Differential inhibition of platelet function by cilostazol in combination with clopidogrel.

PURPOSE: To assess the antiplatelet effect of cilostazol clinically, we compared the effects of cilostazol in combination with clopidogrel on various platelet function tests. METHODS: We recruited patients with ischemic stroke at high risk of recurrence who were treated with clopidogrel alone within 180 days after stroke onset. Subjects underwent baseline platelet function tests, and were then randomly assigned to receive dual antiplatelet therapy (DAPT) comprising clopidogrel and cilostazol or clopidogrel monotherapy (SAPT). After 6 months, platelet function was measured again and compared to that at baseline in each group, and the rate of change was compared between groups. RESULTS: Thirty-four patients were enrolled, but 4 patients were excluded for various reasons. In total, 30 subjects (13 in DAPT and 17 in SAPT group) were analyzed. Adenosine diphosphate- and collagen-induced aggregation, VerifyNow P2Y12 reaction units, vasodilator-stimulated phosphoprotein (platelet reactivity index: PRI) and plasma p-selectin concentration were significantly lower (P = 0.004, 0.042, 0.049, 0.003 and 0.006 respectively), while VerifyNow % inhibition was significantly higher at 6 months compared to baseline (P = 0.003) in the DAPT group only. Comparison of the rate of change in each parameter from baseline to 6 months showed that while PRI decreased at a greater rate (P = 0.012), VerifyNow % inhibition increased at a greater rate (P = 0.003) in the DAPT group than the SAPT group. CONCLUSIONS: The inhibitory effects of adjunctive cilostazol added to clopidogrel on platelet function differed by type of platelet function test. VerifyNow % inhibition and PRI were more inhibited than the other platelet function tests. TRIAL REGISTRATION: CSPS.com substudy in TWMU (UMIN000026672), registered on April 1, 2017. This study was performed as a substudy of CSPS.com (UMIN000012180, registered on October 31, 2013) and was retrospectively registered.

Urinary L-Type Fatty Acid-Binding Protein Predicts Oxygen Demand of COVID-19 in Initially Mild Cases.

Early detection of illness trajectory in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients is crucial for patients and healthcare workers. An effective, noninvasive approach, with simple measurement for decision-making, is necessary in a pandemic to discriminate between high- and low-risk patients, even though both groups may exhibit mild symptoms in the beginning. OBJECTIVES: To predict COVID-19 disease severity within 10 days, distinguishing cases that will progress to moderate or severe versus mild, patient urinary L-type fatty acid-binding protein (L-FABP) was assayed within 4 days of receiving a diagnosis. The study also examined whether L-FABP point of care (POC) test is helpful in risk screening. DESIGN: Symptomatic subjects who tested positive for SARS-CoV-2 and were hospitalized were prospectively enrolled at the National Center for Global Health and Medicine (NCGM), Yamanashi Prefectural Central Hospital (YPCH), and Sinai Hospital in Maryland. The outcome of each case was evaluated 7 days after admission and the diagnostic performance of L-FABP was assessed. SETTING AND PARTICIPANTS: Subjects were treated for COVID-19 at public healthcare centers in Japan from January 31, 2020, to January 31, 2021, to NCGM, YPCH, and at Sinai Hospital in Baltimore, MD, during the same period. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine whether urinary L-FABP within 48 hours of admission can predict the patient's severity of COVID-19 1 week later. We obtained demographic data, information on clinical symptoms, radiographic images, and laboratory data. RESULTS: Diagnostic performance was assessed using receiver operating characteristic analysis. Of the 224 participants in the study, 173 initially had a mild form of COVID-19. The area under the curve (AUC) for a severe outcome was 93.5%. L-FABP POC risk prediction of a severe outcome had an AUC of 88.9%. CONCLUSIONS AND RELEVANCE: Urinary L-FABP can predict patient risk of COVID-19 illness severity. L-FABP POC is implementable for patient management. (ClinicalTrials.gov number, NCT04681040).

