Anti-Factor Xa Activity of Standard and Japan-Specific Doses of Rivaroxaban in Thai Patients With Non-Valvular Atrial Fibrillation

Abstract

Background: Recommended rivaroxaban doses for stroke prevention in atrial fibrillation (SPAF) are 20 and 15 mg/day in patients with normal and reduced renal function, respectively, but lower doses (15 and 10 mg) have been tested and approved in Japan. It is not known whether 15 and 10 mg rivaroxaban are appropriate in other Asian populations. This study compared the anti-Factor Xa (FXa) activity of 20 and 15 mg rivaroxaban in Thai patients with normal renal function and 15 and 10 mg rivaroxaban in patients with reduced renal function.

Methods and Results: Sixty non-valvular atrial fibrillation patients receiving rivaroxaban (mean [±SD] age 69.3±9.1 years, mean creatinine clearance 59.2±22.7 mL/min) were enrolled. The anti-FXa activity of standard rivaroxaban and Japan-specific doses was measured at peak and trough concentrations. Median anti-FXa activity at peak concentrations was significantly higher for the standard than Japan-specific dose. Median anti-FXa activity measured at the trough was significantly higher for the standard dose only in those with impaired renal function. A higher proportion of patients receiving the Japan-specific rather than standard dose had anti-FXa activity at peak concentrations within the expected range (87.7% vs. 64.4%; P=0.001). One-third of those receiving the standard dose had anti-FXa activity higher than the expected range.

Conclusions: A significantly higher proportion of Thai patients receiving the Japan-specific dose of rivaroxaban had anti-FXa activity at peak concentrations within the expected range.

The long-term use of oral anticoagulants is strongly recommended in patients with atrial fibrillation (AF) and a high risk of stroke.^1,2 Warfarin, a vitamin K antagonist, has long been the main therapy for stroke prevention in patients with AF. However, large randomized controlled trials have demonstrated that non-vitamin K oral anticoagulants (NOACs) have better net clinical benefit than warfarin in patients with non-valvular AF in terms of efficacy and safety.^3–7 Thus, current international guidelines recommend that NOACs are preferred over warfarin in patients with non-valvular AF.^2,8

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a large randomized control trial, demonstrated that rivaroxaban was non-inferior to warfarin in terms of stroke prevention and major bleeding.⁷ In addition, rivaroxaban was associated with a lower risk of intracranial bleeding and fatal bleeding.⁷ The dose of rivaroxaban used in ROCKET AF trial was 20 mg once daily, reduced to 15 mg once daily if creatinine clearance (CrCl) was 15–49 mL/min. The Japanese ROCKET-AF (J-ROCKET AF) study was similar trial to the ROCKET AF study, but was conducted entirely in Japan.⁹ A lower dose of rivaroxaban was selected for use in Japanese patients in the J-ROCKET AF study because pharmacokinetic modeling data had indicated that the distribution of both the maximum concentration (C_max) and the area under the curve from 0 to 24 h (AUC_0–24) of a 15-mg once-daily dose of rivaroxaban was comparable to the C_max and AUC_0–24 of a 20-mg once-daily dose in Caucasians at steady state.¹⁰ The results of J-ROCKET AF showed that a Japan-specific dose of rivaroxaban was non-inferior to warfarin in both efficacy and safety.⁹ In addition, patients receiving the Japan-specific dose of rivaroxaban had fewer ischemic strokes and less gastrointestinal bleeding than those receiving warfarin.⁹

However, the appropriate dose of rivaroxaban in other Asian populations is uncertain. In Thailand, the recommended dose of rivaroxaban in patients with non-valvular AF is 20 mg once daily (15 mg once daily in those with CrCl 15–49 mL/min). Similar to the Japanese population, Thai patients with non-valvular AF have a lower CrCl and body mass index (BMI) than Caucasian patients.^11,12 It is not known whether the Japan-specific or standard dose of rivaroxaban is appropriate for use in Thai patients with non-valvular AF.

Previous studies have shown that inhibition of anti-Factor Xa (FXa) activity by rivaroxaban is closely correlated to its plasma concentration.¹³ Consequently, anti-FXa activity can be measured as an indication of rivaroxaban exposure.^2,14 Thus, the aim of the present study was to compare anti-FXa activity between standard and Japan-specific doses of rivaroxaban to determine the appropriate dose of rivaroxaban for use in Thai patients with non-valvular AF.

