Electrophysiological evaluation following development of new and persistent left bundle branch block after transcatheter aortic valve replacement: A single center pilot study.

INTRODUCTION: New and persistent left bundle branch block (NP-LBBB) following Transcatheter Aortic Valve Replacement (TAVR) is an ongoing concern with incidence ranging from as low as 4% to up to 65% (varying for different types of valves). Such patients are at risk of developing high-grade atrioventricular block (HAVB) warranting permanent pacemaker (PPM) implantation. However, currently, there are no consensus guidelines or large prospective studies to risk stratify these patients for safer discharge after TAVR. OBJECTIVES: To provide insight from a single center study on using modified electrophysiology (EP) study to risk stratify post-TAVR patients to outpatient monitoring for low-risk versus pacemaker implantation for high-risk patients. METHODS AND RESULTS: Between June 2020 and March 2023, all patients who underwent a TAVR procedure (324 patients) at our institution were screened for development of NP-LBBB post-operatively. Out of 26 patients who developed NP-LBBB, after a pre-specified period of observation, 18 patients were deemed eligible for a modified EP study to assess His-Ventricular (HV) interval. 11 out of 18 patients (61.1%) had normal HV interval (HV < 55 ms). Three out of 18 patients (16.7%) had HV prolongation (55 ms < HV < 70 ms) without significant HV prolongation (defined as an increase in HV interval > 30%) with intra-procedural procainamide challenge. Four out of 18 patients (22.2%) had significant HV prolongation (HV > 70 ms) warranting PPM implantation based on a multidisciplinary approach and shared decision-making with the patients. Total of 50% of patients discharged with PPM (two out of four patients) were noted to be pacemaker dependent based on serial device interrogations. All patients who did not receive PPM were discharged with ambulatory monitoring with 30-day event monitor and did not develop HAVB on serial follow-up. CONCLUSION: Normal HV interval up to 55 ms on modified EP study after TAVR and development of NP-LBBB can be utilized as a threshold for risk stratification to facilitate safe discharge. The optimal upper limit of HV interval threshold remains unclear in determining appropriate candidacy for PPM.

Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies.

Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.

Entrapment of diagnostic catheter within Advisor HD grid mapping catheter.

The potential for catheter entanglement with the HD Grid mapping catheter is explicitly stated in the manufacturer's product manual. A case of an entrapped 6 French quadripolar diagnostic catheter within an HD Grid mapping catheter is presented. We discuss the diagnosis, management, and resolution of this complication in our patient. The patient's arrhythmia was successfully eliminated, and no vascular complication in the postprocedural setting nor arrhythmia recurrence at follow-up were observed. Strategies to prevent and safely manage this complication, while salvaging access, are also discussed.

Predictors of myocardial recovery in arrhythmia-induced cardiomyopathy: A multicenter study.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is characterized by improvement in left ventricular ejection fraction (LVEF) following arrhythmia treatment. Predictors of recovery in LVEF are not well understood. OBJECTIVE: We evaluated predictors of AIC recovery in a large multicenter cohort. METHODS: In total, 243 patients (age 65 ± 11, 73% male) with AIC caused by atrial fibrillation (49%), atrial tachycardia (20%), and premature ventricular contractions (PVCs; 31%) were treated and included. LVEF was assessed before and after treatment. Patients were stratified by arrhythmia duration (known [KN, n = 132] vs. unknown [UKN, n = 111]), arrhythmia type, LVEF, and presence of structural heart disease (SHD). RESULTS: Arrhythmia treatment was rhythm control in 95%. Median arrhythmia duration in the KN group was 47 months (25-75th percentile, 24-80 months). Post treatment LVEF was higher in KN group (55.9 ± 7 vs. 46.2 ± 12%; p < .0001) but the degree of LVEF improvement was similar (21.2 ± 9 vs. 19.4 ± 11; p = .16). Comparing highest quartile (longest arrhythmia duration) versus the rest of the KN group, the extent of LVEF improvement was similar (21.5 ± 8 vs. 21 ± 9%; p = .1). Patients in lowest index LVEF quartile (n = 74) had more PVC-induced AIC, greater EF improvement after treatment (24 ± 17 vs. 19 ± 7%; p < .0001) but lower post treatment EF (45 ± 14 vs. 54 ± 8%; p < .0001) versus other patients. Patients with SHD had lower index EF (28 ± 8 vs. 34 ± 8%; p < .0001) and lower final EF (47 ± 12 vs. 56 ± 7; p ≪ .0001). In multivariate regression, low index LVEF predicted myocardial recovery (odds ratio, 11.4; p < .005). CONCLUSIONS: In this AIC cohort, LVEF improved regardless of arrhythmia duration or type but those with PVCs had lower index LVEF and had less recovery. Low index LVEF predicted LVEF recovery following arrhythmia treatment.

