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Objectives This global, multicenter, prospective study, initiated to meet U.S. Food and Drug Administration condition-of-approval requirements, evaluated the safety and efficacy of the Medtronic magnetic resonance imaging (MRI)–conditional pacing system when used in an MRI environment in routine clinical practice. The primary endpoint was MRI-related complications. The secondary endpoint was the cumulative change in pacing capture threshold (PCT) for patients undergoing multiple MRI scans. Background Large-scale, real-world evaluation of MRI in patients implanted with an MRI-conditional pacing system remains limited, with few published data for patients who undergo multiple MRI scans. Methods Patients were enrolled and followed up prospectively from the time of implantation. Evaluation of the pacemaker function was performed before and after MRI. The MRI-related complication-free rate was evaluated. Changes in electrical performance after each scan and cumulative changes over multiple scans were analyzed. Results In 81 centers, 2,629 patients were implanted with a complete SureScan pacing system (41.8% women, age 70.2 ± 12.5 years). A total of 526 patients (28.5%) received 872 clinically indicated MRI scans, including 58 thoracic scans. No MRI-related complications occurred during or after MRI, meeting the primary objective. Six (1%) MRI-related observations (atrial fibrillation, PCT increase, and chest symptoms) were reported. A total of 171 patients (32.5%) underwent 2 or more scans with no cumulative increase in PCT. Conclusions This report constitutes the largest longitudinal MRI experience in patients implanted with an MRI-conditional pacing system. Results support the safety profile of the SureScan system and demonstrate for the first time that patients may safely undergo multiple MRI scans. (SureScan Post-Approval Study; NCT01299675)

Introduction The paradigm for preventing clinically significant cytomegalovirus (CMV) infection and CMV disease after hematopoietic cell transplantation (HCT) has shifted from preemptive treatment to antiviral prophylaxis with the approval of letermovir. Previously, our group validated the use of quantitative CMV DNA viral load as a surrogate endpoint for tissue-invasive CMV disease (ASBMT 2018) in the pre-emptive treatment setting. Objectives To address whether CMV viral load kinetics could serve as valid surrogate endpoints for CMV disease in the prophylactic setting, we performed CMV viral load testing of frozen serum samples collected during a placebo-controlled randomized trial of ganciclovir (GCV) given at engraftment (Goodrich et al. Ann Intern Med 1993). Because this study pre-dated the approval of ganciclovir, CMV disease occurred in an extremely high proportion of patients, allowing us to link viral load kinetics with CMV disease, which would not be possible in the modern treatment environment. Methods We calculated each patient's CMV viral load kinetics (mean, peak, maximum change, percentage of positive viral loads) from samples collected during the first five weeks after randomization and analyzed their value as surrogates for CMV disease by 24 weeks after randomization. First, we tested each marker for fulfillment of the Prentice criteria for valid surrogate endpoints using multivariable logistic regression, including quantifying the degree to which each marker captured the effect of ganciclovir on CMV disease. Secondly, to determine the ability of the viral load markers to predict CMV disease, we developed a ‘SuperLearner' machine learning model and quantified prediction accuracy by cross-validated area under the receiver-operator characteristic curves (cv-AUCs). Results Mean, peak, change, and percentage of positive viral loads were significantly higher in the placebo group than in the ganciclovir group. See viral loads by group in Fig 1. Percentage of positive viral load satisfied Prentice criteria as a valid surrogate endpoint for CMV disease by week 24 after randomization (Fig 2). All kinetics explained greater than 80% of ganciclovir's reduction in CMV disease (mean: 86%, peak: 83%, maximum change: 95%, percent positive: 94%). We found that a SuperLearner model that included all four viral load kinetics, CMV donor serostatus, acute graft-versus-host disease, and baseline viral load predicted CMV disease with 91% cv-AUC in the placebo group, 78% in the ganciclovir group, and 82% in the combined groups (Fig 3). Conclusion We have shown for the first time in a clinical endpoint-rich, placebo-controlled antiviral prophylaxis trial that CMV viral load kinetics fulfill the Prentice criteria as valid surrogate endpoints and have high predictive value for CMV disease after HCT.

