Abstract
Enoxaparin and daikenchuto are commonly administered to prevent venous thromboembolism and intestinal obstruction after gynecological malignancy surgery. However, the effects of their combined use on hepatic function are not well studied. This study aimed to clarify the effects of the coadministration of enoxaparin and daikenchuto on hepatic function. First, Japanese Adverse Drug Event Report (JADER) data were analyzed to identify signals of hepatic disorders. Second, a retrospective observational study of patients who underwent surgery for gynecological malignancies was conducted. This study defined hepatic disorders as an increase in aspartate aminotransferase (AST) or alanine aminotransaminase (ALT) levels above the reference values, using 1-h postoperative values as the baseline. The analysis of JADER data revealed an increased risk for hepatic disorders with the coadministration of enoxaparin and daikenchuto. An observational study also showed higher odds ratios (95% confidence intervals) for the occurrence of hepatic disorders in the coadministration group (4.27; 2.11–8.64) and enoxaparin alone group (2.48; 1.31–4.69) than in the daikenchuto alone group. The median increase in the ALT level was also higher in the coadministration group (34; 15–59) than in the enoxaparin alone (19; 6–38) and daikenchuto alone groups (8; 3–33). In conclusion, our study suggests that compared with the use of enoxaparin or daikenchuto alone, enoxaparin and daikenchuto coadministration increases the risk of hepatic disorders, with more significant increases in AST and ALT levels. Healthcare workers need to be aware of these potential side effects when combining these drugs after surgery for gynecological malignancies.
INTRODUCTION
Enoxaparin is a low-molecular-weight heparin recommended for preventing venous thromboembolism (VTE) in individuals undergoing surgical intervention. Enoxaparin’s weaker inhibition of thrombin and higher selectivity for factor Xa result in a lower risk of bleeding compared to unfractionated heparin.1–3) In addition to the low risk of bleeding, enoxaparin is easy to administer subcutaneously and does not require therapeutic monitoring of laboratory values like unfractionated heparin does.4) Although enoxaparin is easy to administer, it has a higher tendency to cause hepatic disorders than other low-molecular-weight heparins.5)
Daikenchuto is a commonly used herbal medicine in Japan that is composed of processed ginger, ginseng, and zanthoxylum fruit. It is prescribed to treat bloating, abdominal pain, and colds. This herbal medicine is known to help in the recovery of bowel function and is frequently administered after abdominal surgery to prevent postoperative bowel obstruction.6–8) Herbal medicines are commonly used due to their perceived low risk of side effects. However, daikenchuto has been found to cause liver disorders, which is believed to be a result of an allergic reaction.9)
Abdominal surgery is a widely used procedure for treating gynecological cancer. However, abdominal surgery has potential risks, such as VTE and bowel obstruction. To reduce the occurrence of these risks, a combination of enoxaparin and daikenchuto is frequently given after surgery. Although enoxaparin and daikenchuto have been reported to cause hepatic disorders, it is not clear whether the concurrent administration of these medications increases the incidence of hepatic disorders. It is common for patients to receive postoperative chemotherapy after undergoing surgery for gynecologic cancer. However, if a patient develops a hepatic disorder, they may not be able to receive adequate chemotherapy, which can negatively impact their prognosis. In addition, severe hepatic disorders need to be avoided, as they can lead to liver transplantation or, as the worst-case scenario, death.10,11) Identifying background factors in patients is crucial to prevent hepatic disorders. This study aimed to determine whether the coadministration of enoxaparin and daikenchuto induces hepatic disorders compared to single-agent use and to identify factors that influence the development of hepatic disorders in database and observational studies.
MATERIALS AND METHODS
Database StudyOur study analyzed the Japanese Adverse Drug Event Report (JADER) database, which encompasses data from April 2004 to August 2022. The adverse events are categorized using the definitions from the 19.0 version of the Medical Dictionary for Regulatory Activities (MedDRA). We used preferred terms from standardized MedDRA queries (SMQs) to identify hepatic disorders.
