Long-term hearing prognosis after vestibular schwannoma surgery with retrolabyrinthine approach.

PURPOSE: The retrolabyrinthine approach is a surgical method designed to preserve hearing after surgery. When paired with intraoperative monitoring and an endoscope, this approach has demonstrated high rates of postoperative hearing preservation. However, the long-term prognosis of hearing preservation after utilizing this approach for vestibular schwannomas remains unexplored. This study aimed to examine the long-term outcomes of preserved hearing, providing insights into the suitability of the retrolabyrinthine approach for hearing preservation surgery. METHODS: This study included 34 patients with preserved hearing after vestibular schwannoma surgery using the retrolabyrinthine approach at a single center. Long-term hearing prognosis and requirement for additional interventions were retrospectively examined. RESULTS: Immediate after post-operative hearing preservation rate was 71.7%. Among the 34 patients with preserved hearing post-vestibular schwannoma surgery, four (11.8%) required additional interventions. Other patients experienced a gradual deterioration in their hearing status, with an approximate 10 dB decline during the 5-year follow-up; however, a serviceable hearing level persisted long after the surgery in these individuals. CONCLUSIONS: This study indicated the rationale for the retrolabyrinthine approach as a hearing preservation surgery for vestibular schwannomas, emphasizing its long-term hearing prognosis.

Binaural hearing aid intervention for a patient with nonserviceable hearing loss after surgery for vestibular schwannoma: A case report.

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner-Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable.

Sarcopenia accompanied by systemic inflammation can predict clinical outcomes in patients with head and neck cancer undergoing curative therapy.

Objectives: Evaluation of sarcopenia accompanied by systemic inflammation status is a more beneficial prognostic marker than sarcopenia alone in various cancers. However, few studies have focused on this combination in patients with head and neck squamous cell cancer (HNSCC). In this study, we investigated how the combination of sarcopenia and systemic inflammation could affect survival in patients with HNSCC. Moreover, we explored which systemic inflammation markers could be better prognostic indicators when accompanied by sarcopenia. Materials and methods: We retrospectively reviewed the medical records of patients with HNSCC treated between 2012 and 2016. Sarcopenia was defined by the skeletal muscle area measured on a computed tomography image slice at the level of the third cervical vertebra. The neutrophil/lymphocyte, platelet/lymphocyte, and lymphocyte/monocyte ratios (NLR, PLR, and LMR, respectively) were used as systemic inflammation markers that were combined with sarcopenia to evaluate prognosis. Results: A total of 100 patients were enrolled, and 71 patients were considered sarcopenia. Patients with sarcopenia had significantly lower LMR and higher NLR and PLR. They also showed worse overall survival (OS) and progression-free survival (PFS). The comparative assessment of multiple combination patterns of sarcopenia and systemic inflammation indices proved that sarcopenia plus LMR considered as most reliable indicator for prognosis in HNSCC patients. Sarcopenia plus low LMR was a significantly poor prognostic factor both for OS and PFS with greater HR values than sarcopenia alone. Conclusions: The combination of sarcopenia and LMR was considered the most sensitive prognostic factor in patients with HNSCC, suggesting it might be beneficial for identifying poor outcome risks.

Prognostic Significance of Asymptomatic Cerebral Infarction in Patients After Cardiac Catheterization.

Recent studies have showed that asymptomatic cerebral infarction (ACI) developed in a reasonable number of patients after cardiac catheterization. However, no study has investigated the long-term prognostic impact of ACI after cardiac catheterization. We investigated whether ACI after cardiac catheterization affects long-term mortality and subsequent cardiovascular events.We retrospectively enrolled patients who underwent cardiac catheterization before cardiac surgery and cerebral diffusion-weighted magnetic resonance imaging (DWI). The incidence and clinical features of ACI were investigated. The long-term prognosis, including all-cause mortality and subsequent major cardiovascular events (MACE; all-cause mortality, stroke, acute myocardial infarction, fatal arrhythmia, and hospitalized heart failure), was also assessed.A total of 203 patients were enrolled. Of these, 10.3% had ACI diagnosed by DWI. There were no differences in baseline characteristics between patients with and without ACI, except more frequent history of symptomatic stroke in patients with ACI. In the Kaplan-Meier analysis during a median follow-up of 1009 days, the patients with ACI showed worse mortality and a slightly higher occurrence of MACE compared with those without ACI (P = 0.01 and P = 0.08, respectively). In addition, ACI was a prognostic marker independent of age, surgery type, and history of stroke.ACI after cardiac catheterization frequently developed and was also associated with long-term prognosis. It may be an independent prognostic marker in high-risk patients who underwent subsequent cardiac surgery.

