Author + information
- Received September 17, 2015
- Revision received February 18, 2016
- Accepted February 23, 2016
- Published online May 10, 2016.
- Anne B. Curtis, MDa,∗ (, )
- Seth J. Worley, MDb,
- Eugene S. Chung, MDc,
- Pei Li, PhDd,
- Shelly A. Christman, PhDd and
- Martin St. John Sutton, MBBSe
- aDepartment of Medicine, University at Buffalo, Buffalo, New York
- bThe Heart Group, Lancaster General Health, Lancaster, Pennsylvania
- cOhio Heart and Vascular, The Christ Hospital Health Network, Cincinnati, Ohio
- dMedtronic, PLC, Mounds View, Minnesota
- eCardiovascular Medicine Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Anne B. Curtis, University at Buffalo, 100 High Street, D2-76, Buffalo, New York 14203.
Background Sustained right ventricular (RV) apical pacing may lead to deterioration in ventricular function and an increased risk of heart failure, especially in patients with pre-existing systolic dysfunction. The BLOCK HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) trial demonstrated that biventricular-paced patients had a reduced incidence of a composite endpoint of death, heart failure–related urgent care, and adverse left ventricular remodeling.
Objectives In a pre-specified analysis, this study examined clinical outcomes, including clinical composite score, quality of life (QOL), and change in New York Heart Association (NYHA) functional classification.
Methods The BLOCK HF trial randomized patients with atrioventricular block, NYHA symptom class I to III heart failure, and left ventricular ejection fraction ≤50% to biventricular or RV pacing. NYHA functional classification, QOL, and clinical composite score were assessed at 6, 12, 18, and 24 months. Bayesian statistical methods were used, with the pre-specified metric of benefit being a posterior probability ≥0.95.
Results Patients with biventricular pacing showed greater improvement in NYHA functional class at 12 months, with 19% improved, 61% unchanged, and 17% worsened, compared with 12%/62%/23% in the RV arm. QOL was improved through 12 months. At 6 months, clinical composite score was improved/unchanged/worsened in 53%/24%/24% in the biventricular arm compared with 39%/33%/28% in the RV arm. This improvement in clinical composite score was sustained through 24 months.
Conclusions For patients with atrioventricular block and systolic dysfunction, biventricular pacing not only reduces the risk of mortality/morbidity, but also leads to better clinical outcomes, including improved QOL and heart failure status, compared with RV pacing. (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block [BLOCK HF]; NCT00267098)
- atrioventricular block
- biventricular pacing
- cardiac resynchronization therapy
- heart failure
- quality of life
Clinical trials have shown that long-term right ventricular (RV) pacing can lead to worse outcomes compared with low-rate (backup) ventricular pacing in patients with pacemakers and implantable cardioverter defibrillators who have intact atrioventricular conduction (1,2). For such patients, algorithms that minimize ventricular pacing yet provide ventricular rate support when needed have become widely adopted (3). However, patients with atrioventricular block may require pacing all or most of the time. The BLOCK HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) study (4) tested the hypothesis that, in patients with atrioventricular block, left ventricular ejection fraction (LVEF) ≤50%, and New York Heart Association (NYHA) functional class I to III symptoms, biventricular pacing would be superior to RV pacing with respect to a combined endpoint of death, heart failure–related urgent care, or adverse left ventricular remodeling as manifested by a ≥15% increase in left ventricular end systolic volume index. The trial showed a 26% reduction in the combined endpoint in favor of biventricular pacing (5). In addition to morbidity and mortality, clinical outcomes are also vitally important in patients with atrioventricular block and left ventricular dysfunction. In a pre-specified analysis, our specific aim was to examine clinical outcomes, including quality of life (QOL), NYHA functional classification, and clinical composite score in patients in BLOCK HF.
Enrollment criteria for the prospective, multicenter, randomized, double-blind, controlled BLOCK HF trial have been published previously (4). All patients had a standard class I or IIa indication for permanent pacing due to atrioventricular block, NYHA functional class I to III systolic heart failure, and LVEF ≤50%. Patients with permanent atrial arrhythmias who had intrinsic atrioventricular block or atrioventricular block due to atrioventricular node ablation, as well as patients meeting class I indications for implantable cardiac defibrillators, were enrolled. All subjects received either a cardiac resynchronization therapy (CRT) pacemaker (CRT-P) or defibrillator (CRT-D) and received RV pacing for 30 to 60 days while heart failure medical therapy was optimized. Subjects were subsequently randomly assigned in a 1:1 ratio to receive biventricular (both RV and left ventricular pacing outputs ON) or RV (RV pacing output ON, left ventricular pacing output OFF) pacing, and underwent an echocardiographic examination at randomization and 6, 12, 18, and 24 months post-randomization.
