Cardiovascular toxicity profiles of immune checkpoint inhibitors with or without angiogenesis inhibitors: a real-world pharmacovigilance analysis based on the FAERS database from 2014 to 2022.

Background: Immune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors (AGIs) have become increasingly available for multiple types of cancers, although the cardiovascular safety profiles of this combination therapy in real-world settings have not been elucidated to date. Therefore, we aimed to comprehensively investigate the cardiovascular toxicity profiles of ICIs combined with AGIs in comparison with ICIs alone. Methods: The Food and Drug Administration Adverse Event Reporting System (FAERS) database from the 1st quarter of 2014 to the 1st quarter of 2022 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with ICIs alone, AGIs alone and combination therapy. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant. Results: A total of 18 854 cardiovascular AE cases/26 059 reports for ICIs alone, 47 168 cases/67 595 reports for AGIs alone, and 3 978 cases/5 263 reports for combination therapy were extracted. Compared to the entire database of patients without AGIs or ICIs, cardiovascular AEs were overreported in patients with combination therapy (IC025/ROR025 = 0.559/1.478), showing stronger signal strength than those taking ICIs alone (IC025/ROR025 = 0.118/1.086) or AGIs alone (IC025/ROR025 = 0.323/1.252). Importantly, compared with ICIs alone, combination therapy showed a decrease in signal strength for noninfectious myocarditis/pericarditis (IC025/ROR025 = 1.142/2.216 vs. IC025/ROR025 = 0.673/1.614), while an increase in signal value for embolic and thrombotic events (IC025/ROR025 = 0.147/1.111 vs. IC025/ROR025 = 0.591/1.519). For outcomes of cardiovascular AEs, the frequency of death and life-threatening AEs was lower for combination therapy than ICIs alone in noninfectious myocarditis/pericarditis (37.7% vs. 49.2%) as well as in embolic and thrombotic events (29.9% vs. 39.6%). Analysis among indications of cancer showed similar findings. Conclusion: Overall, ICIs combined with AGIs showed a greater risk of cardiovascular AEs than ICIs alone, mainly due to an increase in embolic and thrombotic events while a decrease in noninfectious myocarditis/pericarditis. In addition, compared with ICIs alone, combination therapy presented a lower frequency of death and life-threatening in noninfectious myocarditis/pericarditis and embolic and thrombotic events.

Inflammatory biomarkers in assessing severity and prognosis of immune checkpoint inhibitor-associated cardiotoxicity.

AIMS: Inflammatory biomarkers, including CRP, the neutrophil-to-lymphocyte ratio (NLR), and the neutrophil-to-eosinophil ratio (NER), may predict outcomes in cancer. However, their value in immune checkpoint inhibitor (ICI) therapy-associated cardiotoxicity remains elusive. We aimed to characterize the relationship of inflammatory markers with severity of ICI-related cardiotoxicities (iRCs) and prognosis among patients with iRCs. METHODS: Patients who were diagnosed with iRCs between January 2019 and December 2021 were retrospectively enrolled and were dichotomized based on iRC severity into low-grade (grade 1-2) vs. high-grade (grade 3-4) groups. RESULTS: Forty-seven patients were included. The median time-to-event from first ICI infusion to onset of iRCs was 35 days (IQR: 19.0-65.5 days). When compared with respective baseline values, cardiac biomarkers and inflammatory markers were significantly elevated at onset of iRCs. Compared with low-grade iRCs, NER at iRC onset was significantly increased among patients with high-grade iRCs (Group × Time, P < 0.01). When grouped by the median NER (184.33) at iRC onset, NER ≥ 184.33 was associated with high-grade iRCs (OR: 10.77, P < 0.05) and had a 36.3% increased mortality compared to the lower NER group (HR: 2.67, P < 0.05). CONCLUSIONS: In patients who develop iRCs, NER is significantly elevated at iRC onset, and higher NER correlates with greater iRC severity and higher mortality. Larger datasets are needed to validate these findings.

Immune-related interstitial lung disease induced by different immune checkpoint inhibitors regimens: A real-world study from 2014 to 2022 based on FAERS databases.