Prediction of Cochlear Implant Effectiveness With Surface-Based Morphometry.

OBJECTIVE: This study aimed to determine whether surface-based morphometry of preoperative whole-brain three-dimensional T1-weighted magnetic resonance imaging (MRI) images can predict the clinical outcomes of cochlear implantation. STUDY DESIGN: This was an observational, multicenter study using preoperative MRI data. SETTING: The study was conducted at tertiary care referral centers. PATIENTS: Sixty-four patients with severe to profound hearing loss (≥70 dB bilaterally), who were scheduled for cochlear implant (CI) surgery, were enrolled. The patients included 19 with congenital hearing loss and 45 with acquired hearing loss. INTERVENTIONS: Participants underwent CI surgery. Before surgery, high-resolution three-dimensional T1-weighted brain MRI was performed, and the images were analyzed using FreeSurfer. MAIN OUTCOME MEASURES: The primary outcome was monosyllable audibility under quiet conditions 6 months after surgery. Cortical thickness residuals within 34 regions of interest (ROIs) as per the Desikan-Killiany cortical atlas were calculated based on age and healthy-hearing control regression lines. RESULTS: Rank logistic regression analysis detected significant associations between CI effectiveness and five right hemisphere ROIs and five left hemisphere ROIs. Predictive modeling using the cortical thickness of the right entorhinal cortex and left medial orbitofrontal cortex revealed a significant correlation with speech discrimination ability. This correlation was higher in patients with acquired hearing loss than in those with congenital hearing loss. CONCLUSIONS: Preoperative surface-based morphometry could potentially predict CI outcomes and assist in patient selection and clinical decision making. However, further research with larger, more diverse samples is necessary to confirm these findings and determine their generalizability.

A novel intraoperative continuous monitoring method combining dorsal cochlear nucleus action potentials monitoring with auditory nerve test system.

Highly accurate real-time cochlear nerve monitoring to preserve cochlear nerve function is essential for simultaneous cochlear implantation and ipsilateral vestibular schwannoma resection. In the present study, we developed a novel real-time monitoring system that combines dorsal cochlear nucleus action potential monitoring with intracochlear stimulating electrodes (Auditory Nerve Test System, ANTS). We used this system for a case with vestibular schwannoma resection via the translabyrinthine approach. The monitoring system developed in this study detected highly reliable evoked potentials from the cochlear nerve every two seconds continuously during tumor resection. Near-total tumor resection was achieved, and cochlear implantation was performed successfully after confirming the preservation of cochlear nerve function in a case. The patient's hearing was well compensated by cochlear implantation after surgery. Our novel method continuously achieved real-time monitoring of the cochlear nerve every two seconds during vestibular schwannoma resection. The usefulness of this monitoring system for simultaneous tumor resection and cochlear implantation was demonstrated in the present case. The system developed in this study is compatible with continuous facial nerve monitoring. This highly accurate and novel monitoring method will broaden the number of candidates for this type of surgery in the future.

Impact of quantitative flow ratio on graft function in patients undergoing coronary artery bypass grafting.

