Bretylium, a Class III Antiarrhythmic, Returns to the Market.

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.

Inappropriate sinus tachycardia.

Inappropriate sinus tachycardia (IST) is a clinical syndrome, oftentimes debilitating, defined by fast sinus rates (>100 b.p.m. at rest or >90 b.p.m. on average over 24 h and not due to underlying causes) associated with symptoms that may include palpitations, as described in some guidelines and consensus documents. While heart rates may vary by patient, especially based upon gender and age, some individuals experience sinus tachycardia or persistent fast sinus rates with no symptoms; these individuals would not necessarily be considered to have the syndrome of IST. Various explanations for IST have been considered but a definitive common mechanism is not yet known; the true aetiology may be multifactorial. A thorough evaluation of secondary causes of tachycardia is required in the work-up of all cases and if found, must be treated before a diagnosis of IST can be made. Finally, effective treatments vary but can include ivabradine, beta-blockers, or calcium channel antagonists; ablation is seldom advised.

Conventional management of inappropriate sinus tachycardia.

Inappropriate sinus tachycardia is a challenging problem to manage. There are limited data on the best method to evaluate and treat the problem. Here, we consider a conventional approach to inappropriate sinus tachycardia.

Syncope in Patients with Organic Heart Disease.

Patients with syncope and organic heart disease remain a small but important subset of those patients who experience transient loss of consciousness. These patients require thoughtful and complete evaluation in an attempt to better understand the mechanism of syncope and its relationship to the underlying disease, and to diagnose and treat both properly. The goal is to reduce the risk of further syncope, to improve long-term outcomes with respect to arrhythmic and total mortality, and to improve patients' quality of life.

Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial.

BACKGROUND: Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin. OBJECTIVES: This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. METHODS: Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization. RESULTS: In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant. CONCLUSIONS: Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone.

Hormone replacement therapy and adverse outcomes in women with atrial fibrillation: an analysis from the atrial fibrillation follow-up investigation of rhythm management trial.

BACKGROUND AND PURPOSE: Hormone replacement therapy (HRT) use has been related to thromboembolism, but whether HRT increases adverse outcomes in females with atrial fibrillation is uncertain. METHODS: We used the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data set that included 1594 women (39.3% of the population, mean age 71±8), of whom 376 (23.6%) were taking HRT at baseline. The primary end point, a composite of all-cause death, stroke, systemic/pulmonary embolism, and myocardial infarction, and secondary outcomes (ie, each individual end point) and major bleeding, were considered. RESULTS: HRT was not independently associated with the primary end point (hazard ratio=0.894; 95% confidence interval, 0.658-1.214; P=0.473) or any secondary outcome. Age (P<0.001), diabetes mellitus (P<0.001), previous stroke (P=0.011), and heart failure (P<0.001) predicted the primary end point. Lack of association between HRT and the primary end point was confirmed in a propensity score-matched control group (hazard ratio=0.966; 95% confidence interval, 0.663-1.409; P=0.858). CONCLUSIONS: HRT does not independently predict mortality, thromboembolism, or bleeding in a large cohort of women with atrial fibrillation.

Sports and exercise cardiology in the United States: cardiovascular specialists as members of the athlete healthcare team.

In recent years, athletic participation has more than doubled in all major demographic groups, while simultaneously, children and adults with established heart disease desire participation in sports and exercise. Despite conferring favorable long-term effects on well-being and survival, exercise can be associated with risk of adverse events in the short term. Complex individual cardiovascular (CV) demands and adaptations imposed by exercise present distinct challenges to the cardiologist asked to evaluate athletes. Here, we describe the evolution of sports and exercise cardiology as a unique discipline within the continuum of CV specialties, provide the rationale for tailoring of CV care to athletes and exercising individuals, define the role of the CV specialist within the athlete care team, and lay the foundation for the development of Sports and Exercise Cardiology in the United States. In 2011, the American College of Cardiology launched the Section of Sports and Exercise Cardiology. Membership has grown from 150 to over 4,000 members in just 2 short years, indicating marked interest from the CV community to advance the integration of sports and exercise cardiology into mainstream CV care. Although the current athlete CV care model has distinct limitations, here, we have outlined a new paradigm of care for the American athlete and exercising individual. By practicing and promoting this new paradigm, we believe we will enhance the CV care of athletes of all ages, and serve the greater athletic community and our nation as a whole, by allowing safest participation in sports and physical activity for all individuals who seek this lifestyle.

Does change in device detected frequency of non-sustained or diverted episodes serve as a marker for inappropriate shock therapy? Analyses from the INTRINSIC RV and ALTITUDE-REDUCES Trials.

