Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main ...dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nonadherence to antihypertensive drugs is a primary reason for suboptimal clinical outcomes among hypertensive patients. We assessed adherence to newly initiated antihypertensive medications in ...non-elderly Japanese patients and examined which patient and facility characteristics were associated with low adherence. We selected new oral antihypertensive drug users, aged 30-74 years, between 2014 and 2016 from a large administrative claims database. We measured adherence as the proportion of days covered (PDC) during a 1-year follow-up and divided patients into three groups of low (PDC < 40%), intermediate (PDC ≥ 40% to <80%), and high (PDC ≥ 80%) adherence. Factors associated with low adherence were assessed by logistic regression analysis with generalized estimating equations. Among 31,592 patients (mean age, 51.7 years; 41.2% female), the median 1-year PDC was 88.5% (IQR: 41.9-98.1%). In total, 59.2%, 16.6%, and 24.2% of patients were categorized as having high, intermediate, and low adherence, respectively. Female sex (odds ratio OR 1.15, 95% confidential interval 95% CI 1.08-1.22), younger age, and the initiation of angiotensin-converting enzyme inhibitors (OR 1.37, 95% CI 1.12-1.66), beta-blockers and thiazide diuretics (OR 4.82, 95% CI 4.34-5.36 and OR 3.91, 95% CI 2.79-5.46, respectively; compared with angiotensin II receptor blockers) were associated with low adherence. Patients initiating antihypertensives at larger hospitals (≥200 beds) were more likely to be adherent. While adherence to antihypertensive drugs in non-elderly Japanese patients was relatively high compared with that reported in previous studies in Western countries, patients with intermediate-low adherence may benefit from targeted interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a ...pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Low-dose prasugrel (3.75 mg) is used as maintenance therapy for percutaneous coronary intervention; however, data on long-term outcomes are scarce.Methods and Results: We analyzed 5,392 ...participants in the KiCS-PCI registry who were administered low-dose prasugrel or clopidogrel at discharge between 2008 and 2018 and for whom 2-year follow-up data were available. We adjusted for confounders using matching weight analyses and multiple imputations. Similarly, we used inverse probability- and propensity score-weighted analyses. We also performed instrumental variable analyses. The primary outcomes were acute coronary syndrome (ACS) and bleeding requiring readmission. Secondary outcomes were all-cause death and a composite outcome of ACS, bleeding, heart failure, stroke, coronary bypass requiring admission, and all-cause death. In this cohort, 12.2% of patients were discharged with low-dose prasugrel. Compared with clopidogrel, low-dose prasugrel was associated with a reduced risk of ACS (hazard ratio HR 0.58; 95% confidence interval CI 0.39–0.85), bleeding (HR 0.62; 95% CI 0.40–0.97), and the composite outcome (HR 0.71; 95% CI 0.59–0.86). Inverse probability-weighted analysis yielded similar results; however, matching weight analysis without multiple imputations and propensity score-matched analyses showed similar outcomes in both groups. Instrumental variable analyses showed reduced risks of ACS and composite outcome for those on low-dose prasugrel. All-cause mortality did not differ in all analyses.Conclusions: Low-dose prasugrel demonstrates comparable outcomes to clopidogrel in terms of ACS and bleeding.
Background:
The benefit of dual antiplatelet therapy (DAPT) for reducing ischemic events is greatest in the early period of acute coronary syndrome, and recent randomized controlled trials have ...investigated the unguided de-escalation strategy of changing potent P2Y
12
inhibitors to less potent or reduced-dose P2Y
12
inhibitors 1 month after acute coronary syndrome. However, it remains unclear which strategy is more effective and safer: the uniform unguided de-escalation strategy versus the personalized guided selection of DAPT with genotype or platelet function tests.
