Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.

Improving Electrocardiography Diagnostic Accuracy in Emergency Medical Services Personnel.

BACKGROUND: Accuracy of electrocardiogram (ECG) interpretation is important for identification of ST-elevation myocardial infarction (STEMI) by Emergency Medical Services (EMS) personnel who recognize STEMI in the field and activate the coronary catheterization laboratory. According to previous research, there is improvement in diagnosis of STEMIs for healthcare providers who read an average of > 20 ECGs per week. This study evaluated the effectiveness of online ECG modules on improving diagnostic accuracy. METHODS: EMS personnel received 25 ECGs per week to interpret via an online program. Diagnostic accuracy was assessed for improvement via completion of an ECG evaluation package before and after the intervention. Job satisfaction data were collected to determine the impact of the educational initiative. RESULTS: A total of 64 participants completed the study. Overall, there was an improvement in ECG diagnostic accuracy from 50.8% to 61.2% (95% confidence interval [CI], 7.7-13.2; P < 0.0001). Specifically, there was significant improvement in the diagnosis of STEMI (8.5%; 95% CI, 4.9-12.3; P < 0.003) and supraventricular tachycardia (39.0%; 95% CI, 17.2-60.8; P < 0.008), with a trend toward improvement in all other diagnoses. These effects were sustained to 3 months (9.6%; 95% CI, 6.4-12.7; P < 0.0001). Improvement was seen regardless of employment experience and training. There was no significant impact on job satisfaction. CONCLUSIONS: ECG exposure remains an important factor in improving the accuracy of ECG diagnosis in EMS personnel. Online education modules provide an easily accessible way of improving ECG interpretation with the opportunity for positive downstream effects on patient outcomes and resource use.

INTRODUCTION: L'interprétation de l'électrocardiogramme (ECG) doit être précise pour détecter l'infarctus du myocarde avec élévation du segment ST (STEMI) puisque le personnel des services médicaux d'urgence (SMU) doit reconnaître sur le terrain le STEMI et faire démarrer le processus vers le laboratoire de cathétérisme coronarien. Selon une étude antérieure, on note une amélioration dans le diagnostic du STEMI chez les prestataires de soins de santé qui lisent en moyenne > 20 ECG par semaine. La présente étude a permis d'évaluer l'efficacité des modules d'ECG en ligne en fonction de l'amélioration de la précision du diagnostic. MÉTHODES: Le personnel des SMU recevait chaque semaine 25 ECG à interpréter au moyen d'un programme en ligne. On évaluait la précision du diagnostic en fonction de son amélioration en remplissant un module d'évaluation d'ECG avant et après l'intervention. Les données sur la satisfaction professionnelle étaient collectées pour déterminer les répercussions de l'initiative éducative. RÉSULTATS: Un total de 64 participants ont complété l'étude. Dans l'ensemble, on a noté une amélioration de la précision du diagnostic à l'ECG, soit de 50,8 % à 61,2 % (intervalle de confiance [IC] à 95 %, 7,7-13,2; P < 0,0001). Notamment, on a noté une amélioration importante dans le diagnostic du STEMI (8,5 %; IC à 95 %, 4,9-12,3; P < 0,003) et de la tachycardie supraventriculaire (39,0 %; IC à 95 %, 17,2-60,8; P < 0,008), ainsi qu'une tendance à l'amélioration pour tous les autres diagnostics. Ces effets se sont maintenus jusqu'à 3 mois (9,6 %; IC à 95 %, 6,4-12,7; P < 0,0001). On a observé une amélioration, quelles que soient l'expérience professionnelle et la formation. Il n'y a eu aucune répercussion importante sur la satisfaction professionnelle. CONCLUSIONS: L'exposition à l'ECG demeure un facteur important dans l'amélioration de la précision du diagnostic à l'ECG chez le personnel des SMU. Les modules éducatifs en ligne constituent des outils facilement accessibles pour améliorer l'interprétation de l'ECG en plus d'offrir la possibilité d'effets positifs en aval sur les résultats cliniques des patients et l'utilisation des ressources.

Nitroglycerin-Derived Pd/Pa for the Assessment of Intermediate Coronary Lesions.

