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Reviews in Cardiovascular Medicine  2021, Vol. 22 Issue (3): 1019-1027     DOI: 10.31083/j.rcm2203111
Special Issue: State-of-the-Art Cardiovascular Medicine in Asia 2021
Original Research Previous articles | Next articles
Simulation of anticoagulation in atrial fibrillation patients with rivaroxaban—from trial to target population
Chi Zhang1, 2, 3, Wei-Wei Wang4, Mang-Mang Pan1, Zhi-Chun Gu1, 3, *()
1Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
2School of Medicine, Tongji University, 200092 Shanghai, China
3Shanghai Anticoagulation Pharmacist Alliance, Shanghai Pharmaceutical Association, 200040 Shanghai, China
4Department of S/4HANA Research & Development, SAP (China) Co., Ltd., 201203 Shanghai, China
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Abstract:

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.

Key words:  Rivaroxaban      Atrial fibrillation (AF)      Simulation      Randomized controlled trial (RCT)      Observational study     
Submitted:  29 June 2021      Revised:  03 August 2021      Accepted:  16 August 2021      Published:  24 September 2021     
Fund: RJTJ-JX-001/Renji Boost Project of National Natural Science Foundation of China;20184Y0022/Research Funds of Shanghai Health and Family Planning commission;320.6750.2020-04-30/WU JIEPING medical foundation;CXYJY2019ZD001/Clinical Pharmacy Innovation Research Institute of Shanghai Jiao Tong University School of Medicine;SHWJRS (2019) 072/Shanghai “Rising Stars of Medical Talent” Youth Development Program – Youth Medical Talents – Clinical Pharmacist Program;SHWRS (2020) 087/Shanghai “Rising Stars of Medical Talent” Youth Development Program – Youth Medical Talents – Clinical Pharmacist Program
*Corresponding Author(s):  Zhi-Chun Gu     E-mail:  guzhichun213@163.com

Cite this article: 

Chi Zhang, Wei-Wei Wang, Mang-Mang Pan, Zhi-Chun Gu. Simulation of anticoagulation in atrial fibrillation patients with rivaroxaban—from trial to target population. Reviews in Cardiovascular Medicine, 2021, 22(3): 1019-1027.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm2203111     OR     https://rcm.imrpress.com/EN/Y2021/V22/I3/1019

Fig. 1.  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.

Table 1.  Baseline characteristics of rivaroxaban patients in ROCKET AF, XANTUS (2016) [6], Laliberté (2014) [7] and Amin (2017) [11].
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 ± SD 71.95 ± 9.64 73.3 ± 8.4 77.7 ± 7.2 71.5 ± 10
Female sex, no. (%) 2831 (39.7) 1865 (51.0) 27,135 (51.7) 2768 (40.8)
BMI, mean ± SD 28.54 ± 5.12 - - 28.3 ± 5
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) - - -
CHADS2 risk of stroke
CHADS2 score, mean ± SD 3.48 ± 0.94 2 ± 1 2.7 ± 1.4 2 ± 1.3
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; CHADS2 score, the measure of the stroke risk ranges from 0 to 6.
Table 2.  The risk difference between observed and simulated results for ROCKET AF.
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).
Table 3.  Comparisons of each outcome between observed results and simulated results in ROCKET AF, XANTUS, and two observational studies.
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.
Table 4.  Simulated results and the risk difference for rivaroxaban arms in the simulation.
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.
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