Acute Ischemic Insult Research Articles

Operative Timing in Cervical Spine Trauma.

Narrative review. To review existing literature regarding surgical timing in cervical trauma with a focus on acute traumatic central cord syndrome. Traumatic central cord syndrome is the most common incomplete spinal cord injury. Substantial basic science literature has proposed ischemic and secondary injury-driven mechanisms underpinning the urgency of operative intervention. However, only recently has a relative consensus emerged in the clinical literature regarding the safety, efficacy, and necessity of early operative intervention for acute traumatic central cord syndrome. A literature search was conducted of studies in PubMed Central and Cochrane Database related to timing in cervical spine trauma. Recently, several major systematic reviews and consensus statements have endorsed the importance and safety of early (<24h) operative decompression in the setting of traumatic spinal cord injury. Despite decades of conflicting data, a similar trend appears to be emerging for traumatic central cord syndrome. These clinical developments join a large body of basic science work regarding the importance of early decompressive surgery in relieving acute ischemic insult and minimizing the effects of secondary injury. However, further work is needed to delineate optimal surgical timing, especially regarding "ultra-early" (<8 h) protocols, and to aid in creating accelerated screening pathways.

An Analytical Study of NSAIDs Affecting Heart Functions

Local production of vasodilating prostaglandins is necessary to sustain renal perfusion in a number of clinical situations, such as congestive heart failure, cirrhosis, and renal insufficiency. Inhibition of these prostaglandins permits unopposed vasoconstriction to occur when patients with these illnesses are given nonsteroidal anti-inflammatory medicines (NSAIDs), putting them at risk for an acute ischemic insult to the kidney. Acute kidney injury (AKI) and chronic kidney disease are only two of the many nephrological problems that can result from using NSAIDs (CKD). Nonsteroidal anti-inflammatory medicines (NSAIDs) have been shown to increase blood pressure and to antagonize the blood pressure-lowering action of antihypertensive therapy, both of which have the potential to enhance hypertension-related morbidity. Diclofenac was the drug that caused the most noticeable decrease in COX-2 activity, increase in blood pressure, and decrease in heart rate. In a complicated way, non-aspirin, non-steroidal anti- inflammatory medicines (NANSAIDs) can either protect against or contribute to the development of coronary heart disease. The cardiovascular effects of all the medicines studied were unclear, although Naproxen looked the safest. When compared to lumiracoxib, the findings show that ibuprofen may increase the incidence of thrombotic and CHF events in aspirin users with high cardiovascular risk. Before giving a non-steroidal anti-inflammatory medicine, doctors should evaluate the patient for cardiovascular risk.

Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair

The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis.

Effects of preoperative high-oral protein loading on short- and long-term renal outcomes following cardiac surgery: a cohort study

BackgroundPost-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects.MethodsThe prospective “Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation” study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations.ResultsThe AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI − 1.4, − 1.7] vs. − 3.3 [95% CI − 4.4, − 2.2] ml/min/1.73 m2) and 12 months (− 2.7 [95% CI − 4.2, − 1.2] vs − 10.2 [95% CI − 11.3, − 9.1] ml/min/1.73 m2; p < 0.001 for both). On stratification based on AKI development, the eGFR loss after 12 months was also found to be lower in the former (− 8.0 [95% CI − 14.1, − 1.9] vs. − 18.6 [95% CI − 23.3, − 14.0] ml/min/1.73 m2; p = 0.008). A dose–response analysis of the protein treatment of the primary human proximal and distal tubule epithelial cells in culture showed significantly increased IGFBP7 and TIMP-2 expression.ConclusionsA preoperative high-oral protein load did not reduce AKI development but was associated with greater renal function preservation in patients with and without AKI at 12 months post-cardiac surgery. The potential mechanisms of action by which protein loading may induce a kidney-protective response might include cell cycle inhibition of renal tubular epithelial cells.Clinical trial registration ClinicalTrials.gov: NCT03102541 (retrospectively registered on April 5, 2017) and ClinicalTrials.gov: NCT03092947 (retrospectively registered on March 28, 2017).