To determine the likelihood of adverse events occurring as a result of drug interactions, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for both single-agent use groups and coadministration groups.12–14)
Observational StudyWe conducted a retrospective observational study at Shinshu University Hospital between January 2019 and December 2021. The study included patients who were 20 years or older, underwent surgery for gynecologic cancer (including ovarian, cervical, or uterine cancer), and received treatment with either enoxaparin or daikenchuto. We excluded patients who met any of following criteria: 1) patients who had taken enoxaparin or daikenchuto before surgery; 2) those who received enoxaparin or daikenchuto treatment for less than four days; and 3) those whose aspartate aminotransferase (AST) or alanine aminotransaminase (ALT) levels exceeded the upper limit of normal for the study institution (AST >30 IU/L, ALT >23 IU/L) one hour after surgery. In this study, we defined patients with hepatic disorders as patients with elevated AST or ALT levels above the upper limit of normal within two weeks after receiving enoxaparin or daikenchuto treatment. In addition, the AST and ALT levels obtained one hour after surgery were considered baseline values, and the degree of elevation of these enzymes was assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The Institutional Review Board of Shinshu University Hospital approved the study protocol (Approval Number: 5414), and we obtained informed consent through the opt-out procedure.
Statistical AnalysisFisher’s exact test was employed to assess the significance of categorical variables, while the Kruskal–Wallis or Wilcoxon rank sum test was used to analyze continuous variables. We present continuous variables as medians and interquartile ranges (IQRs) and categorical variables as numbers and percentages. Logistic regression analysis was used to establish the development of hepatic disorders as an objective variable with the aim of identifying factors associated with hepatic disorders and determining the factors associated with elevated AST and ALT levels using multiple regression analysis. In these analyses, factors with p-values less than 0.1 in univariate analyses were included as candidate factors, and covariates were selected using a forward and backward stepwise selection method. All statistical analyses were carried out using R (version 4.3.2, R Foundation for Statistical Computing). We set the threshold of statistical significance at a p-value less than 0.05.
RESULTS
RORs of Hepatic Disorders in the Database StudyThe present database study included a total of 781629 reports, of which 28635 were related to hepatic disorders. The number of hepatic disorders and RORs for the single-use and coadministration groups are shown in Table 1. The ROR of the coadministration group was higher than those of the single-use groups.
Table 1. Number of Reports and Reporting Odds Ratio (ROR) of Hepatic Disorders
| Drugs | Cases (n) | Non-cases (n) | Total (n) | ROR | 95% CI |
|---|
| Enoxaparin | 33 | 504 | 537 | 1.60 | 1.13–2.28 |
| Daikenchuto | 240 | 3580 | 3820 | 1.65 | 1.45–1.88 |
| Coadministration | 4 | 11 | 15 | 8.91 | 2.84–28.00 |
CI, confidence interval; ROR, reporting odds ratio.
In this observational study, a total of 231 patients were included and divided into three groups: the enoxaparin alone group, the daikenchuto alone group, and the coadministration group (Table 2). Although there were significant differences in age (p < 0.001), cancer type (p = 0.004), estimated creatinine clearance (p = 0.002), and AST levels (p = 0.011) one hour after the operation among the three groups, no significant clinical differences were found.