OBJECTIVES: To assess the predictive value of Pd/Pa after nitroglycerin administration (Pd/Pa[N]) as compared with standard fractional flow reserve (FFR). METHODS: Consecutive patients with intermediate coronary lesions assessed by FFR between January 2014 and October 2015 were included. We measured Pd/Pa at baseline, Pd/Pa(N), and Pd/Pa after incremental doses of intracoronary adenosine. RESULTS: A total of 134 patients (27% females; mean age, 65 years) were included. The diagnostic performance of Pd/Pa(N) and identification of cut-off value for Pd/Pa(N) compared with FFR threshold of 0.8 using receiver-operating characteristic (ROC) area under the curve analysis was between 0.98 (95% confidence interval, 0.95-1.00; P<.05) for 48 µg and 0.86 (95% confidence interval, 0.79-0.94; P<.05) for 240 µg adenosine. Pd/Pa(N) ≤0.8 had 100% positive predictive value. Pd/Pa(N) ≥0.94 provided 100% negative predictive value with a high sensitivity (>92%). Optimal diagnostic accuracy of Pd/Pa(N) was achieved for values ≤0.84. The Pearson's correlation between Pd/Pa(N) and FFR varied between 0.89 for 24 µg adenosine and 0.77 for 240 µg (P<.01). CONCLUSION: Pd/Pa(N) values can be used for diagnosis of hemodynamically significant lesions. Pd/Pa(N) correlates well with standard FFR. Pd/Pa(N) cut-off of ≤0.8 can be considered significant without need for adenosine injection. The value of using adenosine whenever Pd/Pa(N) is ≥0.94 is limited.

Randomized Trial of Compression Duration After Transradial Cardiac Catheterization and Intervention.

BACKGROUND: Radial artery occlusion is a known complication following transradial cardiac catheterization. A shorter duration of postprocedural radial clamp time may reduce radial artery occlusion (RAO) but might be associated with incomplete hemostasis. METHODS AND RESULTS: In total, 568 patients undergoing transradial diagnostic cardiac catheterization were randomly assigned to either 20 minutes (ultrashort) or 60 minutes (short) hemostatic compression time using patent hemostasis. Subsequently, clamp pressure was reduced gradually over 20 minutes. Access site hemostasis and RAO were assessed after clamp removal. Repeated assessment of RAO was determined at 1 week in 210 (37%) patients. Mean age was 64±11 years, and 30% were female. Percutaneous coronary intervention was performed in 161 patients. RAO immediately after clamp removal was documented in 14 (4.9%) and 8 (2.8%) patients in the 20- and 60-minute clamp application groups, respectively (P=0.19). The incidence of grade 1 hematoma was higher in the 20-minute group (6.7% versus 2.5%, P=0.015). RAO at 1 week after the procedure was 2.9% and 0.9% in the 20- and 60-minute groups, respectively (P=0.36). Requirement for clamp retightening (36% versus 16%, P=0.01) was higher among patients who had RAO. Need for clamp retightening was the only independent predictor of RAO (P=0.04). CONCLUSIONS: Ultrashort radial clamp application of 20 minutes is not preferable to a short duration of 60 minutes. The 60-minute clamp duration is safe and provides good access site hemostasis with low RAO rates. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02269722.

Long-term outcome following remote ischemic postconditioning during percutaneous coronary interventions-the RIP-PCI trial long-term follow-up.

The clinical value of ischemic conditioning during percutaneous coronary intervention (PCI) and mode of administration is controversial. Our aim was to assess the long-term effect of remote ischemic postconditioning among patients undergoing PCI. We randomized 360 patients undergoing PCI who presented with a negative troponin T at baseline into 3 groups: 2 groups received remote ischemic postconditioning (with ischemia applied to the arm in 1 group and to the thigh in the other group), and the third group acted as a control group. Remote ischemic postconditioning was applied during PCI immediately following stent deployment, by 3, 5-minute cycles of blood pressure cuff inflation to >200 mm Hg on the arm or thigh (20 mm Hg to the arm in the control), with 5-minute breaks between each cycle. There were no differences in baseline characteristics among the 3 groups. Periprocedural myocardial injury occurred in 33% (P = 0.64). After 1 year, there was no difference between groups in death (P = 0.91), myocardial infarction (P = 0.78), or repeat revascularization (P = 0.86). During 3 years of follow-up, there was no difference in death, myocardial infarction, and revascularization among the groups (P = 0.45). Remote ischemic postconditioning during PCI did not affect long-term cardiovascular outcome. A similar effect was obtained when remote ischemia was induced to the upper or lower limb. ClinicalTrials.gov Identifier: NCT00970827.

