Perioperative Safety and Early Patient and Device Outcomes Among Subcutaneous Versus Transvenous Implantable Cardioverter Defibrillator Implantations : A Randomized, Multicenter Trial.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) improve survival in patients at risk for cardiac arrest, but are associated with intravascular lead-related complications. The subcutaneous ICD (S-ICD), with no intravascular components, was developed to minimize lead-related complications. OBJECTIVE: To assess key ICD performance measures related to delivery of ICD therapy, including inappropriate ICD shocks (delivered in absence of life-threatening arrhythmia) and failed ICD shocks (which did not terminate ventricular arrhythmia). DESIGN: Randomized, multicenter trial. (ClinicalTrials.gov: NCT02881255). SETTING: The ATLAS trial. PATIENTS: 544 eligible patients (141 female) with a primary or secondary prevention indication for an ICD who were younger than age 60 years, had a cardiogenetic phenotype, or had prespecified risk factors for lead complications were electrocardiographically screened and 503 randomly assigned to S-ICD (251 patients) or transvenous ICD (TV-ICD) (252 patients). Mean follow-up was 2.5 years (SD, 1.1). Mean age was 49.0 years (SD, 11.5). MEASUREMENTS: The primary outcome was perioperative major lead-related complications. RESULTS: There was a statistically significant reduction in perioperative, lead-related complications, which occurred in 1 patient (0.4%) with an S-ICD and in 12 patients (4.8%) with TV-ICD (-4.4%; 95% CI, -6.9 to -1.9; P = 0.001). There was a trend for more inappropriate shocks with the S-ICD (hazard ratio [HR], 2.37; 95% CI, 0.98 to 5.77), but no increase in failed appropriate ICD shocks (HR, 0.61 (0.15 to 2.57). Patients in the S-ICD group had more ICD site pain, measured on a 10-point numeric rating scale, on the day of implant (4.2 ± 2.8 vs. 2.9 ± 2.2; P < 0.001) and 1 month later (1.3 ± 1.8 vs. 0.9 ± 1.5; P = 0.035). LIMITATION: At present, the ATLAS trial is underpowered to detect differences in clinical shock outcomes; however, extended follow-up is ongoing. CONCLUSION: The S-ICD reduces perioperative, lead-related complications without significantly compromising the effectiveness of ICD shocks, but with more early postoperative pain and a trend for more inappropriate shocks. PRIMARY FUNDING SOURCE: Boston Scientific.

Rationale and design of the randomized prospective ATLAS study: Avoid Transvenous Leads in Appropriate Subjects.

BACKGROUND: The defibrillator lead is the weakest part of the transvenous (TV) implantable cardioverter defibrillation (ICD) system and a frequent cause of morbidity. Lead dislodgement, cardiac perforation, insertion-related trauma including pneumothorax and vascular injury, are common early complications of TV-ICD implantation. Venous occlusion, tricuspid valve dysfunction, lead fracture and lead insulation failure are additional, later complications. The introduction of a totally sub-cutaneous ICD (S-ICD) may reduce these lead-related issues, patient morbidity, hospitalizations and costs. However, such benefits compared to the TV-ICD have not been demonstrated in a randomized trial. DESIGN: ATLAS (Avoid Transvenous Leads in Appropriate Subjects) is a multi-centered, randomized, open-label, parallel group trial. Patients younger than 60 years are eligible. If older than 60 years, patients are eligible if they have an inherited heart rhythm disease, or risk factors for ICD-related complication, such as hemodialysis, a history of ICD or pacemaker infection, heart valve replacement, or severe pulmonary disease. This study will determine if using an S-ICD compared to a TV-ICD reduces a primary composite outcome of perioperative complications including pulmonary or pericardial perforation, lead dislodgement or dysfunction, tricuspid regurgitation and ipsilateral venous thrombosis. Five hundred patients will be enrolled from 14 Canadian hospitals, and data collected to both early- (at 6 months) and mid-term complications (at 24 months) as well as mortality and ICD shock efficacy. SUMMARY: The ATLAS randomized trial is comparing early- and mid-term vascular and lead-related complications among S-ICD versus TV-ICD recipients who are younger or at higher risk of ICD-related complications.