COVID-19’s effects on the Egyptian population’s brain: Could MRI and specialized MR spectroscopic analysis be beneficial?

BackgroundThe recent pandemic of COVID‐19 has thrown the world into chaos due to its high rate of transmissions. Recently viewed neurological manifestations among hospitalized Egyptian patients with COVID‐19 in quarantine centres. Ataxia, disturbed consciousness and convulsions should be further evaluated by MRI and MRS for CNS involvement by SARS‐CoV‐2. How COVID-19 targeting the CNS is still under study, as it is difficult to predict which diagnostic neurological tests will be used to identify high-risk COVID19 patients. MR spectroscopy represents a non-invasive in vivo diagnostic technique for evaluation of metabolic profile of the brain and can reveal important information about the underlying pathologies. Multiple recent reports in the medical literature had confirmed the neurological complications in COVID-19 infection, though few studies has reported the MR spectroscopic findings in these patients. This cross-sectional study aimed to use MRI and MR spectroscopic findings for evaluation of the neurological manifestation of Egyptian COVID‐19 patients.ResultsNinety-one male and twenty-seven female met the inclusion criteria, with a mean age of 52 years ± 10 (SD) (age range; 12–78 years). The commonest neurological manifestations were disturbed conscious level (82.2%). The most common MRI findings were acute ischemic insult with/without haemorrhagic areas (42.3%), demyelinating patches of altered signal intensity (31.3%). Sixty cases who had haemorrhagic areas were excluded to perform MRS due to contamination of the spectra by blood component. However, the remaining 67 patients had NAA reduction, choline elevation, glutamate/glutamine and lactate elevation in short TE35, with mean of NAA/Cr ratio = 1.04 ± 0.14, Choline/Cr = 0.49 ± 0.04 and Glx/Cr = 1.56 ± 0.22.ConclusionsDuring the current pandemic of COVID-19, radiologists should be aware of wide spectrum of MRI and MRS findings of COVID-19-related CNS involvement.

Non-invasive vagus nerve stimulation reduced neuron-derived IL-1β and neuroinflammation in acute ischemic rat brain

ObjectiveWe previously demonstrated that non-invasive vagus nerve stimulation (nVNS) provided during middle cerebral artery occlusion (MCAO) reduces infarct volume and blood–brain barrier disruption. However, the neuroprotective mechanisms of nVNS in stroke damages remain to be examined. This study tested the hypothesis that nVNS attenuates neuron-derived interleukin-1β (IL-1β), a pro-inflammatory cytokine, and neuroinflammation in ischemic brain. MethodsSpontaneously hypertensive rats were subjected to a 90-minute MCAO with 24-hour reperfusion (RP). nVNS treated rats received 5 doses of nVNS beginning 30 min after MCAO onset. Results1) MCAO/RP induced a significant increase of active IL-1β at 24 h and ischemic neurons were the main resource of IL-1β, which were significantly attenuated by nVNS. 2) The activation of the neuronal IL-1β was non-caspase-1-dependent. Both in vivo and in vitro data showed a correlation of intracellular matrix metalloproteinase-9 (MMP-9) activation with IL-1β expression in ischemic neurons. 3) nVNS significantly reversed stroke-induced decrease of neuronal nicotinic acetylcholine receptor α7 subtype (α7nAChR) and reduced neurodegeneration. ConclusionThe results suggest that acute ischemic insult triggers a unique molecular injury cascade involving in activation of the MMPs/IL-1β signaling pathway in neurons. nVNS downregulates this signaling pathway via α7nAChR to reduce brain injury.

Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress

Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2−/−) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. “reductomiRs”) associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these “reductomiRs” as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.