Pre-specified outcomes included the Packer clinical composite score (6), QOL, and NYHA functional class. The Packer clinical composite score classifies each patient into 1 of 3 categories (improved, worsened, unchanged), and is determined using clinical outcomes, heart failure status, and patient symptoms. Subjects are assigned a score of worsened if they have died, experienced a heart failure hospitalization, discontinued therapy due to worsening heart failure, experienced worsening symptoms as defined by higher NYHA functional classification, or have developed moderately or markedly worse symptoms relative to baseline as determined by the subject. In the absence of a score of worsened, the subject receives a score of improved if they have experienced improvement in NYHA functional classification relative to baseline or have had moderately or markedly reduced symptoms as determined by the subject. A score of unchanged is assigned if none of these criteria are met. QOL was measured using the Minnesota Living With Heart Failure Questionnaire. Each endpoint was assessed at 6, 12, 18, and 24 months. Changes at follow-up were compared with randomization.
An adaptive Bayesian study design was used, including sample size re-estimation that would halt enrollment once pre-specified criteria for either futility or eventual success were met. There were 2 interim analyses to curtail follow-up if there was sufficient evidence to conclude the primary objective was met. The trial was designed to follow all randomized subjects through at least 12 months of follow-up unless the trial was halted at an interim analysis.
Clinical endpoints at the 6-, 12-, 18-, and 24-month visits were a subject’s clinical composite score, absolute change in NYHA functional classification from randomization, and absolute change in QOL from randomization. For the QOL and NYHA analyses, at each time point, only subjects with paired data (values at randomization and the time point of interest) were included in the analysis. In the case of the clinical composite score, the last observation carried forward (LOCF) method was used, which did not require a subject to complete a follow-up visit at the time point of interest to be included in the corresponding analysis. However, to prevent artificial extension of a subject’s status due to study closure, subjects were excluded from the analysis at a given time point if: 1) the subject had not died, experienced a heart failure hospitalization or discontinuation of randomized therapy due to worsening heart failure; and 2) did not complete a visit at that time point due to the study being stopped before the subject having the opportunity to complete the visit.
NYHA functional class change from randomization was assigned a value from −3 to +3 depending on how many classes the subject worsened or improved at that time point. For clinical composite score, the scores coded worsened were assigned a value of −1, unchanged, a value of 0, and improved, a value of +1. In the case of QOL, the difference between randomization and follow-up served as the endpoint. The primary metrics of analysis were: 1) the posterior distribution, which for an endpoint reflects the likely set of values the endpoint can take based on pre-trial assumptions and accumulated data; and 2) the 95% credible interval, which is generated from the 2.5th and 97.5th percentiles of the posterior distribution and reflects the range of values the endpoint can take with 95% probability. For each endpoint, the pre-specified threshold for demonstrating biventricular therapy superiority statistically was a posterior probability (PP) of at least 0.95, which would indicate that, on average, patients with biventricular therapy had superior endpoint measures compared with patients with RV therapy.
A nonparametric method was used to compare clinical composite score and changes in NYHA functional class over time between randomization arms. For each time point (e.g., 6 months), the endpoints were ranked across randomization arms. Letting μBiV and μRV denote the average rank in each arm, flat priors were assigned to these quantities, ensuring the posterior means would be the respective sample means (ӯBiV, ӯRV), and the posterior standard deviations would be the sample standard errors (sBiV/√nBiV, sRV/√nRV). The posterior distribution for μBiV − μRV is N(ӯBiV − ӯRV, s2BiV/nBiV + s2RV/nRV). Under this distribution, if P(μBiV − μRV < 0) ≥0.95, it was concluded that the difference between therapy groups was important and patients with biventricular pacing performed better at that time point than patients with RV pacing.
In the analysis of QOL, for each time point, let XBiV and XRV denote the (randomization − time point of interest) change in QOL score of randomly selected subjects from the biventricular pacing arm and RV pacing arm, respectively. Then XBiV ∼ N(μBiV, σ2BiV) and XRV ∼ N(μRV, σ2RV). The prior distributions for μBiV and μRV were assumed to be N(0, 102), and the prior distributions for 1/σ2BiV and 1/σ2RV were assumed to be gamma (0.001, 0.001), which had a mean of 1 and variance of 1,000. The marginal posterior distribution for μBiV − μRV was computed, and if the PP denoting P (μBiV − μRV > 0|data, prior) ≥0.95, it was concluded that patients with biventricular pacing saw greater improvement in QOL at that time point than patients with RV pacing.