Novel electrocardiographic criteria for diagnosis of premature ventricular complexes arising from the base of left ventricle.

PURPOSE: We report new electrocardiographic criteria (ECG) for localizing premature ventricular complexes (PVCs) originating from the base of the left ventricle (LV). METHODS: QRS deflection (positive negative or negative positive) in lead aVR and aVL respectively, were evaluated in 41 PVC/VT cases. RESULTS: There were a total of 41 patients, age 64 ± 11 years. Twelve patients had QRS deflection in aVR which were completely opposite to the deflection in aVL. If the PVC originated from basal septum, aVR was negative while aVL positive and vice versa when it was from the baso-lateral LV. PVCs from other LV sites had aVR and aVL deflection in the same direction. The ECG criteria had a sensitivity and specificity of 91% and 84%, respectively. CONCLUSION: We propose a new ECG criterion to localize PVCs originating from the base of the LV.

Unique features of epicardial ventricular arrhythmias/premature ventricular complexes ablated from coronary venous system in veteran population.

INTRODUCTION: Ventricular arrhythmias/premature ventricular complexes (VA/PVCs) that can be ablated from within the coronary venous system (CVS) have not been described in the United States Veterans Health Administration (VHA) population. We retrospectively studied the VA/PVCs ablations that were performed in the VHA population. METHODS: Data from 42 consecutive patients who underwent VA/PVCs ablation at Veterans Affairs Hospital, Indianapolis, IN, with 44 VA/PVCs was included in the study. Patients were divided into two groups (CVS group [n = 10], and non-CVS group [n = 32]) based on where the earliest pre-systolic activation was seen with >95% pacematch. RESULTS: The mean age in CVS group was 65 ± 8 years versus 64 ± 12 years (p = 0.69) in non-CVS group. Overall there was a statistically significant reduction in PVC burden post ablation (27.7% (pre-ablation) versus 4.7% (post-ablation). In the 10 patients in the CVS group, either ablation or catheter-related mechanical trauma resulted in complete (n = 6 [60%]) or partial (n = 4 [40%]) long-term suppression of VA/PVCs. Right bundle branch block-type VA/PVC (9/11: 82%) was the most common morphology in the CVS group, whereas in the non-CVS group, this type was seen in only 3/33 (9%). The CVS group (25% of total VA/PVCs) had shorter activation time compared to non CVS group. CONCLUSION: In our experience VA/PVCs with electrocardiograms suggestive of epicardial origin can often be safely and successfully ablated within the coronary venous system. These arrhythmias have unique features in Veterans patient population.

His Bundle Pacing in Heart Failure-Concept and Current Data.

PURPOSE OF REVIEW: His bundle pacing (HBP) has continued to emerge as a viable alternative to both right ventricular pacing (RVP) and cardiac resynchronization therapy. In recent years, a considerable amount of research has been published with regard to using HBP to treat congestive heart failure (CHF) and this article presents a concise yet comprehensive review of this literature. RECENT FINDINGS: Studies have demonstrated that HBP is useful for CHF patients who are non-responders to biventricular pacing (BiVP) or have a history of previously failed coronary sinus lead placement, right/left bundle branch block cardiomyopathy, or pacing-induced cardiomyopathy. Additionally, HBP is useful in patients with an indication for pacing who are expected to have a RVP burden exceeding 20%. The theoretical benefit of utilizing the native His Purkinje system to excite cardiac tissue is appealing as it can result in true cardiac resynchronization. Limited studies have shown its benefit in reducing heart failure symptoms and improving cardiac function. Larger randomized clinical trials and further investments into developing better technologies are highly desired to make its clinical use sustainable in the long run.

Orthostatic hypotension for the cardiologist.