AIMS: Implantable cardioverter-defibrillators (ICDs) treat ventricular tachycardia or fibrillation but may also deliver unnecessary shocks. We sought to determine if the frequency of ICD-detected non-sustained or diverted (NSD) episodes increases before appropriate or inappropriate ICD shocks. METHODS AND RESULTS: We evaluated NSD episodes in the INTRINSIC RV Trial and their relationship to ICD shocks (appropriate and inappropriate). Time from NSD to shock was analysed. Results were validated by utilizing 1495 adjudicated ICD and cardiac resynchronization therapy-defibrillator shocks following NSD episodes collected through the LATITUDE remote monitoring system as part of the ALTITUDE-REDUCES Study. In INTRINSIC RV, 185 participants received 373 shocks; 148 had at least 1 NSD episode. Non-sustained or diverted frequency increased 24 h before the first shock for those receiving an inappropriate (P < 0.01) but not an appropriate shock (P = 0.17). Patients with NSD episodes within 24 h of a shock were significantly more likely to receive inappropriate therapy [odds ratio (OR) = 3.12, P < 0.01]. At the receiver operator curve determined optimal cutoff, an NSD episode within 14 min before shock strongly predicted inappropriate therapy (sensitivity 48%, specificity 91%; OR = 8.8, and P < 0.001). The 14 min cut-off evaluated on an independent dataset of 1495 shock episodes preceded by an NSD in the ALTITUDE-REDUCES Study confirmed these results (sensitivity = 47%, specificity = 85%, OR = 5.0, and P < 0.001). CONCLUSION: Device-detected NSD episodes increase before inappropriate but not appropriate shocks. Novel alerts or automated algorithms based on NSD episodes may reduce inappropriate shocks.

Left ventricular geometry and outcomes in patients with atrial fibrillation: the AFFIRM Trial.

BACKGROUND: Echocardiographically determined left ventricular hypertrophy (LVH) is a marker of cardiovascular disease related to prognosis and clinical outcomes. We sought to determine if LVH is a measure of outcomes in atrial fibrillation (AF) patients. METHODS: We performed a post-hoc analysis of patients with echocardiographic data enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Trial. Patients were stratified based on gender-adjusted echocardiography derived interventricular septal (IVS) thickness, relative wall thickness (RWT), gender-adjusted LV mass, and type of LV remodeling (normal LV geometry, concentric hypertrophy, eccentric hypertrophy, and concentric remodeling). RESULTS: Of 4060 patients in AFFIRM, echocardiographic data were available in 2433 patients (60%). Multivariate analysis revealed that LVH defined as moderately or severely abnormal IVS thickness was an independent predictor of both all cause mortality (HR 1.46, 95%CI 1.14-1.86, p=0.003) and stroke (HR 1.89, 95%CI 1.17-3.08, p=0.01). This association was confirmed when IVS thickness was assessed as continuous or categorical variable. Concentric LV hypertrophy was associated with the highest rates of all cause mortality (HR 1.53; 95%CI 1.11-2.12; p=0.009). CONCLUSION: An easily obtained echocardiographic index of LVH (IVS thickness) may enhance risk stratification of patients with AF, and raise the possibility that LVH regression should be a therapeutic target in this population.

Amiodarone, Anticoagulation, and Clinical Events in Patients With Atrial FibrillationInsights From the ARISTOTLE Trial

Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin.Objectives This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.Methods Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization.Results In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98)...

Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score.

BACKGROUND: When oral anticoagulation with adjusted-dose vitamin K antagonist (VKA) is used, the quality of anticoagulation control (as reflected by the time in therapeutic range [TTR] of the international normalized ratio [INR]) is an important determinant of thromboembolism and bleeding. Our objective was to derive a validated scheme using patient-related clinical parameters to assess the likelihood of poor INR control among patients with atrial fibrillation (AF) on VKA therapy. METHODS: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial population was randomly divided into derivation and internal validation cohorts using a 1:1 ratio. We used linear regression analysis to detect the clinical factors associated with TTR and binary logistic regression to evaluate the predictive performance of a model incorporating these factors for different cutoff values of TTR. The derived model was validated externally in a cohort of patients receiving anticoagulant therapy who were recruited prospectively. RESULTS: In the linear regression model, nine variables emerged as independent predictors of TTR: female sex (P < .0001), age < 50 years (P < .0001), age 50 to 60 years (P = .02), ethnic minority status (P < .0001), smoking (P = .03), more than two comorbidities (P < .0001), and being treated with a ß-blocker (P = .02), verapamil (P = .02), or, inversely, with amiodarone (P = .05). We incorporated these factors into a simple clinical prediction scheme with the acronym SAMe-TT2R (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]). The score demonstrated good discrimination performance in both the internal and external validation cohorts (c-index, 0.72; 95% CI, 0.64-0.795; and c-index, 0.7; 95% CI, 0.57-0.82, respectively). CONCLUSIONS: Common clinical and demographic factors can influence the quality of oral anticoagulation. We incorporated these factors into a simple score (SAMe-TT2R2) that can predict poor INR control and aid decision-making by identifying those patients with AF who would do well on VKA (SAMe-TT2R2 score = 0-1), or conversely, those who require additional interventions to achieve acceptable anticoagulation control (SAMe-TT2R2 score ≥ 2).