Methods

The present study was a prospective cohort study. The study was approved by the Institutional Research Board of the Faculty of Medicine, Chiang Mai University (Approval no. 205/2561) and all procedures followed the Declaration of Helsinki and ethical standards of the responsible committee on human experimentation. The study was registered in the Thai Clinical Trials Registry (TCTR; ID TCTR20181104002).

The study was conducted in Maharaj Nakorn Chiang Mai Hospital from June 2018 to January 2019. All patients provided written informed consent before study entry. Patients aged ≥18 years with non-valvular AF who had been receiving rivaroxaban were included in the study. Patients were excluded from the study if they had severe renal impairment (CrCl <15 mL/min) or poor compliance to medications.

Standard doses of rivaroxaban were defined as 20 mg once daily in patients with CrCl ≥50 mL/min and 15 mg once daily in patients with CrCl 15–49 mL/min. Japan-specific doses of rivaroxaban were defined as 15 mg once daily in patients with CrCl ≥50 mL/min and 10 mg once daily in patients with CrCl 15–49 mL/min.

At steady state, anti-FXa activity was measured at peak and trough concentrations for both the standard and Japan-specific doses of rivaroxaban. Because platelets could affect the FXa activity, serum was collected only from the upper half of the collection tube to avoid platelet contamination.

After patients had been on a standard dose of rivaroxaban for at least 1 week, anti-FXa activity was measured at peak (2–4 h after oral intake of rivaroxaban) and trough (22–24 h after the last dose of rivaroxaban) concentrations. Then, patients were instructed to reduce their dose of rivaroxaban to the Japan-specific dose for at least 1 week, after which anti-FXa activity was again measured at peak and trough concentrations (Figure 1). All patients were instructed to take the rivaroxaban tablets with a meal to increase drug bioavailability.¹⁵

Figure 1.

Schematic diagram showing the schedule for measurement of the anti-Factor Xa (FXa) activity of standard and Japan-specific doses of rivaroxaban. Standard doses were 20 and 15 mg rivaroxaban, once daily, in patients with normal and impaired renal function, respectively; Japan-specific doses of rivaroxaban were 15 and 10 mg, once daily, in patients with normal and impaired renal function, respectively.

The primary outcome was anti-FXa activity in Thai patients with non-valvular AF measured at peak and trough concentrations following administration of 20 and 15 mg rivaroxaban once daily in patients with CrCl ≥50 mL/min or 15 and 10 mg rivaroxaban once daily in patients with CrCl 15–49 mL/min.

According to previous clinical pharmacokinetic studies, the 5th–95th percentiles for trough and peak concentrations are 12–137 and 178–419 µg/L, respectively.^15–17 In the present study, the anti-FXa activity of rivaroxaban was specifically calibrated and translated into values of blood rivaroxaban concentration (i.e., µg/L). As such, we defined the expected range of anti-FXa activity at trough and peak rivaroxaban concentrations as 12–137 and 178–419 µg/L, respectively, and determined the proportion of patients receiving the standard and Japan-specific doses with anti-FXa activity in the expected range.

The anti-FXa activity of rivaroxaban in plasma samples was measured using the BIOPHEN DiXal kit (chromogenic anti-FXa; Dasit, Milan, Italy) and analyzed on a Sysmex CS 2500 System (Siemens Health Care, Milan, Italy). All reagents and instruments were used in accordance with the manufacturers’ instructions.

Statistical Analysis

Continuous variables are presented as the mean±SD or as the median with either the interquartile range (IQR) or 5th–95th percentile range, as appropriate. Categorical variables are presented as percentages. Normally distributed continuous variables were compared between groups using t-tests; for non-normally distributed variables, comparisons were made using the Mann-Whitney U-test. Paired t-tests were used to compare the anti-FXa activity of different doses of rivaroxaban within the same renal function group. Proportions were compared by Chi-squared or Fisher’s exact tests as appropriate. Correlations were analyzed using non-parametric (Spearman) correlation and are expressed as Spearman’s ρ. Two-tailed P<0.05 was considered significant.