Mexiletine as an adjunctive therapy to amiodarone reduces the frequency of ventricular tachyarrhythmia events in patients with an implantable defibrillator.

The most effective pharmacological management of frequent ventricular tachyarrhythmia events in patients with an implantable defibrillator who failed or did not tolerate amiodarone is unknown. The aim of this retrospective cohort study was to assess the efficacy and tolerability of mexiletine in such patients. The patients served as self-controls. The number of treated ventricular tachyarrhythmia episodes (primary outcome); mortality, shocks from the defibrillator, and electrical storm events (secondary outcomes) during mexiletine therapy was compared with a matched duration of observation just before initiating mexiletine in 29 patients who were treated with a median dose of 300 mg/d of mexiletine and were followed for a median of 12 months. None of the patients had to stop mexiletine due to side effect. There was a significant reduction in the incidence of ventricular tachycardia/fibrillation episodes (median 2 vs. 12 events, P = 0.001) and shocks (median 0 vs. 2 events, P = 0.003) in the first 3 months of treatment, but long-term efficacy was only observed among patients who continued amiodarone therapy. In conclusion, mexiletine, when added to amiodarone in case of amiodarone inefficacy, reduces ventricular tachycardia/fibrillation events and appropriate therapies in patients with an implantable cardioverter defibrillator. A randomized trial should validate the efficacy and safety of mexiletine as an adjunctive therapy to amiodarone.

Electrogram-based optimal atrioventricular and interventricular delays of cardiac resynchronization change individually during exercise.

BACKGROUND: Limited data suggest that optimal atrioventricular (AV) and interventricular (VV) delays are different at rest than during exercise in patients with heart failure. We assessed the feasibility and reproducibility of an electrogram-based method of optimization called QuickOpt at rest and during exercise. METHODS: Patients with a St Jude Medical cardiac resynchronization therapy implantable cardioverter-defibrillator were subjected to a graded treadmill test, and QuickOpt was repeatedly measured prior to, during, and after the exercise. RESULTS: Twenty-four patients (16 males, aged 67.4 ± 7.7 years) participated. At rest, delays (in ms) were 110.4 ± 20.1 for sensed AV delay and -70 (LV pacing first) to +20 (RV pacing first) for VV delay. The changes in QuickOpt-derived delays at rest were not significant despite change in body position. During exercise, QuickOpt-derived AV delays did not change in 11 patients, were shorter during peak exercise in 8 patients, and were longer in 3 patients (average value during peak exercise was 126.5 ± 15.8 ms, P = 0.04 compared to baseline). The QuickOpt-derived VV delay gradually shifted toward earlier right ventricular pacing during exercise in 19 patients, while no changes were seen in 3 patients, and a shift occurred toward earlier left ventricular pacing in 2 patients (average value during peak exercise was -30.7 ± 22.2; P = 0.001 compared to baseline). There was no correlation between changes in the QuickOpt-derived AV and VV delays and heart rate. CONCLUSIONS: The application of electrogram-based algorithm is feasible both at rest and during exercise. The results are reproducible. QuickOpt-derived AV and VV delays individually change during exercise.

Limitations in the current screening practice of assessing left ventricular ejection fraction for a primary prophylactic implantable defibrillator in southern Ontario.