Diagnosis and treatment of acute ischemic insults

In cases of stroke adistinction is made between a transient ischemic attack (TIA), a manifest ischemic infarction and cerebral hemorrhage. Cerebral ischemia can be caused by large vessel disease, small vessel disease, embolic causes, rare causes or stroke of unknown etiology. Acute diagnostic tests include a neurological examination, computed tomography (CT) and/or magnetic resonance imaging (MRI) with angiography, electrocardiography (ECG), and laboratory tests. The basic treatment of patients with TIA or acute ischemic infarction is performed in the stroke unit and includes monitoring of respiratory function, cardiac function, treatment of potential heart failure, detection of swallowing disorders, prophylaxis of thromboembolism, control of blood pressure and elevated blood sugar levels, and lowering of elevated body temperature. In patients with cardioembolic infarction, oral anticoagulation is initiated depending on the severity of the stroke and the size of the stroke on imaging.

Ischaemic stroke as an initial presentation in patients with COVID-19: evaluation of a case series in an emergency in Brazil.

The disease caused by the new coronavirus, initially described in China in December 2019, became known as coronavirus disease 2019 and quickly spread to countries on all continents, becoming a pandemic with an important global impact. Despite being a virus that typically affects the respiratory tract, some studies have already described neurological manifestations associated with this infection, including acute ischaemic vascular insult. We report a case series including 30 patients, who presented with neurological symptoms during admission to our service, being diagnosed with ischaemic stroke and, concomitantly, coronavirus disease 2019. In the subgroup of patients analysed, a state of hypercoagulability and pro thrombosis was observed through laboratory tests, probably related to the cytokine storm syndrome associated with infection by this virus. With that, we discussed the possibility of this finding being an aggravating factor in the occurrence of stroke in these patients.

Hypoxia and its preconditioning on cardiac and vascular remodelling in experimental animals

Since oxygen (O2) is indispensable for mammalian life, every cell in the body is endowed with mechanisms to detect and to respond to changes in the O2 levels in the microenvironment. The heart and the brain are the two most vital, life-supporting organs requiring a continuous supply of O2 to sustain their high metabolic rate. On being challenged with hypoxia, maintenance of O2 supply to these organs even at the cost of others becomes a priority. This review describes the cardiovascular, skeletal muscle vascular, pulmonary vascular and cerebrovascular remodelling in face of chronic mild hypoxia exposure and the underlying mechanisms, with special reference to the role of oxidative stress, hypoxia signalling, autonomic nervous mechanisms. The significance of the normalized wall index (NWI) in assessing the remodelling of the vessels particularly of the intramyocardial coronary artery has been underscored. The review also highlights the basic concepts of hypoxic preconditioning and the subsequent protection of the brain against an acute ischemic insult in preclinical studies hinting towards its possible therapeutic potential in the management of ischemic stroke.

Restricted Water Intake and Hydration with Fructose-Containing Beverages during Infancy Predispose to Aggravate an Acute Renal Ischemic Insult in Adolescent Rats.

We aimed to investigate the effects of chronic fluid restriction and hydration with a sweetened beverage (SB) in rats from weaning until adolescence, in a posterior acute kidney injury (AKI) event induced by ischemia-reperfusion (I/R). We followed 5 groups of weaning rats: control group (C); two groups with 22 h/day fluid restriction, a group hydrated for two hours with water (-W) and a group hydrated with SB; one group receiving SB ad libitum all day (+SB); and one group in which water consumption was increased using a gel diet. The rats that reached adolescence were submitted to I/R. Fluid restriction and/or SB hydration induced mild renal alterations that were significantly accentuated in the -SB group and resulted in worse outcomes after I/R-induced AKI that resulted in a catastrophic fall in creatinine clearance and diffuse acute tubular necrosis. In summary, low tap water intakes, as well as SB intake in infancy, prompt kidney worse outcomes in a later event of AKI during adolescence and both insults magnify kidney damage. Studies on hydration habits in children are recommended to disclose the potentially harmful effects that those behavioral patterns might carry to future renal health.

Arteriogenesis of the Spinal Cord-The Network Challenge.