Results

Baseline Characteristics of the Study Population

In all, 60 patients were enrolled in the study. The baseline characteristics of the study population are given in Table 1. The mean age of the study population was 69.4±9.2 years, 63.3% were male, and mean body weight was 64.0±14.1 kg. The median BMI was 24.4 kg/m² (IQR 21.5–26.9 kg/m²) and mean CrCl was 59.0±22.8 mL/min. For the 39 patients (65%) with CrCl ≥50 mL/min, mean CrCl was 72.1±16.9 mL/min, whereas for the 21 patients (34%) with CrCl 15–49 mL/min, mean CrCl was 34.9±7.0 mL/min. Twenty-eight patients (46.7%) had persistent or permanent AF and 32 (53.3%) had paroxysmal AF. The median duration of rivaroxaban use before study enrollment was 707.5 days (IQR 348.3–1,219.8 days).

Table 1. Baseline Characteristics of the Study Patients (n=60)

Age (years)	69.4±9.2
Male sex	38 (63.3)
Body weight (kg)	64.0±14.1
Body mass index (kg/m2)	24.4 [21.5–26.9]
Creatinine (mg/dL)	1.1±0.3
Creatinine clearance (mL/min)	59.0±22.8
CHADS2 score	2 [1–2]
CHA2DS2-VASC score	3 [2–4]
HAS-BLED score	2 [1–2]
Underlying diseases
Hypertension	46 (76.7)
Congestive heart failure	15 (25.0)
Ischemic heart disease	8 (13.3)
Diabetic	16 (26.7)
Dyslipidemia	35 (58.3)
Ischemic stroke	7 (11.7)
Concomitant drugs
Amiodarone	1 (1.7)
Dronedarone	3 (5.0)
Antiviral drug (Ledipasvir/Sofosbuvir)+Ribavirin	1 (1.7)
Aspirin (81 mg)	1 (1.7)
Clopidogrel (75 mg)	1 (1.7)

Data are given as the mean±SD, median [interquartile range], or n (%).

Anti-FXa Activity of Rivaroxaban

Of the 60 patients, 4 had received inappropriate rivaroxaban dosing: 1 patient with CrCl <50 mL/min had received inappropriate overdosing (20 mg once daily) and 3 patients with CrCl ≥50 mL/min had received inappropriate underdosing (10 mg once daily).

The anti-FXa activity of rivaroxaban with appropriate dosing (20 or 15 mg once daily in those with normal renal function; 15 or 10 mg once daily in those with impaired renal function) is summarized in Table 2.

Table 2. Anti-FXa Activity of Rivaroxaban at Peak and Trough Concentrations According to Dose and Renal Function

	Anti-FXa activity (μg/L)
	Peak	Trough
Normal renal function (CrCl ≥50 mL/min)
20 mg once daily (standard dose; n=35)	364 (154–636)	40 (10–90)
15 mg once daily (Japan-specific dose; n=35)	298 (150–474)*	32 (9–115)
Impaired renal function (CrCl 15–49mL/min)
15 mg once daily (standard dose; n=21)	331 (222–652)	29 (7–148)
10 mg once daily (Japan-specific dose; n=21)	263 (121–439)*	24 (3–88)*

Data are presented as the median (5th–95th percentile range). *P<0.05 compared with the standard dose within the same renal function group. CrCl, creatinine clearance; FXa, Factor Xa.

In patients with normal renal function (CrCl ≥50 mL/min), anti-FXa activity measured at the peak concentration was significantly higher after administration of the standard 20-mg dose than the Japan-specific 15-mg dose (median [5th–95th percentile] anti-FXa activity 364 [154–636] and 298 [150–474] µg/L, respectively; P=0.001). Similarly, in those with impaired renal function (CrCl 15–49 mL/min), anti-FXa activity measured at peak concentration was significantly higher after administration of the standard 15-mg dose than the Japan-specific 10-mg dose (median [5th–95th percentile] anti-FXa activity 331 [222–652] and 263 [121–439] µg/L, respectively; P<0.001).

In contrast, anti-FXa activity measured at the trough did not differ between the 20-mg (standard) and 15-mg (Japan-specific) doses, with median anti-FXa activity (5th–95th percentile) in those with normal renal function of 40 (10–90) and 32 (9–115) µg/L, respectively (P=0.207). However, in patients with impaired renal function, anti-FXa activity at the trough was higher following administration of the standard 15-mg dose than the Japan-specific 10-mg dose (median [5th–95th percentile] anti-FXa activity 29 [7–148] and 24 [3–88] µg/L, respectively; P<0.001).