Table 2. Patient Characteristics at Baseline and after Surgery
| Enoxaparin (n = 84) | Daikenchuto (n = 76) | Coadministration (n = 71) | Kruskal–Wallis p-value |
|---|
| Age (years) | 60 (51–69) | 54 (49–58)*** | 66 (58–73) | <0.001 |
| BMI (kg/m2) | 23.31 (20.01–26.71) | 24.42 (21.30–27.33) | 22.89 (20.72–27.01) | 0.305 |
| Cancer type (ovary/other) | 23/61 (27.4) | 40/36 (52.6) | 25/46 (35.2) | 0.004 |
| eCCr (mL/min) | 76.78 (64.52–94.43) | 90.39 (75.80–115.29)** | 75.34 (57.35–101.24) | 0.002 |
| Anesthesia time (h) | 6.66 (4.83–9.65) | 6.67 (5.06–8.14) | 7.30 (5.40–9.59) | 0.274 |
| Blood transfusion therapy | 13 (15.5) | 15 (19.7) | 14 (19.7) | 0.723 |
| Prophylactic antibiotics use | 84 (100) | 76 (100) | 71 (100) | 1.000 |
| Cephem | 83 (98.8) | 75 (98.7) | 69 (97.2) | 0.690 |
| Fluoroquinolone + Lincomycin | 1 (1.2) | 1 (1.3) | 2 (2.8) | 0.690 |
| Therapeutic antibiotics use after surgery | 11 (13.1) | 17 (22.4) | 17 (23.9) | 0.175 |
| Acetaminophen use | 14/60 (16.7) | 21/55 (27.6) | 11/60 (15.5) | 0.119 |
| AST (IU/L) |
| Baseline | 17 (15–19) | 14 (12–18) | 16 (14–19) | 0.011 |
| After treatment | 30 (19–45) | 18 (14–39) | 41 (24–59) | |
| Amount of change | 17 (09–32) | 10 (03–27) | 27 (15–45) | |
| ALT (IU/L) |
| Baseline | 10 (09–13) | 9 (07–15) | 10 (08–12) | 0.533 |
| After treatment | 30 (18–50) | 20 (14–44) | 48 (24–68) | |
| Amount of change | 19 (06–38) | 8 (03–33) | 34 (15–59) | |
| CTCAE grade for AST and/or ALT elevation |
| Grade 1 | 43 | 17 | 36 | |
| Grade 2 | 4 | 10 | 12 | |
| Grade 3 | 6 | 3 | 5 | |
| Grade 4 | 0 | 1 | 0 | |
| Hepatic disorder | 53 (63.1) | 31 (40.8)*** | 53 (74.6) | <0.001 |
Data are shown as median (interquartile range) or frequency (percentage). Significant differences compared with coadministration: * p < 0.05, ** p < 0.01, *** p < 0.001. BMI, body mass index; eCCR, estimated creatinine clearance; ALT, alanine aminotransaminase; AST, aspartate aminotransferase.
The study found that hepatic disorders occurred in 53/84 (63.1%) patients in the enoxaparin alone group, 31/76 (40.8%) patients in the daikenchuto alone group, and 53/71 (74.6%) patients in the coadministration group. The coadministration group had a significantly higher incidence of hepatic disorders (p < 0.001, Fisher’s exact test). The median ALT levels after treatment were 30 IU/L (IQR, 18–50) for patients who received enoxaparin, 20 IU/L (14–44) for patients who received daikenchuto, and 48 IU/L (24–68) for patients with the coadministration of both drugs (p < 0.001; Table 2). The coadministration group also had the highest median AST level after treatment (Table 2). The range of increase in the AST level was 27 IU/L (15–45), 17 IU/L (9–32), and 10 IU/L (3–27) in the coadministration group, the enoxaparin alone group, and the daikenchuto alone group, respectively (p < 0.001; Table 2), and the range of increase in the ALT level was 34 IU/L (15–59), 19 IU/L (6–38), and 8 IU/L (3–33) among the three groups, respectively (p < 0.001; Table 2). The coadministration group showed a significant increase not only in the absolute values of AST and ALT but also in their ranges of increase (Fig. 1).
Next, we conducted logistic regression analysis for hepatic disorders, taking the daikenchuto alone group as a reference; the odds ratios were significantly higher in the enoxaparin alone and coadministration groups, with values of 2.48 (1.31–4.69) and 4.27 (2.11–8.64), respectively. Moreover, we carried out linear regression analysis for AST and ALT levels after treatment (Tables 3, 4). We found that both AST and ALT level changes were significantly affected by coadministration, ovarian cancer, and anesthesia duration. For the AST level, BMI and enoxaparin use alone also had an effect.