PURPOSE OF REVIEW: Orthostatic hypotension is a phenomenon commonly encountered in a cardiologist's clinical practice that has significant diagnostic and prognostic value for a cardiologist. Given the mounting evidence associating cardiovascular morbidity and mortality with orthostatic hypotension, cardiologists will play an increasing role in treating and managing patients with orthostatic hypotension. RECENT FINDINGS: The American College of Cardiology, American Heart Association, and Heart Rhythm Society recently published consensus guidelines on the diagnosis, treatment, and management of syncope and their instigators, including orthostatic hypotension. Additionally, consensus guidelines have also been recently updated, reinforcing the universal definition orthostatic hypotension and its closely associated pathologies. Finally, the United States Food and Drug Administration (FDA) recently approved droxidopa, a synthetic oral norepinephrine prodrug, in 2014 for the treatment of neurogenic orthostatic hypotension (nOH), and it represents a well tolerated, effective, and easy to use intervention for nOH. This represents only the second drug approved by the FDA for orthostatic hypotension, the first being midodrine in 1986. A handful of smaller head-to-head studies have pitted not only pharmacologic agents to one another but also nonpharmacologic interventions to pharmacologic agents. Additionally, recent studies have also reported on more convenient screening tools for orthostatic hypotension. SUMMARY: Though there have been many advances in the management of orthostatic hypotension, nOH remains a chronic, debilitating, and often progressively fatal condition. Cardiologists can play a very important role in optimizing hemodynamics in this patient population to improve quality of life and minimize cardiovascular risk.

Incidence and predictors of MRI scan utilization in MRI-conditional pacemaker recipients: A multicenter experience.

BACKGROUND: Patient characteristics, higher device cost, and vendor contracts likely prevent use of magnetic resonance imaging (MRI)-conditional pacemakers (MRC) in all pacemaker (PM)-eligible patients. We sought to identify the incidence and predictors of MRI scan utilization in MRC recipients. METHODS: Patients receiving an MRC or non-MRI-conditional PM (NMRC) at four centers were included. Incidence of MRI scans following PM insertion was obtained from hospital records and patient phone calls. RESULTS: Of 1,244 patients (74 ± 12 years, 54.6% male), 927 had MRC and 317 had NMRC. At baseline, MRC recipients had a higher incidence of atrial tachycardia and MRI risk factors (syncope, recurrent falls, neurological disease, severe musculoskeletal disease, malignancy). In the MRC group, more patients had commercial health insurance (26% vs 15%, P < 0.001). Sixty MRC patients (6.5%) had an MRI during 21 ± 17 months' follow-up. Using the Weilbull parametric survival model, the projected percentage of MRC patients receiving an MRI scan at 7- and 11-year follow-up were 45% and 73%, respectively. By multivariate regression, a prior history of MRI (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.2-9.1, P < 0.001) and active smoking (OR 2.65, 95% CI 1.1-6.7, P  =  0.039) independently predicted the performance of an MRI following MRC implant. CONCLUSIONS: In this MRC cohort, MRI scan utilization during follow-up was low but projection analyses showed a higher incidence over the lifetime of the MRC. A history of prior MRI and active smoking independently predicted the performance of an MRI scan during follow-up.

Perioperative predictors of permanent pacing and long-term dependence following tricuspid valve surgery: a multicentre analysis.

AIMS: Permanent pacemaker placement (PPM) is often required after valvular surgery and is especially common following tricuspid valve surgery [tricuspid valve repair or replacement (TVR)]. Literature suggests that surgical intervention for isolated tricuspid valve disease is becoming more prevalent. Predictors of PPM dependency following TVR are currently unknown and would be clinically useful from a prognostication standpoint. METHODS AND RESULTS: We conducted a multicentre, retrospective study to assess perioperative factors of TVR that predispose to PPM placement and long-term PPM dependency from 2008 to 2014. Regression analysis was used to determine independent predictors of PPM implantation. A total of 237 patients (age 66 ± 15 years, 29% male) were studied, and the incidence of PPM placement following TVR was 27% (65/237). No significant differences were observed between those who received PPM and those who did not in age (P = 0.092), gender (P = 0.359), and co-morbidities. Regression analysis identified cross-clamp time >60 min (OR 4.1, 95% CI 1.3-12.9, P = 0.015) and concomitant mitral valve surgery (OR 3.8, 95% CI 1.2-12.2, P = 0.026) as independent risk factors for PPM following TVR. Long-term PPM dependency data were only available in 28 patients who received PPM with 14 of these patients developing long-term dependence. The only statistically significant difference noted was an increased frequency of coronary artery disease in the long-term dependent group vs. the non-dependent group (64% vs. 14%, P = 0.018). CONCLUSION: Cross-clamp time >60 min and concomitant mitral valve surgery were independent predictors of PPM implantation following TVR. Long-term PPM dependency is more prevalent after TVR than other types of valvular surgery.

Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline).

Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine (NE) (noradrenaline). We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma NE. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based on standing NE, patients were dichotomized into a hyperadrenergic OH group [hyperOH: upright NE ≥ 3.55 nmol/l (600 pg/ml), n=19] or a non-hyperadrenergic OH group [nOH: upright NE < 3.55 nmol/l (600 pg/ml), n=64]. Medical history and data from autonomic testing, including the Valsalva manoeuvre (VM), were analysed. HyperOH patients had profound orthostatic falls in blood pressure (BP), but less severe than in nOH [change in SBP (systolic blood pressure): -53 ± 31 mmHg compared with -68 ± 33 mmHg, P=0.050; change in DBP (diastolic blood pressure): -18 ± 23 mmHg compared with -30 ± 17 mmHg, P=0.01]. The expected compensatory increase in standing heart rate (HR) was similarly blunted in both hyperOH and nOH groups [84 ± 15 beats per minute (bpm) compared with 82 ± 14 bpm; P=0.6]. HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM and a shorter VM phase 4 BP recovery time (16.5 ± 8.9 s compared with 31.6 ± 16.6 s; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic OH, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand whether hyperOH patients will progress to nOH or whether this represents a different disorder.

Hemodynamic profiles and tolerability of modafinil in the treatment of postural tachycardia syndrome: a randomized, placebo-controlled trial.

BACKGROUND: Postural tachycardia syndrome (POTS) is characterized clinically not only by an exaggerated increase in heart rate (HR), but an associated cognitive impairment that disables many patients. Modafinil might be effective in improving the cognitive symptoms, but modafinil may stimulate the sympathetic nervous system and worsen tachycardia in POTS. We tested the hypothesis that modafinil would worsen tachycardia and orthostatic symptoms in POTS. METHODS: Patients with POTS (n = 54) underwent a randomized crossover trial with modafinil 100 mg versus placebo. Heart rate and systolic blood pressure (SBP) were measured seated and standing before modafinil or placebo administration and then hourly for 4 hours. RESULTS: Over 4 hours, standing HR was not significantly different between the modafinil and placebo groups (analysis of variance [ANOVA] Pdrug = 0.328), but seated SBP was significantly higher in the modafinil group (mean [SD], 109 [12] mm Hg vs 104 [10] mm Hg; P = 0.004). Modafinil also significantly increased both the seated SBP (ANOVA Pdrug = 0.004) and the standing SBP (ANOVA Pdrug = 0.041) over time. There was no significant difference between modafinil and placebo over the 4-hour period with regard to POTS symptom burden scores (14 [12] vs 14 [12]; P = 0.962). CONCLUSIONS: Modafinil did not significantly worsen standing HR or acute orthostatic symptoms in patients with POTS compared with the placebo group and improved upright blood pressure. Therefore, modafinil could be tested as a potential treatment for the cognitive impairment in POTS.

Radiation-associated Arrhythmias: Putative Pathophysiological Mechanisms, Prevalence, Screening and Management Strategies.

Radiation-associated cardiovascular disease, an increasingly recognised disease process, is a significant adverse effect of radiation therapy for common malignancies that involve the chest, and include lymphomas, lung, mediastinal and breast cancers. Two factors contribute to the increasing incidence of radiation-associated cardiovascular disease: advances in malignancy detection and the improved survival of cancer patients, by which many symptoms of radiation-associated cardiovascular disease, specifically radiation-associated arrhythmias, present years and/or decades following initial radiotherapy. We present a focused overview of the currently understood pathophysiology, prevalence and management strategies of radiation-associated arrhythmias, which include bradyarrhythmias, tachyarrhythmias and autonomic dysfunction.

Comparison of quantifiable electrocardiographic changes associated with severe hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is a life-threatening condition that is frequently evaluated by electrocardiogram (ECG). ECG changes in severe HK (≥ 6.3 mEq/L) are not well-characterized. This study sought to compare and correlate ECG metrics in severe HK to baseline normokalemic ECGs and serum potassium. METHODS: A retrospective analysis of 340 severe HK encounters with corresponding normokalemic ECGs was performed. RESULTS: Various ECG metrics were analyzed. P wave amplitude in lead II, QRS duration, T wave slope, ratio of T wave amplitude: duration, and ratios of T wave: QRS amplitudes were significantly different between normokalemic and HK ECGs. P wave amplitude attenuation in lead II correlated better with serum potassium than in V1. T wave metrics that incorporated both T wave and QRS amplitudes correlated better than metrics utilizing T wave metrics alone. CONCLUSION: Multiple statistically significant and quantifiable differences among ECG metrics were observed between normokalemic and HK ECGs and correlated with increasing degrees of serum potassium and along the continuum of serum potassium. When incorporated into a logistic regression model, the ability to distinguish HK versus normokalemia on ECG improved significantly. These findings could be integrated into an ECG acquisition system that can more accurately identify severe HK.

