Immediate Post-Procedural and Discharge Assessment of Mitral Valve Function Following Transcatheter Edge-to-Edge Mitral Valve Repair: Correlation and Association with Outcomes

The correlation between residual mitral regurgitation (rMR) grade or mitral valve pressure gradient (MVPG), at transcatheter edge-to-edge mitral valve repair (TEEMr) completion and at discharge, is unknown. Furthermore, there is disagreement regarding rMR grade or MVPG from which prognosis diverts. We retrospectively studied 82 patients that underwent TEEMr. We tested the correlation between rMR or MVPG and evaluated their association, with outcomes. Moderate or less rMR (rMR ≤ 2) at TEEMr completion was associated with improved survival, whereas mild or less rMR (rMR ≤ 1) was not. Patients with rMR ≤ 1 at discharge demonstrated a longer time of survival, of first heart failure hospitalization and of both. The correlation for both rMR grade (r = 0.5, p < 0.001) and MVPG (r = 0.51, p < 0.001), between TEEMr completion and discharge, was moderate. MR ≤ 2 at TMEER completion was the strongest predictor for survival (HR 0.08, p < 0.001) whereas rMR ≤ 1 at discharge was independently associated with a lower risk of the combined endpoint (HR 4.17, p = 0.012). MVPG was not associated with adverse events. We conclude that the assessments for rMR grade and MVPG, at the completion of TEEMr and at discharge, should be distinctly reported. Improved outcome is expected with rMR ≤ 2 at TEEMr completion and rMR ≤ 1 at discharge. Higher MVPG is not associated with unfavorable outcomes.

A Polygenic DNA Damage Repair Pharmacogenomics (DDR_PGx8) Score Predicts GO Response in AML

Gemtuzumab Ozogamicin (GO) is a CD33-directed antibody conjugated to calicheamicin used in AML immunotherapy. Children's Oncology Group led pediatric AML phase II trial COG-AAML03P1 (NCT00070174) established that GO could be safely added to the standard chemotherapy regimen consisting of ara-C, daunorubicin and etoposide (ADE+GO) and improved outcome(Cooper et al., 2012). Subsequent COG-AAML0531 phase III trial (NCT00372593) randomized patients to receive either standard chemotherapy alone (ADE) or with addition of two doses of GO (ADE+GO) and showed that addition of GO improved outcome in newly diagnosed AML patients (Gamis et al., 2014). Our group previously established that CD33 genetic variation impacts GO response in AML patients (Lamba et al., 2017). Given that the antileukemic effect of GO is primarily driven by calicheamicin induced DNA damage, in this study we investigated pharmacogenomic impact of SNPs in DNA damage response (DDR) pathway genes on GO treatment response. We genotyped 132 SNPs in 42 genes involved in DNA damage repair pathway in DNA samples from 470 patients treated with standard chemotherapy in AAML0531 trial (ADE arm) and 755 patients treated with addition of GO to standard therapy in AAML03P1 and AAAML0531 trials (ADE+GO arm). Univariate analysis to test for association between OS, EFS, DFS and RR after induction 1 in both ADE+GO and ADE arms identified 20 SNPs in 16 genes that were significantly associated with at least one of the clinical endpoints tested in the only ADE+GO arm but not in ADE arm of the trials. We tested these 20 SNPs in all possible combinations with a maximum of 3 SNP/model using multivariable Cox proportional hazard models for association with EFS and OS in patients treated with ADE+GO. Drastically increased number of models arising from higher SNP combination numbers was a computational challenge thus we restricted our analysis to a maximum of 3 SNP combinations. We performed 1000 permutation tests per model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model. Those withleast BIC and a 1000 permutation p≤0.05 were selected for development of DDR pharmacogenomics score. DDR_PGx8 score was defined by adding the genotype scores of 8 SNPs in 7 genes (AKT1, ATR, DDB2, PARP1, PI3KCA, PTEN and RAD51) accounting for mode of inheritance (additive, dominant or recessive) and direction of their association with outcome (positive for beneficial and negative for detrimental association) Fig 1A shows overall study design. The DDR_PGx8 score ranged from -5 to 3 in patients treated with ADE+GO (n=755) or ADE alone (N=470). Based on the distribution, the scores were stratified into high (score ≥0, n=212 in ADE group and n=357 in ADE+GO group) and low score (score &lt;0, n=241 in ADE group and n=329 in ADE+GO group) groups. The distribution of DDR_PGx8 score groups did not differ by risk groups or MRD1 status. However, it differed significantly within race with 81.81% (108/132) of black or African American patients compared to 43.75% (364/832) of white patients in the low DDR_PGx8 score group. Patients with low-DDR-PGx8 score had significantly worse EFS (HR=1.52, 95%CI (1.22-1.90), p&lt;0.001; Fig 1B), OS (HR=1.62, 95%CI(1.24-2.11), p&lt;0.001), DFS (HR=1.88, 95%CI(1.42-2.50), p&lt;0.00001;), and higher RR1 (HR=1.89, 95%CI(1.40-2.40), p&lt;0.00001) compared to high-DDR-PGx8 score patients when treated with GO (ADE+GO cohort). This impact of DDR_PGx8 was not observed in patients treated with standard chemotherapy alone (ADE arm), with no difference between low and high DDR_PGx8 score groups in EFS (Fig 1B), OS, DFS and RR (all p&gt;0.28). In multivariable Cox proportional hazard models for DDR-PGx8 score groups, initial risk group assignment, WBC at diagnosis and age, low-DDR-PGx8 score remained a significant and independent predictor of inferior EFS (HR=1.6, 95%CI=1.21-2.02, p&lt;0.001; Fig 1C) and OS (HR=1.6, 95%CI=1.17-2.22, p=0.003) in ADE+GO arm but not in ADE arm. We establish a DNA damage repair response-based pharmacogenomics score predicting outcome in patients treated with addition of GO to standard chemotherapy. The score was not predictive of outcome in patients treated with standard chemotherapy alone implying its impact is GO-specific. Our results in conjunction with existing CD33 SNPs provide a rationale for use of pharmacogenomics in personalizing GO treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Combined anticoagulant and antiplatelet therapy is associated with an improved outcome in hospitalised patients with COVID-19: a propensity matched cohort study