The effect of fresh versus standard blood transfusion on microvascular endothelial function.

BACKGROUND: The duration of red blood cell (RBC) storage may have a negative impact on endothelial nitric oxide bioavailability. We tested the hypothesis that transfused fresh blood will have a more favorable effect on microvascular endothelial function as compared to older standard issue blood. METHODS: Participants requiring chronic RBC transfusions were enrolled in a crossover design study to receive fresh (<7 days of storage) or standard (up to 42 days of storage) blood on 2 separate visits. Endothelial function was assessed by reactive hyperemia peripheral arterial tonometry that was measured before and after transfusions. For each participant, the difference between endothelial function pretransfusion and posttransfusion was assessed in relation to blood storage time. RESULTS: Twenty-one patients (71 ± 16 years, 52% females) were enrolled. Mean age of fresh blood was 5.5 days (±1.0), and that of standard blood was 24.5 days (±7.9 days). The pretransfusion hemoglobin was 83.1 ± 2.5 g/L; and posttransfusion, 98.9 ± 2.6 g/L. An average of 2 U of packed RBCs was transfused. Microvascular endothelial function decreased more frequently after transfusion of standard blood compared to fresh blood. Standard issue blood transfusion was associated with decrease in reactive hyperemia peripheral arterial tonometry index (-0.25 ± 0.63) compared to fresh blood (+0.03 ± 0.49); P = .026. CONCLUSION: Transfusions of standard issue blood are associated with less favorable effect on microvascular endothelial function as compared to fresh blood.

Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial infarction.

BACKGROUND: Coronary no-reflow during primary percutaneous coronary intervention (PPCI) is a predictor of poorer cardiovascular outcome. Both endothelial dysfunction and no-reflow involves abnormal vascular function and hemostasis. Our aim was to assess the association between endothelial dysfunction and no reflow during primary PCI. METHODS: Thirty consecutive patients with ST elevation myocardial infarction (STEMI) and normal flow during primary PCI were compared to 19 consecutive patients who had no reflow. All subjects underwent assessment of peripheral endothelial function by reactive hyperemia index (RHI) 48-72h post PCI using the EndoPAT device. RESULTS: Age, sex and hypertension were similar in both groups. Smokers were less likely to have no-reflow. Post PPCI there was less ST segment resolution in the no-reflow group (48%±7 vs. 81%±6; p=0.001). Patients who had no reflow had subsequently lower ejection fraction (39%±10 vs. 47%±10; p=0.015). There was no difference in vascular function (RHI), between the no-reflow and normal flow groups (1.91±0.3 vs. 2.09±0.11; p=0.24). CONCLUSIONS: Systemic peripheral endothelial function does not differ between STEMI patients with and without no reflow during primary PCI.

The Impact of Peripheral Nerve Stimulation on Coronary Blood Flow and Endothelial Function.

PURPOSE: The geko™ device is a small transcutaneous nerve stimulator that is applied non-invasively to the skin over the common peroneal nerve to stimulate peripheral blood flow. The purpose of this study was to investigate the effect of peripheral nerve stimulation on coronary flow dynamics and systemic endothelial function. METHODS: We enrolled 10 male patients, age 59 ± 11 years, with symptomatic obstructive coronary disease undergoing percutaneous coronary intervention (PCI). Coronary flow dynamics were assessed invasively using Doppler flow wire at baseline and with nerve stimulation for 4 min. Measurements were taken in the stenotic coronary artery and in a control vessel without obstructive disease. At a separate visit, peripheral blood flow at the popliteal artery (using duplex ultrasound assessment) and endothelial function assessed by peripheral artery tonometry (PAT) were measured at baseline and after one hour of nerve stimulation. RESULTS: Compared to baseline, there was a significant increase in coronary blood flow as measured by average peak velocity (APV) in the control vessel with nerve stimulation (20.3 ± 7.7 to 23.5 ± 10 cm/s; p = 0.03) and non-significant increase in the stenotic vessel (21.9 ± 12 to 23.9 ± 12.9 cm/s; p = 0.23). Coronary flow reserve did not change significantly. Reactive hyperemia-peripheral arterial tonometry (Rh-PAT) increased from 2.28 ± 0.39 to 2.67 ± 0.6, p = 0.045. CONCLUSIONS: A few minutes of peripheral nerve stimulation may improve coronary blood flow. This effect is more prominent in non-stenotic vessels. Longer stimulation improved endothelial function.