Recent studies showed that preoperative functional assessment with fractional flow reserve (FFR) could predict a long-term patency of arterial bypass grafts in patients with coronary artery bypass grafting (CABG). Quantitative flow ratio (QFR) is a novel angiography-based approach to estimate FFR. This study aimed to investigate whether preoperative QFR could discriminate arterial bypass function at 1 year after surgery. The PRIDE-METAL registry was a prospective, multicenter observational study that enrolled 54 patients with multivessel coronary artery disease. By protocol, left coronary stenoses were revascularized by CABG with arterial grafts, whereas right coronary stenoses were treated with coronary stenting. Follow-up angiography at 1 year after surgery was scheduled to assess arterial graft patency. QFR was performed using index angiography by certified analysts, blinded to bypass graft function. The primary end point of this sub-study was the discriminative ability of QFR for arterial graft function, as assessed by receiver-operating characteristic curve. Among 54 patients enrolled in the PRIDE-METAL registry, index and follow-up angiography was available in 41 patients with 97 anastomoses. QFR were analyzed in 35 patients (71 anastomoses) with an analyzability of 85.5% (71/83). Five bypass grafts were found to be non-functional at 1 year. The diagnostic performance of QFR was substantial (area under the curve: 0.89; 95% confidence interval: 0.83 to 0.96) with an optimal cutoff of 0.76 to predict functionality of bypass grafts. Preoperative QFR is highly discriminative for predicting postoperative arterial graft function.Trial registration: Clinical.gov reference: NCT02894255.

Risk factors related to psychological distress among elderly patients with cardiovascular disease.

AIMS: Psychological distress is associated with poor prognosis in patients with cardiovascular disease (CVD). However, factors related to psychological distress in elderly patients with CVD are less understood. We aim to investigate the rate of psychological distress in elderly patients with CVD in comparison with that of patients without CVD and to examine the clinical, socio-economic, and lifestyle factors associated with this condition. METHODS AND RESULTS: Data from a nationwide population-based study in Japan of patients aged ≥60 years were extracted, and 1:1 propensity score matching was conducted of patients with and without CVD. Psychological distress was assessed using the K6 scale, on which a score ≥6 was defined as psychological distress. Of the 24 388 matched patients, the rate of psychological distress was significantly higher among patients with CVD compared with those without CVD (29.8 vs. 20.5%, P < 0.0001). The multivariate analysis revealed that female sex, comorbidities, except for hypertension, current smoking status, daily sleep duration of <6 vs. ≥8 h, home renter vs. owner, retired status, having a walking disability, and lower monthly household expenditure were independently associated with psychological distress. Walking disability was observed to be in greatest association with psychological distress (odds ratio 2.69, 95% confidence interval 2.46-2.93). CONCLUSION: Elderly patients with CVD were more likely to have psychological distress compared with those without CVD. Multiple factors, including clinical, socio-economic, and lifestyle variables, were associated with psychological distress. These analyses may help healthcare providers to identify high-risk patients with psychological distress in a population of older adults with CVD.

Cancer screening: Possibility of underscreening in older adult population with a history of cardiovascular disease.

BACKGROUND: Cardiovascular disease and cancer share a number of risk factors and pathophysiologic mechanisms. Although risk management and early detection of cancer in patients with cardiovascular disease are important, preventive efforts in cardiology and oncology have been relatively disconnected. This study aimed to investigate the rate of cancer screening in a population of older adults with cardiovascular disease. METHODS: This study used data from the 2019 Comprehensive Survey of Living Conditions. Data on participants aged 60 years or older were extracted. The rate of cancer screening and cancer type were investigated between participants with and without cardiovascular disease. RESULTS: Of the 132,442 individuals, participants with cardiovascular disease had a significantly lower rate of cancer screening than those without cardiovascular disease [male: 4401 of 7972 participants (55.2%) vs. 33,744 of 52,106 participants (64.8%), p < 0.001; female: 2500 of 4984 participants (50.2%) vs. 41,319 of 67,380 participants (61.3%), p < 0.001]. The rate of cancer screening was significantly lower in participants with cardiovascular disease than in those without cardiovascular disease, regardless of cancer type, including gastric, colorectal, lung, breast, and gynecologic cancer screening. A history of cardiovascular disease was a negative factor for cancer screening (odds ratio 0.71, 95% confidence interval 0.67-0.74 in male participants; odds ratio 0.80, 95% confidence interval, 0.75-0.85 in female participants). CONCLUSIONS: The rate of cancer screening in elderly participants with cardiovascular disease was lower than that in participants without cardiovascular disease. Physicians should raise awareness regarding early cancer detection in patients with cardiovascular disease.

Plaque characteristics and prognosis in patients with peripheral arterial disease by angioscopic analysis.