Methods:
PubMed, EMBASE, and Cochrane Central were searched for articles published from database inception to September 10, 2021. Randomized controlled trials investigating DAPT using clopidogrel, low-dose prasugrel, standard-dose prasugrel, ticagrelor, unguided de-escalation strategy, and guided selection strategy for patients with acute coronary syndrome were included. Hazard ratios and relative risk estimates were extracted from each study. The estimates were pooled using a random-effects network meta-analysis. The primary efficacy outcome was major adverse cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding. Secondary outcomes were all-cause death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and major bleeding.
Results:
This study included 19 randomized controlled trials with 69 746 patients. Compared with guided selection of DAPT, unguided de-escalation of DAPT was associated with a decreased risk of the primary safety outcome (hazard ratio, 0.48 95% CI, 0.33–0.72) without increased risks of major adverse cardiovascular events (hazard ratio, 0.82 95% CI, 0.53–1.28) or any secondary outcomes. The results were similar when the guided selection strategy was divided into platelet function–guided and genotype-guided strategies.
Conclusions:
Compared with guided selection of DAPT, unguided de-escalation of DAPT decreased bleeding without increasing ischemic events in patients after acute coronary syndrome. If a strategy of de-escalation is chosen, these findings do not support the routine use of personalized guiding tests.
Registration:
URL:
https://www.crd.york.ac.uk/PROSPERO/
; Unique identifier: CRD42021273082.
Acute renal failure requiring dialysis after heart transplantation remains a significant clinical issue because of its increasing incidence. We aimed to investigate its time trends, clinical ...predictors, and long-term outcomes.
Adult heart transplantation recipients registered in the United Network for Organ Sharing registry between 2009 and 2020 were identified. The patients were grouped according to the requirement for dialysis in the postoperative heart transplantation period. The independent risk predictors were identified, and the association between post-heart transplantation renal failure requiring dialysis and long-term mortality accounting for re-transplantation was investigated.
A total of 28,170 patients were included in the study, of which 3,371 (12%) required dialysis immediately post-heart transplantation. The incidence increased from 7.9% to 13.9% during the study period. Longer ischemic time, serum creatinine at transplantation >1.2 mg/dL, prior cardiac surgery, higher recipient body mass index, support of mechanical ventilation or extracorporeal membrane oxygenation, and history of congenital heart disease or restrictive/hypertrophic cardiomyopathy were its predictors (all p < 0.05). Patients on posttransplant dialysis had a higher risk of all-cause mortality (adjusted hazard ratio aHR: 5.2, 95% CI: 4.7-5.7, p < 0.001), 30 day mortality (aHR: 7.7, 95% CI: 6.3-9.6, p < 0.001) and 1 year mortality (aHR: 7.5, 95% CI: 6.6-8.6, p < 0.001). Post-transplant dialysis was associated with a risk of treated rejection at 1 year.
Acute renal failure requiring dialysis after heart transplantation is associated with significantly worse 30 day and long-term mortalities, and thus, early identification of high-risk patients is crucial to prevent severe renal complications.
Toxicity resulting from retained contrast media may cause adverse cardiovascular outcomes (e.g., heart failure and cardiogenic shock) for dialysis patients. However, the association between the ...administered contrast volume and outcomes of dialysis patients after percutaneous coronary intervention (PCI) has not been sufficiently investigated. We evaluated 953 consecutive dialysis patients (age, 67.9 ± 9.9 years; 30.1% with acute coronary syndrome) who underwent PCI between September 2008 and March 2019. Patients were divided into two groups: those with a contrast volume ≥ 200 ml and those with a contrast volume < 200 ml. The cutoff was 200 ml because 100 ml increment of contrast volume is known to raise the risk of acute kidney injury, and 200 ml is more than the average volume used at most PCI centers. The primary endpoint was a composite of in-hospital death, post-PCI cardiogenic shock and post-PCI heart failure. A multivariable logistic regression model and smooth spline curve were constructed to assess the association between contrast volume and the primary endpoint. The median contrast volume was 157 ml (interquartile range, 115-210 ml). The overall primary endpoint incidence was 6.8% (N = 65). A contrast volume ≥ 200 ml was associated with a higher risk of the primary endpoint (odds ratio 2.91; 95% confidence interval 1.42-6.05; P = 0.004). The smooth spline curve demonstrated a linear relationship between the contrast volume and primary endpoint. In conclusions, the contrast volume was associated with adverse in-hospital outcomes of dialysis patients undergoing PCI. Attention should be focused on the contrast volume used for dialysis patients undergoing PCI.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aims: P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events ...in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population. Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines. Results: In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 6.9, 22.8 versus 7.8 4.4, 14.5 pg/mL; P＜0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05–2.62; P=0.030). This correlation was consistent among various subgroups and was particularly evident in those aged ＜65 years or those without a history of hypertension. Conclusions: In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.