Poorer outcomes associated with more invasive lead management strategies for Abbott Riata® leads: a large, multicenter experience.

BACKGROUND: Over 100,000 Abbott Riata® were implanted in the United States before they were recalled in 2010. There are still a significant number of Abbott Riata® leads in use, and it is unclear how these leads should be managed at the time of generator change or lead malfunction. Although data comparing both Sprint Fidelis® and Abbott Riata® leads in this setting is available, there are no multicenter comparative studies of outcomes for various lead management strategies, including lead extraction (LE), lead abandonment/revision (LA), and generator change (GC) only at the time of device at elective replacement interval (ERI) for Abbott Riata® leads. METHODS: A retrospective, multicenter study was undertaken to compare short-term outcomes (major complications-MC, death, extended or re-hospitalizations within 60 days-RH, lead malfunction-LM) and total outcomes (short-term outcomes & lead malfunction during follow-up) of patients with Riata® leads undergoing LE, LA, or GC. RESULTS: 152 patients (65 ± 13 years, 68% male) were followed for a mean 33 ± 30 months following intervention. Out of 166 procedures, 13 patients underwent LE, 16 patients underwent LA, and 137 patients underwent GC. There was 1 major complication in each group, yielding an event rate of 7.7% for LE, 6.3% for LA, and 0.7% for GC cohorts. There were significantly more short-term and total adverse outcomes in the group of patients getting LE and LA versus GC only (38.5% & 31.3% vs 7.3%, P < 0.001). Total Riata® lead dwell time follow-up was 17,067 months. A total of 3 Riata® lead malfunctions were noted during long-term follow-up. Inappropriate shocks were similar between LE 7.7% (1/13), LA 6.3% (1/16). and GC 11.0% (4/136); P = 0.57. CONCLUSIONS: There were more short-term and total adverse outcomes in more invasive management strategies (LE and LA) versus GC alone. The failure rate of Riata® leads was substantially lower compared to previous reports. Therefore, we recommend only performing battery exchange when a device with an active Riata® lead is at ERI, unless there is malfunction of the Riata® lead noted on testing. There were significantly more short-term adverse outcomes in the lead extraction (5/13) and lead abandonment/revision (5/16) groups than the generator only (8/137) group (P < 0.001). GIB - Gastrointestinal bleed, CHF - congestive heart failure, NSTEMI - non-ST elevation MI.

Echocardiographic changes and heart failure hospitalizations following rhythm control for arrhythmia-induced cardiomyopathy: results from a multicenter, retrospective study.

BACKGROUND: The incidence and prevalence of arrhythmia-induced cardiomyopathy (AIC) are unclear but likely underrecognized. LV dysfunction is common among patients with atrial fibrillation (AF), atrial flutter (AFL), and frequent premature ventricular contractions (PVC). The hallmark of AIC is the improvement of left ventricular ejection fraction (LVEF) following arrhythmia treatment. Changes in echocardiographic parameters and their effect on outcomes after rhythm control for AIC are not well understood. We aimed to study echocardiographic parameters and outcomes following rhythm control for AIC. METHODS: A multicenter, retrospective study was conducted at 4 different medical centers involving patients with AIC. Clinical, echocardiographic, and outcome (mortality and heart failure hospitalizations [HFH]) parameters were extracted from the medical record. RESULTS: Two hundred fifty-five patients (age 66 ± 11 years, 73% male) with AIC caused by AF (51%), atrial tachycardia/AFL (20%), and PVCs (29%) were included and followed for a median period of 6 months after successful rhythm control. Significant improvements in left ventricular (LV) ejection fraction (P < 0.0001), LV end-systolic volume (ml) (90 ± 48 to 58 ± 30; P < 0.0001), LV internal diameter end diastole (cm) (5.5 ± 0.78 to 5.3 ± 0.64; P = 0.0001) and end systole (4.7 ± 0.95 to 4.3 ± 1.02; P < 0.0001), right atrial pressure (mmHg) (11.3 ± 5.0 to 7.4 ± 3.2; P = 0.0001), and right ventricular function (n (%)) (42 (44) to 9 (11); P < 0.0001) were noted following arrhythmia treatment. No deaths occurred during follow-up. HFH occurred in 7 patients. Arrhythmia recurrence rate was 50.5%. Neither echocardiographic parameters nor recurrence of arrhythmia correlated with HFH. CONCLUSION: Arrhythmia treatment significantly improved echocardiographic LV dimensions, LVEF, and RAP in this multicenter AIC cohort, underscoring the need for early recognition and aggressive rhythm control in suspected AIC patients. The event rate was too low to assess for outcome predictors.