Sensitivity analyses were performed to account for crossovers. For both NYHA functional class and QOL, subjects who crossed over in their first 24 months had their most recent pre-crossover value substituted for all post-crossover endpoint values (LOCF). Because clinical composite score includes discontinuation of therapy due to heart failure as a component, sensitivity analyses were not necessary for this endpoint.
Poolability analyses were performed for each endpoint to assess differences between device groups. This was done by performing the analyses previously discussed within each device group, then determining the posterior distribution for the CRT-P − CRT-D difference with respect to μBiV − μRV. A 95% 2-sided credible interval for this difference was generated, and if that interval contained 0 (reflecting equivalence between the device groups), the data were considered poolable across device groups.
A total of 918 patients were enrolled from December 2003 through November 2011 at 58 sites in the United States and 2 sites in Canada. Of enrolled subjects, 691 were randomized, with 349 allocated to biventricular pacing and 342 allocated to RV pacing (Figure 1). Within device groups (CRT-P and CRT-D), demographics were comparable between arms at randomization (Table 1). Poolability analyses did not show significant differences between CRT-D and CRT-P groups in the biventricular–RV comparison, and so data were pooled across device groups for the main analyses. Follow-up compliance across the 6-, 12-, 18-, and 24-month visits was 94.7%, 94.2%, 92.7%, and 92.7%, respectively. Crossovers were more prevalent in the RV arm than the biventricular arm (Figure 1). There were 104 crossovers (86 in the RV arm, 18 in the biventricular arm) that occurred post-randomization. Among the biventricular-paced subjects, 11 crossovers were due to diaphragmatic stimulation. Fourteen of the crossovers occurred within 24 months of randomization. Among the 86 RV-paced subjects who crossed over, 71 did so due to worsening heart failure, whereas 7 were due to programming errors. Fifty-four of the 86 subjects who crossed over to biventricular pacing met a primary endpoint before crossover.
Packer clinical composite score
Biventricular pacing was superior to RV pacing at all time points (Table 2) (PP ≥ 0.99). At 6 months, 53% of biventricular subjects improved, 24% were unchanged, and 24% worsened, whereas with RV subjects, 39% improved, 33% were unchanged, and 28% worsened. This was a consistent finding at each time point and typifies the magnitude of response to biventricular pacing in heart failure patients (7–9). The greater percentage worsening observed in the RV arm was driven by heart failure hospitalizations and crossovers due to worsening heart failure. Only crossovers for worsening heart failure were included in the clinical composite score results; crossovers for other reasons were not. Table 2 shows a breakdown of the components of the clinical composite score that contributed to a finding of worsened or improved at 6 and 12 months.
NYHA functional classification
At randomization, 13.2% of biventricular-paced subjects and 18.4% of the RV-paced subjects (Table 1) were NYHA functional class I and therefore could not show improvement over time. At 12 months, the biventricular arm had greater improvement in NYHA functional class (PP = 0.99), with more than 19% improved, 61% unchanged, and more than 17% worsened, compared with the RV arm, which had more than 12% improved, 62% unchanged, and more than 23% worsened (Figure 2A). The differences between biventricular and RV pacing at the other time points did not meet the threshold of statistical benefit. Because subjects who crossed over from RV to biventricular pacing due to worsening heart failure may benefit from biventricular pacing, a sensitivity analysis was done substituting NYHA functional classification values at the time of crossover or the most recent value before crossover for post-crossover scores. Bayesian analysis using LOCF also showed superior improvement in NYHA functional class at 18 and 24 months among biventricular-paced subjects (PP ≥0.95) (Figure 2B), suggesting that in addition to having fewer subjects at later time points due to the trial design, the results at 18 and 24 months may have been influenced by the imbalance in crossovers between the 2 arms.
Quality of life
QOL was superior (PP ≥0.95) for biventricular-paced compared with RV-paced patients through 12 months of follow-up. The average QOL scores at randomization among subjects randomized to the biventricular and RV arms were 26.8 and 24.9, respectively. Subjects in the biventricular arm improved from randomization by an average of 5 units at 6 months and 3.9 units at 12 months, compared with a negligible improvement in the RV arm over a similar time frame (Central Illustration). At later time points, average improvements of 2.3 to 2.6 units were observed in the biventricular arm, but the differences were not significant compared with the RV arm. However, when the analysis was redone mitigating the effect of crossovers (similar LOCF analysis as with NYHA functional class), the observed average improvements in the RV arm at 18 and 24 months observed in the main analysis did not occur. Superiority of biventricular pacing was demonstrated at 6, 12, and 18 months (Central Illustration), whereas at 24 months, the difference had high PP (PP = 0.93).