Clinical Utility of a Biomarker to Detect Contrast-Induced Acute Kidney Injury during Percutaneous Cardiovascular Procedures.

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a major clinical complication of percutaneous cardiovascular procedures requiring iodinated contrast. Despite its relative frequency, practicing physicians are unlikely to identify or treat this condition. METHODS: In a 2-round clinical trial of simulated patients, we examined the clinical utility of a urine-based assay that measures liver-type fatty acid-binding protein (L-FABP), a novel marker of CI-AKI. We sought to determine if interventional cardiologists' ability to diagnose and treat potential CI-AKI improved using the biomarker assay for 3 different patient types: pre-procedure, peri-procedure, and post-procedure patients. RESULTS: 154 participating cardiologists were randomly divided into either control or intervention. At baseline, we found no difference in the demographics or how they identified and treated potential complications of AKI, with both groups providing less than half the necessary care to their patients (46.4% for control vs. 47.6% for intervention, p = 0.250). The introduction of L-FABP into patient care resulted in a statistically significant improvement of 4.6% (p = 0.001). Compared to controls, physicians receiving L-FABP results were 2.9 times more likely to correctly identify their patients' risk for AKI (95% CI 2.1-4.0) and were more than twice as likely to treat for AKI by providing volume expansion and withholding nephrotoxic medications. We found the greatest clinical utility in the pre-procedure and peri-procedure settings but limited value in the post-procedure setting. CONCLUSION: This study suggests L-FABP as a clinical marker for assessing the risk of potential CI-AKI, has clinical utility, and can lead to more accurate diagnosis and treatment.

First Experience Addressing the Prognostic Utility of Novel Urinary Biomarkers in Patients With COVID-19.

Urine 11-dehydro-thromboxane B2 (u11-dh-TxB2), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and liver-type fatty acid binding protein levels (L-FABP) at the time of hospitalization were higher in coronavirus disease 2019 (COVID-19) patients with adverse events vs without events. Higher u11-dh-TxB2 and L-FABP levels were associated with longer hospitalization, more thrombotic events, and greater mortality, providing evidence for potential utility as early prognostic biomarkers for COVID-19.

Measuring the Variation in the Prevention and Treatment of CI-AKI Among Interventional Cardiologists.

Contrast-induced acute kidney injury (CI-AKI) occurs in up to 10% of cardiac catheterizations and coronary interventions, resulting in increased morbidity, mortality, and cost. One main reason for these complications and costs is under-recognition of CI-AKI risk and under-treatment of patients with impaired renal status. 157 interventional cardiologists each cared for three simulated patients with common conditions requiring intravascular contrast media in three typical settings: pre-procedurally, during the procedure, and post-procedure. We evaluated their ability to assess the risk of developing CI-AKI, make the diagnosis, and treat CI-AKI, including proper volume expansion and withholding nephrotoxic medications. Overall, the quality-of-care scores averaged 46.0% ± 10.5, varying between 18% to 78%. The diagnostic scores for accurately assessing risk of CI-AKI were low at 57.1% ± 21.2% and the accuracy of diagnosis pre-existing chronic kidney disease was 50.2%. Poor diagnostic accuracy led to poor treatment: proper volume expansion done in only 30.7% of cases, in-hospital repeat creatinine evaluation performed in 32.1%, and avoiding nephrotoxic medications occurred in 14.2%. While volume expansion was relatively similar across the three settings (P = 0.287), the cardiologists were less likely to discontinue nephrotoxic medications in pre-procedurally (9.7%) compared to the other settings (27.0%), and to order in-hospital creatinine testing in peri-procedurally (18.8%) compared to post-procedure (57.8%) (P < 0.05 for both). The overall care of patients at risk for contrast-induced acute kidney injury varied widely and showed room for improvement. Improving care for this condition will require greater awareness by cardiologists and better diagnostic tools to guide them.

Finding the clinical utility of 1,5-anhydroglucitol among primary care practitioners.

