AF receiving rivaroxaban [3, 16]. The model was
designed to predict treatment outcomes, based on patients’ baseline
characteristics. The CHADS
The structure of discrete event simulation (DES) model. DES model structure was built based on a priori knowledge about disease progression and possible outcomes of AF patients. The model was designed to predict treatment outcomes conditional on patients’ baseline characteristics. Patients at different stroke and major bleeding risk would trace different probabilistic pathways in the model based on their treatment assignment (rivaroxaban or warfarin). DES could keep track of patient-level covariates and account for the changes in patients’ stroke and bleeding risk factors over time. Therefore, the stroke and major bleeding risk could be modified as the patient got older age or greater comorbidity burden.
To validate the DES model, we compared the simulated results and observed
results of the ROCKET AF study. The RDs and relative HRs (RHRs) of each outcome
were calculated. RDs were estimated as the absolute risk difference of each
outcome, and were calculated by subtracting the observed incidence from the
simulated incidence [22]. HRs and 95% confidence intervals (CI) were calculated
using the Cox proportional-hazards models. The RHRs were calculated by dividing
the simulated HRs by the observed HRs for each outcome [22]. Both RDs and RHRs
reflected the model error, which could have been caused by misspecification of
the simulation structure or assumptions about input parameters. RDs around 0
(
The simulated outcomes for hypothetical cohorts of patients with marginal covariate distributions similar to the XANTUS and two observational studies were predicted. Hypothetical cohorts of 7000 rivaroxaban patients and 7000 warfarin patients were simulated for the XANTUS and other two observational studies. As XANTUS was a single-arm study, and there was no baseline information about patients using warfarin; therefore, the baseline characteristics of patients using rivaroxaban were used in the simulation. The DES model developed and validated in patients with RCT was used to estimate outcomes of the three observational study populations. This process was conducted by replacing the baseline characteristics of the RCT cohorts with the simulated cohorts of the observational studies. The event rates, RDs, HRs, and RHRs were estimated.
Demographics and clinical characteristics at baseline for cohorts of involved
studies and simulated cohorts are summarized descriptively as means
Table 1 (Ref. [5, 6, 7, 11]) and Supplementary Table 3 outline the
baseline characteristics of the observed and simulated patients in the four
studies. The average age in each of these four studies was above 70 years. The
proportion of each comorbidity varied among the different studies. A larger
proportion (54.9%) of patients on rivaroxaban with prior stroke/TIA was included
in the ROCKET AF study than that in the three observational studies. Meanwhile,
the proportion of patients with HF, hypertension, or DM was also higher
in the ROCKET AF study. The mean CHADS
Variables | ROCKET AF [5] | Laliberté (2014) [7] | Amin (2017) [11] | XANTUS (2016) [6] | |
No. of patient on rivaroxaban | 7131 | 3654 | 52,467 | 6784 | |
Age (year), mean |
71.95 |
73.3 |
77.7 |
71.5 | |
Female sex, no. (%) | 2831 (39.7) | 1865 (51.0) | 27,135 (51.7) | 2768 (40.8) | |
BMI, mean |
28.54 |