Table 3. Univariate and Multivariate Linear Regression Analysis of AST Change
| AST change |
|---|
| Univariate linear regression analysis | Multivariate linear regression analysis |
|---|
| Coefficient (95% CI) | p-Value | Coefficient (95% CI) | p-Value |
|---|
| Age (years) | 0.005 (−0.008, −0.017) | <0.474 | | |
| BMI (kg/m2) | −0.057 (−0.096, −0.017) | <0.005 | −0.040 (−0.078, −0.002) | <0.040 |
| Ovarian cancer | 0.461 (−0.094, −0.828) | <0.014 | −0.644 (−0.278, −1.011) | <0.001 |
| eCCr (mL/min) | −0.001 (−0.006, −0.005) | <0.834 | | |
| Acetaminophen use | −0.135 (−0.587, −0.316) | <0.558 | | |
| Anesthesia time (h) | 0.066 (−0.001, −0.131) | 0.046 | −0.072 (−0.010, −0.135) | <0.023 |
| Transfusion use | 0.406 (−0.062, −0.873) | 0.089 | | |
| Therapeutic Antibiotics use | 0.419 (−0.036, −0.874) | 0.071 | | |
| AST postoperative 1 h | −0.018 (−0.059, −0.023) | <0.385 | | |
| ALT postoperative 1 h | −0.058 (−0.095, −0.021) | <0.003 | | |
| Coadministration | 0.752 (−0.374, −1.131) | <0.001 | −1.022 (−0.594, −1.450) | <0.001 |
| Single enoxaparin use | −0.005 (−0.380, −0.370) | <0.979 | −0.563 (−0.147, −0.980) | <0.008 |
BMI, body mass index; CI, confidence interval; eCCR, estimated creatinine clearance; ALT, alanine aminotransaminase; AST, aspartate aminotransferase.
Table 4. Univariate and Multivariate Linear Regression Analysis of ALT Change
| ALT change |
|---|
| Univariate linear regression analysis | Multivariate linear regression analysis |
|---|
| Coefficient (95% CI) | p-Value | Coefficient (95% CI) | p-Value |
|---|
| Age (years) | −0.003 (−0.022, −0.017) | 0.772 | | |
| BMI (kg/m2) | −0.065 (−0.126, −0.004) | 0.037 | −0.042 (−0.100, −0.017) | 0.163 |
| Ovarian cancer | 0.646 (−0.084, −1.207) | 0.025 | −0.932 (−0.368, −1.497) | 0.001 |
| eCCr (mL/min) | −0.002 (−0.007, −0.010) | 0.713 | | |
| Acetaminophen use | −0.205 (−0.895, −0.485) | 0.561 | | |
| Anesthesia time | 0.131 (−0.032, −0.229) | 0.009 | 0.142 (−0.046, −0.238) | <0.004 |
| Transfusion | 0.464 (−0.252, −1.180) | 0.203 | | |
| Therapeutic antibiotics use | 0.642 (−0.053, −1.336) | 0.070 | | |
| AST postoperative 1 h | −0.021 (−0.083, −0.042) | 0.521 | | |
| ALT postoperative 1 h | −0.020 (−0.078, −0.038) | 0.506 | | |
| Coadministration | −1.191 (−0.613, −1.768) | <0.001 | −1.429 (−0.769, −2.089) | <0.001 |
| Single enoxaparin use | −0.250 (−0.822, −0.323) | 0.393 | −0.555 (−0.087, −1.197) | 0.090 |
BMI, body mass index; CI, confidence interval; eCCR, estimated creatinine clearance; ALT, alanine aminotransaminase; AST, aspartate aminotransferase.
DISCUSSION
This study found that the coadministration of enoxaparin and daikenchuto increases the risk of hepatic disorders. First, we analyzed the JADER database to investigate the potential risk of hepatic disorders with the coadministration of enoxaparin and daikenchuto. The ROR of the coadministration of enoxaparin and daikenchuto was significantly higher than that of the use of enoxaparin or daikenchuto alone. This suggests that the coadministration of enoxaparin and daikenchuto is a risk factor for hepatic disorders. Second, we conducted an observational study in our hospital and found results similar to those of the database study. The observational study revealed that the coadministration of enoxaparin and daikenchuto was associated with a more significant increase in AST and ALT levels compared to monotherapy.
This is the first report showing that the coadministration of enoxaparin and daikenchuto is a risk factor for hepatic disorders and increases the severity. The findings from this study may prove valuable in clinical practice, as postoperative adjuvant chemotherapy is commonly administered following surgery for gynecological cancers. Elevated hepatic enzyme levels may delay the initiation of postoperative chemotherapy or hinder adequate dosing. To elucidate the potential risk of liver dysfunction, we defined hepatic disorder as a grade 1 increase in liver enzyme levels. The majority of the hepatic disorders observed in this observational study were grade 1, and of the 137 patients who developed hepatic disorders, 118 had returned to normal levels by the first follow-up after discharged from the hospital. According to our observational study, the risk of hepatic disorders associated with the use of daikenchuto or enoxaparin was 40.8 and 63.1%, respectively, which is a higher frequency than that associated with the respective package inserts. The high incidence of increased AST and ALT levels with enoxaparin use alone may explain why there was no significant difference between the frequency of increased AST and ALT levels with the coadministration of enoxaparin and daikenchuto (74.6%). However, there was a trend toward increased AST and ALT levels with the coadministration of enoxaparin and daikenchuto. This suggests that, as in the JADER database, the risk of increased AST and ALT levels is higher with the coadministration of enoxaparin and daikenchuto. The large increases in AST or ALT levels above the reference values in observational studies could be due to differences in the criteria used in clinical trials, in the reference values among centers, and in patient backgrounds.
