Pharmacokinetics of hydroxychloroquine in Japanese systemic lupus erythematosus patients with renal impairment.

OBJECTIVES: Reduction of the hydroxychloroquine (HCQ) dosage is recommended in systemic lupus erythematosus (SLE) patients with renal impairment, but a pharmacokinetics (PK) study of patients with renal impairment has not yet been performed. METHODS: We investigated the PK of both single and multiple doses of HCQ and its metabolites in SLE patients with renal impairment who newly started HCQ at a daily dose of 300 mg based on an ideal body weight dosage of 6.5 mg/kg. Population PK analysis was performed using a non-linear mixed-effects model. RESULTS: In total, 219 samples from 21 patients were analysed. The PK of HCQ in blood after single and multiple oral administrations followed the two-compartment model. At steady state, the concentration ratio of HCQ to each metabolite was HCQ:desethylhydroxychloroquine:desethylchloroquine:bisdesethylchloroquine = 1:0.28:0.1:0.06. The HCQ concentration correlated positively with that of each metabolite. The estimated values (relative standard error) of the population PK parameters were the total clearance at 110 l/h (31%) and a central volume of distribution of 398 l (19%). Co-administration of prednisolone and age, but not renal impairment, were factors affecting the total clearance of HCQ. CONCLUSIONS: From the PK perspective, a dosage reduction is unnecessary in SLE patients with impaired renal function.

Latent class analysis of patients' background factors affecting the risk of specific adverse drug reactions to dipeptidyl peptidase 4 inhibitors.

BACKGROUND AND PURPOSE: Spontaneous reporting is widely used to identify adverse drug reactions (ADRs), but relatively little is known about the relationships between specific ADRs and background factors of affected patients. Here, we applied latent class analysis (LCA) to identify background factors associated with different ADRs in type 2 diabetes patients treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, using the Japanese Adverse Drug Event Report (JADER) database. MATERIALS AND METHODS: Patients using only a DPP-4 inhibitor who encountered ADRs were selected from the JADER database up to April 2019 (N = 3,577). LCA was employed to classify these cases based on underlying diseases and lifestyle factors (alcohol, tobacco, diet, and exercise) and to identify characteristic ADRs in each class. The optimum number of classes was determined by selecting the model with the lowest value of the Bayesian information criterion (BIC). RESULTS: A six-class model had the lowest BIC, and these classes were characterized by specific background factors and ADRs. For example, one class included diabetes complications, while another class included exercise and diet as background factors. Increased risk of a specific ADR(s), such as pancreatitis or pemphigoid, was found in each class. The nine DPP-4 inhibitors were not uniformly distributed among the classes, though individual classes included patients receiving different inhibitors. CONCLUSION: Our findings indicate that characteristic background factors of patients experiencing specific DPP-4 inhibitor-induced ADRs reported in the JADER database are different and can be classified by LCA. This methodology may be useful for predicting ADRs not detected during drug development.

Meta-analysis comparing inappropriately low dose versus standard dose of direct oral anticoagulants in patients with atrial fibrillation.

BACKGROUND: The appropriateness of direct oral anticoagulant (DOAC) dosing has been the issue in the real-world setting, and inappropriately lower DOAC dose may not be as effective or safe as the standard dose in patients with atrial fibrillation (AF). Multiple real-world studies compared the inappropriately lower DOAC dose versus the standard dose, but their main findings were contradictory. METHODS: A meta-analysis was performed to compare the efficacy and safety of the inappropriately lower DOAC dose with the standard DOAC dose in patients with AF. Database searches through May 30, 2021, were performed using Medline and Google Scholar. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. The secondary outcome was all-cause mortality. RESULTS: A total of 16 studies were included in this meta-analysis. It revealed that the inappropriately lower DOAC dose was significantly associated with a higher event rate of stroke or systemic embolism compared with the DOAC standard dose (odds ratio 1.21 [95% CI 1.02-1.43], P = 0.03, I2 = 66%). There was no significant difference in the major bleeding event rate between these groups (1.03, [0.92-1.15], P = 0.62; I2 = 27%). CONCLUSION: The inappropriately lower DOAC dose should be avoided to optimize DOAC effectiveness in patients with AF.