Spinal cord ischemia (SCI) is a clinical complication following aortic repair that significantly impairs the quality and expectancy of life. Despite some strategies, like cerebrospinal fluid drainage, the occurrence of neurological symptoms, such as paraplegia and paraparesis, remains unpredictable. Beside the major blood supply through conduit arteries, a huge collateral network protects the central nervous system from ischemia—the paraspinous and the intraspinal compartment. The intraspinal arcades maintain perfusion pressure following a sudden inflow interruption, whereas the paraspinal system first needs to undergo arteriogenesis to ensure sufficient blood supply after an acute ischemic insult. The so-called steal phenomenon can even worsen the postoperative situation by causing the hypoperfusion of the spine when, shortly after thoracoabdominal aortic aneurysm (TAAA) surgery, muscles connected with the network divert blood and cause additional stress. Vessels are a conglomeration of different cell types involved in adapting to stress, like endothelial cells, smooth muscle cells, and pericytes. This adaption to stress is subdivided in three phases—initiation, growth, and the maturation phase. In fields of endovascular aortic aneurysm repair, pre-operative selective segmental artery occlusion may enable the development of a sufficient collateral network by stimulating collateral vessel growth, which, again, may prevent spinal cord ischemia. Among others, the major signaling pathways include the phosphoinositide 3 kinase (PI3K) pathway/the antiapoptotic kinase (AKT) pathway/the endothelial nitric oxide synthase (eNOS) pathway, the Erk1, the delta-like ligand (DII), the jagged (Jag)/NOTCH pathway, and the midkine regulatory cytokine signaling pathways.

Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

Acetylcholine (ACh) has been suggested to facilitate plasticity and improve functional recovery after different types of brain lesions. Interestingly, numerous studies have shown that striatal cholinergic interneurons are relatively resistant to acute ischemic insults, but whether ACh released by these neurons enhances functional recovery after stroke is unknown. We investigated the role of endogenous striatal ACh in stroke lesion volume and functional outcomes following middle cerebral artery occlusion to induce focal ischemia in striatum-selective vesicular acetylcholine transporter-deficient mice (stVAChT-KO). As transporter expression is almost completely eliminated in the striatum of stVAChT-KO mice, ACh release is nearly abolished in this area. Conversely, in other brain areas, VAChT expression and ACh release are preserved. Our results demonstrate a larger infarct size after ischemic insult in stVAChT-KO mice, with more pronounced functional impairments and increased mortality than in littermate controls. These changes are associated with increased activation of GSK-3, decreased levels of β-catenin, and a higher permeability of the blood–brain barrier in mice with loss of VAChT in striatum neurons. These results support a framework in which endogenous ACh secretion originating from cholinergic interneurons in the striatum helps to protect brain tissue against ischemia-induced damage and facilitates brain recovery by supporting blood–brain barrier function.

Regulating heart repair with cardiac-specific T lymphocytes.

Cardiac tissue necrosis secondary to coronary artery occlusion is one of the most common and deadly sterile injuries in developed countries. In this issue of the JCI, Rieckmann et al. identified and characterized antigen-specific CD4+ T helper (Th) cells that developed in the context of myocardial infarction (MI) in mice. They showed that myosin heavy chain α (MYHCA) is a dominant cardiac autoantigen and that T cells with T cell receptor (TCR) specificity to MYHCA acquired a Treg phenotype when adoptively transferred into infarcted mice, which mediated a cardioprotective healing response. Thus, Rieckmann et al. showed that an acute ischemic insult to the heart, which induces sterile inflammation, promoted, rather than limited, protective T cell autoimmunity. Notably, strategies that support an antigen-specific Treg response may limit the immune-inflammatory response and promote cardiac repair after acute MI.

The Plasminogen Activation System Promotes Neurorepair in the Ischemic Brain.

