Risk Factors for Rivaroxaban-Related Bleeding Events-Possible Role of Pharmacogenetics: Case Series.

Non-vitamin K antagonist oral anticoagulants' interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P-glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug-drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach.

How does age affect outcomes after left ventricular assist device implantation: results from the PCHF-VAD registry.

AIMS: Use of left ventricular assist devices (LVADs) in older patients has increased, and assessing outcomes in older LVAD recipients is important. Therefore, this study aimed to investigate associations between age and outcomes after continuous-flow LVAD (cf-LVAD) implantation. METHODS AND RESULTS: Cf-LVAD patients from the multicentre European PCHF-VAD registry were included and categorized into those <50, 50-64, and ≥65 years old. The primary endpoint was all-cause mortality. Among secondary outcomes were heart failure (HF) hospitalizations, right ventricular (RV) failure, haemocompatibility score, bleeding events, non-fatal thromboembolic events, and device-related infections. Of 562 patients, 184 (32.7%) were <50, 305 (54.3%) were aged 50-64, whereas 73 (13.0%) were ≥65 years old. Median follow-up was 1.1 years. Patients in the oldest age group were significantly more often designated as destination therapy (DT) candidates (61%). A 10 year increase in age was associated with a significantly higher risk of mortality (hazard ratio [HR] 1.34, 95% confidence interval [CI] [1.15-1.57]), intracranial bleeding (HR 1.49, 95% CI [1.10-2.02]), and non-intracranial bleeding (HR 1.30, 95% CI [1.09-1.56]), which was confirmed by a higher mean haemocompatibility score (1.37 vs. 0.77, oldest vs. youngest groups, respectively, P = 0.033). Older patients suffered from less device-related infections requiring systemic antibiotics. No age-related differences were observed in HF-related hospitalizations, ventricular arrhythmias, pump thrombosis, non-fatal thromboembolic events, or RV failure. CONCLUSIONS: In the PCHF-VAD registry, higher age was associated with increased risk of mortality, and especially with increased risk of major bleeding, which is particularly relevant for the DT population. The risks of HF hospitalizations, pump thrombosis, ventricular arrhythmia, or RV failure were comparable. Strikingly, older patients had less device-related infections.

Transcatheter Aortic Valve Implantation Induces Transient Drop in Platelet Reactivity.

ABSTRACT: Although recent studies described platelet reactivity (PR) changes in days after transcatheter aortic valve implantation (TAVI), precise time course and duration of these changes have not been fully investigated. The aim of this study was to investigate PR pattern during and after TAVI in multiple time points. Study included 40 consecutive patients undergoing TAVI. All patients underwent the procedure on dual antiplatelet therapy. PR was measured in 7 time points: before induction of anesthesia (T1), after heparin administration (T2), 10 minutes after initial valve implantation (T3), at the end of procedure (T4), and on 3rd, 6th, and 30th postoperative day (T5-T7). PR was measured using impedance aggregometer using 3 different platelet aggregation agonists (arachidonic acid in ASPItest, adenosine diphosphate in ADPtest and thrombin receptor activating peptide 6 in TRAPtest). All patients underwent successful TAVI procedure. Mean PR on T1 was 22.9 ± 23.0 U for ASPItest, 40.5 ± 23.7 U for ADPtest and 91.7 ± 32.5 U for TRAPtest. There was no significant difference in PR on T2. On T3, significant reduction of PR in all 3 tests was observed [ASPI 10.4 ± 11.6 U (P = 0.001), ADP 24.2 ± 14.1 U (P < 0.001) and TRAP 69.3 ± 26.6 U (P < 0.001)]. PR nadir for all tests was reached on T5, with subsequent PR incline. PR values in all tests returned to baseline levels on T7. Our results show that successful TAVI procedure induces transient decrease in PR regardless of the platelet activation pathway.

Intra-procedural three-dimensional rotational angiography in cryoballoon ablation for atrial fibrillation.