Figure 2 shows median and IQR anti-FXa activity measured at peak and trough rivaroxaban concentrations in the 4 groups (different rivaroxaban doses in subjects with normal and impaired renal function). Figure 3 shows individual changes in anti-FXa activity measured at peak and trough rivaroxaban concentrations between the standard and Japan-specific doses.

Figure 2.

Median anti-Factor Xa (FXa) activity of different doses of rivaroxaban at (A) peak and (B) trough in patients with normal and impaired renal function (creatinine clearance ≥50 and <50 mL/min, respectively). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. Circles indicate outliers.

Figure 3.

Individual changes in anti-Factor Xa (FXa) activity between standard and Japan-specific doses of rivaroxaban at (A) peak and (B) trough. Standard doses were 20 and 15 mg rivaroxaban, once daily, in patients with normal and impaired renal function, respectively; Japan-specific doses of rivaroxaban were 15 and 10 mg, once daily, in patients with normal and impaired renal function, respectively.

We also examined anti-FXa activity in the 4 patients who had received inappropriate dosing of rivaroxaban. Anti-FXa activity higher than the expected range at peak (569 µg/L) was noted in 1 patient with CrCl of 31 mL/min who had received rivaroxaban 20 mg once daily. However, anti-FXa activity measured at trough (93 µg/L) was within the expected range. Conversely, anti-FXa activity lower than the expected range at peak was found in the 3 patients who had received rivaroxaban 10 mg once daily despite normal renal function (65, 168, and 173 µg/L). Anti-FXa activity measured at trough in these patients was relatively low, but was still within the expected range of 12–137 µg/L (16, 16, and 15 µg/L).

Proportion of Patients With Anti-FXa Activity Within the Expected Range

In the present study, 87.7% of patients receiving the Japan-specific dose of rivaroxaban had anti-FXa activity at peak within the expected range, compared with only 64.4% of patients receiving the standard dose of rivaroxaban (P=0.001). Of note, 32.2% of those receiving the standard dose had rivaroxaban concentrations higher than the expected range. Anti-FXa activity measured at the trough was within the expected range in 91.5% and 93% of patients receiving the standard and Japan-specific doses, respectively (P=0.614; Figure 4).

Figure 4.

Proportion of patients with anti-Factor Xa (FXa) activity within the expected range at (A) peak and (B) trough after administration of standard and Japan-specific doses of rivaroxaban. Standard doses were 20 and 15 mg rivaroxaban, once daily, in patients with normal and impaired renal function, respectively; Japan-specific doses of rivaroxaban were 15 and 10 mg, once daily, in patients with normal and impaired renal function, respectively.

After the anti-FXa activity of rivaroxaban has been assessed at the standard and Japan-specific doses, all patients continued with the standard dose of rivaroxaban. At the 1-year follow-up, 1 patient had developed ischemic stroke; in this patient, anti-FXa activity measured at peak was above the expected range, whereas anti-FXa activity measured at trough was within the expected range. Three patients experienced major bleeding while on rivaroxaban. In these patients, anti-FXa activity measured at peak was within the expected range in 1 and above and below the expected range in the remaining 2 patients. Because of the small sample size and relatively low event rate, correlations between anti-FXa activity and clinical outcomes were not evaluated.

Discussion

Rivaroxaban, an orally administered direct inhibitor of Factor Xa, was proved in ROCKET-AF to be non-inferior to warfarin in reducing stroke and systemic embolism, as well as in terms of the occurrence of major bleeding, in patients with non-valvular AF.⁷ In addition, rivaroxaban is associated with a lower risk of fatal bleeding and intracranial hemorrhage than warfarin.⁷ The doses of rivaroxaban used in the ROCKET-AF trial were 20 mg once daily in patients with normal renal function and 15 mg once daily in patients with moderate renal impairment. A previous simulation pharmacokinetic study in Caucasian patients with AF showed similar exposure between 15 mg rivaroxaban once daily in patients with CrCl 30–49 mL/min and 20 mg rivaroxaban once daily in patients with CrCl ≥50 mL/min.¹⁸