One-year outcome of the sevoflurane in acute myocardial infarction randomized trial.

BACKGROUND: Sevoflurane is an inhalation anesthetic that has cardioprotective effects. There is limited information regarding its use outside of the operating room and its potential protective effect for patients presenting with myocardial infarction. METHODS: In the Sevoflurane In Acute Myocardial Infarction trial, patients with a first acute ST-elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention were randomized to inhalation of sevoflurane or oxygen (control). From the time of the patient's arrival for cardiac catheterization, the anesthesia team administered sevoflurane or oxygen for 30 min using a tight-fitting mask. In this substudy, we report the one-year outcomes. Patients were followed clinically for one year; they underwent a thallium cardiac viability study at six months and an echocardiogram at one year. RESULTS: Forty-six patients completed follow-up. One patient in the sevoflurane group died. The mean [standard deviation (SD)] ejection fraction by single-photon emission computed tomography at six months was 51.7 (7.7)% in the sevoflurane group and 51 (9.1)% in the control group (mean difference, 0.7%; 95% confidence interval [CI], -5.9 to 7.3; P = 0.831). The median [interquartile range] amount of scarring at six months was 0% [0 - 8] in the sevoflurane group and 2.5% [0 - 7.1] in control group (mean difference, -0.1%; 95% CI, -4.6 to 4.4; P = 0.700). The mean (SD) percentage of hibernating myocardium was similar in both groups 0% [0, 5] (mean difference, -1.3%; 95% CI, -3.4 to 0.9; P = 0.259). The mean (SD) ejection fraction at one year increased compared with baseline by 8.0 (9.1)% (P < 0.001). CONCLUSIONS: In this study, we did not find an effect of sevoflurane on left ventricular function or myocardial injury at one year post STEMI. This trial was registered at www.clinicaltrials.gov ; identifier: NCT00971607.

Clinical presentation and outcome of patients with ST-segment elevation myocardial infarction without culprit angiographic lesions.

Patients diagnosed with ST-segment elevation myocardial infarction (STEMI) are occasionally found to have no culprit lesion on coronary angiography and are classified as presenting with false-positive STEMI. The clinical presentation and outcomes of these patients need to be further explored. In this case-controlled study, 259 consecutive patients with true code STEMI were compared to 104 consecutive STEMI patients without culprit lesions on emergent coronary angiography. We compared the clinical presentation, electrocardiographic features, etiology, and outcomes of the two groups. STEMI patients without culprit lesions were less likely to have typical chest pain (46% vs. 79%, P < 0.01). The ST-elevation in the group without culprit lesion was more likely to be concave (56% vs. 31%, P < 0.01), with less reciprocal ST-depression (19% vs. 71%, P < 0.01). The group without culprit lesions had a higher rate of ventilator support requirement (12.4% vs. 5.4%, P = 0.02), and higher rate of 30-day mortality (11.0% vs. 5.9%, P = 0.02). However, after excluding the patients with out-of-hospital cardiac arrests from both groups, the difference was no longer significant (P = 0.40 and 0.34 respectively). The relative poor outcomes of patients with false-positive code STEMI reflect the severity of their underlying medical condition. Careful history and review of ECG may help differentiate this group from true STEMI.

Diagnostic accuracy of ST-segment elevation myocardial infarction by various healthcare providers.