Drug Interactions Affecting Oral Anticoagulant Use.

Oral anticoagulants (OACs) are medications commonly used in patients with atrial fibrillation and other cardiovascular conditions. Both warfarin and direct oral anticoagulants are susceptible to drug-drug interactions (DDIs). DDIs are an important cause of adverse drug reactions and exact a large toll on the health care system. DDI for warfarin mainly involve moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfarin. However, inhibitor/inducers of CYP3A4 and CYP1A2 may also cause DDI with warfarin. Recognition of these precipitating agents along with increased frequency of monitoring when these agents are initiated or discontinued will minimize the impact of warfarin DDI. Direct oral anticoagulants are mainly affected by medications strongly affecting the permeability glycoprotein (P-gp), and to a lesser extent, strong CYP3A4 inhibitors/inducers. Dabigatran and edoxaban are affected by P-gp modulation. Strong inducers of CYP3A4 or P-gp should be avoided in all patients taking direct oral anticoagulant unless previously proven to be otherwise safe. Simultaneous strong CYP3A4 and P-gp inhibitors should be avoided in patients taking apixaban and rivaroxaban. Concomitant antiplatelet/anticoagulant use confers additive risk for bleeding, but their combination is unavoidable in many cases. Minimizing duration of concomitant anticoagulant/antiplatelet therapy as indicated by evidence-based clinical guidelines is the best way to reduce the risk of bleeding.

Drug Interactions Affecting Antiarrhythmic Drug Use.

Antiarrhythmic drugs (AAD) play an important role in the management of arrhythmias. Drug interactions involving AAD are common in clinical practice. As AADs have a narrow therapeutic window, both pharmacokinetic as well as pharmacodynamic interactions involving AAD can result in serious adverse drug reactions ranging from arrhythmia recurrence, failure of device-based therapy, and heart failure, to death. Pharmacokinetic drug interactions frequently involve the inhibition of key metabolic pathways, resulting in accumulation of a substrate drug. Additionally, over the past 2 decades, the P-gp (permeability glycoprotein) has been increasingly cited as a significant source of drug interactions. Pharmacodynamic drug interactions involving AADs commonly involve additive QT prolongation. Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically significant drug interactions. Recent studies have also demonstrated increased morbidity and mortality with the use of digoxin and other AAD which interact with P-gp. QT prolongation is an important pharmacodynamic interaction involving mainly Vaughan-Williams class III AAD as many commonly used drug classes, such as macrolide antibiotics, fluoroquinolone antibiotics, antipsychotics, and antiemetics prolong the QT interval. Whenever possible, serious drug-drug interactions involving AAD should be avoided. If unavoidable, patients will require closer monitoring and the concomitant use of interacting agents should be minimized. Increasing awareness of drug interactions among clinicians will significantly improve patient safety for patients with arrhythmias.

More Generalizable Models For Sepsis Detection Under Covariate Shift.

Sepsis is a major cause of mortality in the intensive care units (ICUs). Early intervention of sepsis can improve clinical outcomes for sepsis patients1,2,3. Machine learning models have been developed for clinical recognition of sepsis4,5,6. A common assumption of supervised machine learning models is that the covariates in the testing data follow the same distributions as those in the training data. When this assumption is violated (e.g., there is covariate shift), models that performed well for training data could perform badly for testing data. Covariate shift happens when the relationships between covariates and the outcome stay the same, but the marginal distributions of the covariates differ among training and testing data. Covariate shift could make clinical risk prediction model nongeneralizable. In this study, we applied covariate shift corrections onto common machine learning models and have observed that these corrections can help the models be more generalizable under the occurrence of covariate shift when detecting the onset of sepsis.