Factors contributing to the systemic clearance of infliximab with long-term administration in Japanese patients with Crohn's disease: Analysis using population pharmacokinetics
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OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. MATERIALS AND METHODS: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. RESULTS: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. CONCLUSION: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Comparing torsemide versus furosemide in patients with heart failure: A meta-analysis.

OBJECTIVES: To compare the efficacy and safety of torsemide versus furosemide in patients with heart failure (HF). DATA SOURCES: Medline, Cochrane Library, Web of Science, and Google Scholar database searches for relevant articles from 1946 to May 2018 were performed with the use of the key words torsemide and furosemide. STUDY SELECTION: Studies were included if they met the following criteria: (1) cohort studies or randomized controlled trials of adult patients 18 years of age or older who received oral torsemide or furosemide for HF with reduced or preserved ejection fraction; and (2) studies that reported mortality rate, rehospitalization rate for HF or cardiovascular disease (CVD), or New York Heart Association (NYHA) functional class changes. DATA EXTRACTION: Efficacy outcomes were mortality from any cause, rehospitalization for HF, rehospitalization for CVD, and NYHA functional class improvement. Safety outcome included hypokalemia. RESULTS: In the 5 included studies, there was no significant difference in mortality between torsemide and furosemide (odds ratio [OR] 1.00, 95% CI 0.58-1.72; P = 0.99; I2 = 79%). There was no significant difference in rehospitalization rates for HF (OR 0.79, 95% CI 0.57-1.09; P = 0.15; I2 = 64%) or CVD (OR 0.83, 95% CI 0.62-1.12; P = 0.22; I2 = 40%) between torsemide- and furosemide-treated patients. The use of torsemide was associated with significant improvement in NYHA functional class compared with furosemide (OR 1.44, 95% CI 1.18-1.76; P = 0.0004; I2 = 0%). CONCLUSION: Our meta-analysis showed that torsemide is associated with statistically significant improvement in NYHA functional class for patients with HF compared with furosemide. However, torsemide did not provide significant benefits in reducing mortality or rehospitalization rates for HF or CVD compared with furosemide. The authors suggest switching from furosemide to torsemide in patients with HF not achieving symptomatic control with the use of furosemide despite maximizing guideline-directed medical therapy and furosemide dosing.

Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Hospital-Based Cohort Study.

Methotrexate (MTX) is used widely as a first-line drug for the treatment of rheumatoid arthritis (RA) worldwide. There are large interindividual differences in the therapeutic response to MTX, but it is not known which factors influence them. We therefore investigated predictive factors associated with the therapeutic response to MTX in a hospital-based cohort study. Japanese adult RA outpatients prescribed MTX were enrolled and their characteristics were collected from the electronic medical records. The European League Against Rheumatism (EULAR) response criteria were used as the response to MTX therapy. The observation period was 1 year after beginning MTX administration. Sixteen types of single-nucleotide polymorphisms were investigated using the real-time PCR method. Associations between the MTX response and patient characteristics were evaluated using the multivariate logistic regression model. Among 70 Japanese adult RA outpatients, 52 were classified as MTX responders. In multivariate analysis, patients with the solute carrier family 19 member 1 (SLC19A1) 80G>A A/A genotype had a better response than those with the A/G or G/G genotype, and patients with the C allele of γ-glutamyl hydrolase (GGH) 16T>C had a better response than those with the T/T genotype.This study showed that the therapeutic response to MTX in Japanese RA patients was associated with the genetic polymorphisms of SLC19A1 80G>A and GGH 16T>C in actual clinical practice.

