Real-World Direct Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Medicare Beneficiaries With Atrial Fibrillation.

It remains unknown whether the comparative effectiveness of direct oral anticoagulants (DOACs) and warfarin differs between atrial fibrillation patients with and without a history of stroke or transient ischemic attack (TIA). Using 2012 to 2014 Medicare claims data, we identified patients newly diagnosed with AF in 2013 to 2014 who initiated apixaban, dabigatran, rivaroxaban, or warfarin. We categorized patients based on a history of stroke or TIA. We constructed Cox proportional hazard models that included indicator variables for treatment groups, a history of stroke or TIA, and the interaction between them, and controlled for demographics and clinical characteristics. DOACs were generally more effective than warfarin in stroke prevention; however, there were important differences between subgroups defined by a history of ischemic stroke. In particular, the superiority of dabigatran compared with warfarin in ischemic stroke prevention was more pronounced in patients with a history of stroke or TIA (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48 to 0.85) than in patients with no history of stroke or TIA (HR 0.94; 95% CI 0.75 to 1.16; p value for interaction = 0.034). There was no difference in the risk of stroke between apixaban, dabigatran, and rivaroxaban in patients with no history of stroke or TIA. However, in patients with a history of stroke or TIA, the risk of stroke was lower with dabigatran (HR 0.64; 95% CI 0.48 to 0.85) and rivaroxaban (HR 0.70; 95% CI 0.56 to 0.87), compared with apixaban (p value for both interactions <0.05). In conclusion, the comparative effectiveness of DOACs differs substantially between patients with and without a history of stroke or TIA; specifically, apixaban is less effective in patients with a history of stroke or TIA.

Fluoroscopic screening of asymptomatic patients implanted with the recalled Riata lead family.

BACKGROUND: The Food and Drug Administration recently issued a class I recall of the St. Jude Medical Riata implantable cardioverter-defibrillator lead presumably because of increased risk of electric failure and mechanical separation via inside-out abrasion. We sought to examine the incidence and time dependence of inside-out abrasion in asymptomatic patients implanted with the Riata lead. METHODS AND RESULTS: Asymptomatic patients implanted with the Riata lead at our institution were offered voluntary fluoroscopic screening in 3 views. Electric testing of the Riata lead with provocative isometric muscle contraction was performed at the time of fluoroscopic screening. Of the 245 patients undergoing fluoroscopic screening, 53 (21.6%) patients showed clear evidence of lead separation. Of these externalized leads, 0%, 13%, and 26% had a dwell time of <3 years, 3 to 5 years, and >5 years, respectively (P=0.037). Externalized leads had a significantly pronounced decrease in R-wave amplitude (-1.7±2.9 mV versus +0.35±2.5 mV; P<0.001), and more patients with externalized leads had ≥25% decrease in R-wave amplitude from baseline (28.0% versus 8.1%; P=0.018). One patient with externalization exhibited new noise on near-field electrogram. CONCLUSIONS: The Riata lead exhibits time-dependent high rates of cable externalization exceeding 20% at >5 years of dwell time. Externalized leads are associated with a more pronounced decrease in R-wave amplitude, which may be an early marker of future electric failure. The use of fluoroscopic and electric screening of asymptomatic patients with the Riata lead remains controversial in the management of patients affected by the recent Food and Drug Administration recall.

Effect of coronary occlusion on intracardiac electrogram morphology.

AIMS: The effect of coronary occlusion on the morphology of intracardiac electrograms (IKG) may be of diagnostic value in recipients of cardiac implantable electronic device (CIED) and in other patients at risk of ischaemic heart disease (IHD), but remains grossly uncharacterized. The aim of the current study was to examine the effect of total occlusions in the major coronary artery distributions on the IKG. METHODS AND RESULTS: Domestic crossbred pigs (n= 11, 20-30 kg) were implanted with dual-coil right ventricular defibrillators, and bipolar right atrial and left ventricular leads. Through the femoral approach, percutaneous balloon total occlusion of the major coronary arteries was performed in random order in the left anterior descending, left circumflex, and right coronary arteries. Each occlusion was maintained for 3-5 min with 30 min periods of reperfusion in between. Simultaneous 15-vector IKG and 12-lead surface electrocardiograms (ECG) were recorded and analysed at baseline and during coronary occlusions. With coronary occlusions, significant ST-segment disturbances are consistently seen on both surface ECG leads and IKG tracings compared with baseline recordings and are reproducible over time. Given the multiple intracardiac recording vectors, each occluded vessel has a specific signature, allowing coronary localization from the IKG. CONCLUSIONS: Total coronary occlusion induces consistent IKG changes with injury patterns that allow the detection and localization of the culprit coronary artery. If duplicated in patients with IHD, these changes are likely to improve the time to diagnosis of acute coronary syndromes and thus favourably impact clinical outcomes.