J-ROCKET AF is similar to ROCKET-AF, but was conducted exclusively in Japan. The J-ROCKET AF investigators decided to use lower doses of rivaroxaban in their study, namely 15 mg once daily in patients with normal renal function and 10 mg once daily in patients with moderate renal impairment.⁹ This decision was based on pharmacokinetic modeling data that indicated that the anti-FXa activity of rivaroxaban 15 mg once daily in Japanese AF patients was comparable to that of 20 mg once daily in Caucasian AF patients. The median anti-FXa activity measured at peak and trough for the 15-mg once daily dose in the Japanese AF population was reported to be 259 and 44 µg/L, respectively, at steady state. Similarly, the median anti-FXa activity measured at peak and trough following administration of 20 mg rivaroxaban once daily in a Caucasian population was reported to be 289 and 32 µg/L, respectively.¹⁰

The efficacy and safety of the Japan-specific dose of rivaroxaban were proven in J-ROCKET AF. Japanese patients with non-valvular AF receiving the Japan-specific dose of rivaroxaban had a similar rate of major bleeding, a non-significantly lower rate of stroke and systemic thromboembolism, and a significantly lower rate of intracranial bleeding than patients taking warfarin.⁹ The large cohort study in Japan also showed that patients receiving the Japan-specific dose had a lower risk of major bleeding than those receiving warfarin.¹⁹

It has been shown than approximately one-third of rivaroxaban is excreted unchanged via the kidney.^16,20 Correspondingly, previous studies demonstrated that moderate renal impairment increased exposure to rivaroxaban.^16,20 Several observational studies found that Asian patients with AF had lower CrCl than their Caucasian counterparts.^11,12 Therefore, it is possible that Asian populations may need lower doses of rivaroxaban than Caucasian populations.

In the present study we demonstrated that median anti-FXa activity measured at the peak was significantly higher for the standard than Japan-specific dose of rivaroxaban. Interestingly, the median anti-FXa activity measured at the peak for the 20-mg once daily dose reported in a Caucasian AF population (289 µg/L)¹⁶ seems to be more comparable to that of the 15-mg once daily dose (298 µg/L), rather than the 20-mg once daily dose (364 µg/L), in Thai AF patients with normal renal function in the present study. Furthermore, a higher proportion of patients receiving the Japan-specific dose of rivaroxaban in the present study had anti-FXa activity measured at peak within the expected range than patients receiving the standard dose. Of importance, one-third of patients receiving the standard dose of rivaroxaban in the present study had anti-FXa activity measured at peak that was higher than the expected range (>419 µg/L). Testa et al demonstrated that concentrations of NOACs were associated with clinical outcome, with high anti-FXa activity measured at peak associated with increased bleeding events and low anti-FXa activity measured at trough associated with increased thromboembolic events.^21,22 Taking all these findings into consideration, the Japan-specific dose of rivaroxaban may be appropriate for use in the Thai population with non-valvular AF.

Our data are in line with the efficacy and safety data for the Japan-specific dose of rivaroxaban in an Asian population in a real-world setting.^19,23–27 A global cohort study showed that the use of the Japan-specific dose of rivaroxaban is increasing in AF populations from East Asian countries: 44% of an East Asian population received a 15-mg once daily dose of rivaroxaban, compared with approximately 20% of patients from other regions.²⁸

Several retrospective cohort studies from Asian countries have examined the efficacy and safety of different doses of rivaroxaban in patients with non-valvular AF. In these studies, AF patients receiving either 15 or 20 mg rivaroxaban once daily had a significantly lower risk of ischemic stroke and a lower risk of intracranial bleeding than those receiving warfarin.^23,24,26 A cohort study from Taiwan showed that the risks of stroke and bleeding were similar in patients receiving 10 mg rivaroxaban once daily and those receiving 15–20 mg once daily.²⁴ Nevertheless, patients receiving the 10-mg once daily dose had a higher risk of myocardial infarction than those receiving the 15- to 20-mg once daily dose. However, the renal function of patients in that study was not reported.²⁴

A recent cohort study explored the efficacy and safety of the standard and Japan-specific doses of rivaroxaban in a Taiwanese AF population.²⁵ Renal function was examined in all patients. The investigators demonstrated that the efficacy of stroke and systemic thromboembolism prevention was similar between the Japan-specific and standard doses regardless of renal function.²⁵ However, in patients with impaired renal function (estimated glomerular filtration rate <50 mL/min/1.73 m², the standard dose of rivaroxaban was associated with a higher risk of bleeding than the Japan-specific dose.²⁵ These results are in accordance with the present findings that anti-FXa activity measured at peak and trough concentrations following administration of the standard dose was significantly higher than after administration of the Japan-specific dose in patients with CrCl 15–49 mL/min.