BACKGROUND: The plaques with higher grade of yellow color by angioscopy are reported to be associated with vulnerability leading to adverse outcomes in coronary artery diseases. However, no studies have been performed for peripheral artery disease (PAD). We aimed to evaluate the relationship of angioscopic findings of peripheral arteries with the long-term prognosis. METHODS: Angioscopy of iliac or femoropopliteal artery was performed before endovascular therapy in patients with PAD. The local plaque color and presence of thrombus were evaluated. Multivariable Cox regression models were used to estimate hazard ratio (HR) for all-cause mortality or major adverse cardiovascular event (MACE) related to the plaque colors as well as presence of thrombus. RESULTS: Among 67 patients, 49.3% had intensive yellow plaques (group H) and the rest had light yellow to yellow ones (group L). Thrombus was detected in 74.6% of the patients and the presence was not different between the two groups. In Kaplan-Meier analysis during a median follow-up of 976 days and 757 days, group H showed increased mortality and MACE compared with group L (p <0.01 for both). Multivariable analysis demonstrated that the intensive yellow color of plaque was independently associated with mortality and MACE [HR: 11.48, 95% confidence interval (CI): 2.19-211.1 and HR: 3.81, 95% CI: 1.36-13.48, respectively] after adjusting for the presence of thrombus. CONCLUSIONS: The yellow color intensity in local plaques by angioscopy may be a novel predictor of long-term prognosis in patients with PAD, regardless of the presence of thrombus.

Impact of pericardial fluid glucose level and computed tomography attenuation values on diagnosis of malignancy-related pericardial effusion.

BACKGROUND: We evaluated malignancy according to the characteristics of pericardial fluid in symptomatic Japanese patients undergoing pericardiocentesis and computed tomography (CT). METHODS: This was a retrospective, single-center, observational study of 125 symptomatic patients undergoing pericardiocentesis. The patients were classified into two groups: a malignancy group and a non-malignancy group, according to the primary disease and cytology of the pericardial effusion (PE). We compared the pericardial fluid sample and CT measurements between both groups. RESULTS: All patients were diagnosed as having exudative PE by Light's criteria. PE with malignant cells was demonstrated in 76.8% of the malignancy group patients. Pericardial to serum lactate dehydrogenase (LDH) ratio > 0.6, as one of Light's criteria, was associated with malignancy (p = 0.017). Lower serum brain natriuretic peptide (BNP) concentration was also associated with malignancy (BNP: 126.9 ± 89.8 pg/ml vs 409.2 ± 97.7 pg/ml, malignancy vs non-malignancy groups, respectively; p = 0.037). A significant difference was observed in pericardial fluid glucose level between the malignancy and non-malignancy groups (pericardial fluid glucose: 78.24 ± 48.29 mg/dl vs 98.41 ± 44.85, respectively; p = 0.048). Moreover, CT attenuation values (Hounsfield units (HU)) tended to be higher in the malignancy group vs the non-malignancy group (22.7 [interquartile range (IQR), 17.4-26.0] vs 17.4 [IQR, 13.7-26.4], respectively; p = 0.08). The sensitivity and specificity of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 40.9% and 89.6%, respectively, in the malignancy group. The positive- and negative predictive values of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 85.7% and 50.0%, respectively, in the malignancy group. Pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were cutoff values associated with malignancy (p = 0.012). CONCLUSIONS: Lower pericardial fluid glucose level with higher CT attenuation values may suggest malignancy-related PE.

Impact of Neointimal Condition and Platelet Reactivity on Intrastent Thrombus at Long-Term Follow-up After 2nd- and 3rd-Generation Drug-Eluting Stent Implantation　- Insights From a Coronary Angioscopy and Pharmacodynamic Study.