Risk factors for rhabdomyolysis with HMG-CoA reductase inhibitors identified using a postmarketing surveillance database in Japan
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OBJECTIVE: To investigate quantitatively the risk factors for rhabdomyolysis or related symptoms associated with HMG-CoA reductase inhibitors (statins), we used the lipid-lowering drug database (32,157 patients) developed by the RAD-AR Council, Japan, based on the postmarketing surveillance (PMS) data of pharmaceutical companies to perform a nested case-control study. MATERIALS AND METHODS: Of 26,849 patients taking statins, the case group was composed of 51 patients who experienced rhabdomyolysis or related symptoms while taking statins, and the control group was 1,020 patients randomly selected from patients who did not experience rhabdomyolysis or related symptoms while taking statins. Relevant factors that can be extracted from the database were: sex, age, body mass index (BMI), statin use duration, complications, concomitant medication, and clinical laboratory test values. RESULTS: Among those taking statins, 51 experienced rhabdomyolysis or related symptoms. Factors differing significantly between the two groups by univariate analysis were age, duration of statin intake, combination drugs (Ca antagonists, angiotensin II receptor blocker (ARB), cardiac drugs, benzodiazepines, mucoprotective drugs, insulin, α-glucosidase inhibitors), clinical laboratory results (high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase, alkaline phosphatase, total bilirubin), and complications (alcoholic hepatitis). Conditional multivariate logistic analysis of these factors yielded adjusted/odds ratios of 8.82 for the concomitant administration of an ARB and 3.45 for increased AST and 3.20 for increased total bilirubin levels. CONCLUSION: Risk factors for rhabdomyolysis or related symptoms associated with taking statins were combination with ARB and increases in AST or total bilirubin levels.
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Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study.

OBJECTIVES: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study. METHODS: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model. RESULTS: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation. CONCLUSIONS: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

Indirect comparison analysis of efficacy and safety between olanzapine and aripiprazole for schizophrenia.

AIMS: Indirect comparison (IC) and direct comparison (DC) between aripiprazole and olanzapine for schizophrenia were conducted to compare their efficacy and safety. The objective was to determine the usability of IC and consistency of results delivered by the two comparisons. Factors that might influence the inconsistency of results were also investigated. METHODS: ICs and DCs were conducted using the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score as an efficacy endpoint and the dropout rate was selected as a safety endpoint. Placebo and risperidone were used as common comparators for ICs. RESULTS: A literature search identified 20 articles. The efficacy analysis gave results on the mean difference in PANSS change (95% CI) of -5.72 (-10.22, -1.22) in ICs using placebo as a common comparator and -7.41 (-15.96, 1.14) in DCs. When using risperidone as a common comparator, it was -9.15 (-20.12, 1.82). In rate ratio analysis of the all cause dropout rate, the IC result was 1.17 (0.83, 1.65) using placebo as a common comparator and 1.56 (0.57, 4.26) using risperidone as a common comparator. Both analyses gave consistent results between ICs and DCs. A slightly lower estimated value was observed in ICs using placebo. CONCLUSIONS: This study demonstrated that ICs between olanzapine and aripiprazole can deliver results consistent with those of DCs. It is also suggested that the selection of a common comparator is important when control group bias is suspected in the data set.

Contributing factors to the apparent clearance of bepridil in patients with paroxysmal or persistent atrial fibrillation: analysis using population pharmacokinetics.

BACKGROUND: Bepridil is used as an antiarrhythmic drug due to its class I, class III, and class IV electrophysiological properties, but it has serious adverse effects such as QT prolongation and torsade de pointes. Bepridil has complex pharmacokinetic (PK) properties with large interindividual differences in plasma concentrations. The aim of this study was to evaluate the contributing factors to changes in the dose-concentration relationship of bepridil and the risk factors for excessive QT prolongation in patients with paroxysmal or persistent atrial fibrillation (AF). METHODS: A population PK analysis was performed by using NONMEM based on 425 concentration points from 76 patients receiving bepridil. A 1-compartment model approximating an intravenous model was used to examine the interindividual variability of the apparent systematic clearance (CL/F) of bepridil. A population PK-pharmacodynamic analysis was performed using the linear regression. RESULTS: Age was a contributing factor to the CL/F of bepridil in AF patients. The QTc interval increased as the area under the plasma bepridil concentration time curve (AUC) increased. The AUC in patients without a bundle branch block, the baseline QT interval, and the existence of structural heart disease in patients with a bundle branch block were explanatory variables of excessive QTc prolongation (QTc > 500 ms) during bepridil therapy. CONCLUSIONS: Using population PK methodology, this study showed that age was a contributing factor to the apparent clearance of bepridil in Japanese patients with AF and that excessive QT prolongation might be related to a larger AUC.