Another study reported that inappropriate underdosing of rivaroxaban (10 mg once daily in those with normal renal function) was associated with an increased risk of ischemic stroke compared with appropriate dosing (either standard dose or Japan-specific dose).²⁹ These results are consistent with the findings of the present study. In the present study, all 3 patients who had inappropriately received 10 mg rivaroxaban once daily despite normal renal function had anti-FXa activity measured at peak below the expected range and had anti-FXa activity measured at trough below 20 µg/L. Furthermore, the previous study found no difference in the risk of intracranial hemorrhage between inappropriate underdosing and appropriate dosing of rivaroxaban.²⁹ These findings illustrate that the use of 10 mg rivaroxaban once daily in patients with normal renal function should be avoided in clinical practice.

The definition of the expected range of anti-FXa activity of the standard dose of rivaroxaban used in the present study was derived mostly from Caucasian patients.^15–17 Nevertheless, a pharmacokinetic study indicated that average rivaroxaban exposure was comparable between a 15-mg dose of rivaroxaban in Japanese patients and a 20-mg dose in non-Japanese patients.³⁰ There have been several studies on the anti-FXa activity of the Japan-specific dose of rivaroxaban in the Japanese population.^30–34 A previous study in 96 Japanese patients reported that the mean anti-FXa activity of the Japan-specific dose of rivaroxaban measured at peak and trough was 351 µg/L (90% interval 79–585 µg/L) and 24 µg/L (90% interval 2–129 µg/L).³³ Another study in 119 Japanese patients demonstrated that the mean anti-FXa activity of a 15-mg once-daily dose of rivaroxaban in patients with normal renal function measured at peak and trough was 248±112 and 28±13 µg/L, respectively, whereas the mean anti-FXa activity of the 10-mg once-daily dose in patients with moderate renal impairment measured at peak and trough was 202±92 and 28±20 µg/L, respectively.³¹ In addition, the anti-FXa activity of the standard dose of rivaroxaban has been assessed in 30 Singaporeans. In that study, the mean anti-FXa activity of the standard dose of rivaroxaban measured at peak and trough in Singaporeans was lower than the expected range derived from Caucasians.³⁵ This is in contrast with the observations in the present study and other previous Japanese studies, and the disparity may be due to the fact that the Singaporeans in the study had a higher mean BMI (29 kg/m²) that the present study population and the Japanese population in the previous study (BMI 24 kg/m²).³¹

The present study has several limitations. First, the sample size is relatively small. High interindividual variability in rivaroxaban concentrations has been reported.³⁶ A larger study is needed to confirm the results reported here. Second, we did not examine correlations between anti-FXa activity and clinical outcomes due to the very low event rate. Therefore, further studies, particularly randomized controlled trials, are warranted to confirm the efficacy and safety of the Japan-specific dose of rivaroxaban in other Asian populations.

Conclusions

The anti-FXa activity measured at the peak of the standard rivaroxaban dose in Thai patients with non-valvular AF was higher than that measured for the Japan-specific dose. A higher proportion of patients taking the Japan-specific dose than the standard dose had anti-FXa activity within the expected range. Thus, it may be appropriate to use the Japan-specific dose of rivaroxaban in the Thai population with non-valvular AF. Randomized studies are needed to confirm the efficacy and safety outcomes of the Japan-specific dose in other Asian populations.

Acknowledgments

The authors acknowledge the support provided by the Northern Cardiac Center and Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University. The authors also acknowledge laboratory support from the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University.

Sources of Funding

This work was supported by grants from the Thailand Research Fund (Grant no. RSA5780040 [to A.P.] and RSA5780039 [to W.W.]) and the Faculty of Medicine Endowment Fund for Medical Research (Grant no. 020/2562), Chiang Mai University, Thailand.

Conflict of Interest

The authors declare no competing interests for this work.

IRB information

The Institutional Research Board of the Faculty of Medicine, Chiang Mai University approved this study (Approval no. 205/2561).

Data Availability

Deidentified participant data will not be shared.

Author Contributions

W.W., P.P. designed the study, recruited the patients, performed the statistical analyses, evaluated the results, and drafted the paper. W.W., P.P., L.N. and S.G. collected the data and contributed substantially to data preparation and quality assurance. A.P. participated in the conception and design of the study, and revised the paper for important intellectual content.

Authorship

All authors had access to the data used in this study and participated in writing the manuscript.

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