BACKGROUND: Screening echocardiography (ECHO) is commonly performed to determine whether the patient's left ventricular ejection fraction (LVEF) is appropriate for primary prophylactic implantable cardiac defibrillator (ICD) referral. However, radionuclide ventriculography (RNA) is used by many implantation centres for decision making. OBJECTIVE: To determine whether current screening ECHO techniques are effective in identifying patients suitable for primary prophylactic ICD referral. METHODS: Correlation, sensitivity, specificity and likelihood ratios (LRs) of semiquantitative and numerical quantitative ECHO LVEFs were calculated for predicting RNA LVEFs that met implantation criteria (LVEF less than 30% and less than 35%). RESULTS AND DISCUSSION: Among 193 patients, the LRs for a semiquantitative ECHO predicting an RNA LVEF of less than 30% (negative LR was 0.21 to 0.69 and positive LR was 1.22 to 2.83) or RNA LVEF of less than 35% (negative LR was 0.24 to 0.73 and positive LR was 1.33 to 3.46) demonstrated that current screening ECHO techniques are ineffective. However, the positive predictive value of grade 4 ECHO was 93.0%, suggesting that these patients may not require further LVEF investigation before implantation. Among 102 patients, current quantitative ECHO techniques did not improve the screening characteristics. CONCLUSIONS: Current screening ECHO techniques may not be adequate for screening patients for consideration of a primary prophylactic ICD, but a grade 4 ECHO finding has a high positive predictive value in meeting implantation LVEF criteria. Improved screening standards should increase the number of patients referred with appropriate LVEF for primary prophylactic ICD implantation.

Role of antiarrhythmic drugs in patients with implantable cardioverter defibrillators.

The transvenous implantable cardioverter defibrillator (ICD) has emerged as the primary therapy for patients at high risk of life-threatening ventricular arrhythmias. A high number of ICD recipients will require subsequent adjunctive treatment with antiarrhythmic drugs (AADs). This review provides an overview of potential reasons for AAD initiation, candidates for treatment, current medical options, and possible drug-device interactions.

Outcomes in heart failure patients referred for consideration of implantable cardioverter defibrillator for primary prophylaxis of sudden cardiac death: what are the risks of waiting?

BACKGROUND: Clinical trials have confirmed that implantable cardioverter defibrillators (ICDs) reduce mortality in patients with a left ventricular ejection fraction below 30%. The 'real-world' prognosis before ICD implantation in such patients is not known. The estimated risk of death is 0.8% per month, and this forms the basis for wait-time recommendations. OBJECTIVES: To determine the consequences of waiting for ICD implantation among heart failure patients eligible for primary prophylactic ICD. METHODS: The present retrospective study evaluated consecutive patients who were deemed eligible for primary prophylactic ICD implantation. Survival outcomes were tracked for patients who declined an ICD, those who accepted and received an ICD, and patients who accepted an ICD but died while waiting. RESULTS: Of 470 patients referred for evaluation, 218 were deemed eligible for an ICD. A total of 174 of 218 patients (79.8%) accepted an ICD; 39 (17.9%) declined, and five (2.3%) were deemed to be at too great a risk for the procedure. The mortality rate at two years among patients who accepted an ICD was 18.8% before ICD implantation and 12.2% after ICD implantation. Among patients who declined ICD implantation, the two year mortality rate was 5.3%. Among patients waiting for an ICD, five of 19 deaths were out-of- hospital sudden deaths. Of 12 patients who died after ICD implantation, there were no documented out-of-hospital sudden deaths. CONCLUSION: Consistent with current estimates, the mortality rate at two years among patients who accepted and were waiting for an ICD implant was 18.8%. After receiving an ICD, the mortality rate was 12.2% at two years.

Assessment of resynchronization therapy on functional status and quality of life in patients requiring an implantable defibrillator.

BACKGROUND: The effect of cardiac resynchronization therapy (CRT) on physical function and Quality of Life (QoL) in patients who require an implantable defibrillator but do not meet guideline criteria for CRT has not been studied in detail. METHODS AND RESULTS: This was a randomized study of 72 patients with high risk of sudden cardiac death, ejection fraction (EF) < or =35%, mild-to-moderate heart failure symptoms, and QRS > 120 ms. Patients received a CRT defibrillator and were randomized to CRT turned ON or OFF. Objective and subjective measures were performed at baseline and after 6 months. There was no difference in change in left ventricular end-systolic volume (ESV) by radionuclid angiogram scan, the primary endpoint, between the CRT ON group (DeltaESV =-7 +/- 52 mL), and CRT OFF group (DeltaESV =-30 +/- 47 mL). Similarly, echocardiogram measures of ESV and EF showed no difference between the two groups. In the CRT ON group, selected measures of QoL and subjective exercise tolerance but not heart failure symptoms improved significantly. Six-minute walk distance prolonged in the CRT ON group (baseline 313.6 +/- 114.4 m, 6-month 365.0 +/- 122.5 m, P = 0.01), but the difference in change in walk distance between the two groups was not significant. CONCLUSION: Further studies with larger sample size and longer follow-up will be required to allow definite conclusions regarding the potential benefit of CRT in this patient population.