- | - | 28.3 | |
Previous stroke, SE/TIA (%) | 3916 (54.9) | 357 (9.8) | 6331 (12.1) | 1291 (19) | |
HF, no. (%) | 4467 (62.6) | 716 (19.6) | 15,239 (29) | 1265 (18.6) | |
Hypertension, no. (%) | 6436 (90.3) | 2626 (71.9) | 46,544 (88.7) | 5065 (74.7) | |
DM, no. (%) | 2878 (40.4) | 919 (25.2) | 18,989 (36.2) | 1333 (19.6) | |
Previous MI, no. (%) | 1182 (16.6) | - | 6416 (12.2) | 688 (10.1) | |
PAD, no. (%) | 401 (5.6) | - | - | - | |
COPD, no. (%) | 754 (10.6) | - | - | - | |
CHADS |
|||||
CHADS |
3.48 |
2 |
2.7 |
2 | |
Score, no. (%) | |||||
0 | 0 (0) | 0 (0) | 1981 (3.8) | 703 (10.4) | |
1 | 0 (0) | 1464 (40.1) | 9147 (17.4) | 2061 (30.4) | |
2 | 925 (13) | 1304 (35.7) | 15,398 (29.3) | 2035 (30) | |
3 | 3058 (42.9) | 578 (15.8) | 25,950 (49.5) | 1111 (16.4) | |
4 | 2092 (29.3) | 229 (6.3) | 618 (9.1) | ||
5 | 932 (13.1) | 65 (1.8) | 222 (3.3) | ||
6 | 123 (1.7) | 14 (0.4) | 34 (0.5) | ||
BMI, body-mess index; SE, systemic embolism; TIA, transient ischaemic attack;
HF, heart failure; DM, diabetes mellitus; MI, myocardial infarction; PAD,
peripheral vascular disease; COPD, chronic obstructive pulmonary disease;
CHADS |
The DES model accurately replicated the overall results of the ROCKET AF (Fig. 1 and Table 2). The simulation was repeated 1000 times to obtain robust and convergent results (Supplementary Figs. 1,2). The simulated incidence of stroke/SE and major bleeding was 1.718 vs. 1.980, and 3.463 vs. 3.379 per 100 patient-year for rivaroxaban and warfarin, respectively. The RDs between the simulated and observed results were relatively low among each outcome (Table 2). The simulated HRs comparing rivaroxaban and warfarin in the risks of stroke/SE and major bleeding were 0.868 (95% CI, 0.863–0.872) and 1.025 (95% CI, 1.021–1.029), respectively (Table 3, Ref. [5, 6, 7, 11]). The RHRs between the simulated and observed results were approximately 1. The results indicated that the estimated risks and HRs closely matched the observed risks and HRs in the ROCKET AF study, indicating a low error of the simulation model.
Events | Rivaroxaban | Warfarin | ||||
Observed rate | Simulated rate | Risk difference | Observed rate | Simulated rate | Risk difference | |
no./100 patient-year | no./100 patient-year | no./100 patient-year | no./100 patient-year | no./100 patient-year | no./100 patient-year | |
Stroke/SE | 1.7 | 1.718 | 0.018 | 2.2 | 1.980 | –0.220 |
Stroke | 1.65 | 1.677 | 0.027 | 1.96 | 1.804 | –0.156 |
SE | 0.04 | 0.042 | 0.002 | 0.19 | 0.175 | –0.015 |
MB | 3.6 | 3.463 | –0.137 | 3.4 | 3.379 | –0.021 |
ICH | 0.5 | 0.484 | –0.016 | 0.7 | 0.732 | 0.032 |
GIB | 2 | 1.962 | –0.038 | 1.24 | 1.352 | 0.112 |
MI | 0.91 | 0.919 | 0.009 | 1.12 | 1.126 | 0.006 |
SE, systemic embolism; MB, major bleeding; ICH, intracranial hemorrhage; GIB, gastrointestinal bleeding; MI, myocardial infarction; RD, risk difference (simulated event minus observed event rate). |
Events | ROCKET AF [5] | Laliberté (2014) [7] | Amin (2017) [11] | XANTUS [6] | ||||||
Observed HR | Simulated HR | RHR | Observed HR | Simulated HR | RHR | Observed HR | Simulated HR | RHR | Simulated HR | |
(95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | |
Stroke/SE | 0.79 | 0.868 | 1.099 | 0.77 | 0.780 | 1.013 | 0.72 | 0.824 | 1.144 | 0.737 |
(0.65–0.95) | (0.863–0.872) | (0.904–1.335) | (0.55–1.09) | (0.775–0.785) | (0.715–1.435) | (0.63–0.83) | (0.819–0.829) | (0.991–1.322) | (0.732–0.742) | |