This study further approaches immune-related interstitial lung disease adverse event in patients undergoing immune checkpoint inhibitor (ICI) monotherapy, ICI plus chemotherapy and ICI plus anti-VEGF therapy in the postmarketing period. Reports for ICI-related interstitial lung disease adverse event from the FDA Adverse Event Reporting System (FAERS) database between 2014 and 2022 were analysed in this study. The reporting odds ratio (ROR) and Bayesian confidence propagation neural networks of information components (IC) were computed to identify disproportionate reporting of ICI-related interstitial lung disease. 44,964,609 records were extracted from the FAERS database, with 9150 records for interstitial lung disease after ICI treatment. Men had a slightly higher reporting frequency than women (63.07% vs. 25.69%). The morbidity rate (2.05%) of acute respiratory distress syndrome was low, the fatality rate (67.55%) was the highest, the time to onset was relatively short. Within 3 months, the cumulative proportion of ICI-related interstitial lung disease records was 75.03%. The ICI plus anti-VEGF therapy group had the lowest frequency of interstitial lung disease adverse events compared to the ICI monotherapy group and the ICI plus chemotherapy group (IC025 = 1.72, IC025 = 3.21, IC025 = 3.22). Moreover, ICI plus anti-VEGF therapy group had the narrowest spectrum of interstitial lung disease among these three therapeutic regimens. This study showed substantial characteristics of a spectrum of interstitial lung disease adverse events after different ICI regimens. Notably, ICI plus anti-VEGF therapy might be a treatment method that can to some extent control ICI-related interstitial lung disease. These data provide some important information for clinicians to weigh the risks and benefits of different ICI regimens.

Cardiovascular toxicity associated with angiogenesis inhibitors: A comprehensive pharmacovigilance analysis based on the FDA Adverse Event Reporting System database from 2014 to 2021.

Background: The profiles of cardiovascular toxicity associated with angiogenesis inhibitors, including intravenous monoclonal antibodies (mAbs) and oral tyrosine kinase inhibitors (TKIs), targeting vascular endothelial growth factor (VEGF) remain poorly elucidated in real-world settings. This pharmacovigilance analysis aimed to comprehensively investigate the frequency, spectrum, timing, and outcomes of cardiovascular toxicities associated with angiogenesis inhibitors and to explore the differences in such patterns between mAbs and TKIs. Methods: Disproportionality analysis was performed by leveraging reports from the FDA Adverse Event Reporting System (FAERS) database from 2014 to 2021. Cardiovascular adverse events (AEs) were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs). Reporting odds ratio (ROR) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0, with at least three reports being considered statistically significant. Results: A total of 757,577 reports of angiogenesis inhibitors and 70,668 (9.3%) reports of cardiovascular AEs were extracted. Significant disproportionality was detected in angiogenesis inhibitors for cardiovascular AEs (IC025/ROR025 = 0.35/1.27). Bevacizumab (31.8%), a mAb, presented the largest number of reports, followed by sunitinib (12.4%), a TKI. Hypertension (SMQ) was detected with the strongest signal value (IC025/ROR025 = 1.73/3.33), followed by embolic and thrombotic events (SMQ) (IC025/ROR025 = 0.32/1.26). Hypertension showed the shortest time to onset with a median (interquartile range) value of 23 (8, 69) days, while embolic and thrombotic events had the longest value of 51 (16, 153) days. Notably, hypertension presented the lowest proportions of death and life-threatening events (10.9%), whereas embolic and thrombotic events posed the highest (29.3%). Furthermore, both mAbs (IC025/ROR025 = 0.47/1.39) and TKIs (IC025/ROR025 = 0.30/1.23) showed increased cardiovascular AEs. Hypertension was detected in both agents (IC025/ROR025 = 1.53/2.90 for mAbs and IC025/ROR025 = 1.83/3.56 for TKIs) with a shorter time to onset of 17 (6, 48) days for TKIs than mAbs of 42 (14, 131) days. By contrast, embolic and thrombotic events were detected for mAbs (IC025/ROR025 = 0.90/1.87) without TKI (IC025/ROR025 = -0.08/0.95). Conclusion: Angiogenesis inhibitors were associated with increased cardiovascular toxicity with a discrepancy between intravenous mAbs and oral TKIs, deserving distinct monitoring and appropriate management.

Respiratory system toxicity induced by immune checkpoint inhibitors: A real-world study based on the FDA adverse event reporting system database.

