Anne S. Hellkamp

Adverse Effect of Ventricular Pacing on Heart Failure and Atrial Fibrillation Among Patients With Normal Baseline QRS Duration in a Clinical Trial of Pacemaker Therapy for Sinus Node Dysfunction

Background Dual‐chamber (DDDR) pacing preserves AV synchrony and may reduce heart failure (HF) and atrial fibrillation (AF) compared with ventricular (VVIR) pacing in sinus node dysfunction (SND). However, DDDR pacing often results in prolonged QRS durations (QRSd) as the result of right ventricular stimulation, and ventricular desynchronization may result. The effect of pacing‐induced ventricular desynchronization in patients with normal baseline QRSd is unknown. Methods and Results Baseline QRSd was obtained from 12‐lead ECGs before pacemaker implantation in MOST, a 2010‐patient, 6‐year, randomized trial of DDDR versus VVIR pacing in SND. Cumulative percent ventricular paced (Cum%VP) was determined from stored pacemaker data. Baseline QRSd <120 ms was observed in 1339 patients (707 DDDR, 632 VVIR). Cum%VP was greater in DDDR versus VVIR (90% versus 58%, P=0.001). Cox models demonstrated that the time‐dependent covariate Cum%VP was a strong predictor of HF hospitalization in DDDR (hazard ratio [HR], 2.99 [95% CI, 1.15 to 7.75] for Cum%VP >40%) and VVIR (HR 2.56 [95% CI, 1.48 to 4.43] for Cum%VP >80%). The risk of AF increased linearly with Cum%VP from 0% to 85% in both groups (DDDR, HR 1.36 [95% CI, 1.09, 1.69]; VVIR, HR 1.21 [95% CI 1.02, 1.43], for each 25% increase in Cum%VP). Model results were unaffected by adjustment for known baseline predictors of HF hospitalization and AF. Conclusions Ventricular desynchronization imposed by ventricular pacing even when AV synchrony is preserved increases the risk of HF hospitalization and AF in SND with normal baseline QRSd. (Circulation. 2003;107:2932‐2937.)

Prognostic importance of defibrillator shocks in patients with heart failure.

BACKGROUND Patients with heart failure who receive an implantable cardioverter-defibrillator (ICD) for primary prevention (i.e., prevention of a first life-threatening arrhythmic event) may later receive therapeutic shocks from the ICD. Information about long-term prognosis after ICD therapy in such patients is limited. METHODS Of 829 patients with heart failure who were randomly assigned to ICD therapy, we implanted the ICD in 811. ICD shocks that followed the onset of ventricular tachycardia or ventricular fibrillation were considered to be appropriate. All other ICD shocks were considered to be inappropriate. RESULTS Over a median follow-up period of 45.5 months, 269 patients (33.2%) received at least one ICD shock, with 128 patients receiving only appropriate shocks, 87 receiving only inappropriate shocks, and 54 receiving both types of shock. In a Cox proportional-hazards model adjusted for baseline prognostic factors, an appropriate ICD shock, as compared with no appropriate shock, was associated with a significant increase in the subsequent risk of death from all causes (hazard ratio, 5.68; 95% confidence interval [CI], 3.97 to 8.12; P<0.001). An inappropriate ICD shock, as compared with no inappropriate shock, was also associated with a significant increase in the risk of death (hazard ratio, 1.98; 95% CI, 1.29 to 3.05; P=0.002). For patients who survived longer than 24 hours after an appropriate ICD shock, the risk of death remained elevated (hazard ratio, 2.99; 95% CI, 2.04 to 4.37; P<0.001). The most common cause of death among patients who received any ICD shock was progressive heart failure. CONCLUSIONS Among patients with heart failure in whom an ICD is implanted for primary prevention, those who receive shocks for any arrhythmia have a substantially higher risk of death than similar patients who do not receive such shocks.

Atrial High Rate Episodes Detected by Pacemaker Diagnostics Predict Death and Stroke Report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST)