BackgroundCOVID-19 is a respiratory disease that results in a prothrombotic state manifesting as thrombotic, microthrombotic and thromboembolic events. As a result, several antithrombotic modalities have been implicated in the treatment of this disease. This study aimed to identify if therapeutic anticoagulation (TAC) or concurrent use of antiplatelet and anticoagulants was associated with an improved outcome in this patient population.MethodsA retrospective observational cohort study of adult patients admitted to a single university hospital for COVID-19 infection was performed. The primary outcome was a composite of in-hospital mortality, intensive care unit (ICU) admission or the need for mechanical ventilation. The secondary outcomes were each of the components of the primary outcome, in-hospital mortality, ICU admission, or the need for mechanical ventilation.Results242 patients were included in the study and divided into four subgroups: Therapeutic anticoagulation (TAC), prophylactic anticoagulation+antiplatelet (PACAP), TAC+antiplatelet (TACAP) and prophylactic anticoagulation (PAC) which was the reference for comparison. Multivariable Cox regression analysis and propensity matching were done and showed when compared with PAC, TACAP and TAC were associated with less in-hospital all-cause mortality with an adjusted HR (aHR) of 0.113 (95% CI 0.028 to 0.449) and 0.126 (95% CI 0.028 to 0.528), respectively. The number needed to treat in both subgroups was 11. Furthermore, PACAP was associated with a reduced risk of invasive mechanical ventilation with an aHR of 0.07 (95% CI 0.014 to 0.351). However, the was no statistically significant difference in the occurrence of major or minor bleeds, ICU admission or the composite outcome of in-hospital mortality, ICU admission or the need for mechanical ventilation.ConclusionThe use of combined anticoagulant and antiplatelet agents or TAC alone in hospitalised patients with COVID-19 was associated with a better outcome in comparison to PAC alone without an increase in the risk of major and minor bleeds. Sufficiently powered randomised controlled trials are needed to further evaluate the safety and efficacy of combining antiplatelet and anticoagulants agents or using TAC in the management of patients with COVID-19 infection.