Contemporary guidelines emphasize the importance of risk stratification in improving the quality of care for patients undergoing percutaneous coronary intervention (PCI). We aimed to investigate ...whether adding information from a procedure-based academic registry to administrative claims data would improve the performance of risk prediction model.
We combined two nationally representative administrative and clinical databases. The study cohort comprised 43,095 patients; 18,719 and 23, 525 with acute ACS and chronic CCS coronary syndrome, respectively. Each population was randomly divided into the logistic regression model (derivation cohort, 80%) and model validation (validation cohort, 20%) groups. The performances of the following models were compared using C-statistics: (1) variables restricted to baseline claims data (model #1), (2) clinical registry data (model #2), and (3) expanded to both claims and clinical registry data (model #3). The primary outcomes were in-hospital mortality and bleeding.
The primary outcomes occurred in 3.7% (in-hospital mortality)/5.0% (bleeding) of patients with ACS and 0.21%/0.95% of CCS patients. For each event, the model performance was 0.65 (95% confidence interval CI, 0.60–0.69) /0.67 (0.63–0.71) in ACS and 0.52 (0.35–0.76) /0.62 (0.54–0.70) for CCS patients in model #1, 0.83 (0.80–0.87) /0.77 (0.74–0.81) in ACS and 0.76 (0.60–0.92) /0.67 (0.59–0.75) in CCS for model #2, and 0.83 (0.79–0.86) /0.78 (0.75–0.81) in ACS and 0.76 (0.61–0.92) /0.67 (0.58–0.74) in CCS for model #3.
Combining clinical information from the academic registry with claims databases improved its performance in predicting adverse events.
•The claims + registry-based risk models outperformed claims-based only risk models in PCI population.•Severity information such as cardiogenic shock only in the registry would be required for further risk stratification.•Combining claims and registries provide clinically relevant stratification schemes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To assess the applicability of Electronic Frailty Index (eFI) and Hospital Frailty Risk Score (HFRS) algorithms to Japanese administrative claims data and to evaluate their association with long-term ...outcomes.
A cohort study using a regional government administrative healthcare and long-term care (LTC) claims database in Japan 2014-18.
Plan enrollees aged ≥50 years.
We applied the two algorithms to the cohort and assessed the scores' distributions alongside enrollees' 4-year mortality and initiation of government-supported LTC. Using Cox regression and Fine-Gray models, we evaluated the association between frailty scores and outcomes as well as the models' discriminatory ability.
Among 827,744 enrollees, 42.8% were categorised by eFI as fit, 31.2% mild, 17.5% moderate and 8.5% severe. For HFRS, 73.0% were low, 24.3% intermediate and 2.7% high risk; 35 of 36 predictors for eFI, and 92 of 109 codes originally used for HFRS were available in the Japanese system. Relative to the lowest frailty group, the highest frailty group had hazard ratios 95% confidence interval (CI) of 2.09 (1.98-2.21) for mortality and 2.45 (2.28-2.63) for LTC for eFI; those for HFRS were 3.79 (3.56-4.03) and 3.31 (2.87-3.82), respectively. The area under the receiver operating characteristics curves for the unadjusted model at 48 months was 0.68 for death and 0.68 for LTC for eFI, and 0.73 and 0.70, respectively, for HFRS.
The frailty algorithms were applicable to the Japanese system and could contribute to the identifications of enrollees at risk of long-term mortality or LTC use.
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