Background: Immune checkpoint inhibitors (ICIs), the treatment of multiple cancer types, can be associated with respiratory system adverse events (AEs). The aim of this study is to quantify the association of respiratory system AEs and ICIs and to characterize the profiles of ICI-related respiratory system complications from Food and Drug Administration Adverse Event Reporting System (FAERS) data. Methods: The disproportionality of respiratory system AE-related ICIs based on FAERS data from January 2014 to September 2021 was analyzed using the reporting odds ratio (ROR) and information component (IC) as measures of potential risk increase. Results: A total of 38,415,849 records were involved; among these, 36,923 records related to respiratory system AEs after ICI treatment were identified. In the first 3 months, the cumulative proportion of respiratory system AEs was 75.40%. Men had a slightly higher reporting frequency than that of women (ROR = 1.74, 95% CI: 1.70-1.78). Death cases had a slightly higher reporting frequency in ICI-associated respiratory system AEs than that of other drug-associated respiratory system AEs (ROR = 1.40, 95% CI: 1.38-1.41). Anti-programmed cell death 1 (PD-1) drugs and anti-programmed cell death ligand 1 (PD-L1) drugs were significantly associated with respiratory system toxicities. However, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drugs did not demonstrate an association with respiratory system toxicities. Interstitial lung disease and pneumonitis were found to be significantly associated with all eight types of ICIs. In addition, 7 in 10 class-specific respiratory system AEs (lower respiratory tract disorders, pleural disorders, pulmonary vascular disorders, respiratory disorders not elsewhere classified (NEC), respiratory tract infections, respiratory tract neoplasms, and thoracic disorders) were associated with ICIs. The signal values of IC025 were from 0.08 to 2.66. Conclusions: Overall, this study showed a high reporting frequency of respiratory system toxicities caused by ICIs. Early recognition and management of ICI-related respiratory system AEs are of vital importance in practice. Maximizing the benefit while reducing potential respiratory system toxicities of ICIs should become a priority.

Modified Glasgow prognostic score predicts the prognosis of patients with advanced esophageal squamous cell carcinoma: A propensity score-matched analysis.

OBJECTIVE: The aim of this study is to evaluate the prognostic value of the modified Glasgow prognostic score (mGPS) in advanced esophageal squamous cell carcinoma (SCC) patients. METHODS: The study enrolled 311 patients with advanced esophageal SCC from January 2012 to December 2018. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model in advanced esophageal SCC patients. The Kaplan-Meier method was used to evaluate the ability of the mGPS for survival rates. Propensity score-matched (PSM) analysis was carried out to balance imbalanced variables. RESULTS: The Cox proportional hazards analysis showed that factors including M stage, ECOG, mGPS group, and sex were identified as independent predictors. The mGPS presented a good level of overall survival (OS) prediction with a risk-adopted classification for advanced esophageal SCC patients. The survival rates in advanced esophageal SCC patients with mGPS 0, 1, and 2 were 18.8%, 8.4%, and 4.2%, respectively (p < 0.001). Moreover, before and after PSM, the mGPS was associated with 3-year survival rates of advanced esophageal SCC patients in the Kaplan-Meier survival analysis. In addition, the mGPS for OS prediction demonstrated better performance than sex and ECOG score. The area under curve (AUC) of the mGPS combined with M stage for the prognosis of advanced esophageal SCC was 0.677 (0.592-0.763). CONCLUSION: The mGPS is a cost-effective, accessible tool capable of prognosticating in this cohort. It could be a useful surveillance system of prognosis in advanced esophageal SCC patients.

Conditional catheter-related thrombosis free probability and risk-adapted choices of catheter for lung cancer.

BACKGROUND: Current predictive tools assess catheter-related thrombosis (CRT) in patients with lung cancer in a static manner at a single time point of catheterization. The subsequent hazard changes over time are unknown. The conditional catheter-related thrombosis-free probability (CCFP) can provide dynamic information on continual CRT-free expectations. This study aimed to assess the CCFP and hazard rates based on risk categories and various venous access devices (VADs). METHODS: This retrospective study reviewed 939 patients with lung cancer with peripherally inserted central venous catheters (PICCs) or central venous catheters (CVCs) identified at the National Clinical Research Center for Cancer between January 1, 2015 and December 31, 2018. The incidence of CRT has also been reported. Patients were stratified into low- and high-risk groups according to multivariate Cox regression analyses. CCFP is defined as the CRT-free probability given that patients have no CRT for a definite time. RESULTS: A total of 507 patients with PICCs and 432 patients with CVCs were included in this study. The 3-month CCFP increased from 74.2% at catheter insertion to 93.6% at 3 months. The hazards of CRT in the first month were highest (16.4%) and slightly thereafter. The high-risk group initially had a higher (21.4%) but significantly decreased CRT hazard after 2 months (8.3%), whereas the low-risk group maintained a comparable lower risk hazard of less than 5% after 1 month. In the overall cohort, patients with CVCs had lower CRT probability than those with PICCs (HR, 1.76; 95% CI: 1.28-2.41; p < 0.01). Further analysis demonstrated that compared with PICCs, CVCs provided a CRT-free benefit in low-risk patients (p = 0.02) but not in high-risk patients (p = 0.06). CONCLUSIONS: CCFP increased, and the hazards of CRT decreased over time in a risk-dependent manner in patients with lung cancer. These valuable dynamic data may help optimize risk-adjusted choices of VADs and risk-adjusted prophylactic anticoagulation strategies for patients.