Background—Some current pacing systems can automatically detect and record atrial tachyarrhythmias that may be asymptomatic. We prospectively studied a 312-patient (pt) subgroup of MOST (MOde Selection Trial), a 2010-patient, 6-year randomized trial of DDDR versus VVIR pacing in sinus node dysfunction (SND). The purpose of the study was to correlate atrial high rate events (AHREs) detected by pacemaker diagnostics with clinical outcomes. Methods and Results—Pacemakers were programmed to log an AHRE when the atrial rate was >220 bpm for 10 consecutive beats. Analysis was confined to patients with at least 1 AHRE duration exceeding 5 minutes. The 312 patients were median age 74 years, 55% female, and 60% had a history of SVT. 160 of 312 (51.3%) patients enrolled had at least 1 AHRE >5 minutes duration over median follow-up of 27 months. Cox proportional hazards analysis assessed the relationship of AHREs with clinical events, adjusting for prognostic variables and baseline covariates. The presence of any AHRE was an independent predictor of the following: total mortality (hazard ratio AHRE versus no AHRE and 95% confidence intervals=2.48 [1.25, 4.91], P =0.0092); death or nonfatal stroke (2.79 [1.51, 5.15], P =0.0011); and atrial fibrillation (5.93 [2.88, 12.2], P =0.0001). There was no significant effect of pacing mode on the presence or absence of AHREs. Conclusions—AHRE detected by pacemakers in patients with SND identify patients that are more than twice as likely to die or have a stroke, and 6 times as likely to develop atrial fibrillation as similar patients without AHRE.

Heart Failure During Cardiac Pacing

Background— Right ventricular apical (RVA) pacing creates abnormal left ventricular contraction, hypertrophy, and reduced pump function. The adverse effects of ventricular desynchronization may explain the association of RVA pacing with an increased risk of heart failure hospitalization (HFH) in clinical trials. Methods and Results— Baseline and postimplantation variables were used to predict HFH in the Mode Selection Trial, a 2010-patient, 6-year trial of dual-chamber (DDDR) versus ventricular (VVIR) pacing in sinus node dysfunction. A Cox model showed that New York Heart Association (NYHA) class at baseline and follow-up predicted HFH (hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.74–5.79 for NYHA class III/IV and HR, 2.17; 95% CI, 1.54–3.04 for NYHA class II versus class I); other predictors were heart failure (HR, 2.30; 95% CI, 1.70–3.11), atrioventricular (AV) block (HR, 1.48; 95% CI, 1.11–1.97), and myocardial infarction (MI)(HR, 1.37; 95% CI, 1.00–1.86). Postimplantation predictors were VVIR cumulative percent ventricular pacing (Cum%VP) >80 (HR, 3.58; 95% CI, 1.72–7.45), DDDR Cum%VP >40 or VVIR Cum%VP ≤80 (HR, 1.81; 95% CI, 0.94–3.50) versus DDDR Cum%VP ≤40; whether QRS duration (QRSd) was paced or spontaneous (HR, 2.21; 95% CI, 1.39–3.54; spontaneous versus paced); and drugs for atrial fibrillation (HR, 1.60; 95% CI, 1.19–2.15). Low baseline ejection fraction (EF) and postimplantation RVA-paced or spontaneous QRSd predicted HFH; the increased risk with QRSd was steeper for normal versus low EF (HR, 1.18; 95% CI, 1.11–1.27; versus HR, 1.08; 95% CI, 1.01–1.15; for a 10-ms increase); at a QRSd of ≈200 ms, normal- and low-EF patients had equivalent risk. HFH risk nearly doubled when VVIR Cum%VP was ≤80 or DDDR Cum%VP was >40 versus DDDR Cum%VP ≤40 and was additive with other risk factors. Conclusions— Differences in HFH risk can be explained by interactions between substrate (atrial fibrillation, AV conduction, heart failure, MI, EF) and pacing promoters (ventricular desynchronization-paced QRSd and Cum%VP, and AV desynchronization-pacing mode). Management of RVA pacing is important for reducing the risk of HFH, particularly among patients with low EF and heart failure.

Non-Evidence-Based ICD Implantations in the United States

CONTEXT Practice guidelines do not recommend use of an implantable cardioverter-defibrillator (ICD) for primary prevention in patients recovering from a myocardial infarction or coronary artery bypass graft surgery and those with severe heart failure symptoms or a recent diagnosis of heart failure. OBJECTIVE To determine the number, characteristics, and in-hospital outcomes of patients who receive a non-evidence-based ICD and examine the distribution of these implants by site, physician specialty, and year of procedure. DESIGN, SETTING, AND PATIENTS Retrospective cohort study of cases submitted to the National Cardiovascular Data Registry-ICD Registry between January 1, 2006, and June 30, 2009. MAIN OUTCOME MEASURE In-hospital outcomes. RESULTS Of 111,707 patients, 25,145 received non-evidence-based ICD implants (22.5%). Patients who received a non-evidence-based ICD compared with those who received an evidence-based ICD had a significantly higher risk of in-hospital death (0.57% [95% confidence interval {CI}, 0.48%-0.66%] vs 0.18% [95% CI, 0.15%-0.20%]; P <.001) and any postprocedure complication (3.23% [95% CI, 3.01%-3.45%] vs 2.41% [95% CI, 2.31%-2.51%]; P <.001). There was substantial variation in non-evidence-based ICDs by site. The rate of non-evidence-based ICD implants was significantly lower for electrophysiologists (20.8%; 95% CI, 20.5%-21.1%) than nonelectrophysiologists (24.8% [95% CI, 24.2%-25.3%] for nonelectrophysiologist cardiologists; 36.1% [95% CI, 34.3%-38.0%] for thoracic surgeons; and 24.9% [95% CI, 23.8%-25.9%] for other specialties) (P<.001 for all comparisons). There was no clear decrease in the rate of non-evidence-based ICDs over time (24.5% [6908/28,233] in 2006, 21.8% [7395/33,965] in 2007, 22.0% [7245/32,960] in 2008, and 21.7% [3597/16,549] in 2009; P <.001 for trend from 2006-2009 and P = .94 for trend from 2007-2009). CONCLUSION Among patients with ICD implants in this registry, 22.5% did not meet evidence-based criteria for implantation.

Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure Analysis From the Sudden Cardiac Death in Heart Failure Trial

Background— The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown. Methods and Results— SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death. Conclusions— ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000609.

Maximizing Survival Benefit With Primary Prevention Implantable Cardioverter-Defibrillator Therapy in a Heart Failure Population

Background— Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction ≤35%, many such patients do not require ICD shocks over long-term follow-up. Methods and Results— Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), whereas the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest-risk group versus 24% in the highest-risk group (P=0.009 for interaction) and decreased relative risk of total mortality by 54% in the lowest-risk group versus no benefit (2%) in the highest-risk group (P=0.014 for interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0%, and −4.9% across risk quintiles. In highest-risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patients predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. Conclusions— A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

Analysis of Ventricular Activation Using Surface Electrocardiography to Predict Left Ventricular Reverse Volumetric Remodeling During Cardiac Resynchronization Therapy

Background— Cardiac resynchronization therapy for heart failure with left bundle branch block reduces left ventricular (LV) conduction delay, contraction asynchrony, and LV end-systolic volume (“reverse remodeling”). Up to one third of patients do not improve, and the electric requirements for reverse remodeling are unclear. We hypothesized that reverse remodeling is predicted by the left bundle branch block ventricular activation sequence, the paced activation sequence, and interactions between these 2 conditions. Methods and Results— Twelve-lead ECGs during left bundle branch block and cardiac resynchronization therapy were analyzed in 202 consecutive patients (New York Heart Association class III to IV heart failure, ejection fraction ≤35%) for predictors of reverse remodeling (≥10% reduction in end-systolic volume) at 6 months. Greater longest baseline LV activation time predicted increased odds of reverse remodeling (odds ratio [confidence interval]=1.30 [1.11, 1.52] per 10-ms increase), whereas higher QRS scores for LV scar predicted reduced reverse remodeling (odds ratio [confidence interval]=0.49 [0.27, 0.88] for each 1-point increase from 0 to 4; 0.92 [0.83, 1.01] for each 1-point increase >4). After cardiac resynchronization therapy, increasing R amplitudes in leads V1 through V2 (odds ratio [confidence interval]=2.76 [1.01, 7.51] for each 1× increase over [baseline R×4.5]) and left→right frontal axis shift (odds ratio [confidence interval]=2.00 [0.99, 4.02]), indicators of ventricular activation wavefront fusion, were positive predictors of reverse remodeling. Predicted probability of reverse remodeling ranged from <20% for patients with adverse predictors to 99% for those with positive predictors. Conclusions— Ventricular activation with the use of the ECG accurately predicts LV reverse remodeling during cardiac resynchronization therapy. Greater longest baseline LV activation time and smaller scar volume combined with wavefront fusion on the paced ECG, anticipate higher probability of reverse remodeling.

Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation

Background— In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results— The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions— The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up ☆

OBJECTIVES This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI). BACKGROUND Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year. METHODS The Coumadin Aspirin Reinfarction Study (CARS) database contains information on HRT use and menopausal status for women with a recent MI. We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment, new users if they began HRT during the study period or never users. We assessed the incidence of cardiac events (death, MI, unstable angina [UA]) during follow-up. RESULTS In our cohort, 28% (n = 524) used HRT at some point. Of these, 21% (n = 111) began HRT after their MI. New users had a higher incidence of death/MI/UA (41% vs. 28%, p = 0.001) during follow-up than never users, largely due to a higher incidence of UA (39% vs. 20%, p = 0.001). After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]). CONCLUSIONS Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.