Influence of ventriculoatrial timing on hemodynamics and symptoms during supraventricular tachycardia.

AIMS: Patients with reentrant supraventricular tachycardia (SVT) are often highly symptomatic and the mechanism of symptoms is not well understood. We hypothesized that variation in ventriculoatrial interval (QRS to P) modulates the left atrial pressure and symptoms during tachycardia. METHODS AND RESULTS: Three hundred twenty-six patients awaiting electrophysiological study completed a questionnaire regarding "neck pounding" or "shirt flapping" during tachycardia. Mean left atrial pressure was measured during simulated atrioventricular reentry tachycardia (AVRT) and atrioventricular nodal reentry tachycardia (AVNRT) in 18 patients. Pulmonary venous flow reversal was assessed using transesophageal echocardiography in 12 dogs when pacing at 220 bpm with different VA delays (0 to 250 ms). "Shirt flapping" is present more often during AVNRT than during AVRT (58.6% vs 43.8%, respectively, P < 0.05). Simulated AVNRT is associated with higher left atrial pressure compared with AVRT (19.4 +/- 4.8 mmHg vs 13.7 +/- 3.9 mmHg, respectively, P < 0.05). In dogs, pulmonary venous flow reversal during atrial systole was observed with significantly decreasing amplitude as VA delays increased: 668 +/- 167% at 0 ms; 492 +/- 138% at 100 ms; 278 +/- 148% at 180/ms; and 134 +/- 91% at 220 ms. CONCLUSION: "Shirt flapping" and "neck pounding" frequently occur during AVNRT. LA contractions during AV valve closure increase left atrial pressure and may explain differences in certain symptoms between AVNRT and AVRT.

An unusual case of chronic coronary artery dissection: did cisplatin play a role?

Spontaneous coronary artery dissection is an unusual cause of acute myocardial ischemia. The natural history of spontaneous coronary artery dissection that persists on angiography after the acute event has not been well characterized. A case of a 36-year-old man who presented with monomorphic ventricular tachycardia 12 years following a myocardial infarction that occurred during his last course of bleomycin-etoposide-cisplatin therapy for testicular cancer is reported. On further investigation, coronary angiography revealed a long chronic dissection of the right coronary artery. The patient was successfully treated with medical management and insertion of an implantable cardioverter defibrillator. The case also highlights the increased cardiovascular morbidity in testicular cancer survivors and evokes the possibility of mechanisms of myocardial ischemia other than atherosclerotic disease in these young patients.

The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans.

OBJECTIVES: To determine the acute effects of vernakalant (RSD1235) on electrophysiologic (EP) properties in humans. BACKGROUND: Vernakalant is an investigational mixed ion channel blocker that can terminate acute atrial fibrillation (AF) in humans at 2 to 5 mg/kg and may be more "atrial-selective" than available agents. METHODS: Patients (N=19; 53% male; age, 48+/-11 years) underwent EP study before and after 25 minutes of intravenous vernakalant administration: 2 mg/kg over 10 min+0.5 mg/kg/hr for 35 min or 4 mg/kg over 10 min+1 mg/kg/hr for 35 min. EP measurements, including atrial refractory period (AERP) and ventricular refractory period (VERP), were obtained. RESULTS: The lower dose prolonged AERP at 600, but not at 400 or 300 msec paced cycle length. The higher dose significantly prolonged AERP from 203+/-31 msec to 228+/-24 msec at 600 msec, 182+/-30 msec to 207+/-27 msec at 400 msec, and 172 msec+/-24 to 193+/-21 msec at 300 msec. There was no significant prolongation of VERP at either dose or at any cycle length. There was a small but significant prolongation of AV nodal refractoriness; Wenckebach cycle length prolonged by 18+/-12 msec (from baseline 343+/-54 msec) at the higher dose (P<0.05). Sinus node recovery time also increased by 123+/-158 msec (from baseline 928+/-237 msec) at the higher dose (P<0.05). There was a slight prolongation of QRS duration at the higher dose, during ventricular pacing at CL=400 msec (15+/-15 msec, P=0.0547). QT and HV intervals were unchanged. CONCLUSIONS: At doses similar to those tested clinically, vernakalant dose-dependently prolonged atrial refractoriness, prolonged AV nodal conduction and refractoriness, and slightly prolonged QRS duration, but it had no effect on ventricular refractoriness.