Value of TAT and PIC with D-dimer for cancer patients with metastasis.

INTRODUCTION: The hypercoagulability of blood is related to the development and metastasis of cancer. High levels of D-dimer have been reported to be associated with the metastasis and poor prognoses of cancer. Here, we investigated the performance of biomarkers-TAT, PIC, TM, and tPAI·C by new method-for monitoring cancer patients with metastasis. METHODS: A total of 197 cancer patients were enrolled. TM, TAT, PIC, and tPAI·C were detected by the chemiluminescence immunoassay. RESULTS: Results showed that the levels of TAT and PIC were higher in the metastasis group than those in the nonmetastasis group (P < .01). In the nonmetastasis group, there were 16 patients with elevated levels of D-dimer. But, TAT and PIC in these 16 patients were all at normal level (<0.55 mg/L FEU). After dilution, D-dimer was also decreased to normal levels in these 16 patients. The ROC was used to show the performance of D-dimer, TAT, and PIC on indicating cancer with metastasis. The AUC of PIC was higher than that of D-dimer (0.825 vs. 0.770). The specificity and PPV of TAT and PIC were higher than those of D-dimer. Serial test of TAT, PIC, and D-dimer improved the specificity and positive predictive value to 90.91% [80.61%, 96.25%] and 89.29% [77.45%, 95.57%], respectively. CONCLUSION: Combining TAT and PIC with D-dimer could be useful surveillance biomarkers for cancer with metastasis.

Prenatal Plasma Fibrinogen Level Predicts Postpartum Hemorrhage of Patients With HELLP Syndrome.

Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious complication of pregnancy. Postpartum hemorrhage indicates poor prognosis of pregnant women with HELLP syndrome. The aim of our study is to investigate the predictive value of coagulation markers for postpartum hemorrhage of pregnant women with HELLP syndrome. In a retrospective cohort study, 106 patients who were diagnosed as pregnant women with HELLP syndrome in Peking University Third Hospital from August 2010 to January 2017 were analyzed. The demographic characters of maternal and fetus, days of hospital stay, postpartum complications, and the laboratory tests of coagulation markers within 3 days before delivery were collected. In addition, 100 healthy pregnant women were collected as a control group. The result showed that the incidence of preeclampsia in pregnant women with postpartum hemorrhage was higher than that in pregnant women without hemorrhage (P = .011). The level of fibrinogen (FIB) in postpartum hemorrhage pregnant women with HELLP syndrome was lower than that in nonpostpartum hemorrhage pregnant women with HELLP syndrome and healthy pregnant women (2.3 [1.68-2.81] vs 3.64 ± 0.95, P = .000; 2.3 [1.68-2.81] vs 4.48 ± 0.62, P = .000). Multivariate analysis showed that decreased FIB levels independently predicted the postpartum hemorrhage of pregnant women with HELLP syndrome (odds ratio = 7.374, 95% confidence interval [CI], 1.551-35.05, P = .012). The receiver operating characteristic curve showed that the area under the curve of FIB level when predicting postpartum hemorrhage is 0.841 (95% CI, 0.708-0.976). When the cutoff value of FIB was 3.04 g/L, the sensitivity was 90.90% and the specificity was75.80%. Therefore, the low level of prenatal FIB is a reliable biomarker to predict postpartum hemorrhage of pregnant women with HELLP syndrome, which make it useful for pregnant women with HELLP syndrome in guiding surveillance therapy and prognosis assessment.

Establishing and validating of an laboratory information system-based auto-verification system for biochemical test results in cancer patients.