Psychotherapeutic drug-induced life-threatening arrhythmias: A retrospective analysis using the Japanese adverse drug event report database.

Background: Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database. Methods: From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP. Results: Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3). Conclusions: This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

Detection of Vaccine Adverse Events Before Package Insert Revisions Using a Japanese Spontaneous Reporting System.

The usefulness of disproportionality analysis for the pharmacovigilance of vaccines in the Japanese Adverse Drug Event Report (JADER) database is yet to be proven. This study aimed to verify whether significant disproportionality could be detected before adding new vaccine adverse event information to package inserts. Information on package insert revisions related to vaccine adverse drug events from January 2013 to March 2023 was extracted from the Pharmaceuticals and Medical Devices Agency website. This period was set as the maximum period for which early disproportionalities could be detected by the latest JADER database (April 2004 to December 2022). From JADER data, 15 revision histories (10 types of vaccines) of package inserts were identified, and 823,662 cases were obtained. Of the 15, 12 (80%) adverse events were identified as significant disproportionalities before package insert revisions were made. Nine of the 15 (60%) events were identified as significant disproportionalities earlier than at least 12 months. These findings suggest that the JADER database may detect vaccine adverse events earlier than package insert revisions, indicating its usefulness for the safety surveillance of vaccines.

Sacubitril/Valsartan Does Not Change the Use and Dose of Loop Diuretics in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: There is no standard approach for managing the use or dose of loop diuretics after initiating sacubitril/valsartan. OBJECTIVE: To investigate longitudinal trends in loop diuretic therapy use and doses during the initial 6 months following sacubitril/valsartan initiation. METHODS: This retrospective cohort study included adult patients who were initiated on sacubitril/valsartan in cardiology clinics. Inclusion criteria were patients diagnosed with heart failure with reduced ejection fraction (ejection fraction ≤40%) and initiated on sacubitril/valsartan in an outpatient setting. We investigated longitudinal trends in the prevalence of loop diuretic use and furosemide equivalent dose at baseline, 2 weeks, 1 month, 3 month and 6 months following sacubitril/valsartan initiation. RESULTS: A total of 427 patients were included in the final cohort. Compared to the baseline loop diuretic use and dose, there were no significant longitudinal changes in the prevalence of loop diuretic use or the furosemide equivalent dose over the 6 months following sacubitril/valsartan initiation. The use of sacubitril/valsartan was not significantly associated with reductions in the use or dose of loop diuretics over a 6-month follow-up period. CONCLUSION: The use of sacubitril/valsartan did not significantly change the use or dose of loop diuretics over 6-month follow-up period. Initiation of sacubitril/valsartan may not need a pre-emptive loop diuretic dose reduction.

Exploring Factors Affecting the Occurrence of Hypersensitivity Reactions Induced by Nonionic Iodine Contrast Media.

