Jason Matos

Left ventricular sphericity independently predicts appropriate implantable cardioverter-defibrillator therapy

BACKGROUND Whether echocardiographic markers of remodeling are associated with ventricular tachyarrhythmias is unknown. OBJECTIVE The purpose of this study was to determine whether a transthoracic echocardiographic (TTE) marker of spherical left ventricular (LV) remodeling is associated with appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with primary prevention ICDs. METHODS From TTE images, we calculated sphericity index (SI), the ratio of biplane LV end-diastolic volume to the volume of a hypothetical sphere with a diameter of the LV end-diastolic length, and examined the relation between SI and therapy for ventricular tachyarrhythmias in 278 patients with primary prevention ICDs and in 50 controls without structural heart disease or ventricular arrhythmias. RESULTS SI in normal healthy adult subjects and in subjects receiving ICDs was 0.44 ± 0.02 and 0.65 ± 0.04, respectively (P <.001). Median time to first appropriate ICD therapy was significantly shorter in ICD patients with SI in the upper vs lower 50% of SI values (1.40 vs 2.38 years, P = .02 for conventional ICD patients; 1.54 vs 2.65 years, P = .02 for cardiac resynchronization therapy-defibrillator [CRT-D] patients). In multivariable Cox regression analysis, SI in the upper 50% was independently associated with appropriate ICD therapy after multivariable adjustment (hazard ratio 2.2, P = .03 for ICD cohort; hazard ratio 4.4, P = .01 for CRT-D cohort). SI was not associated with total mortality in either cohort. CONCLUSION SI is associated with appropriate ICD therapy, but not total mortality, in patients receiving primary prevention ICDs. These observations suggest spherical LV remodeling may predispose to ventricular arrhythmias. Furthermore, SI appears to add predictive accuracy for appropriate ICD therapy in patients with reduced ejection fraction.

Controversy Surrounding ROCKET-AF: A Call for Transparency, But Should We Be Changing Practice?