Stroke | 0.85 | 0.930 | 1.094 | - | 0.835 | - | 0.70 | 0.883 | 1.261 | 0.789 |
(0.70–1.03) | (0.924–0.935) | (0.897–1.335) | (0.829–0.840) | (0.59–0.83) | (0.878–0.889) | (1.057–1.505) | (0.784–0.794) | |||
SE | 0.23 | 0.253 | 1.100 | - | 0.233 | - | 0.52 | 0.257 | 0.494 | 0.221 |
(0.09–0.61) | (0.246–0.260) | (0.411–2.944) | (0.225–0.242) | (0.28–0.94) | (0.249–0.266) | (0.261–0.936) | (0.213–0.229) | |||
MB | 1.04 | 1.025 | 0.986 | 1.08 | 0.940 | 0.870 | 1.17 | 1.034 | 0.884 | 0.899 |
(0.90–1.20) | (1.021–1.029) | (0.850–1.142) | (0.71–1.64) | (0.936–0.944) | (0.570–1.328) | (1.10–1.26) | (1.030–1.039) | (0.822–0.950) | (0.895–0.903) | |
ICH | 0.67 | 0.663 | 0.990 | 1.17 | 0.606 | 0.518 | 0.71 | 0.669 | 0.942 | 0.582 |
(0.47–0.93) | (0.656–0.669) | (0.697–1.406) | (0.66–2.05) | (0.600–0.613) | (0.291–0.923) | (0.59–0.87) | (0.662–0.676) | (0.768–1.156) | (0.576–0.588) | |
GIB | 1.66 | 1.450 | 0.873 | 1.27 | 1.333 | 1.050 | 1.35 | 1.468 | 1.087 | 1.278 |
(1.34–2.05) | (1.442–1.459) | (0.702–1.087) | (0.99–1.63) | (1.324–1.341) | (0.813–1.355) | (1.23–1.48) | (1.460–1.477) | (0.986–1.200) | (1.27–1.286) | |
MI | 0.81 | 0.817 | 1.009 | - | 0.813 | - | - | 0.811 | - | 0.807 |
(0.63–1.06) | (0.811–0.823) | (0.772–1.318) | (0.807–0.819) | (0.805–0.816) | (0.801–0.813) | |||||
SE, systemic embolism; MB, major bleeding; ICH, intracranial hemorrhage; GIB, gastrointestinal bleeding; MI, myocardial infarction; HR, hazard ratio; 95% CI, 95% confidence interval; RHR, relative hazard ratio. RHR was calculated by dividing the simulated HR by observed HR. An RHR of 1 indicates no difference between simulated outcomes and observed outcomes. |
Cohorts of equal size and similar covariate distributions were generated in the XANTUS, Laliberté (2014) [7] and Amin (2017) [11] studies, respectively (Table 1). The baseline characteristics of the ROCKET AF study were replaced with those of the simulated cohorts to repeat the simulation. The predicted outcomes are shown in Table 3, Table 4 (Ref. [5, 6, 7, 11]), and SupplementaryTables 3,4,5. The predicted rates of stroke/SE were 1.718, 1.118, 1.097, and 1.318 per 100 patient-year, while the predicted rates of major bleeding were 3.463, 2.817, 2.804, and 3.238 per 100 patient-year in rivaroxaban arms for simulated ROCKET AF, XANTUS, Laliberté (2014) [7], and Amin (2017) [11] studies, respectively. Both predicted rates of stroke/SE and major bleeding were lower in the three observational studies than those in the simulated ROCKET AF (Table 4), with RDs being 0.22–0.66 per 100 patient-year. However, the RDs of stroke/SE and major bleeding were similar among the predicted outcomes of the three observational studies, ranging from 0.02–0.43 per 100 patient-year (Supplementary Tables 4,5). Consistent effects were observed in other simulated outcomes such as stroke, ICH, GI bleeding, and MI. Considering the HRs between rivaroxaban and warfarin in each outcome, the simulated HRs of stroke/SE were 0.780 (95% CI, 0.775–0.785) and 0.824 (95% CI, 0.819–0.829) for Laliberté (2014) [7] and Amin (2017) [11] studies, respectively, which were close to the observed HRs of 0.77 (95% CI, 0.55–1.09) and 0.72 (95% CI, 0.63–0.83) (Table 3). The simulated HRs of major bleeding were 0.940 (95% CI, 0.936–0.944) for Laliberté (2014) [7] study and 1.034 (95% CI, 1.030–1.039) for Amin (2017) [11] study, which seemed to be relatively lower than the observed HRs of 1.08 (95% CI, 