This analysis of the BLOCK HF trial demonstrates that important clinical outcomes are improved with biventricular pacing compared with RV pacing in patients with atrioventricular block, left ventricular dysfunction, and NYHA functional class I to III symptoms.
Clinical outcomes with CRT in advanced heart failure
A number of prior studies of CRT for the treatment of advanced heart failure with prolonged QRS duration have demonstrated favorable changes in QOL, exercise capacity, and NYHA functional class with biventricular pacing. The MIRACLE (Multicenter InSync Randomized Clinical Evaluation) study found that, in patients with NYHA functional class III to IV symptoms, LVEF ≤35%, and QRS duration >130 ms, CRT compared with a control group was associated with improvement in 6-min walk time (+39 vs. +10 m, p = 0.005), functional class (p < 0.001), and QOL using the Minnesota Living With Heart Failure Questionnaire (−18.0 vs. −9.0 points, p = 0.001) (7). Sixty-eight percent (68%) of the CRT patients had improvement of 1 or more NYHA functional classes, 30% were unchanged, and only 2% were worse. The clinical composite score also significantly improved with biventricular pacing. In the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial, the findings of an exercise substudy were that 6-min walk distance, NYHA functional class, and QOL improved at 6 months compared with the group on optimal medical therapy (10). The CARE-HF (Cardiac Resynchronization–Heart Failure) study had long-term follow-up of QOL in patients with moderate-to-severe heart failure who received CRT and found that, with a median follow-up of 29.6 months, QOL was significantly improved at every time point (p < 0.0001) compared with optimal medical therapy (mean difference in disease-specific QOL score of 10.7, mostly due to improved physical functioning) (11). Of note, in all these trials, the patients studied had more advanced heart failure, which is associated with worse QOL at baseline and thus with a correspondingly greater room for improvement with effective therapy.
Clinical outcomes with CRT in mild heart failure
Several more recent studies have investigated the use of CRT in less advanced heart failure. In the REVERSE (Remodeling in Systolic Left Ventricular Dysfunction) study, patients with NYHA functional class I to II symptoms, QRS ≥120 ms, and an LVEF ≤40% received CRT devices (CRT-P or CRT-D) and were randomized to CRT-ON or CRT-OFF (9). The primary endpoint was the clinical composite score at 12 months, which worsened in 16% of the patients with CRT-ON versus 21% in the CRT-OFF group (p = 0.10). Although there was not a significant difference in clinical composite score between the 2 groups at 12 months, the European cohort of the study was followed out to 2 years, and in this group, 19% of CRT-ON patients worsened versus 34% in the CRT-OFF group (p = 0.01). There was also favorable left ventricular reverse remodeling and a delay in time to death or first heart failure hospitalization (12).
The MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) randomized patients with an LVEF ≤30%, QRS ≥130 ms, and NYHA functional class I to II symptoms to a CRT-D or an implantable cardioverter defibrillator alone (13). The CRT-D group had a significant reduction in the primary endpoint, death or nonfatal heart failure event. The QOL substudy used the Kansas City Cardiomyopathy Questionnaire. During a mean follow-up of 2.4 years, the CRT-D group had a greater improvement in all measures (p < 0.05), although the benefit was limited to those with left bundle branch block at baseline (p < 0.01 vs. p = not significant in those without left bundle branch block) (14).
The RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure) trial randomized patients with NYHA functional class II to III heart failure, QRS >120 ms, and an LVEF <30% to CRT-D or implantable cardioverter defibrillator alone (15). The primary outcome, death or hospitalization for heart failure, was significantly reduced in the CRT-D arm. In addition, patients treated with CRT-D showed a trend for a greater improvement in Minnesota Living With Heart Failure score between baseline and 6 months (CRT-D 41 ± 21 to 31 ± 21; implantable cardioverter defibrillator 33 ± 20 to 28 ± 20; p = 0.057) (16).
The MIRACLE ICD II (Multicenter InSync ICD Randomized Clinical Evaluation II) trial randomized patients with NYHA functional class II symptoms, LVEF ≤35%, and a QRS ≥130 ms to CRT-D or implantable cardioverter defibrillator therapy alone (8). The primary outcome measure, change in peak Vo2 at 6 months, was not significantly different between the 2 arms of the study. Among the pre-specified secondary outcome measures, LVEF improved, ventricular volumes decreased, and there were significant improvements in NYHA functional class and clinical composite score in patients randomized to CRT-D therapy. On the other hand, there was no difference in 6-min walk distance or QOL score.