Prior to the emergence of novel oral anticoagulants (NOACS), nearly all patients were prescribed vitamin K antagonists for thromboembolic prophylaxis in non-valvular atrial fibrillation (AF). Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, is now one of the most frequently prescribed NOACs used for this indication.1,2 ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), published in the New England Journal of Medicine in 2011, demonstrated the non-inferiority of rivaroxaban compared with warfarin for the primary prevention of stroke or systemic embolism in patients with AF. This double-blinded randomised trial, which included 14,264 patients across 45 countries, also showed no significant difference in the risk of major bleeding between these two groups.3 Rivaroxaban use in AF has become widespread since the publication of this trial and US Food and Drug Administration (FDA) approval. Two additional Factor Xa inhibitors, apixaban and edoxaban, have also been evaluated in similar randomised trials and have demonstrated non-inferiority to warfarin for stroke or systemic embolism prophylaxis in patients with non-valvular AF with no significant difference in major bleeding.4,5 In recent months, the results of ROCKET-AF have come into question after the FDA issued a recall notice for the device used to obtain International Normalised Ratio (INR) measurements in the warfarin control group. The FDA found that lower INR values were seen with the ‘point-of-care’ INRatio Monitor System (Alere) compared with a plasma-based laboratory in patients with certain medical conditions.2 These conditions included abnormal haemoglobin levels, abnormal bleeding and abnormal fibrinogen levels.6 Since the FDA recall of this device, there has been widespread concern that falsely low INR readings in ROCKET-AF may have led to warfarin overdosing. Inappropriately high warfarin dosing could have increased bleeding rates in the control group and therefore made the rivaroxaban arm appear falsely favourable.7 This point-of-care device recall also highlighted a lack of transparency of the specifics of devices used in large clinical trials. In response, the authors from ROCKET-AF released a correspondence in February 2016, citing the FDA recall. They also provided a post hoc analysis of patients who may have been affected by the recall. They found that major bleeding was greater in patients with conditions affected by the recall, but, reassuringly, the bleeding risk was greater in those who were on rivaroxaban and not warfarin.6 Despite this post hoc analysis, concern has arisen regarding the generalisability of ROCKET-AF given the faulty point-of-care INR readings. There has been a call for complete transparency of the data from this trial and a better explanation of the mechanism of the incorrect INR measurements.7 Once published, the data supporting an FDA-approved treatment should be available for independent analysis. One issue is that rivaroxaban was approved in the US prior to 1 January 2014, before a new transparency policy on clinical trial data sharing was approved by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA).2 Drug companies are refusing to share any data on pharmaceuticals approved before 2014. A device malfunction in a large clinical trial also should raise concern, especially when that trial has altered clinical practice for millions of patients. On review of Patel et al’s correspondence regarding the point-of-care malfunction, there is inadequate explanation of the mechanism of these faulty readings. Why are they only seen only in patients with abnormal haemoglobin and fibrinogen levels? How inaccurate could the readings be – within 0.1 or 1.0 of a gold standard value? Most alarming is the revelation that the manufacturer had evidence of faulty readings in similar models dating back to 2002.2 Despite legitimate concerns regarding the absence of data transparency and the faulty point-of-care device, rivaroxaban need not be removed from clinical practice for AF patients. In ROCKET-AF, the drug demonstrated non-inferiority to warfarin in preventing thromboembolic events. In addition, data has shown that patients potentially affected by the faulty point-of-care device actually bled more on rivaroxaban than warfarin.6 Therefore, the original risk–benefit ratio presented in ROCKET-AF remains true. There are other, albeit smaller, randomised trials with shorter follow-up times that compare rivaroxaban and warfarin for thromboembolic prophylaxis.8,9 For example, Cappato et al in 2014, randomised 1,504 patients to show that oral rivaroxaban was non-inferior to warfarin in preventing a composite endpoint of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction and cardiovascular death in patients with AF undergoing cardioversion. Major bleeding rates in the rivaroxaban and warfarin arms were similar (0.6 % versus 0.8 % respectively).8 The prospective observational trial XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation) followed 6.784 patients on rivaroxaban for AF during a mean time of 329 days at 311 different hospitals. Major bleeding occurred in 128 patients (2.1 events/100 patient years) and 43 patients (0.7 events/100 patient years) suffered a stroke. These numbers are more reassuring than those seen in ROCKET-AF, though the patient population had a lower risk profile, with an average CHADS2 score of 2.0 compared with 3.5 in ROCKET-AF.10 To further mitigate concern regarding inaccuracies of bleeding rates in the ROCKET-AF control group, it is helpful to compare bleeding rates in the warfarin arms of the other major NOAC trials. The RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial, had a warfarin-arm major bleeding rate of 3.4%/year.11 The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, had a warfarin-arm major bleeding rate of 3.1%/year.4 The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, had a warfarin-arm major bleeding rate of 3.4 %/year.5 The warfarin arm of ROCKET-AF had a 3.4 %/year major bleeding rate, comparable to the other studies. Furthermore, the ROCKET-AF patients are known to be at higher risk for stroke and bleeding; their average CHADS2 score was highest among these studies (3.5 compared with 2.1–2.8).3 In addition, ROCKET-AF had a very high percentage of patients with a HAS-BLED score ≥3 (62 %) compared with the other studies (23 % in ARISTOTLE and 51 % in ENGAGE AF-TIMI 48).12–14 Several large randomised trials have compared the safety and efficacy of rivaroxaban versus warfarin for venous thromboembolic disease. The warfarin arm of the EINSTEIN-PE trial (Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Pulmonary Embolism), which randomised patients with pulmonary embolism to warfarin or rivaroxaban, had a major bleeding rate of 2.2 %. The bleeding rate was lower in the rivaroxaban arm (1.1 %) and notably patients received a higher loading dose of rivaroxaban for the first 3 weeks (15 mg twice daily) compared with the daily 20 mg daily in ROCKET-AF.15 The recent uncertainties surrounding ROCKET-AF demonstrate the need for widespread data transparency for major trials with the capability of so greatly affecting patients’ lives. These are complicated issues both for the companies’ manufacturing products and the clinical trial organisations who carry out these studies and analyse the data. Ultimately the goal of full transparency to allow increased confidence in trial results should be sought. In this instance there is no compelling evidence of imminent danger of excessive bleeding with rivaroxaban. We should take notice of the recent findings, but there is no need to change practice.