The Plasminogen Activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: Tissue-type Plasminogen Activator (tPA) and Urokinase-type Plasminogen Activator (uPA). However, experimental evidence accumulated over the last 30 years indicates that tPA and uPA are also found in the Central Nervous System (CNS), where they have a plethora of functions that not always require plasmin generation or fibrin degradation. For example, plasminogen-dependent and -independent effects of tPA and uPA play a central role in the pathophysiological events that underlie one of the leading causes of mortality and disability in the world: cerebral ischemia. Indeed, recent work indicates that while the rapid release of tPA from the presynaptic compartment following the onset of cerebral ischemia protects the synapse from the deleterious effects of the ischemic injury, the secretion of uPA and its binding to its receptor (uPAR) during the recovery phase promotes the repair of synapses that have been lost to the acute ischemic insult. This restorative role of uPA has high translational significance because to this date there is no effective approach to induce neurorepair in the ischemic brain. Here we will discuss recent evidence that bridges the gap between basic research in the field of the PA system and the bedside of ischemic stroke patients, indicating that uPA and uPAR are potential targets for the development of therapeutic strategies to promote neurological recovery among ischemic stroke survivors.

Tight coronary artery stenosis and takotsubo syndrome triggered each other: Well-illustrated in a case

Post-ischemic myocardial stunning (PIMS) is defined as a prolonged and reversible left ventricular dysfunction induced by an acute coronary ischemic insult. Takotsubo syndrome (TS) is a recognized acute cardiac disease entity, characterized by a unique pattern of transient circumferential left ventricular wall motion abnormality (LVWMA). The LVWMA in TS has all the characteristic features of myocardial stunning. Herein, the case of a 76-year-old woman with severe three-vessel coronary artery disease presented with acute coronary syndrome inducing PIMS with features identical to mid-apical pattern of TS is reported. The stunned myocardium caused incessant (throughout systole and diastole) compression of a segment of left anterior descending artery (LAD) with myocardial bridging during the acute and sub-acute stages of the disease. The systo-diastolic compression of LAD was relieved after recovery of LVWMA 26 days later. This novel observation suggests that the myocardial stunning in TS is in a cramp state during the acute and sub-acute stages of the disease. The cramp state of myocardial stunning may also explain the microvascular dysfunction seen in some patients with TS.

The Beneficial Effects of Melatonin Administration Following Hypoxia-Ischemia in Preterm Fetal Sheep.

Melatonin (MLT) is an endogenous hormone that controls circadian cycle. MLT has additional important properties that make it appealing as a neuroprotective agent—it is a potent anti-oxidant, with anti-apoptotic and anti-inflammatory properties. MLT is safe for administration during pregnancy or to the newborn after birth, and can reduce white matter brain injury under conditions of chronic fetal hypoxia. Accordingly, in the current study, we examined whether an intermediate dose of MLT could restore white matter brain development when administered after an acute hypoxic ischemic (HI) insult in preterm fetal sheep. Fifteen fetal sheep at 95–98 days gestation were instrumented with femoral artery and vein catheters, and a silastic cuff placed around the umbilical cord. At 102 days gestation, the cuff was inflated, causing complete umbilical cord occlusion for 25 min in 10 fetuses, to induce acute severe HI. Five HI fetuses received intravenous MLT for 24 h beginning at 2 h after HI. The remaining five fetuses were administered saline alone. Ten days after HI, the fetal brain was collected from each animal and white and gray matter neuropathology assessed. HI caused a significant increase in apoptotic cell death (TUNEL+), activated microglia (Iba-1+), and oxidative stress (8-OHdG+) within the subventricular and subcortical white matter. HI reduced the total number of oligodendrocytes and CNPase+ myelin density. MLT administration following HI decreased apoptosis, inflammation and oxidative stress within the white matter. MLT had intermediate benefits for the developing white matter: it increased oligodendrocyte cell number within the periventricular white matter only, and improved CNPase+ myelin density within the subcortical but not the striatal white matter. MLT administration following HI was also associated with improved neuronal survival within the cortex. Neuropathology in preterm infants is complex and mediated by multiple mechanisms, including inflammation, oxidative stress and apoptotic pathways. Treatment with MLT presents a safe approach to neuroprotective therapy in preterm infants but appears to have brain region-specific benefits within the white matter.

Remote ischemic preconditioning does not prevent acute mountain sickness after rapid ascent to 3,450 m.

P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases.