BACKGROUND: To establish and validate an laboratory information system (LIS)-based auto-verification (AV) system by using large amounts of biochemical test results in cancer patients. METHODS: An algorithm of the AV process was designed for pre-analysis, analysis, and post-analysis. The limit range check was adjusted three times, while the delta check criteria were first replaced by the same patients' historical extremum results. AV rules of 51 biochemical test items were tested by using data of 121 123 samples (6 177 273 tests) in 2016 that were manually reviewed through the simulative i-Vertification software of Roche. The improved and optimal AV rules were programed into our LIS and validated by using 140 113 clinical specimens in 2018. RESULTS: The AV passing rate for samples tested in our laboratory increased from 15.57% to the current overall passing rate of 49.70%. The passing rate of each item for rule 3 was between 71.16% and 99.91%. Different cancer groups had different passing rate, while the disease group of liver, gallbladder, and pancreas always had the lowest passing rate. A total of 9420 reports (6.72%) were not verified by AV but could be verified by MV in 2018, while there were no reports that were verified by AV but not by MV. The TAT of March 2018 decreased with increase in sample size compared with the same time in 2017. CONCLUSION: We have firstly established an LIS-based AV system and implemented it in actual clinical care for cancer patients.

Tissue Factor-bearing MPs and the risk of venous thrombosis in cancer patients: A meta-analysis.

Cancer patients with Tissue Factor (TF)-bearing MPs have been presented association with increased risk of venous thromboembolism (VTE), but results of these studies have not been consistent. We aimed to conduct a meta-analysis to assess the relationship between TF-bearing MPs and risk of VTE in patients with cancer. PubMed, Web of Science and EMBASE Databases were systematically retrieved up to1th June 2017. Two case-control studies and four cohort studies met the entry requirements in this analysis. The summary odd ratio (OR) were estimated by a random effect model. The overall OR was 1.76 (95% CI: 1.21-2.56, I2 = 62.0%). The OR of case-control studies was 3.41 (95% CI: 1.45-8.02, I2 = 0.0%) and that of cohort studies was1.53 (95% CI: 1.05-2.24, I2 = 66.1%). The association between TF-bearing MPs and the risk of VTE in cancer patients was found in this meta-analysis. Publication bias testing and sensitivity subgroup analysis suggested that results of this meta-analysis were robustness. In conclusion, TF-bearing MPs were associated with increased risk of VTE in patients with cancer. Whereas, more well-designed studies and more comprehensive adjustments for confounders in further studies are warranted to affirm the association.

Trimester-specific coagulation and anticoagulation reference intervals for healthy pregnancy.

BACKGROUND: Due to the normal physiological need of pregnancy and childbirth, the haemostatic system of pregnant women is different from that of healthy non-pregnant women. The aim of this study was to establish trimester-specific reference intervals of coagulation screening tests and thrombophilia markers in pregnancies without complications of females with Han ethnicity from North China. METHODS: In total 744 Han healthy pregnant women (first trimester 207 cases, second trimester 222 cases and third trimester 315 cases) and 121 healthy non-pregnant women were recruited in North China. Eight tests-activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fib), d-Dimer, antithrombin (AT), protein C (PC) and free protein S (fPS)-were processed on ACL TOP automated coagulation analyzer. The non-parametric 2.5th-97.5th percentiles reference intervals were calculated to establish trimester-specific reference intervals. RESULTS: The reference intervals for APTT, PT, TT, Fib, d-Dimer, AT, PC, and fPS at first trimester were 26.4-41.9s, 9.7-12.5s, 11.7-17.0s, 2.38-4.44g/L, 0.01-0.31µg/mL, 72-120%, 29-150%, 21-143%, respectively. At second trimester, the reference intervals were 24.4-35.8s, 8.5-13.2s, 10.0-16.0s, 2.40-5.97g/L, 0.05-0.73µg/mL, 68-125%, 20-138%, 24-155%, respectively. At third trimester, the reference intervals were 25.6-34.9s, 8.6-12.4s, 11.1-15.5s, 2.79-5.91g/L, 0.14-2.82µg/mL, 56-119%, 20-134%, 17-140%, respectively. From the first trimester to the third trimester, APTT, PT and TT presented shortened trends, Fib and d-Dimer presented increasing trends, AT, PC and fPS activity presented decreasing trends, respectively. CONCLUSIONS: The trimester-specific reference intervals of coagulation screening tests and thrombophilia markers in pregnancies without complications of females with Han ethnicity from North China are presented in this study, which may provide effective evidence for doctors to accurately diagnose and treat the disease during pregnancy.