BACKGROUND: This study aimed to compare the accuracy of ECG interpretation for diagnosis of STEMI by different groups of healthcare professionals involved in the STEMI program at our institution. METHODS: We selected 21 ECGs from patients with typical symptoms of MI that were diagnosed with STEMI, and 10 ECGs of STEMI mimics. STEMI mimic ECGs were repeated in the package with a story of typical and atypical chest pain. ECGs were interpreted to diagnose STEMI and identify need for initiation of the cardiac catheterization lab (CCL). Participants identified confidence in STEMI recognition, and average number of ECGs read per week. RESULTS: A total of 64 participants completed the study package. Cardiologists were more likely to provide correct interpretation compared to other groups. False positive diagnoses were more likely made by paramedics when compared to cardiologists (p < 0.01). There was a positive correlation between increased exposure to ECGs and accurate STEMI diagnosis (r = 0.482, p < 0.001). A threshold of ≥ 20 ECGs read per week showed a statistically significant improvement in accuracy (p < 0.001). Self-reported confidence correlated positively with accuracy (r = 0.402, p =< 0.001). Changing the ECG narrative of the STEMI mimic ECGs had a significant effect on interpretation between groups (p = 0.043). CONCLUSIONS: Our study showed that healthcare profession and number of ECGs reviewed per week are predictive of the accuracy of ECG interpretation of STEMI. Cardiologists are the most accurate diagnosticians, and are the least likely to falsely activate the CCL. Weekly exposure of ≥ 20 ECGs may improve diagnostic accuracy regardless of underlying experience.

ß-Arrestin2 regulates lysophosphatidic acid-induced human breast tumor cell migration and invasion via Rap1 and IQGAP1.

ß-Arrestins play critical roles in chemotaxis and cytoskeletal reorganization downstream of several receptor types, including G protein-coupled receptors (GPCRs), which are targets for greater than 50% of all pharmaceuticals. Among them, receptors for lysophosphatidic acid (LPA), namely LPA(1) are overexpressed in breast cancer and promote metastatic spread. We have recently reported that ß-arrestin2 regulates LPA(1)-mediated breast cancer cell migration and invasion, although the underlying molecular mechanisms are not clearly understood. We show here that LPA induces activity of the small G protein, Rap1 in breast cancer cells in a ß-arrestin2-dependent manner, but fails to activate Rap1 in non-malignant mammary epithelial cells. We found that Rap1A mRNA levels are higher in human breast tumors compared to healthy patient samples and Rap1A is robustly expressed in human ductal carcinoma in situ and invasive tumors, in contrast to the normal mammary ducts. Rap1A protein expression is also higher in aggressive breast cancer cells (MDA-MB-231 and Hs578t) relative to the weakly invasive MCF-7 cells or non-malignant MCF10A mammary cells. Depletion of Rap1A expression significantly impaired LPA-stimulated migration of breast cancer cells and invasiveness in three-dimensional Matrigel cultures. Furthermore, we found that ß-arrestin2 associates with the actin binding protein IQGAP1 in breast cancer cells, and is necessary for the recruitment of IQGAP1 to the leading edge of migratory cells. Depletion of IQGAP1 blocked LPA-stimulated breast cancer cell invasion. Finally, we have identified that LPA enhances the binding of endogenous Rap1A to ß-arrestin2, and also stimulates Rap1A and IQGAP1 to associate with LPA(1). Thus our data establish novel roles for Rap1A and IQGAP1 as critical regulators of LPA-induced breast cancer cell migration and invasion.

Beta-arrestin/Ral signaling regulates lysophosphatidic acid-mediated migration and invasion of human breast tumor cells.

The lipid mediator lysophosphatidic acid (LPA) plays a role in cancer progression and signals via specific G protein-coupled receptors, LPA(1-3). LPA has been shown to enhance the metastasis of breast carcinoma cells to bone. However, the mechanisms by which LPA receptors regulate breast cancer cell migration and invasion remain unclear. Breast cancer cell proliferation has been shown to be stimulated by Ral GTPases, a member of the Ras superfamily. Ral activity can be regulated by the multifunctional protein beta-arrestin. We now show that HS578T and MDA-MB-231 breast cancer cells and MDA-MB-435 melanoma cells have higher expression of beta-arrestin 1 mRNA compared with the nontumorigenic mammary MCF-10A cells. Moreover, we found that the mRNA levels of LPA1, LPA2, beta-arrestin 2, and Ral GTPases are elevated in the advanced stages of breast cancer. LPA stimulates the migration and invasion of MDA-MB-231 cells, but not of MCF-10A cells, and this is mediated by pertussis toxin-sensitive G proteins and LPA1. However, ectopic expression of LPA1 in MCF-10A cells caused these cells to acquire an invasive phenotype. Gene knockdown of either beta-arrestin or Ral proteins significantly impaired LPA-stimulated migration and invasion. Thus, our data show a novel role for beta-arrestin/Ral signaling in mediating LPA-induced breast cancer cell migration and invasion, two important processes in metastasis.