Rivaroxaban for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation and Active Cancer

Rivaroxaban is broadly used for the primary prevention of stroke and systemic embolism in the general population with nonvalvular atrial fibrillation (AF). However, there is little published evidence on the safety and efficacy of rivaroxaban for AF in patients with active cancer. The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and AF. The use of rivaroxaban in patients with cancer at the Memorial Sloan Kettering Cancer Center is monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and AF, treated with rivaroxaban from January 1, 2014, to March 31, 2016, are included in this analysis. Clinical end points were defined a priori and assessed through text searches of medical records. A total of 163 evaluable patients were identified. After adjusting for competing risks, the estimated 1-year cumulative incidence of ischemic stroke was 1.4% (95% CI 0% to 3.4%) and major bleeding was 1.2% (95% CI 0% to 2.9%). The risk of clinically relevant nonmajor bleeding leading to discontinuation of anticoagulation at 1year was 14.0% (95% CI 4.2% to 22.7%). The cumulative incidence of mortality was 22.6% (95% CI 12.2% to 31.7%) at 1 year, reflecting an active cancer population. One patient died after developing an acute ischemic cerebrovascular insult. In conclusion, the safety and efficacy of rivaroxaban treatment for nonvalvular AF in patients with active cancer is comparable to the results of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study in the general population.

Rivaroxaban for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation and Active Cancer

BACKGROUNDThe link between aging, cancer and atrial fibrillation is well known and the appropriate anticoagulation management of non-valvular atrial fibrillation (NVAF) in patients with active cancer is of growing clinical concern. Rivaroxaban has been broadly used for the primary prevention of stroke and systemic embolism in the general population of patients with NVAF. However, individuals with a serious concomitant illness associated with a life expectancy of less than 2 years were excluded from pivotal trials including the ROCKET-AF study, limiting the generalizability of results to patients with active cancer. There is little published evidence on the safety and efficacy of rivaroxaban for NVAF in this specific subgroup. OBJECTIVESThe aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and NVAF. METHODSThe use of rivaroxaban in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) was monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and NVAF treated with rivaroxaban from 1/1/2014 through 3/31/2016 are included in this analysis. Endpoints of interest were defined a priori and include stroke, systemic embolism, major bleeding and clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days (CRNMB). Clinical events were assessed through text searches of medical records. The analysis was performed respecting different times on previous anticoagulation, considering the first 90 days as the acute phase of treatment and contrasting it with the subsequent chronic phase. RESULTSA total of 163 evaluable patients were included in the analysis, with a median age of 72.0 years (interquartile range=67.0-77.5 years) and 56% of these individuals being men. The majority had a solid tumor (85%), with stage IV disease reported in 50% of cases. The mean CHA2DS2-Vasc score was 3.2 (standard deviation=1.5) and 64% of patients were already in the chronic phase of anticoagulation. Results for the acute, chronic and combined phases of anticoagulation are presented in the Table and plotted in the Figure. The estimated cumulative incidence of ischemic stroke, major bleeding, and CRNMB at 1 year were 1.4% (95% CI=0-3.4%), 1.2% (95% CI=0-2.9%) and 14.0% (95% CI=4.2-22.7%) respectively, after adjusting for competing risks. Interestingly, the cumulative incidence of major bleeding in our cohort is lower than the value reported for the ORBIT-AF registry of cancer patients on dabigatran or a vitamin K antagonist for NVAF, in which the estimated rate of this complication was 5.1/100 patient-years. Lastly, the 1-year cumulative incidence of mortality was 22.6% (95% CI=12.2-31.7%). This high risk of death was present throughout the observation period and reflects the cancer population. One patient died after developing an acute ischemic cerebrovascular insult and a myocardial infarction. There were no deaths related to bleeding and no recorded systemic embolism episodes. CONCLUSIONSThe safety and efficacy profile of rivaroxaban treatment for NVAF in patients with active cancer seems comparable to what was observed for the general population in the ROCKET-AF study, but ideally a prospective study would be required to confirm these findings. [Display omitted] [Display omitted] DisclosuresYu:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding. Mantha:Janssen Scientific Affairs, LLC: Research Funding.