0.71–1.64) and 1.17 (95% CI, 1.10–1.26) for Laliberté and Amin, respectively. Besides, the simulated HRs of XANTUS study were similar with the observed HRs in ROCKET AF study, with relatively lower HR for GIB (1.278 [95% CI, 1.27–1.286]) detected in the simulation of XANTUS study (Table 3 and Supplementary Table 6). Even though some differences were observed between the event rates of each study, most of the simulated HRs were similar to the corresponding observed HRs, with most RHRs around 1 (Table 3 and SupplementaryTable 6).
Events | ROCKET AF [5] | Laliberté (2014) [7] | Amin (2017) [11] | XANTUS (2016) [6] |
Stroke/SE | 1.718 | 1.097 | 1.318 | 1.118 |
(1.711–1.724) | (1.091–1.102) | (1.312–1.324) | (1.113–1.124) | |
RD (95% CI) | ref | 0.62 | 0.40 | 0.60 |
(0.21–1.02) | (–0.02–0.82) | (0.20–1.01) | ||
Stroke | 1.677 | 1.07 | 1.287 | 1.092 |
(1.670–1.684) | (1.065–1.076) | (1.281–1.293) | (1.086–1.097) | |
RD (95% CI) | ref | 0.61 | 0.39 | 0.59 |
(0.20–1.0) | (–0.03–0.80) | (0.19–0.99) | ||
SE | 0.042 | 0.026 | 0.032 | 0.026 |
(0.040–0.043) | (0.025–0.027) | (0.031–0.033) | (0.026–0.027) | |
RD (95% CI) | ref | 0.02 | 0.01 | 0.02 |
(–0.08–0.11) | (–0.08–0.11) | (–0.08–0.11) | ||
MB | 3.463 | 2.804 | 3.238 | 2.817 |
(3.453–3.473) | (2.795–2.812) | (3.228–3.247) | (2.809–2.826) | |
RD (95% CI) | ref | 0.66 | 0.22 | 0.65 |
(0.07–1.25) | (–0.39–0.82) | (0.05–1.23) | ||
ICH | 0.484 | 0.391 | 0.452 | 0.393 |
(0.480–0.487) | (0.388–0.395) | (0.449–0.456) | (0.390–0.397) | |
RD (95% CI) | ref | 0.09 | 0.03 | 0.09 |
(–0.13–0.34) | (–0.21–0.27) | (–0.15–0.32) | ||
GIB | 1.962 | 1.585 | 1.84 | 1.603 |
(1.954–1.969) | (1.579–1.592) | (1.832–1.847) | (1.597–1.610) | |
RD (95% CI) | ref | 0.38 | 0.12 | 0.36 |
(–0.08–0.82) | (–0.35–0.58) | (–0.09–0.81) | ||
MI | 0.919 | 0.913 | 0.914 | 0.912 |
(0.914–0.924) | (0.908–0.918) | (0.909–0.919) | (0.907–0.917) | |
RD (95% CI) | ref | 0.01 | 0.01 | 0.01 |
(–0.33–0.33) | (–0.33–0.33) | (–0.33–0.33) | ||
SE, systemic embolism; MB, major bleeding; ICH, intracranial hemorrhage; GIB, gastrointestinal bleeding; MI, myocardial infarction; RD, risk difference (simulated event rate of observational studies minus simulated event rate of ROCKET AF). The lower and upper limits of the 95% confidence interval for the RD between two studies were calculated using the website of http://vassarstats.net/ based on methods described by Robert Newcombe derived from a procedure outlined by E.B.Wilson in 1927. |
The ROCKET AF study and three observational studies (XANTUS, Laliberté (2014) [7] and Amin (2017) [11]) contributed to the clinical evidence for rivaroxaban in stroke prevention in patients with AF. However, the effectiveness and safety of rivaroxaban varied among the four studies. In this study, a DES model was proposed to predict the counterfactual outcomes of ROCKET AF study that could have been observed in larger observational study populations. The DES accurately replicated the overall results of the ROCKET AF study. Counterfactual results of the ROCKET AF study obtained by using the populations in observational studies showed relatively lower stroke/SE rates and major bleeding rates than those in the simulated ROCKET AF. Moreover, most of the simulated HRs between the rivaroxaban and warfarin arms were similar to the corresponding observed HRs, indicating similarities in benefits and harms of rivaroxaban in patients with AF in the ROCKET AF study.