Hypersensitivity reactions induced by nonionic iodine contrast media sometimes occur and can be life threatening. However, independent factors affecting their occurrence remain to be fully established. Therefore, the purpose of this study was to clarify independent factors affecting the occurrence of hypersensitivity reactions induced by nonionic iodine contrast media. Patients who received nonionic iodine contrast media at Keiyu Hospital from April 2014 to December 2019 were included. The adjusted odds ratio (OR) and 95% confidence interval (CI) for factors affecting hypersensitivity reactions induced by contrast media were calculated by logistic regression analysis. The multiple imputation method was used to impute missing data. Hypersensitivity reactions occurred in 0.72% (163 cases) of 22,695 cases enrolled in this study. In univariate analysis, 10 variables met the criteria of P < .05 and proportion of missing data <50%. In multivariate analysis, age (OR, 0.98; 95% CI, 0.97-0.99), outpatient status (OR, 2.08; 95% CI, 1.20-3.60), contrast medium iodine content (OR, 1.02; 95% CI, 1.01-1.04), history of drug allergy (OR, 2.41; 95% CI, 1.50-3.88), and asthma (OR, 17.4; 95% CI, 7.53-40.1) were identified as independent factors affecting contrast media-induced hypersensitivity reactions. Among these factors, history of drug allergy and asthma appear to be clinically relevant and reliable due to their high OR and plausible biological mechanisms, but the other three factors require further validation.

Estimating the range of incremental cost-effectiveness thresholds for healthcare based on willingness to pay and GDP per capita: A systematic review.

BACKGROUND: Decision-making in healthcare policy involves assessing both costs and benefits. In determining the cost-effectiveness (CE) threshold, willingness to pay (WTP) per quality-adjusted life year (QALY), GDP per capita, and other factors are important. However, the relationship between WTP/QALY or GDP per capita and the CE threshold is unclear. It is important to clarify the relationship between WTP/QALY and GDP to provide a clear basis for setting the CE threshold. OBJECTIVE: The purpose of this study was to compare WTP/QALY and GDP per capita, and to develop a new CE threshold range based on WTP using GDP per capita. The relationship between WTP/QALY and healthy life expectancy (HALE) was also investigated. METHODS: We searched MEDLINE, EMBASE and Web of Science from 1980/01/01 to 2020/12/31 using the following selection criteria (latest search: Dec 2021):1, studies that estimated WTP/QALY; 2, the general population was surveyed; 3, the article was in English. From the collected articles, we obtained average values of WTP/QALY for various countries and compared WTP/QALY with GDP per capita. The correlation between WTP/QALY and HALE was also examined. RESULTS: We identified 20 papers from 17 countries. Comparison of mean WTP/QALY values with GDP per capita showed that most WTP/QALY values were in the range of 0.5-1.5 times GDP per capita, though the median values were less than 0.5 times. Comparison of WTP/QALY with HALE showed a statistically significant positive correlation when Taiwan was excluded as an outlier. CONCLUSIONS: Our results suggest a CE threshold range of 0.5-1.5 times GDP per capita is appropriate but lower than the WHO-recommended range of 1-3 times. The correlation between WTP/QALY and HALE suggests that investment in healthcare is reflected in an increased healthy life expectancy. Since WTP is based on consumer preferences, this range could be used to set a generally acceptable criterion.

Classification of patient characteristics associated with reported adverse drug events to neuraminidase inhibitors: an applicability study of latent class analysis in pharmacovigilance.

BACKGROUND: Signal detection in reports of spontaneous adverse drug reactions is useful in pharmacovigilance, but does not adequately consider potential confounding factors such as patient background information contained in the report data. Multiple indicators should be considered when generating safety hypotheses. AIM: The aim of this study was to evaluate whether latent class analysis (LCA) can complement conventional methods in pharmacovigilance. METHOD: We conducted LCA of 2732 reports of adverse drug reactions involving four widely used anti-influenza neuraminidase inhibitors in the Japanese Adverse Drug Event Report (JADER) database covering April 2004 to June 2020. LCA classifies the target population into multiple clusters based on response probability. The same data was subjected to multivariate logistic regression using an adjusted reporting odds ratio. RESULTS: LCA grouped the target population into three classes. Cluster 1 (46.4%) contained patients who developed adverse events other than neuropsychiatric events; these events were specific to adult females. Cluster 2 (28.7%) contained patients who developed abnormal behavior; these events were specific to underage males. Cluster 3 (24.8%) contained patients who developed adverse neuropsychiatric events other than abnormal behavior, such as hallucinations and convulsion; these events were specific to minors. Logistic regression of adverse events for which a signal was detected identified factors similar to those found in LCA. CONCLUSION: LCA classified adverse events in JADER with similar incidence tendencies into the same cluster. The results included signals identified by conventional logistic regression, suggesting that LCA may be useful as a complementary tool for generating drug safety hypotheses.