BACKGROUND: HbA1c is widely used as the standard measure to track glycemic control in patients with diabetes and pre-diabetes but measures average levels of glycated hemoglobin over two to three months, with limited utility in the presence of recent and/or short-term fluctuations in glycemic control, which are correlated with worse patient outcomes. METHODS: We examined the clinical utility of 1-5-anhydroglucitol (1,5-AG) in six different, but common, case types of diabetes patients with short-term glycemic variability. We conducted a randomized controlled trial of simulated patients to examine the clinical practice patterns of primary care physicians before and after introducing 1,5-AG. The 145 participants were randomly assigned into standard care or standard care + 1,5-AG arms. Provider care was reviewed against explicit evidence-based care standards. RESULTS: At baseline, we saw no difference between the two study arms in clinical quality of care provided (p = 0.997). After introduction of 1,5-AG, standard care + 1,5-AG providers performed 3.2% better than controls (p = 0.025. In diagnosis and treatment, there was a slight, but nonsignificant trend toward better care (+1.1%, p = 0.507) for intervention providers. Upon disaggregation by case, almost all the improvement occurred in the medication-induced hyperglycemia patients (+8.1%, p = 0.047). CONCLUSIONS: A nationally representative sample of primary care physicians demonstrated that of six different cases used in this study, 1,5-AG was found to be most effective increasing awareness of poor glucose control in medication-induced hyperglycemia. If 1,5-AG is used in this particular circumstance, the overall savings to the healthcare system is estimated to be $28 million.

Variation in Diabetes Management: A National Assessment of Primary Care Providers.

BACKGROUND: Glucose control is monitored primarily through ordering HbA1c levels, which is problematic in patients with glycemic variability. Herein, we report on the management of these patients by board-certified primary care providers (PCPs) in the United States. METHODS: We measured provider practice in a representative sample of 156 PCPs. All providers cared for simulated patients with diabetes presenting with symptoms of glycemic variability. Provider responses were reviewed by trained clinicians against evidence-based care standards and accepted standard of care protocols. RESULTS: Care varied widely-overall quality of care averaged 51.3%±10.6%-with providers performing just over half the evidence-based practices necessary for their cases. More worryingly, provider identified the underlying etiology of the poor glycemic control only 36.3% of the time. HbA1c was routinely ordered in 91.3% of all cases but often (59.5%) inappropriately. Ordering other tests of glycemic control (done in 15% of cases) led to significant increases in identifying the etiology of the hyperglycemia. Correctly modifying their patient's treatment was more likely to occur if doctors first identified the underlying etiology (65.9% vs 49.0%, P<0.001). We conservatively estimated a US $65/patient/visit in unnecessary testing and US $389 annually in additional care costs when the etiology was missed, translating potentially into millions of dollars of wasteful spending. CONCLUSION: Despite established evidence that HbA1c misses short-term changes in diabetes, we found PCPs consistently ordered HbA1c, rarely using other available blood tests. However, if the factors leading to poor glycemic control were recognized, PCPs were more likely to correctly alter their patient's hypoglycemic therapy.

Total Thrombus-Formation Analysis System (T-TAS): Clinical Application of Quantitative Analysis of Thrombus Formation in Cardiovascular Disease.