As an RCT, the ROCKET AF study investigating the efficacy and safety of
rivaroxaban in AF patients is regarded as the gold standard. Nevertheless, the
study was performed in selected AF patients with moderate-to-high risk of stroke
(CHADS2 score
To estimate the real-world effectiveness and safety of rivaroxaban in patients with AF accurately, we used the DES method to model the pathways and 2-year outcomes of rivaroxaban anticoagulation in AF patients. It is known that DES is a strategy for modeling disease pathway and outcomes over time as a function of treatment and patient-level covariates [9]. Several studies have used DES to simulate LLT in patients with atherosclerotic cardiovascular disease [14, 15, 24]. Besides, a recent study used baseline characteristics from two observational studies to replicate the efficacy and safety of dabigatran compared to warfarin in the RE-LY study with a DES model [25]. The study found that differences in patient populations can explain a substantial portion of observed differences in outcomes across studies. In this study, a Monte Carlo simulation was used to generate hypothetical cohorts of patients. The DES built in this study could keep track of patient-level covariates and account for the changes in patients’ stroke and bleeding risk factors over time [9]. Therefore, the stroke and major bleeding risks could be modified as the patient grew older or had a greater comorbidity burden. Event rates and treatment effects could then be estimated based on predefined relationships between the outcomes and risk factors of stroke and bleeding. The baseline characteristics of ROCKET AF patients were generalized to match the baseline of patients treated in routine care, which facilitated the generation of evidence for the effectiveness and safety of rivaroxaban in excluded AF populations.
Our results indicated that the observed outcomes of the ROCKET AF, XANTUS, Laliberté (2014) [7], and Amin (2017) [11] studies differed from each other. However, the differences were insignificant among the corresponding simulated studies. In the Laliberté (2014) [7] study, wide discrepancies were found in the stroke incidence in the rivaroxaban arm in both observed and simulated results, with an observed rate of 4.6 and a simulated rate of 1.097 per 100 patient-year. A similar trend was found in the observed and simulated incidence of major bleeding in the Amin (2017) [11] study. This inconsistency might be caused by the inherent limitations of real-world studies, such as short follow-up, unbalanced confounding bias, etc. Interestingly, stroke/SE incidence in the rivaroxaban group was similar in the simulated XANTUS, Laliberté (2014) [7], and Amin (2017) [11] studies (1.118, 1.097, and 1.318 per 100 patient-year, respectively), which was much lower than that in the simulated ROCKET AF study (1.718 per 100 patient-year). It is known that patients enrolled in the ROCKET AF study were of moderate-to-high stroke risk. In comparison, the baseline characteristics of the three observational studies were similar and could represent the whole AF population. The stroke risk of patients in the three observational studies was much lower than that in the ROCKET AF study. Accordingly, the simulated stroke/SE incidence of the three observational studies might reflect the real-world stroke/SE rate in AF patients using rivaroxaban to some extent, same as the other simulated outcomes.