Drug-Induced QT Prolongation and Torsade de Pointes in Spontaneous Adverse Event Reporting: A Retrospective Analysis Using the Japanese Adverse Drug Event Report Database (2004-2021).

BACKGROUND: Drugs with new mechanisms of action are continually being developed, but it is difficult to capture whether a drug induces QT prolongation/torsade de pointes (TdP) in preclinical and preapproval clinical trials. OBJECTIVE: To evaluate drugs associated with drug-induced QT prolongation/TdP using a real-world database in Japan. PATIENTS AND METHODS: A search was performed in the Japanese Adverse Drug Event Report (JADER) database for QT prolongation and TdP. The reporting odds ratio (ROR) was calculated to identify potential drug-induced QT prolongation/TdP association. RESULTS: Among the reported 4,326,484 data entries, 3410 patients exhibited QT prolongation/TdP (2707 with QT prolongation, 703 with TdP) with the suspected drugs. Of these patients, 53.9% were females. The highest occurrence was in the 70- to 79-year-old age group (24.7%). The most common types of drugs involved were cardiovascular drugs, central nervous system (CNS) drugs, anticancer drugs, and anti-infective drugs; the rate of overdose was reportedly very low at 1.6%. The highest adjusted RORs were observed for nifekalant (351.41, 95% confidence interval (CI) 235.85-523.59), followed by vandetanib (182.55, 95% CI 108.11-308.24), evocalcet (181.59, 95% CI 132.96-248.01), bepridil (160.37, 95% CI 138.17-186.13), diarsenic trioxide (79.43, 95% CI 63.98-98.62), and guanfacine (78.29, 95% CI 58.51-104.74). Among the drugs launched in Japan during the last decade, vandetanib had the highest adjusted RORs. CONCLUSIONS: This study using the JADER database showed that antiarrhythmic drugs, calcium-sensing receptor agonists, small-molecule targeted anticancer drugs, and CNS drugs are associated with QT prolongation/TdP. Further pharmacoepidemiological studies, such as cohort studies using large databases, are needed to prove these causal relationships.

Meta-Analysis Comparing Bivalirudin Versus. Unfractionated Heparin in Adult Patients With Extracorporeal Membrane Oxygenation.

Introduction: Unfractionated heparin (UFH) has traditionally been the agent of choice in patients on extracorporeal membrane oxygenation (ECMO). However, direct thrombin inhibitors (DTI) have recently garnered more attention in ECMO because of their advantages over UFH. Given the heterogeneous results of multiple recent published studies, we performed a meta-analysis to describe pooled outcomes between bivalirudin and UFH anticoagulation in patients on ECMO. Methods: Relevant studies were identified from MEDLINE and Google Scholar database searches through April 23, 2022. The primary efficacy outcome was thromboembolism (TE), and secondary efficacy outcomes included all-cause mortality and circuit thrombosis. The primary safety outcome was major bleeding. Results: A total of 6 studies were included in the meta-analysis. Bivalirudin use was associated with significantly lower risk of TE (OR 0.61; 95% CI 0.38-.99; P = .05; I2 = 0%) and circuit thrombosis (OR 0.51; 95% CI .32-.80; P = .004; I2 = 0%) compared with UFH. There was no significant difference in all-cause mortality risk (OR 0.75; 95% CI .52-1.09; P = .13; I2 = 30%) between the bivalirudin and UFH groups. No significant difference in the risk of major bleeding between 2 groups was found (OR 0.67; 95% CI 0.25-1.81; P = .43; I2 = 80%). Conclusion: These data support that bivalirudin is a reasonable alternative to UFH in patients on ECMO. Randomized controlled trials are needed to confirm bivalirudin's efficacy and safety results compared with UFH.