Lithium-induced sinus node disease at therapeutic concentrations: linking lithium-induced blockade of sodium channels to impaired pacemaker activity.

The present report describes a case of sinus node arrest in a manic-depressive patient being treated with lithium carbonate with a therapeutic serum level of lithium. A permanent rate-modulated ventricular pacemaker was inserted and lithium therapy was continued. A review of literature revealed several other similar case reports in which both therapeutic and toxic levels of serum lithium levels were associated with sinus node dysfunction and bradyarrhythmias. Because lithium is a potent blocker of cardiac sodium channels, and given the critical importance of sodium channels in pacemaker activity, lithium-induced sodium channel blockade is likely an important mechanism in sinus node dysfunction.

Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS).

BACKGROUND: The implantable cardioverter defibrillator (ICD) is superior to amiodarone for secondary prophylaxis of sudden cardiac death. However, the magnitude of this benefit over long-term follow-up is not known. Thus, our objective was to evaluate the long-term consequences of using amiodarone versus an ICD as first-line monotherapy in patients with a prior history of sustained ventricular tachycardia/ventricular fibrillation or cardiac arrest. METHODS AND RESULTS: A total of 120 patients were enrolled at St Michael's Hospital in the Canadian Implantable Defibrillator Study (CIDS) and were randomly assigned to receive either amiodarone (n=60) or an ICD (n=60). The treatment strategy was not altered after the end of CIDS unless the initial assigned therapy was not effective or was associated with serious side effects. After a mean follow-up of 5.6+/-2.6 years, there were 28 deaths (47%) in the amiodarone group, compared with 16 deaths (27%) in the ICD group (P=0.0213). Total mortality was 5.5% per year in the amiodarone group versus 2.8% per year in the ICD group (hazard ratio of amiodarone: ICD, 2.011; 95% confidence interval, 1.087 to 3.721; P=0.0261). In the amiodarone group, 49 patients (82% of all patients) had side effects related to amiodarone, of which 30 patients (50% of all patients) required discontinuation or dose reduction; 19 patients crossed over to ICD because of amiodarone failure (n=7) or side effects (n=12). CONCLUSIONS: In a subset of CIDS, the benefit of the ICD over amiodarone increases with time; most amiodarone-treated patients eventually develop side effects, have arrhythmia recurrences, or die.

The burden of atrial fibrillation: should we abandon antiarrhythmic drug therapy?

Atrial fibrillation (AF) is the most common sustained arrhythmia, exacting a substantial toll in cardiovascular morbidity and mortality. Until recently, the prevailing philosophy has been that restoration and maintenance of normal sinus rhythm, as opposed to control of ventricular response rate, was the optimal approach to treatment of AF. A series of landmark trials (AFFIRM, RACE, STAF, and PIAF) have called this strategy into question, suggesting outcomes are equivalent with both approaches. These data do not mean that rhythm control is not beneficial, but highlight the limitations of current therapies to achieve and maintain sinus rhythm. Limitations of the rhythm-control strategy may be related to our difficulty in accurately documenting symptomatic benefit from this approach, the lack of efficacy and excessive adverse-effect burden associated with currently available antiarrhythmic agents, and selection biases in the enrollment of patients in clinical trials of rhythm control versus rate control, making the trials incompletely representative of the population eligible for therapy. New pharmacologic agents under development feature increased atrial selectivity or multi-channel-blocking properties (or both). As a result, these compounds may be more effective in prolonging atrial refractoriness and may also have reduced proarrhythmic potential. It is premature to abandon the concept of rhythm control in AF until we have trials designed to include younger and highly symptomatic patients, more sensitive tools to measure symptomatic improvement, and safer, more effective antiarrhythmic agents.