Cryoballoon (CB) is an established technology for atrial fibrillation (AF) ablation and is usually performed using solely fluoroscopy. We aimed to study the feasibility of three-dimensional rotational angiography (3DRA) as intra-procedural imaging in CB ablation. Analyzed data were retrospectively collected from patients that underwent second generation CB ablation from February 2015 to August 2017. We studied 68 consecutive patients that received 3DRA (3DRA group). Sixty-six patients who received conventional X-ray imaging served as a control group. 3DRA was performed via an introducer placed in the left atrium. Angiographic images were segmented and fused with live fluoroscopy to guide the ablation. We have analyzed 134 CB patients (73.8% male, 56.9 ± 11.4 years). Paroxysmal AF was present in 77.6% of patients. 3DRA was successfully performed in all 3DRA group patients. The mean procedure time was significantly shorter in the control group (82.4 ± 26.3 min) than in the 3DRA group (121.1 ± 21.4 min) (p < 0.0001). Total radiation dose (419.3 ± 317.9 vs 998.3 ± 673 mGy, p < 0.0001) and contrast administration (83.2 ± 22.3 mL vs 191.6 ± 33.4 mL, p < 0.0001) were significantly lower in control group. There was no significant difference in 2-year success rate, 35.2% of patients had AF recurrence in the 3DRA group and 30.3% in the control group (p = 0.584). Major complications occurred in 2.9% and 1.5% of patients in 3DRA group and control group, respectively (p = 1.000). 3DRA is a feasible method of intra-procedural imaging to guide CB ablation. However, it prolongs procedure time, increases radiation dose and contrast administration with no significant effect on procedure outcomes and complication rates.

Use of figure of eight suture for groin closure with no heparin reversal in patients undergoing cryoballoon ablation for atrial fibrillation.

PURPOSE: We aimed to demonstrate the feasibility of figure of eight (FoE) suture for groin access closure in cryoballoon (CB) ablation and its impact on the lab workflow. METHODS: We retrospectively analyzed all patients who underwent CB ablation in our institution from June 2018. From June 2019, we have been consistently using FoE suture for hemostasis (FoE+ group), and before that conventional manual compression was utilized (FoE- group). Ablations were performed under uninterrupted oral anticoagulant strategy. Both femoral veins were punctured, and a single introducer was placed in each vein. In the FoE- group, after ablation, protamine was administered, and manual compression was applied. In the FoE+ group, the suture was placed in both groins without protamine administration and manual compression. All patients were in decubitus position until the next morning. RESULTS: A total of 190 consecutive patients (73.2% male, 59.7 ± 11.0 years old) were evaluated, 90 being in the FoE+ group. There was no difference in the mean procedure duration between two groups (72.7 ± 23.1 min vs 73.7 ± 27.1 min, p = 0.784). However, the total lab time was significantly longer in FoE- group (132.9 ± 35.3 min vs 109.9 ± 32.6 min, p < 0.0001). There was no difference in complication rates. No major vascular complications were found in our cohort. CONCLUSIONS: Utilization of FoE sutures for hemostasis seems to be a safe and effective after cryoballoon ablation. It abolishes the need for protamine administration which can cause serious adverse events. As manual compression is unrequired, EP lab workflow improves due to significantly shortened total lab time per patient.

Improved real-time recordings using the fourth-generation cryoballoon technology-detection of dual fascicle electrograms.