Sudden death risk in syncope: the role of the implantable cardioverter defibrillator.

Syncope is generally benign but when it is due to an underlying cardiovascular condition, the prognosis can be guarded. Patients with syncope may be at risk of dying suddenly from a ventricular arrhythmia especially if the collapse is caused by a poorly-tolerated, self-terminating, ventricular tachycardia (VT). If a similar VT recurs, and persists, it could initiate cardiac arrest, leading to sudden cardiac death. However, distinguishing which patient with syncope may benefit most from implantable cardioverter defibrillator (ICD) therapy, which can stop life-threatening and poorly tolerated VT, thereby preventing sudden cardiac death, remains an ongoing challenge. Careful assessment of the patient's underlying cardiovascular conditions, scrupulous attention to historical detail to assess potential causes for syncope, and risk stratification based upon clinical characteristics and short and long-term risks can help. This review focuses on the sudden death risk in patients with syncope and explores the role of the ICD to treat ventricular arrhythmias, prevent symptoms, and prevent death.

Inappropriate sinus tachycardia.

Inappropriate sinus tachycardia (IST) is a syndrome in which the sinus heart rate is inexplicably faster than expected and associated symptoms are present. The heart rate at rest, even in a supine position, can exceed 100 beats/min; minimal activity accelerates the rate rapidly and substantially. Patients with IST may require restriction from physical activity. Mechanisms responsible for IST are understood incompletely. It is important to distinguish IST from so-called appropriate sinus tachycardia and from postural orthostatic tachycardia syndrome, with which overlap may occur. Because the long-term outcome seems to be benign, treatment may be unnecessary or may be as simple as physical training. However, for patients with intolerable symptoms, therapeutic measures are warranted. Even at high doses, ß-adrenergic blockers, the first-line therapy, often are ineffective; the same is true for most other medical therapies. In rare instances, catheter- or surgically- based right atrial or sinus node modification may be helpful, but even this is fraught with limited efficacy and potential complications. Overtreatment, in an attempt to reduce symptoms, can be difficult to avoid, but is discouraged.

Do baseline diastolic echocardiographic parameters predict outcome after resynchronization therapy? Results from the PROSPECT trial.

INTRODUCTION: Cardiac resynchronization therapy (CRT) can improve clinical and cardiac structural status in heart failure patients. The role of baseline diastolic echocardiographic parameters to characterize the likelihood of positive outcomes is not well known. We explored relationships between diastolic parameters and outcomes 6 months after CRT implant in the Predictors of Response to CRT (PROSPECT) Trial. HYPOTHESIS: We hypothesized that diastolic echocardiographic parameters were associated with clinical and structural outcomes in CRT patients. METHODS: For 426 patients in PROSPECT, a prospective observational trial of CRT, baseline E/A ratio, left atrial (LA) area, isovolumic relaxation time, left ventricular inflow deceleration time, E' velocity, and E/E' ratio were evaluated and related to 6-month clinical composite score (CCS) and left ventricular end-systolic volume (LVESV) reduction using Spearman rank-order correlations. Parameters associated with outcomes were analyzed further by discrete categorization. RESULTS: As continuous variables, only E/A ratio and LA area correlated with CCSs (P = 0.017, P = 0.045, respectively) and relative change in LVESV at 6 months (P < 0.0001, P = 0.001, respectively). As discrete variables, E/A ratio and LA area also correlated with CCSs and LVESV. CONCLUSION: Diastolic echo parameters E/A ratio and LA area were associated with clinical and structural outcomes in CRT patients at 6 months.

Relation of gender-specific risk of ischemic stroke in patients with atrial fibrillation to differences in warfarin anticoagulation control (from AFFIRM).