BACKGROUND: Although the incidence of very late stent failure (VLSF) is reduced with newer generation drug-eluting stent (DES), the mechanism of VLSF has not been fully explored.Methods and Results:This study evaluated both local vascular healing using coronary angioscopy and systemic factors determined by platelet reactivity at long-term follow-up after 2nd- and 3rd-generation DES implantation in patients with acute coronary syndrome. Coronary angioscopy was performed to assess neointimal coverage (NIC), yellow color (YC) grade and presence of thrombus. The obtained findings were compared with 2nd- and 3rd-DES. Platelet aggregation was assessed by light transmittance aggregometry. 100 consecutive patients were prospectively enrolled: 2nd- (n=50) and 3rd-DES (n=50). 3rd-DES patients had significantly higher NIC grade and lower YC grade compared with 2nd-DES. The presence of thrombus was tended to be lower with 3rd-DES than with 2nd-DES (8% vs. 18%, P=0.11). Patients with thrombus had significantly higher maximum platelet aggregation and higher prevalence of high on-treatment platelet reactivity (HPR) than those without thrombus. Multivariable analysis showed stent strut exposure and HPR as independent predictors of thrombus. CONCLUSIONS: Newer generation DES contribute to better vascular healing depending on the degree of neointimal coverage. In addition to local factors at the stented lesion, systemic factors such as degree of platelet reactivity might also contribute to VLSF.

Long-term effects of non-retrieved inferior vena cava filters on recurrences of venous thromboembolism in cancer and non-cancer patients: From the COMMAND VTE registry.

BACKGROUND: There is a paucity of data comparing the long-term outcomes after inferior vena cava (IVC) filters placement for patients with acute venous thromboembolism (VTE) between those with and without active cancer. METHODS: In the COMMAND VTE Registry, we evaluated the effects of IVC filter use on the long-term clinical outcomes stratified by the presence and absence of active cancer. RESULTS: Among 2,626 patients with acute symptomatic VTE, there were 604 patients with active cancer, and 2022 patients without active cancer. IVC filters were placed and not retrieved in 455 patients (17%) in the entire cohort, in 150 patients (24.8%) in the active cancer stratum, and in 305 patients (15.1%) in the non-cancer stratum. In the entire cohort, non-retrieved IVC filter placement was not associated with a lower adjusted risk for PE recurrence (HR 0.59, 95% CI 0.30-1.15, P = 0.122), but with an increased adjusted risk for DVT recurrence (HR 2.27, 95% CI 1.43-3.60, P<0.001). In the non-cancer stratum, the non-retrieved IVC filter placement was associated with a decreased risk for PE (HR 0.29, 95% CI 0.09-0.93, P = 0.037), but not with an increased risk for DVT (HR 1.73, 95% CI 0.89-3.38, P = 0.108), while in the active cancer stratum, it was associated with an increased risk for DVT (HR 2.47, 95% CI 1.24-4.91, P = 0.010), but not with a decreased risk for PE (HR 0.82, 95% CI 0.34--1.96, P = 0.650). CONCLUSIONS: There were some differences in the risk-benefit balance between VTE patients with and without active cancer.

Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease.

BACKGROUND: Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated. OBJECTIVES: The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations. METHODS: Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y12 antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y12 ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 µM) of clopidogrel's active metabolite (Clop-AM). Exposure to Clop-AM was also determined. RESULTS: PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y12 signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients. CONCLUSIONS: The present study suggests that among DM patients, impaired P2Y12 inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel's PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y12 signaling pathway.

Impact of smoking on long-term outcomes in patients with atherosclerotic vascular disease treated with aspirin or clopidogrel: insights from the CAPRIE trial (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events).