BACKGROUND: We aimed to analyze the rate of visualization of real-time (RT) recordings and dual fascicle electrograms in our first series of patients treated with the fourth-generation cryoballoon (CB) device. METHODS: All consecutive patients who underwent CB ablation using the fourth-generation technology were included in the analysis. In all procedures, we used a 28-mm CB placed via a single transseptal puncture guided by intracardiac ultrasound. A 20-mm octapolar intraluminal circular catheter was used for intracardiac recordings. A single 180-s freeze strategy was employed. RESULTS: A total of 129 patients (72.9% male, mean age 60.1 ± 10.9 years) were enrolled in the study. RT recordings were detected in 445 (86.2%) pulmonary veins (PVs). Specifically, RT recordings were visualized in 115 left superior PVs (89.2%), 107 left inferior PVs (82.9%), 118 right superior PVs (91.4%), and 105 right inferior PVs (81.3%). Dual fascicle electrograms could be observed only in patients in sinus rhythm, in 23 of 396 PVs (5.8%). They were most commonly observed in the left superior PV (8.1%), somewhat less in both inferior veins (6.1%), while this phenomenon was least frequent in the right superior PV (3.0%). CONCLUSIONS: By using the fourth-generation CB, we report a specific pattern of isolation represented by a sequential isolation of two apparently distinct PV fascicles during a single CB freeze delivery. This phenomenon occurred in 5.8% of PV ablations. Of note, the rate of visualization of RT isolation with this novel CB was very high and could be documented in 86.2% of PVs.

Learning curves in atrial fibrillation ablation - A comparison between second generation cryoballoon and contact force sensing radiofrequency catheters.

OBJECTIVE: To examine the learning curves of atrial fibrillation (AF) ablation comparing the cryoballoon (CB) and radiofrequency (RF) catheters. METHODS: We performed a retrospective data analysis from the initiation of AF ablation program in our center. For CB ablation, a second generation 28 mm balloon was utilized and for RF ablation. RESULTS: A total of 100 consecutive patients (50 in each group) have been enrolled in the study (male 74%, mean age 58.9 ± 10 years, paroxysmal AF 85%). The mean procedure time was shorter for CB (116.6 ± 39.8 min) than RF group (191.8 ± 101.1 min) (p < 0.001). There was no difference in the mean fluoroscopy time, 24.2 ± 10.6 min in RF and 22.4 ± 11.7 min in CB group, (p = 0.422). Seven major complications occurred during the study; 5 in RF group (10%) and 2 in CB group (4%) (p = 0.436). After the mean follow up of 14.5 ± 2.4 months, 15 patients in RF group (30%) and 11 in CB group (26%) experienced AF recurrences (P = 0.300). CONCLUSION: When starting a new AF ablation program, our results suggest that CB significantly shortens procedure while fluoroscopy time and clinical outcomes are comparable to RF ablation.

Severe bleeding caused by piperacillin/tazobactam-induced platelet dysfunction
.

OBJECTIVE: Piperacillin/tazobactam (TZP ) is commonly used against multi-resistant nosocomial Pseudomonas infections. While TZP-induced thrombocytopenia is a well-known and easily diagnosed complication, we herein present an unusual case of spontaneous TZP-induced bleeding caused by platelet dysfunction. CASE SUMMARY: A 73-year-old-man experienced severe pulmonary hemorrhage and bloody diarrhea during the treatment with TZP for Pseudomonas aeruginosa ventilator-associated pneumonia. While both platelet count and coagulation tests were normal, platelet functional test revealed severely impaired ADP-dependent platelet aggregation. CONCLUSION: Platelet dysfunction is a little-known mechanism of TZP-induced bleeding. This is the second reported case of TZP-related bleeding that has been attributed to platelet dysfunction, and the first case report that has not been associated with surgery. While thrombocytopenia is easily recognized, this form of TZP-induced bleeding can be detected only by platelet functional tests.

Impact of Continuous P2Y12 Inhibition Tailoring in Acute Coronary Syndrome and Genetically Impaired Clopidogrel Absorption.

Clopidogrel is still widely used in acute coronary syndrome despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial that evaluated serial clopidogrel dose adjustment based on platelet function testing in acute coronary syndrome patients with initial high on-treatment platelet reactivity (HTPR). In this substudy, we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and noncarriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and noncarriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high-risk patient management.