Warfarin decreases risk of stroke for patients with atrial fibrillation (AF) dependent on percent time in the therapeutic range (TTR) with an international normalized ratio (INR) of 2 to 3. We hypothesized that gender differences in ischemic stroke risk are related to TTR. From the AFFIRM database of 4,060 patients with AF, we determined the incidence of ischemic stroke by gender. We evaluated the INR at time of ischemic stroke and calculated TTR. We determined the relation between gender and ischemic stroke by TTR. Women had CHADS(2) Scores (3.7 ± 1.3 vs 2.5 ± 1.3, p <0.0001) and more ischemic strokes than men (5% vs 3%, odds ratio 1.6, 95% confidence interval 1.19 to 2.26, p = 0.002). Mean INR near time of ischemic stroke was 2 for women and men; median values were subtherapeutic (1.7 and 1.8, respectively). Women spent more time outside the therapeutic range (40 ± 0.7% vs 37 ± 0.5%, p = 0.0001), with more time below the therapeutic range (29 ± 0.7% vs 26 ± 0.5%, p = 0.0002). A higher TTR protected against ischemic stroke for women but not for men. Women who had a comparably high TTR (≥66%) still had more ischemic strokes (p = 0.009). A fitted Cox proportional hazard regression model showed that gender, TTR <46% versus >80%, age, and previous stroke were significantly related to stroke incidence. In conclusion, women in AFFIRM were at greater risk of ischemic stroke than men, in part related to differences in TTR. Women with AF may benefit from more aggressive or novel anticoagulation to decrease their risk of stroke.

Does cardiac resynchronization therapy provide unrecognized benefit in patients with prolonged PR intervals? The impact of restoring atrioventricular synchrony: an analysis from the COMPANION Trial.

BACKGROUND: The influence of PR prolongation on outcomes after cardiac resynchronization therapy (CRT) is uncertain. OBJECTIVE: To determine whether PR prolongation predicts outcomes in potential CRT candidates and whether CRT benefits these candidates regardless of baseline PR interval. METHODS: A database of 1520 patients fulfilling criteria for CRT implant (the COMPANION Trial) was examined. Patients assigned to normal (PR < 200 ms) or prolonged (PR ≥ 200 ms) cohorts were compared within the optimal pharmacologic therapy (OPT) and CRT groups regarding an endpoint of all-cause mortality or heart failure hospitalization. CRT was compared with OPT in normal and prolonged PR interval groups. An interaction test was performed to determine whether CRT influenced outcome as a function of PR interval. RESULTS: PR prolongation was present in 52% of COMPANION subjects. Randomization to CRT was associated with a reduction in the endpoint, but the strength of the association was greater for those with prolonged PR (hazard ratio = 0.54; P <.01) versus normal PR (hazard ratio = 0.71; P = .02) intervals. CRT (vs OPT) was associated with reduction in the endpoint for subjects with normal or prolonged PR intervals. Reduction in relative risk (CRT vs OPT) was 29% (P = .02) for those with normal PR intervals but was 46% (P <.01) for those with PR prolongation. No interaction was detected between PR interval cohort and treatment (P = .17). CONCLUSIONS: PR prolongation may affect mortality and heart failure hospitalizations in patients with systolic dysfunction, heart failure, and wide QRS complexes. The effect of PR prolongation may be attenuated by CRT.

Arrhythmia rate distribution and tachyarrhythmia therapy in an ICD population: results from the INTRINSIC RV trial.

BACKGROUND: Appropriate implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) depends, in part, on the programming of tachycardia zones. OBJECTIVE: We assessed events treated with ICD shocks or antitachycardia pacing (ATP) in the Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) trial. METHODS: ATP and shock episodes from 1530 patients with dual-chamber ICDs were analyzed. RESULTS: For episodes in which electrograms were stored and adjudicated, ATP was delivered for 763 episodes (182 patients), shock-only was delivered for 300 episodes (146 patients), and shock following ATP was delivered for 81 episodes (56 patients). ATP was delivered appropriately for 507 episodes (130 patients), with 93% success, and inappropriately for 256 episodes (89 patients). For ATP episodes, appropriate (VT: 170 ± 28 bpm) and inappropriate (not VT: 165 ± 21 bpm) rates did not differ (P = .16). When the initial therapy was shock, onset rates were higher for appropriate therapy than for inappropriate therapy (224 ± 46 bpm vs 187 ± 31 bpm; P <.001). Inappropriate ATP was more likely to be followed by a shock (odds ratio 2.49; 95% confidence interval 1.56-3.97; P <.001). Fifty-eight percent (225 of 381) of shocked episodes had rates <200 bpm. For episodes between 200 and 250 bpm, 20% (23 of 113) were polymorphic VT or VF, 59% were monomorphic VT, 19% were supraventricular, and <1% was artifact. For episodes >250 bpm, 37% were VF, 28% polymorphic VT, 23% monomorphic VT, 7% supraventricular, and 5% artifact. CONCLUSIONS: In a general ICD population, ATP treated VT effectively or obviated the need for shock. Most ventricular arrhythmias <250 bpm were not VF. Proper zone programming may identify and treat VT without shock.