Comparison of Modified Impedance Whole Blood Platelet Aggregation Method Detecting Platelet Function in ACS Patients with Different CYP2C19 Genotypes.

BACKGROUND: A reliable laboratory test to monitor onclopidogrel platelet reactivity (PR) is very necessary. In addition, genetic factors also play an important part in onclopidogrel PR. This study aimed to modify the original impedance whole blood platelet aggregation assay associated with the release assay to monitor onclopidogrel PR and assess their relationship with genotype. METHODS: We adjusted the concentration of calcium in the in vitro reaction system of platelet aggregation to modify the original impedance whole blood platelet aggregation assay. Meanwhile, chronolume, which quantified the adenosine triphosphate (ATP) released from platelet dense granules, is added to this reaction system to reflect the platelet release function. In the modified assay, platelet magnified activation time (MAT) and the maximal platelet ATP release value (RV) were used to reflect platelet function parameters. In the original assay, the electrical resistance (omega) and RV were used to reflect platelet function parameters. Onclopidogrel PR was detected by the original impedance whole blood platelet aggregation assay, modified assay, and flow cytometric vasodilator stimulated phosphoprotein (VASP) assay in 168 patients with acute coronary syndromes (ACS). CYP2C19*2 and CYP2C19*3 polymorphisms were also detected in all of these patients. RESULTS: This modified method showed that when 12.5 microL CaCl2 (0.2 mmol/L) was added to the reaction system, MAT was appropriate (93 +/- 23 seconds). The CVs for the modified impedance assay and release assay were 9.31% and 6.13%, respectively. The mean VASP-PRI in the patient group treated with clopidogrel was significantly lower than that in the control group without antiplatelet therapy (54.88 +/- 16.81% vs. 79.86 +/- 10.24%, p < 0.001). MAT of the modified method in VASP PRI > 50% group were shorter than that in the PRI < 50% group [185 (154-241) vs. 214 (184-250), p < 0.051. Meanwhile, the RV of the modified method in VASP PRI > 50% group were higher than that in the PRI < 50% group [1.00 (0.72-1.47) vs. 0.82 (0.62-1.08), p < 0.051. However, the electrical resistance (omega) and RV of the original method showed no differences between the two groups [0 (0-2) vs. 0 (0-1.25), 0.05 (0-0.25) vs. 0.08 (0-0.24); p > 0.05, p > 0.05, respectively). Moreover, neither the original method nor the modified method showed differences in patients with CYP2C19 (*2 and *3) wild type and mutant type. CONCLUSIONS: The consistency of the modified assay and VASP assay is good. The modified assay may be a potentially good laboratory method to monitor antiplatelet therapy.

Angiotensin-Converting Enzyme Inhibitors' Influence on Antiplatelet Therapy of Clopidogrel in ACS.

BACKGROUND: Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel. METHODS: We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay. RESULTS: It showed that the allele frequency of CES1 c.428A was 0% in these patients. 45.22% (227/502) of these patients were carriers of CYP2C19*2 or CYP2C9*3 loss-of-function alleles. Among them, 57.71% (131/227) of the patients with CYP2C19 variants received ACEIs therapy. In a total of 502 patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between the ACEIs group and non-ACEIs group [56.26 ± 14.55% versus 57.76 ± 13.56%, p = 0.241; 0 (0 - 2) Ω vs. 0 (0 - 2) Ω, p = 0.856]. In the CYP2C19 variant patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between ACEIs group and non-ACEIs group [57.24 ± 15.12% versus 58.07 ± 13.90%, p = 0.667; 0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.536]. In the subgroups of ACS patients (unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction), there was no difference in the VASP-PRI between the ACEIs group and non-ACEIs group [55.81 ± 15.24% versus 58.37 ± 13.31%, p = 0.103; 55.76 ± 15.20% versus 49.09 ± 15.22%, p = 0.098; 58.13 ± 11.48% versus 61.87 ± 10.34%, p = 0.221], and there was no difference in the impedance whole blood platelet aggregation assay between ACEIs group and non-ACEIs group [0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.936; 0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.625; 0 (0 - 1.25) Ω versus 0 (0 - 1.5) Ω, p = 0.788]. CONCLUSIONS: In our study, when ACEIs were used with clopidogrel, platelet response to clopidogrel was not affected. These findings suggest that the drug interaction between clopidogrel and ACEI is of little relevance in platelet function.