Logistic regression analysis showed that the coadministration of enoxaparin and daikenchuto increased the risk of hepatic disorders. Multiple regression analysis showed that coadministration of enoxaparin and daikenchuto and ovarian cancer were associated with increased AST and ALT levels. The mechanism of the increase in AST and ALT levels with the use of enoxaparin alone may be that enoxaparin directly causes hepatocellular damage since it has been suggested that heparin causes hepatocellular necrosis. The presence of hepatocellular damage was noted in the histopathology of patients treated with enoxaparin.15,16) Enoxaparin may directly cause hepatocellular damage. Herbal medicines, including daikenchuto, are thought to cause hepatocellular damage through an allergic mechanism.9) A possible reason why the coadministration of enoxaparin and daikenchuto was suggested as a risk factor could be the additive effect of both drugs on hepatic disorders. Daikenchuto has been reported to increase portal blood flow, so it is possible that the increase in portal blood flow caused by daikenchuto results in an increase in the amount of enoxaparin to which hepatocytes are exposed per unit time, leading to hepatic disorders.17) However, it is difficult to determine the extent of hepatic exposure to enoxaparin in clinical practice, and the detailed mechanism is unknown.
Although ovarian cancer was mentioned as a factor, compared to other gynecological cancers, the surgical procedures did not change significantly. Since all subjects were from our hospital, the anesthetics used did not change either. The duration of anesthesia was also recognized as a factor that could be influenced by the degree of invasiveness of the surgical procedure. However, the influence of the duration of anesthesia was considered insignificant because liver enzymes can be elevated after both short and long operations lasting >20 h.18,19) Because surgery is performed for ovarian cancer at a more advanced stage than other gynecological cancers, our patients likely had advanced stages of cancer. The advanced cancer stage may have influenced the results since surgery is performed for ovarian cancer at a more advanced stage than for other gynecological cancers.
Since both drugs cause AST and ALT levels to increase when used as single agents, the results of this study suggest that even drugs described as infrequently causing increased AST and ALT levels on the package insert should be noted as having increased risk when coadministered. In addition, the spontaneous reporting system and in-hospital big data showed that coadministration is a risk factor. Signal detection using the spontaneous reporting system is considered useful for such unpredictable drug-drug interaction-induced adverse effects.12,13,20)
This study has limitations. First, hepatic function has three components: coagulability, excretory capacity, and liver enzyme levels; however, coagulability was not observed in this study because measurements were not available. Second, hepatic disorders were diagnosed when AST or ALT levels became higher than the postoperative value within 14 d after the start of treatment or after coadministration for at least four days; therefore, if daikenchuto or enoxaparin was started first, hepatic disorders caused by the use of a single drug may have been underestimated. Third, although the ROR is a commonly used method for signal analysis, the likelihood of false positives increases when the number of reports is small. In this study, there were four reports in the coadministration group; therefore, false positives could not be ruled out. However, as similar results have been obtained in observational studies, the likelihood of false positives was not high.
In conclusion, the analysis using the JADER database and the observational study indicated that the coadministration of enoxaparin and daikenchuto after gynecological cancer surgery may induce hepatic disorders compared to single-agent use. Regular monitoring of liver function is considered necessary during the coadministration of enoxaparin and daikenchuto.
Funding
This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Contributions
H.W., K.H., H.T., and T.N. designed the study. H.W., Y.N., and A.K. conducted the study. H.W. and K.H. analyzed the data. H.W. and K.H. wrote the manuscript. All the authors have read and approved the final manuscript.
Conflict of Interest
The authors declare no conflict of interest.
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