The United States Food and Drug Administration recently issued guidance that CMV DNAemia (quantitative CMV viral load as measured by PCR) could be used in a composite endpoint along with tissue-invasive CMV disease as the primary endpoint in allogeneic HCT CMV prophylaxis trials. However, the specific time points after antiviral treatment initiation at which to measure viral load and the viral load thresholds that most accurately predict clinical CMV disease have not been identified. In order to estimate the treatment effect of an antiviral agent on CMV clinical outcomes, placebo-controlled, randomized trial data with accompanying viral load measurements are needed. Unfortunately, in the modern era of PCR and early preemptive treatment, ethically, placebo-controlled, randomized trials that allow for the development of CMV disease after HCT can no longer be performed. To overcome this limitation, we performed CMV DNA PCR testing on frozen plasma samples collected during the first 100 days post-HCT in the only placebo-controlled, double-blind RCT of ganciclovir for the early treatment of CMV infection after HCT (Goodrich et al. NEJM 1991). We used three analytic methods (Cox proportional hazards models, machine learning, and a novel non-parametric method) to determine which of 14 viral load markers, measured in the first four weeks of treatment, are the most useful surrogates of antiviral treatment for the prevention of CMV disease. All methods identified peak viral load and percentage of positive samples by week 4 as highly associated with or predictive of tissue-invasive CMV disease by week 8 post-randomization. Cox proportional hazards models (Figure 1) yielded significant associations for peak viral load measured by week 4 (HR 1.4, 95% CI 1.1-1.9) and percentage of positive samples by week 4 (HR 1.6, CI 1.1-2.3). The machine-learning ensemble algorithm SuperLearner implemented in R (Figure 2) demonstrated cross-validated area under the receiver-operator curves of at least 75% for peak viral load (75%, CI 62-87%) and percentage of positive plasma samples (77%, CI 63-90%) measured by week 4. Using a novel statistical technique that allows direct estimation of biomarker surrogacy (Parast et al. Stat Med 2017), we estimated that the percentage of ganciclovir treatment effect explained by peak viral load and percentage of positive samples measured by week 4 was greater than 85%—peak viral load 89%, CI 56-100%; percent positive samples 91%, CI 60-100% (Figure 3). Peak viral load and percentage of positive samples by week 4 are highly predictive of CMV disease and the treatment effect of ganciclovir. Our analysis suggests that these may be the best surrogate markers of ganciclovir treatment and introduces novel methods for identifying optimal candidate biomarkers as surrogates for clinical endpoints.

Objectives Our purpose was to demonstrate that strategically chosen implantable cardioverter-defibrillator (ICD) ventricular tachycardia (VT) or ventricular fibrillation (VF) detection and therapy parameters can reduce the combined incidence of device-delivered shocks, arrhythmic syncope, and untreated sustained symptomatic VT/VF (morbidity index). Background Strategically chosen ICD VT/VF detection and therapy parameters have been shown in previous studies to reduce the number of shocked episodes. In the PREPARE (Primary Prevention Parameters Evaluation) study, these prior strategies were combined with additional strategies specific to primary prevention patients. Methods The PREPARE study was a prospective, cohort-controlled study that analyzed 700 patients (biventricular [Bi-V] ICD and non–Bi-V ICD) with primary prevention indications for an ICD from 38 centers followed for 1 year. VT/VF was detected for rates ≥182 beats/min that were maintained for at least 30 of 40 beats. Antitachycardia pacing was programmed as the first therapy for regular rhythms with rates of 182 to 250 beats/min, and supraventricular tachycardia discriminators were used for rhythms ≤200 beats/min. The control cohort consisted of 689 primary prevention patients from the EMPIRIC (Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators Trial) (non–Bi-V ICD, physician arm only) and MIRACLE ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation) (Bi-V ICD) trials for whom VT/VF detection and therapy programming were not controlled. Results The PREPARE programming significantly reduced the morbidity index incidence density (0.26 events/patient-year for PREPARE study patients vs. 0.69 control cohort, p = 0.003). The PREPARE study patients were less likely to receive a shock in the first year compared with control patients (9% vs. 17%, p Conclusions Strategically chosen VT/VF detection and therapy parameters can safely reduce shocks and other morbidities associated with ICD therapy in patients receiving an ICD for primary prevention indications. (PREPARE-Primary Prevention Parameters Evaluation; NCT00279279)