Biphasic versus monophasic cardioversion in shock-resistant atrial fibrillation:.

UNLABELLED: Biphasic versus Monophasic Cardioversion. INTRODUCTION: Cardioversion of atrial fibrillation using monophasic transthoracic shocks occasionally is ineffective. Biphasic cardioversion requires less energy than monophasic cardioversion, but its efficacy in shock-resistant atrial fibrillation is unknown. Thus, we compared the efficacy of cardioversion using biphasic versus monophasic waveform shocks in patients with atrial fibrillation previously refractory to monophasic cardioversion. METHODS AND RESULTS: Fifty-six patients with prior failed monophasic cardioversion were randomized to either a 360-J monophasic damped sinusoidal shock or biphasic truncated exponential shocks at 150 J, followed by 200 J and then 360 J, if necessary. If either waveform failed, patients were crossed over to the other waveform. The primary endpoint was defined as the proportion of patients achieving sinus rhythm following initial randomized therapy. Stepwise multivariate logistic regression examined independent predictors of shock success, including patient age, sex, left atrial diameter, body mass index, drug therapy, and waveform. Twenty-eight patients were randomized to the biphasic shocks and 28 to the monophasic shocks. Sinus rhythm was restored in 61% of patients with biphasic versus 18% with monophasic shocks (P = 0.001). Seventy-eight percent success was achieved in patients who crossed over to the biphasic shock after failing monophasic cardioversion, whereas only 33% were successfully cardioverted with a monophasic shock after crossover from biphasic shock (P = 0.02). Overall, 69% of patients who received a biphasic shock at any point in the protocol were cardioverted successfully, compared to 21% with the monophasic shock (P < 0.0001). The type of shock was the strongest predictor of shock success (P = 0.0001) in multivariate logistic regression. CONCLUSION: An ascending sequence of 150-, 200-, and 360-J transthoracic biphasic cardioversion shocks are successful more often than a single 360-J monophasic shock. Thus, biphasic shocks should be the recommended configuration of choice for all cardioversions.

Left ventricular performance during acute rate control in atrial fibrillation: the importance of heart rate and agent used.

BACKGROUND: The relation between heart rate and left ventricular function during rate control in atrial fibrillation is incompletely understood. METHODS: Twenty-four patients (age 67 +/- 11 years) with symptomatic recent onset rapid atrial fibrillation and rapid ventricular rate (> 110 bpm) were randomly assigned to receive either intravenous digoxin (13 mcg/kg) or intravenous diltiazem (0.25 mg/kg bolus plus a maintenance infusion). A portable radionuclide detector was used to collect validated measures of relative left ventricular volumes, along with heart rate data, every 15 seconds for 6 hours. RESULTS: Heart rate decreased significantly at 15 minutes and 180 minutes in the diltiazem group (from 133 +/- 18 bpm to 111 +/- 26 bpm [P <.01] to 94 +/- 24 bpm [P <.001]) but not in the digoxin group (from 129 +/- 18 bpm to 126 +/- 17 bpm [P = NS] to 118 +/- 15 bpm [P = NS]). Left ventricular ejection fraction improved in both groups to a similar extent (from 39 +/- 10% to 50 +/- 8%, [P <.05] after diltiazem, and from 38 +/- 8% to 52 +/- 11% [P <.05] after digoxin at baseline vs 180 minutes, respectively). The ejection fraction vs heart rate slope was steeper in the digoxin group than in the diltiazem group (-0.34 +/- 0.18 vs -0.16 +/- 0.17, P =.048) indicating a more pronounced improvement in ejection fraction per unit decrease in heart rate. CONCLUSION: In patients with acute atrial fibrillation, digoxin led to similar improvements in ejection fraction compared to diltiazem despite a slower and less potent heart rate slowing.