Various antithrombotic agents are clinically used to inhibit the cascade of arterial or venous thrombosis in cardiovascular diseases. Dual antiplatelet therapy with aspirin and P2Y12 inhibitors is prescribed in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Direct oral anticoagulants (DOACs) are widely used for the prevention or treatment of thromboembolism in patients with atrial fibrillation (AF) and venous thromboembolism. However, there has been no definitive tool to simultaneously monitor the antithrombotic effects of these drugs. The Total Thrombus-Formation Analysis System (T-TAS), a microchip-based flow chamber system that mimics in vivo conditions for evaluating whole blood thrombogenicity, was developed for the quantitative analysis of thrombus formation in whole blood specimens. The utility of T-TAS has been evaluated in CAD patients treated with antiplatelet therapies. The T-TAS PL chip area under the flow pressure curve (AUC) accurately assesses primary hemostasis and is sensitive to the therapeutic effects of various antiplatelet therapies. In addition, low AUC results are a significant predictor of periprocedural bleeding events in CAD patients undergoing PCI. The T-TAS AR chip AUC result is useful for assessing the efficacy of DOACs and warfarin in AF patients undergoing catheter ablation, and it is also a potential independent predictor of periprocedural bleeding events and avoidance of thrombosis in patients having undergone total knee arthroplasty. In conclusion, T-TAS is a useful index for evaluating the total antithrombotic effects of combination antithrombotic agents in patients with various cardiovascular diseases.

Modification of the VerifyNow® P2Y12 test BASE channel to accommodate high levels of P2Y(12) antagonism.

The VerifyNow® P2Y12 (VN-P2Y12) test reports thienopyridine-mediated platelet inhibition relative to a "BASE" channel, potentially eliminating the need for predrug patient assessment, by activating platelets through a P2Y(12)-independent pathway. The original formulation of the BASE channel used a protease activated receptor-1 (PAR-1) peptide as agonist. However, more potent P2Y(12) antagonism required more complete activation of platelet thrombin receptors for the BASE measurement in order to negate any contribution of the P2Y(12) receptor. Accordingly, the current BASE channel formulation consists of both PAR-1 and protease activated receptor-4 (PAR-4) activating peptides to facilitate a higher degree of platelet activation. The aim of this study was to compare the performance of PAR-1 versus PAR-1/PAR-4 activating peptides as the BASE channel formulation using prasugrel's active metabolite, R-138727, in vitro to achieve high-grade P2Y(12) inhibition. Blood samples from 20 healthy donors were spiked in vitro with R-138727 at concentrations that include plasma levels achieved following prasugrel administration and were incubated for 30 minutes at 37°C. All samples were run in triplicate using both the PAR-1 and the PAR-1/PAR-4 BASE formulation in the VN-P2Y12 test device. The data confirmed the sensitivity of the original BASE formulation to high-grade P2Y(12) inhibition as reflected in the concentration-dependent decrease in values. Incorporation of PAR-4 activating peptide eliminated the effect of P2Y(12) blockade at all concentrations of R-138727. Thus, the use of PAR-1/PAR-4 in the BASE channel of the VN-P2Y12 cartridge addresses the impact of high grade P2Y(12) blockade and may allow more accurate reporting of "% inhibition" in patients treated with more effective P2Y(12) antagonists.

Early biomarkers of stroke.

BACKGROUND: The diagnosis and management of acute ischemic stroke are limited by the lack of rapid diagnostic assays for use in an emergency setting. Computed tomography (CT) scanning is used to diagnose hemorrhagic stroke but is relatively ineffective (<33% sensitive) in detecting ischemic stroke. The ability to correlate blood-borne protein biomarkers with stroke phenotypes would aid in the development of such rapid tests. METHODS: ELISAs for >50 protein biomarkers were developed for use on a high-throughput robotic workstation. These assays were used to screen plasma samples from 214 healthy donors and 223 patients diagnosed with stroke, including 82 patients diagnosed with acute ischemic stroke. Marker assay values were first compared by univariate analysis, and then the top markers were subjected to multivariate analysis to derive a marker panel algorithm for the prediction of stroke. RESULTS: The top markers from this analysis were S-100b (a marker of astrocytic activation), B-type neurotrophic growth factor, von Willebrand factor, matrix metalloproteinase-9, and monocyte chemotactic protein-1. In a panel algorithm in which three or more marker values above their respective cutoffs were scored as positive, these five markers provided a sensitivity of 92% at 93% specificity for ischemic stroke samples taken within 6 h from symptom onset. CONCLUSION: A marker panel approach to the diagnosis of stroke may provide a useful adjunct to CT scanning in the emergency setting.