No prospective studies have compared sotalol and amiodarone during electropharmacologic testing. The purpose of this prospective, randomized study was to compare the electrophysiologic effects of sotalol and amiodarone in patients with coronary artery disease and sustained monomorphic ventricular tachycardia (VT). Patients with coronary artery disease and sustained monomorphic VT inducible by programmed stimulation were randomly assigned to receive either sotalol (n = 17) or amiodarone (n = 17). The sotalol dose was titrated to 240 mg twice daily over 7 days. Amiodarone dosing consisted of 600 mg 3 times daily for 10 days. An electrophysiologic test was performed in the baseline state and at the end of the loading regimen. An adequate response was defined as the inability to induce VT or the ability to induce only relatively slow hemodynamically stable VT. During the follow-up electrophysiologic test, 24% of patients taking sotalol and 41% of those taking amiodarone had an adequate response to therapy (p = 0.30). Amiodarone lengthened the mean VT cycle length to a greater degree than sotalol (28% vs 12%, p < 0.01). There were no significant differences in the effects of sotalol and amiodarone on the ventricular effective refractory period. In patients with coronary artery disease, amiodarone and sotalol are similar in efficacy in the treatment of VT as assessed by electropharmacologic testing. The effects of the 2 drugs on ventricular refractoriness are similar, but amiodarone slows VT to a greater extent than sotalol.

Objectives . The purpose of this study was to prospectively compare in random fashion an anatomic and an electrogram mapping approach for ablation of the slow pathway of atrioventricular (AV) node reentrant tachycardia. Background . Ablation of the slow pathway in patients with AV node reentrant tachycardia can be performed by using either an anatomic or an electrogram mapping approach to identify target sites for ablation. These two approaches have never been compared prospectively. Methods . Fifty consecutive patients with typical AV node reentrant tachycardia were randomly assigned to undergo either an anatomic or an electrogram mapping approach for ablation of the slow AV node pathway. In 25 patients randomly assigned to the anatomic approach, sequential radiofrequency energy applications were delivered along the tricuspid annulus from the level of the coronary sinus ostium to the His bundle position. In 25 patients assigned to the electrogram mapping approach, target sites along the posteromedial tricuspid annulus near the coronary sinus ostium were sought where there was a multicomponent atrial electrogram or evidence of a possible slow pathway potential. If the initial approach was ineffective after 12 radiofrequency energy applications, the alternative approach was then used. Results . The anatomic approach was effective in 21 (84%) of 25 patients, and the electrogram mapping approach was effective in all 25 patients (100%) randomly assigned to this technique (p = 0.1). The four patients with an ineffective anatomic approach had a successful outcome with the electrogram mapping approach. On the basis of intention to treat analysis, there were no significant differences between the electrogram mapping approach and the anatomic approach with respect to the time required for ablation (28 ± 21 and 31 ± 31 min, respectively, mean ± SD, p = 0.7) duration of fluoroscopic exposure (27 ± 20 and 27 ±18 min, respectively, p = 0.9) or mean number of radiofrequency applications delivered (6.3 ± 3.9 vs. 7.2 ± 8.0, p s 0.6). With both the anatomic and electrogram mapping approaches, the atrial electrogram duration and number of peaks in the atrial electrogram were significantly greater at successful target sites than at unsuccessful target sites. Conclusions . The anatomic and electrogram mapping approaches for ablation of the slow AV nodal pathway are comparable in efficacy and duration. If the anatomic approach is initially attempted and fails, the electrogram mapping approach may be successful at sites outside the areas targeted in the anatomic approach. With both the anatomic and electrogram mapping approaches, there are significant differences in the atrial electrogram configuration between successful and unsuccessful target sites.