A novel manoeuvre for discerning supraventricular tachycardia mechanism.

AIMS: Discerning supraventricular tachycardia (SVT) mechanism during catheter ablation procedures can be difficult and time-consuming, which, when combined with diagnostic error, places patients at risk of unnecessary complications. Distinguishing atrial tachycardia (AT) from AV nodal re-entry tachycardia (AVNRT) may be particularly vexatious. Value-added techniques are thus always welcome, particularly if they are not time-consuming nor require complex intracardiac lead configurations. In this study, we assessed whether a new technique, simultaneous right atrial and right ventricular pacing (RA + RV) during ongoing SVT, met these criteria. METHODS AND RESULTS: Using a simple intracardiac lead configuration (right atrial appendage, His bundle, right ventricular apex), the response to RA + RV delivered at 80-90% of the SVT cycle length, was examined in 80 patients referred for catheter ablation. In each patient, the actual tachycardia mechanism was adjudicated by standard electrophysiologic criteria ± successful catheter ablation. Mechanisms of SVT included, non-exclusively, AVNRT (24 patients), accessory pathway-mediated (orthodromic) re-entry (AVRT; 23 patients), AT (10 patients), and sinus tachycardia (ST induced with isoproterenol; 49 patients). Immediately after cessation of RA + RV pacing during persistent SVT, the first intracardiac electrogram observed was right atrial in all AT whereas it was His bundle in all AVNRT. The response during AVRT was mixed. CONCLUSIONS: In this preliminary evaluation, RA + RV pacing appears to add value to the existing armamentarium of electrophysiologic indices to discern SVT mechanism, in particular with respect to discriminating between AVNRT and AT.

Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNF-alpha genetic mouse model of congestive heart failure.

T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNF-alpha mice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatory telemetry during 30 min before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNF-alpha mice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNF-alpha mice than in FVB mice (98 +/- 9 and 88 +/- 3 ms, P = 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNF-alpha and FVB mice (P < 10(-4)); however, the 2% difference between the groups in the magnitude of CL changes was not significant. In TNF-alpha mice, the magnitude of TWA was 1.5-2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNF-alpha mice (P = 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice (P = 0.006 and 0.009) but not in TNF-alpha mice. In conclusion, TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias.

Correlation of electrical and mechanical reverse remodeling after cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves clinical outcome in many patients with refractory heart failure (HF). This study examined whether CRT is associated with reverse electrical remodeling by surface electrocardiogram (ECG). METHODS: Consecutive CRT recipients at the University of Pittsburgh Medical Center with >90 days of follow-up were included in this analysis. ECG data were abstracted from medical records. Subjects with a relative increase of > or =15% in left ventricular ejection fraction (LVEF) after CRT were considered responders. RESULTS: A total of 113 patients (age 69 +/- 11 years, men 70%, white 92%) were followed for a mean duration of 407 +/- 290 (92-1439) days. Overall, LVEF increased after CRT (29 +/- 13% vs 24 +/- 9%; P < 0.01) and 50% of patients were responders. The mean native QRS interval among responders was higher than in nonresponders (163 +/- 32 ms vs 148 +/- 29 ms; P < 0.01). More than 3 months after CRT, there was no change in the paced QRS duration compared to baseline. Paced QRS duration, however, decreased among responders and increased among nonresponders and was significantly different by response status (P < 0.001). There was a significant correlation between increase in LVEF and decrease in paced QRS width in the overall population (r =-0.3; P < 0.01). CONCLUSIONS: Among responders to CRT, the paced QRS width decreases significantly, whereas it increases among nonresponders. Given the paced nature of the QRS, the improved conduction probably reflects enhanced cell-to-cell coupling after CRT as opposed to improved conduction within the His-Purkinje system. These findings have significant implications as to the mechanisms of benefit from CRT.

Dual-dye optical mapping after myocardial infarction: does the site of ventricular stimulation alter the properties of electrical propagation?