Spaced education in medical residents: An electronic intervention to improve competency and retention of medical knowledge

Background Spaced education is a novel method that improves medical education through online repetition of core principles often paired with multiple-choice questions. This model is a proven teaching tool for medical students, but its effect on resident learning is less established. We hypothesized that repetition of key clinical concepts in a “Clinical Pearls” format would improve knowledge retention in medical residents. Methods This study investigated spaced education with particular emphasis on using a novel, email-based reinforcement program, and a randomized, self-matched design, in which residents were quizzed on medical knowledge that was either reinforced or not with electronically-administered spaced education. Both reinforced and non-reinforced knowledge was later tested with four quizzes. Results Overall, respondents incorrectly answered 395 of 1008 questions (0.39; 95% CI, 0.36–0.42). Incorrect response rates varied by quiz (range 0.34–0.49; p = 0.02), but not significantly by post-graduate year (PGY1 0.44, PGY2 0.33, PGY3 0.38; p = 0.08). Although there was no evidence of benefit among residents (RR = 1.01; 95% CI, 0.83–1.22; p = 0.95), we observed a significantly lower risk of incorrect responses to reinforced material among interns (RR = 0.83, 95% CI, 0.70–0.99, p = 0.04). Conclusions Overall, repetition of Clinical Pearls did not statistically improve test scores amongst junior and senior residents. However, among interns, repetition of the Clinical Pearls was associated with significantly higher test scores, perhaps reflecting their greater attendance at didactic sessions and engagement with Clinical Pearls. Although the study was limited by a low response rate, we employed test and control questions within the same quiz, limiting the potential for selection bias. Further work is needed to determine the optimal spacing and content load of Clinical Pearls to maximize retention amongst medical residents. This particular protocol of spaced education, however, was unique and readily reproducible suggesting its potential efficacy for intern education within a large residency program.

Tailored Anticoagulation for Thromboembolic Risk Reduction in Paroxysmal Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting up to six million people in the United States and more than 35 million individuals worldwide. Thromboembolism, including stroke, represents the most common AF-related morbidity and mortality and data indicate that anticoagulation can mitigate this risk by 65%. Our understanding of thromboembolism in AF, however, remains incomplete, and the mechanisms by which AF increases thromboembolic risk are areas of ongoing investigation and debate. Current guidelines do not differentiate between the frequency and duration of AF episodes (AF burden) when selecting which patients with AF should be treated with anticoagulation for thromboembolic risk reduction. Recent data, primarily using cardiac implantable electronic devices (CIEDs) such as pacemakers, implantable cardioverter-defibrillators, and implantable loop recorders, however, have challenged this longstanding notion that AF burden does not influence thromboembolic risk. Continuous and automated cardiac rhythm monitoring via CIEDs with accurate and rapid acquisition and transmission of rhythm data also affords the opportunity to study the relationship between AF burden and thromboembolism and novel ways to reduce thromboembolic risk while minimizing the risk associated with chronic anticoagulation use. This manuscript will review the associations between subclinical, CIED-detected atrial arrhythmias and thromboembolic events. It will also discuss the emergence of “tailored anticoagulation,” an anticoagulation strategy wherein CIEDs and remote AF monitoring are employed to allow dynamic administration of oral anticoagulation only around episodes of AF, and the holding of anticoagulation during prolonged periods of sinus rhythm when the thromboembolic risk associated with AF is presumably very low.

Intermittent anticoagulation guided by continuous atrial fibrillation burden monitoring using dual-chamber pacemakers and implantable cardioverter-defibrillators: Results from the Tailored Anticoagulation for Non-Continuous Atrial Fibrillation (TACTIC-AF) pilot study