It is worth noting that most observed and simulated HRs between rivaroxaban and warfarin for each outcome were similar in our study, with most RHRs around 1. In terms of the HR for stroke/SE comparing rivaroxaban and warfarin, the simulated HRs in the Laliberté (2014) [7] and Amin (2017) [11] studies were 0.780 and 0.824, respectively, which were close to the observed HR of 0.79 in the ROCKET AF study. These results confirmed that rivaroxaban was non-inferior or even superior to warfarin for the prevention of stroke/SE in the real-world setting, which were in accordance with the results obtained in two previous meta-analyses reporting that HRs for stroke/SE comparing rivaroxaban and warfarin were 0.75 (95% CI, 0.64 to 0.85) and 0.83 (95% CI, 0.73 to 0.94) in real-world setting, respectively [26, 27]. With respect to the HR for major bleeding, there was no significant difference between groups, with observed HR being 1.04 in ROCKET AF study and simulated HR being 1.034 in Amin (2017) [11] study. The HRs for major bleeding obtained in this study were also similar to those reported in two previous meta-analyses considering real-world studies, with the HRs being 1.02 (95% CI, 0.95 to 1.10) and 0.99 (95% CI, 0.91 to 1.07), respectively [26, 27]. Therefore, similar results for the effectiveness and safety were observed when comparing rivaroxaban and warfarin in patients with AF.
It could be easier to understand the difference in effectiveness between rivaroxaban and warfarin when the molecular mechanisms of these two drugs are clarified. As a traditional oral anticoagulant, warfarin exerts its activity through inhibition of the synthesis of vitamin K dependent coagulation factors II, VII, IX, and X, as well as proteins C and S [28]. By comparison, rivaroxaban, as a NOAC, selectively inhibits free and clot-bound factor Xa, and further inhibits the generation of thrombin, thrombin-mediated activation of coagulation, and thrombin-mediated platelet aggregation [28]. It is notable that rivaroxaban can also exert an antiplatelet effect by acting through protease-activated receptor 1, which may lead to reduced frequency of atherothrombotic events and improved outcomes in patients [29].
This study has some limitations. First, the model error could not be neglected,
as the DES model structure and pathway were built based on a priori
knowledge regarding disease progression and possible outcomes of AF patients
receiving rivaroxaban, which lacked a multivariable outcome prediction component.
Second, the CHA
To estimate the real-world effectiveness and safety of rivaroxaban in patients with AF, the DES method was used to model the pathways and 2-year outcomes of rivaroxaban anticoagulation in these patients. The simulated event incidence of observational studies, such as stroke/SE incidence and major bleeding incidence, which was lower than that in the simulated ROCKET AF study, might reflect the real-world event rate in patients with AF. Moreover, the results confirmed that rivaroxaban was noninferior to warfarin for prevention of stroke/SE with no significance in the risk of major bleeding in large AF populations, which was similar to the results of ROCKET AF study.
ZCG and CZ designed the study. MMP and WWW collected and analyzed the data. WWW was responsible for methodology and software. CZ wrote the original manuscript. All authors have read and agreed to the published version of the manuscript.
Not applicable.
We thank the Jessika for the language editing of this study.
This work was supported by the Renji Boost Project of National Natural Science Foundation of China (RJTJ-JX-001), the Research Funds of Shanghai Health and Family Planning commission (20184Y0022), WU JIEPING medical foundation (320.6750.2020-04-30), Clinical Pharmacy Innovation Research Institute of Shanghai Jiao Tong University School of Medicine (CXYJY2019ZD001), and Shanghai “Rising Stars of Medical Talent” Youth Development Program – Youth Medical Talents – Clinical Pharmacist Program (SHWJRS (2019) 072; SHWRS (2020) 087).
The authors declare no conflict of interest.
The data that support the findings of this study are available on reasonable request from the corresponding author.