OBJECTIVES: The goal of this study was to investigate the differential efficacy of clopidogrel or aspirin monotherapy according to smoking status in patients with atherosclerotic vascular disease. BACKGROUND: Smoking enhances clopidogrel-induced platelet inhibition, which may explain the higher relative benefit among smokers observed in trials evaluating dual antiplatelet therapy. Whether smoking has an impact on clinical outcomes in patients requiring a single antiplatelet agent remains unknown. METHODS: This was a post-hoc analysis of the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial that compared clopidogrel and aspirin monotherapy in patients (N = 19,184) with atherosclerotic vascular disease. RESULTS: Current smokers (n = 5,688) had an increased risk of ischemic events compared with never smokers (n = 4,135; hazard ratio [HR]: 1.24 [95% confidence interval (CI): 1.08 to 1.42]) and ex-smokers (n = 9,381; HR: 1.32 [95% CI: 1.18 to 1.47]) (p < 0.001). Clopidogrel was associated with a reduction in ischemic events among current smokers (8.3% vs. 10.8%; HR: 0.76 [95% CI: 0.64 to 0.90]), whereas no benefit over aspirin was seen in the combined group of ex-smokers/never-smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI: 0.89 to 1.10]; p = 0.01 for interaction). Among current smokers, clopidogrel also reduced myocardial infarction, vascular death, and death from any cause compared with aspirin. No interaction between smoking status and study treatment was observed for bleeding events. CONCLUSIONS: In a post-hoc analysis of the CAPRIE population, current smokers appeared to have enhanced benefit with clopidogrel therapy for secondary prevention compared with aspirin. These results should be considered hypothesis generating for future prospective studies assessing the impact of specific platelet-inhibiting strategies according to smoking status.

Impact of renal function on clopidogrel-induced antiplatelet effects in coronary artery disease patients without diabetes mellitus.

Diabetes mellitus (DM) is the most important predictor of chronic kidney disease (CKD), and pharmacodynamic (PD) studies have shown that DM patients with impaired renal function are characterized by reduced clopidogrel response. However, post-hoc PD studies conducted in unselected cohorts, composed of both DM and non-DM patients, have reached controversial findings on the effects of CKD on clopidogrel response, likely attributed to patient heterogeneity. The impact of renal function on clopidogrel response in non-DM patients remains unexplored and represented the aim of this prospective investigation. We conducted a prospective PD investigation in non-DM patients with and without CKD defined as an estimated glomerular filtration rate (eGFR) below or above 60 mL/min, respectively. All patients had known coronary artery disease and were on maintenance aspirin therapy. PD assessments were assessed at baseline and 2 and 24 h after a 600 mg loading dose of clopidogrel. PD assays included light transmission aggregometry (LTA) using 5 and 20 µmol ADP with and without PGE1 and flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) to determine the platelet reactivity index. A total of 60 patients were studied (n = 30 eGFR ≥60 mL/min; n = 30 eGFR <60 mL/min). At baseline there were no differences between groups. Following clopidogrel loading dose administration, levels of on-treatment platelet reactivity were similar between groups at 2 and 24 h as measured with LTA and VASP. Accordingly, there were no differences in rates of high on-treatment platelet reactivity between groups. In non-DM patients with CAD, the presence of impaired renal function is not associated with differences in clopidogrel-induced antiplatelet effects compared with patients with preserved renal function.

Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation.

Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y(12) receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y(12) reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y(12) receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.

Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have impaired clopidogrel-induced antiplatelet effects, which may be in part attributed to their reduced sensitivity to insulin and consequently, results in upregulation of the P2Y12 signalling pathway. It has been hypothesised that insulin sensitising strategies may enhance clopidogrel-mediated P2Y12 inhibitory effects. The aim of this pilot pharmacodynamics (PD) study was to assess the impact of pioglitazone on clopidogrel-mediated P2Y12 inhibitory effects in patients with T2DM. This was a prospective, randomised, double-blind, placebo-controlled, cross-over PD study. Patients with T2DM and stable coronary artery disease on maintenance aspirin and clopidogrel were randomised to receive either pioglitazone 30 mg or matching placebo daily for 14 days. PD assessments were measured at baseline, 14 days after randomisation, at the end of the wash-out period, and 14 days after cross-over. The primary endpoint measure was maximal platelet aggregation (MPA) to 20 µM adenosine diphosphate (ADP) as assessed by light transmittance aggregometry (LTA). Flow cytometric analysis of vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI), and VerifyNow P2Y12 testing were also performed. A total of 15 randomised patients completed the study. MPA to 20 µM ADP (primary endpoint) was not significantly different with pioglitazone compared with placebo (49.53 ± 4.76 vs. 52.52 ± 3.89%; p = 0.594). Similarly, other PD measures did not differ significantly between the groups. In conclusion, in patients with T2DM on maintenance aspirin and clopidogrel therapy, the adjunctive use of pioglitazone does not result in enhanced inhibition of platelet P2Y12 mediated signalling.