BACKGROUND Chronic anticoagulation is recommended for atrial fibrillation (AF) patients with thromboembolic risk factors regardless of AF duration/frequency. Continuous rhythm assessment with pacemakers (PMs)/implantable cardioverter-defibrillators (ICDs) and use of direct-acting oral anticoagulants (DOACs) may allow anticoagulation only around AF episodes, reducing bleeding without increasing thromboembolic risk. OBJECTIVE The purpose of this study was to evaluate the feasibility/safety of intermittent DOAC use guided by continuous remote AF monitoring via dual-chamber PMs or ICDs. METHODS Patients with nonpermanent AF, current DOAC use, CHADS2 score ≤3, a St. Jude Medical dual-chamber PM or ICD, and rare AF episodes were followed with biweekly and AF-alert based remote transmissions. Patients free of AF episodes lasting ≥6 minutes with a total AF burden <6 hours/day for 30 consecutive days discontinued DOAC. If AF burden surpassed these limits, DOAC was restarted and/or continued. Total days on DOAC and adverse events were assessed. RESULTS Among 48 patients (mean age 71.3 years; 65% male; 79% paroxysmal AF; 87% CHADS2 score 1-2), 14,826 days of monitoring were completed. Patients used DOACs for 3763 days, representing a 74.6% reduction in anticoagulation time compared to chronic administration. Adverse events included 2 gastrointestinal bleeds (both on DOAC), 1 fatal intracerebral bleed (off DOAC), and no thromboembolic/stroke events. CONCLUSION Among patients with rare AF episodes and low-to-moderate stroke risk, PM/ICD-guided DOAC administration is feasible and decreased anticoagulation utilization by 75%. Few adverse events occurred, although the study was not powered to assess these outcomes. PM/ICD-guided DOAC administration may prove a viable alternative to chronic anticoagulation. Future studies are warranted.

Multimodality Assessment of Right Ventricular Strain in Patients With Acute Pulmonary Embolism

Optimal risk stratification is essential in managing patients with an acute pulmonary embolism (PE). There are limited data evaluating the potential additive value of various methods of evaluation of right ventricular (RV) strain in PE. We retrospectively evaluated RV strain by computed tomography (CT), transthoracic echocardiography (TTE), electrocardiography (ECG), and troponin levels in consecutive hospitalized patients with acute PE (May 2007 to December 2014). Four-hundred and seventy-seven patients met inclusion criteria. RV strain on ECG (odds ratio [OR] 1.9, confidence interval [CI] 1.1 to 3.3; p = 0.03), CT (OR 2.7, CI 1.5 to 4.8, p <0.001), TTE (OR 2.8, CI 1.5 to 5.4, p <0.001), or a positive troponin (OR 2.7, CI 2.0 to 6.9, p <0.001) were associated with adverse events. In patients with ECG, CT, and TTE data, increased risk was only elevated with RV strain on all 3 parameters (OR 4.6, CI 1.8 to 11.3, p <0.001). In all patients with troponin measurements, risk was only elevated with RV strain on all 3 parameters plus a positive troponin (OR 8.8, CI 2.8 to 28.1, p <0.001) and was similar in intermediate-risk PE (OR 11.1, CI 1.2 to 103.8, p = 0.04). In conclusion, in patients with an acute PE and evaluation of RV strain by ECG, CT, and TTE, risk of adverse events is only elevated when RV strain is present on all 3 modalities. Troponin further aids in discriminating high-risk patients. Multimodality assessment of RV strain is identified as a superior approach to risk assessment.

EVALUATION OF RIGHT VENTRICULAR STRAIN BY ECHOCARDIOGRAPHY, COMPUTED TOMOGRAPHY, AND ELECTROCARDIOGRAPHY IN PATIENTS WITH ACUTE PULMONARY EMBOLISM

Introduction: Evidence of right ventricular strain (RVS) on either transthoracic echocardiography (TTE), computed tomography (CT), or electrocardiography (ECG) has been shown to increase the risk of adverse outcomes in patients with acute pulmonary embolism (APE). We evaluated the combined

Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity

Gemcitabine is a commonly used antineoplastic agent used to treat a variety of cancers with rarely reported cardiac side effects. We describe a case of a 67‐year‐old woman with follicular lymphoma who experienced a rarely reported side effect of gemcitabine: cardiomyopathy. This case highlights a multiple hit mechanism of myocyte damage that may occur following the use of multiple cardio‐toxic agents despite their administration in doses not associated with cardiotoxicity.

DECLINE IN MITRAL ANNULAR PLANE SYSTOLIC EXCURSION IN ASYMPTOMATIC PATIENTS WITH AORTIC VALVE STENOSIS AND PRESERVED SYSTOLIC FUNCTION PREDICTS THE CLINICAL NEED FOR AORTIC VALVE INTERVENTION

Mitral Annular Plane Systolic Excursion (MAPSE) is an easily acquired metric of left ventricular (LV) longitudinal shortening. We sought to investigate if a decline in MAPSE preceded the need for aortic valve intervention (AVI) in asymptomatic patients with aortic stenosis (AS) and preserved LV