Urgent Heart Retransplant in an Adult Patient With Anthracycline-Induced Cardiomyopathy After Diffuse Large B-Cell Lymphoma - Case Report.

Heart retransplant is a treatment option for some patients with graft failure. With heart donor short-age, it is important to assess candidates carefully for cardiac retransplant. An adult patient had a successful urgent heart retransplant due to severe toxic cardiomyopathy (anthracycline-induced) after posttransplant lymphoproliferative disease that was a diffuse large B-cell lymphoma.

Dynamic tricuspid valve stenosis induced with a pacemaker lead: a case report.

Isolated severe tricuspid valve stenosis due to an endocardial pacemaker lead is extremely rare, and is usually caused by either fibrosis of a perforated or lacerated leaflet, or fibrotic adherence between the lead and the valvular apparatus. Reported cases typically include clinical manifestations of both systemic venous stasis and low cardiac output. The case is presented of a 20-year-old female with a surgically repaired congenital heart disease who developed severe tricuspid stenosis at six years after the implantation of a DDD pacemaker. Unexpectedly, the patient had no signs of venous stasis and suffered only from exercise intolerance. Right heart catheterization under fluoroscopic guidance revealed an atrial lead forming a loop at the level of the tricuspid valve. A paradoxical inspiratory decrease in the transvalvular diastolic gradient, caused by the caudal heart motion and straightening of the loop during inspiration, was noted. Such a dynamic nature with a temporary inspiratory relief of the obstruction may explain the partial clinical presentation of tricuspid stenosis in this case. The lead was removed and the tricuspid valve repaired surgically, after which the patient's recovery was uneventful with normalization of exercise tolerance.

Serial clopidogrel dose adjustment after platelet function testing improves outcome of acute coronary syndrome patients undergoing percutaneous coronary intervention with high on-treatment platelet reactivity.

High on-treatment platelet reactivity (HTPR) on clopidogrel correlates with adverse outcomes in patients treated with percutaneous coronary intervention (PCI). Whether HTPR is a modifiable risk factor for future events is not clear. We evaluated the effect of serial clopidogrel dose adjustment based on platelet function testing (PFT) during 12 months of dual antiplatelet therapy (DAPT) using Multiplate) analyzer in patients with HTPR after PCI in acute coronary syndrome on clinical outcome. Eighty-seven patients were randomized to interventional (n = 43) and control group (n = 44). Blood samples for PFT were drawn at day 1, 2, 3, 7, 30 and at month 2, 3, 6, 9 and 12. Clopidogrel dose was modified at each point of PFT in the interventional group with patients taking up to two additional 600 mg loading doses and a range of 75-300 mg maintenance dose to achieve and maintain optimal platelet reactivity (19-46 U). The incidence of the primary endpoint (composite of cardiovascular death, non-fatal myocardial infarction, target vessel revascularization and ischemic stroke) was significantly higher in the control group (36.3 vs. 16.2%; p = 0.034). There were no differences in total bleeding events (6.8 vs. 4.6%, p = ns). Patients in the interventional group maintained better P2Y12 inhibition during follow-up. We hypothesize that targeting the therapeutic window of platelet reactivity continuously throughout DAPT by dose adjustment of P2Y12 inhibitor may lead to better platelet reactivity control, and thus reduce the rate of ischemic complications in this high risk group of patients.

Antithrombotics in heart failure.

Heart failure is a common clinical condition associated with high morbidity and mortality rate despite significant improvements in pharmacotherapy and implementation of medical procedures. Patients with heart failure are at an increased risk of developing arterial and venous thrombosis, which contribute to the high rate of adverse events and fatal outcomes. Many heart failure patients routinely receive antithrombotic therapy due to the presence of a specific indication for its use, like ischemic heart disease or atrial fibrillation. However, there is no solid evidence to support the routine use of antithrombotic agents in all heart failure patients. This article reviews the evidence for using antithrombotic therapy in heart failure patients.