Some centers have suggested complete elimination of slow pathway function to ensure a successful long-term outcome after slow pathway ablation to eliminate AVNRT. 1 The results of the present study demonstrate that this may not be necessary. As long as an isoproterenol infusion is administered and AVNRT is no longer inducible, residual slow pathway function with or without a single AV nodal echo beat is an adequate end point for the ablation procedure. Once the inducibility of AVNRT has been eliminated, attempts to completely ablate the slow pathway may serve only to prolong the procedure and to expose the patient and the operators to unnecessary radiation exposure.

Implantable cardioverter-defibrillators (ICDs) with nonthoracotomy lead systems are widely available, and are implanted either in the electrophysiology laboratory or the operating room. The purpose of this study was to prospectively evaluate the safety and efficacy of nonthoracotomy ICD implantation in an electrophysiology laboratory versus an operating room. During a 7-month period, 62 consecutive ICDs with nonthoracotomy lead systems were implanted in patients in an electrophysiology laboratory. During the next 10 months, 110 consecutive ICDs were implanted in patients in a surgical operating room. All ICD implantations were performed under general anesthesia by electrophysiologists. There were no differences in age (58 ± 14 vs 62 ± 12 years , p = 0.06), gender distribution ( p = 0.3), frequency of structural heart disease (97% vs 97%, p = 0.9), ejection fraction (0.31 ± 0.15 vs 0.29 ± 0.13, p = 0.3), or presentation with cardiac arrest (65% vs 53%, p = 0.2) between patients undergoing ICD implantation in the electrophysiology laboratory and operating room, respectively. The rate of successful implantation and of complications for systems implanted in the electrophysiology laboratory (95% and 13%, respectively) and in the operating room (98% and 14%, respectively) were similar ( p = 0.4 and p = 0.8, respectively). Specifically, the rate of infection (0% vs 4%, p = 0.3) and hematoma formation (2% vs 4%, p = 0.8) were not statistically significantly different. Three patients who had undergone ICD implantation in an operating room died within 30 days. ICDs with nonthoracotomy lead systems can be implanted with a similarly high rate of success and acceptable complication rate in the electrophysiology laboratory and in the operating room.

The purpose of this study was to determine if the polarity of the first phase of a biphasic shock used with a transvenous lead system affects the defibrillation threshold (DFT). The Endotak (Cardiac Pacemakers, Inc., Model 0074) transvenous defibrillation lead with distal and proximal shocking electrodes was used in this study. In 15 consecutive patients, the DFT was determined twice using a step-down protocol, in random order: with the distal coil as the anode forthe initial phase (anodal biphasic shock), and then with the polarity reversed (cathodal biphasic shock). These patients were 61 ± 11 years old (± standard deviation) and their mean left ventricular ejection fraction was 0.32 ± 0.10. The mean DFT using anodal biphasic shocks was 9.9 ± 4.8 joules, compared to 9.5 ± 4.2 joules using cathodal biphasic shocks (p = 0.8). In 3 patients the DFT was lower by a mean of 6.7 ± 2.9 joules with the former configuration, in 3 patients the DFT was lower by a mean of 6.3 ± 2.5 joules with the latter configuration, and in 9 patients it was the same. Using the standard cathodal configuration, a DFT of 15 joules was obtained in all patients, a DFT of 10 joules or less was obtained in 67% of patients (10/15) and a subcutaneous patch was not required in any patient. The polarity of the first phase of a biphasic shock used with a single transvenous lead does not affect the DFT. With either polarity configuration, a DFT of 10 joules or less is obtainable in approximately 70% of patients, and a subcutaneous patch is rarely, if ever, required.

Protein C deficiency has been associated with a predisposition to venous thrombosis and thromboembolism. Arterial thrombosis has been seen much less frequently and may require other vascular risk factors. Here we describe a young patient with protein C deficiency presenting with an acute myocardial infarction (AMI).