Impact of comorbidities and ablation strategy on outcome after pulmonary vein isolation with cryo-balloon in patients with non- paroxysmal atrial fibrillation

Background Presence of several comorbidities in patients with atrial fibrillation is well known, but impact of them on outcome after pulmonary vein isolation with cryo-balloon is not enough investigated. First aim of the study was analysis of the impact of comorbidities on long term outcome after PVI with cryo-balloon new generation (CBA) and secondary goal was evaluation of the impact of additional posterior roof ablation (PRA) in these patients. Methods Patients with non-paroxysmal AF ablated with CBA in our institution since May 2012 and completed follow up &gt;3 months were enrolled in the study. The history of AF, cardiac comorbidities (CAD, Non ischemic-cardiomyopathy, heart insufficiency, right ventricular dysfunction) diabetes mellitus, and renal failure were assessed at admission, all patients received echocardiographic examination and blood test. After a single trans-septal access and PV angiography PVI was performed using a 28-mm CBA. Mapping of PV signals before, during, and after each cryo application was performed with a 3F lasso catheter. The procedural endpoint after PVI was defined as complete elimination of all fragmented signals at the PV antrum with verification of entrance and exit block. In some patients PRA was performed additionally to PVI at discretion of physician. The primary endpoint of this study was the first documented recurrence of atrial tachyarrhythmia (&gt;30 sec.), hospitalization due to cardio-vascular cause, re-do procedure or re-administration of anti-arrhythmic drugs. Results Among 560 patients 78 (13.9%) had no comorbidity and 299 (53.4%) were lasted with &gt;1 comorbidity. A total of 260 (46.4%) recurrences were obtained within median follow up of 28 (12–57) months. Female gender, long time from first diagnosis &gt;12 months and cardiac comorbidity were revealed to be independent predictors for long term recurrences whereas additional PRA performed in 176 pts independently improved outcome (61.9% vs 49.7%). Conclusion Cardiac comorbidities increased probability of post ablation recurrences, but performing of additional posterior roof ablation improved outcome in our cohort. These results should be confirmed in multi-center randomized study FUNDunding Acknowledgement Type of funding sources: None.

An Unusual Hematologic Manifestation in a COVID-19 Patient Treated with COVID-19 Convalescent Plasma

Introduction/Objective A subset of Chronic Lymphocytic Leukemia (CLL) patients with COVID-19 may manifest rapid elevations in lymphocyte counts and poor clinical outcomes. Here we report our observations regarding this unusual hematologic manifestation in a CLL patient after he experienced a COVID-19 convalescent plasma (CCP) transfusion reaction. Methods/Case Report 56-year-old A Rh- male with stable, treatment-naive CLL (13q deletion positive) diagnosed three years prior was admitted for COVID-19 hypoxia. Before developing COVID-19, baseline white blood cell (WBC) count was stable (~ 64 K/ mm3). Due to worsening hypoxia he was treated with an ARh+ High Titer CCP unit, Remdesivir, tocilizumab, and dexamethasone. The Blood Bank was notified of a possible CCP reaction and performed its standard workup which was adjudicated to be a febrile TACO reaction. During this evaluation it was noted that the patient’s WBC count had initially decreased to 46 K/ mm3, but rose on HD 3, to 78.4 K/mm3 and by discharge on HD 10 had increased to 200 K/ mm3. Flow cytometry revealed a B cell CLL immunophenotype. Post discharge day (PDD) 6 he developed herpes zoster. On post-discharge day (PDD) 7 his WBC count was 124K/mm3. By PDD 77 his WBC count had returned to baseline (~50 K/mm3). Results (if a Case Study enter NA) NA Conclusion The pt’s initial drop in his WBC count followed by a gradual rise has been observed in patients with severe COVID-19 independent of CCP infusion. Lymphocytosis in a subset of CLL patients with COVID-19 has been reported (termed “COVID-19 Induced Lymphocytosis” (CIL)) and, in contrast to our patient with an improved outcome, has been associated with severe/fatal outcomes. Of note these other patients did not receive CCP. Mechanisms related to CIL are unknown. Such poor clinical outcomes heighten the need for further studies of CIL. The role of CCP in affecting this process, if any, also merits further clarification.