Mean Platelet Volume Could Reflect Disease Activity of Adult Patients With Systemic Lupus Erythematosus.

BACKGROUND: In recent years, research regarding mean platelet volume (MPV) has been expanded to numerous diseases. The aim of the present study was to assess whether MPV could reflect disease activity of adult patients with systemic lupus erythematosus (SLE). METHODS: A total of 128 adult patients with SLE were enrolled in the present study and allocated into two subgroups (99 with active phase and 29 with inactive phase) according to SLE disease activity index (SLEDAI). Demographic data, MPV, complement 3 (C3), and complement 4 (C4) were recorded. Independent sample t-test was used for comparison of quantitative variables between the active and inactive groups. Pearson's correlation test was used to evaluate the correlation between the above laboratory indices and the SLEDAI score. RESULTS: The mean MPV level in active patients was significantly higher than inactive subjects (8.3 ± 1.3 vs. 7.7 ± 0.7, p < 0.001). The correlation between MPV level and SLEDAI score was moderate (r = 0.520, p < 0.001). CONCLUSIONS: MPV might be a promising marker to reflect disease activity of adult patients with SLE.

Monitoring Residual Platelet Activity Among Patients With Acute Coronary Syndrome Post-PCI by Modified Impedance Whole Blood Platelet Aggregation and Release Method.

Antiplatelet medicines have been one of the cornerstones in the treatment of patients with acute coronary syndrome (ACS). However, adverse cardiovascular events still occur in some patients on standard antiplatelet therapy. Therefore, a reliable laboratory test to monitor the residual platelet activity (RPA) is urgent. We aim to modify the impedance whole blood platelet aggregation (WBA) assay associated with release assay to monitor RPA, despite antiplatelet therapy and assess their relationship with clinical ischemic events. In this study, RPA was tested in 133 patients with ACS postpercutaneous coronary intervention between 24 and 36 hours after a 300-mg clopidogrel loading dose by modified assay. Then, these patients were followed up for 3 months for clinical ischemic events. Meanwhile, platelet activity of 58 healthy volunteers was also tested by modified assay. Results showed that in modified assay the point of platelet magnified activation time (MAT) and maximal platelet adenosine triphosphate release values (RV) have significant differences between healthy volunteers and patients ([90.86 ± 27.60 seconds] vs [206.44 ± 58.97 seconds] and [2.07 ± 0.64 nmol] vs [0.98 ± 0.49 nmol];P< .001 andP< .001, respectively). During follow-up, 5 patients present ischemic events. Receiver-operator characteristic curve showed that the cutoff values for MAT and RV were 156.5 seconds and 1.05 nmol, respectively, with the sensitivity and specificity of 60.00% and 83.30% and 80.00% and 67.50%, respectively; when MAT combined with RV, the sensitivity can be increased to 100%. Therefore, modified impedance WBA and release assay may be a potentially recommended reliable laboratory assays for monitoring the RPA.

Evaluation of the clinical effectiveness of HIV antigen/antibody screening using a chemiluminescence microparticle immunoassay.

Human immunodeficiency virus (HIV) screening assays have improved from single-antigen detection to detection of antigen-antibody combinations. However, concerns have been raised over the potential for false-positive results in antigen-antibody combination assays. The present study investigated the clinical effectiveness of HIV antigen/antibody (HIV Ag/Ab) combination screening by chemiluminescence microparticle immunoassay (CMIA) in over 88,000 samples from an HIV low-prevalence area of Beijing, China. The HIV Ag/Ab CMIA screening results were consistent with those obtained by Western blot and HIV-RNA testing, and had an accuracy of 99.74% (Kappa index=0.98). False-positive results were more common for women affected by clinical interfering factors (e.g., kidney disease, tumors) than for men (80.95% vs. 15.09%, P<0.001). When CMIA signal-to-cutoff ratio (S/CO) was 11.26, the sensitivity and specificity were highest (100%, 99.43%), and the area under the ROC curve (AUC) was 0.998. Specimens that were negative by CMIA (S/CO <1) were all negative by HIV-RNA testing. These results indicate that HIV Ag/Ab CMIA has a good clinical performance; however, some clinical interfering factors should be considered in HIV low-prevalence areas for their potential to skew testing results.