INTRODUCTION: Myocardial infarction (MI) disrupts electrical conduction in affected ventricular areas. We investigated the effect of MI on the regional voltage and calcium (Ca) signals and their propagation properties, with special attention to the effect of the site of ventricular pacing on these properties. METHODS: New Zealand White rabbits were divided into four study groups: sham-operated (C, n = 6), MI with no pacing (MI, n = 7), MI with right ventricular pacing (MI + RV, n = 6), and MI with BIV pacing (MI + BIV, n = 7). At 4 weeks, hearts were excised, perfused, and optically mapped. As previously shown, systolic and diastolic dilation of the LV were prevented by BIV pacing, as was the reduction in LV fractional shortening. RESULTS: Four weeks after MI, optical mapping revealed markedly reduced action potential amplitudes and conduction velocities (CV) in MI zones, and these increased gradually in the border zone and normal myocardial areas. Also, Ca transients were absent in the infarcted areas and increased gradually 3-5 mm from the border of the normal zone. Neither BIV nor RV pacing affected these findings in any of the MI, border, or normal zones. CONCLUSIONS: MI has profound effects on the regional electrical and Ca signals and on their propagation properties in this rabbit model. The absence of differences in these parameters by study group suggests that altering the properties of myocardial electrical conduction and Ca signaling are unlikely mechanisms by which BIV pacing confers its benefits. Further studies into the regional, cellular, and molecular benefits of BIV pacing are therefore warranted.

Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy.

OBJECTIVES: The purpose of this study was to test the hypothesis that a combined echocardiographic assessment of longitudinal dyssynchrony by tissue Doppler imaging (TDI) and radial dyssynchrony by speckle-tracking strain may predict left ventricular (LV) functional response to cardiac resynchronization therapy (CRT). BACKGROUND: Mechanical LV dyssynchrony is associated with response to CRT; however, complex patterns may exist. METHODS: We studied 190 heart failure patients (ejection fraction [EF] 23 +/- 6%, QRS duration 168 +/- 27 ms) before and after CRT. Longitudinal dyssynchrony was assessed by color TDI for time to peak velocity (2 sites in all and 12 sites in a subgroup of 67). Radial dyssynchrony was assessed by speckle-tracking radial strain. The LV response was defined as > or =15% increase in EF. RESULTS: One hundred seventy-six patients (93%) had technically sufficient baseline and follow-up data available. Overall, 34% were EF nonresponders at 6 +/- 3 months after CRT. When both longitudinal dyssynchrony by 2-site TDI (> or =60 ms) and radial dyssynchrony (> or =130 ms) were positive, 95% of patients had an EF response; when both were negative, 21% had an EF response (p < 0.001 vs. both positive). The EF response rate was lowest (10%) when dyssynchrony was negative using 12-site TDI and radial strain (p < 0.001 vs. both positive). When either longitudinal or radial dyssynchrony was positive (but not both), 59% had an EF response. Combined longitudinal and radial dyssynchrony predicted EF response with 88% sensitivity and 80% specificity, which was significantly better than either technique alone (p < 0.0001). CONCLUSIONS: Combined patterns of longitudinal and radial dyssynchrony can be predictive of LV functional response after CRT.

Cardiac autonomic modulation by estrogen in female mice undergoing ambulatory monitoring and in vivo electrophysiologic testing.

INTRODUCTION: Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice. METHODS: Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring. RESULTS: With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups). CONCLUSION: Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women.

Cardiac electrophysiologic abnormalities in the CREBA133 transgenic mouse model of idiopathic dilated cardiomyopathy.

INTRODUCTION: We hypothesized that the transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter and displaying dilated cardiomyopathy would exhibit electrophysiologic abnormalities similar to those observed in human cardiomyopathy. METHODS AND RESULTS: Invasive electrophysiologic studies were performed on two age groups of mice: 11-week-old mice (n = 20, 9 transgenic mice and 11 wild-type controls) and 17-week-old mice (n = 16, 7 transgenic mice and 9 wild-type controls). Five additional transgenic mice underwent ambulatory ECG monitoring to determine the cause of death. The 11-week-old CREBA133 transgenic mice had longer PR and AH intervals than 11-week-old wild-type controls (P < 0.001), whereas at 17 weeks of age the transgenic mice also demonstrated increased HV intervals and widened QRS duration (P < 0.05). At both 11 weeks and 17 weeks of age, AV Wenckebach cycle length, 2:1 AV cycle length, and AV nodal functional and effective refractory periods were significantly longer in transgenic mice than in controls (P < 0.05). Although no ventricular arrhythmias were inducible at 11 weeks of age, at 17 weeks of age, ventricular tachycardia was induced in 4 of the 7 CREBA133 transgenic mice but in none of the 9 wild-type controls. All 5 CREBA133 transgenic mice that underwent ambulatory ECG monitoring revealed high-grade AV block, but not ventricular arrhythmia, at the time of death. CONCLUSION: These data suggest that CREBA133 transgenic mice manifest abnormalities of AV nodal and infra-Hisian conduction and inducibility of ventricular arrhythmia, which are characteristics of human dilated cardiomyopathy.