In a meta-analysis of CRT trials in less symptomatic heart failure patients that included these aforementioned trials, the overall conclusion was that CRT reduced mortality and heart failure hospitalizations, but it did not have a significant impact on functional outcomes or QOL (17). In a more recent meta-analysis, Chen et al. (18) found that QOL improved with CRT, but only in NYHA functional class III to IV patients, not those with milder heart failure. Given the milder degrees of heart failure in these studies, the likelihood is that longer durations of follow-up would be necessary to demonstrate better clinical outcomes compared to those with more advanced heart failure.
Clinical outcomes in the BLOCK HF study
In the context of the aforementioned clinical trials, it might have been expected that it would be challenging to demonstrate improvement in endpoints such as clinical composite score in the BLOCK HF study, given the relatively milder symptoms in these patients at baseline. Of the total study population, 73% were NYHA functional class I or II. Despite this, we were able to demonstrate improvement in clinical composite score at all time points through 24 months, improvement in NYHA functional class at 12 months, and QOL through 12 months of follow-up. It should also be noted that the relatively high number of crossovers in the study would tend to dilute the differences between the biventricular and RV pacing groups, yet we still found significant differences in favor of biventricular pacing.
One other key factor is that BLOCK HF was a study of different modalities of pacing in patients with left ventricular dysfunction who develop a need for a high percentage of pacing for atrioventricular block. Thus, biventricular pacing in these patients may be preventing future dyssynchrony and heart failure as much as treating currently existing dyssynchrony. In that regard, our findings could reflect a mix of improvement in clinical outcomes as well as prevention of deterioration in clinical condition.
Most crossovers in the RV pacing arm occurred because of worsening heart failure. Investigators were strongly encouraged to keep subjects in their randomized group until they had reached at least 1 of the components of the composite primary endpoint. Given the main conclusion of this study, that biventricular pacing is superior to RV pacing in patients with atrioventricular block and left ventricular dysfunction, then loss of biventricular pacing in the biventricular arm or conversion to biventricular pacing in the RV pacing arm would tend to reduce the differences between the 2 study groups. Despite this, we have shown significant differences between treatment groups in important clinical outcomes.
The primary limitation for the assessment of NYHA functional class, QOL, and clinical composite score was missing data due to either missed visits or study closure. Because the trial was designed to follow subjects through at least 12 months, some subjects did not have the opportunity to complete their 18- or 24-month visits, resulting in reduced sample sizes for assessments at these time points. Additionally, between 5% and 7% of expected visits at each time point were missed. There was an imbalance in crossovers between the arms, and sensitivity analyses showed that results at later time points may have been affected by discontinuation of randomized therapy.
We have shown that clinical outcomes, QOL, and heart failure status are improved with biventricular pacing compared to RV pacing in the BLOCK HF study. These results demonstrate that, in addition to the main findings of the trial (a reduction in the composite endpoint of death, heart failure–related urgent care, and adverse ventricular remodeling with biventricular pacing), important clinical outcomes are improved as well. The findings with biventricular pacing may reflect prevention of future dyssynchrony and heart failure as well as treatment of currently existing dyssynchrony.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with atrioventricular block and mild-to-moderate heart failure, biventricular pacing is associated with improvement in the composite outcome of death, heart failure-related urgent care, and adverse ventricular remodeling compared with right ventricular pacing, and these advantages translate into better functional capacity and quality of life.
TRANSLATIONAL OUTLOOK: Future research should examine whether patients with less advanced atrioventricular block gain comparable benefit from biventricular pacing or strategies that minimize ventricular pacing.
The BLOCK HF study was funded and sponsored by Medtronic. Dr. Curtis has received fees for serving on the advisory boards of St. Jude Medical, Sanofi, Pfizer, Janssen Pharmaceuticals, and Daiichi-Sankyo; consulting fees from Medtronic and Sanofi; and lecture fees from St. Jude Medical and Medtronic. Dr. Worley has received royalties from Pressure Products and Merit Medical; and consulting income from St. Jude Medical and Medtronic. Dr. Chung has received consulting fees from Boston Scientific, Medtronic, and CardioMEMS; payment for development of educational presentations for Boston Scientific; and grant support through his institution from Gambro, Medtronic, and Boston Scientific. Drs. Li and Christman are employees of and hold stock and stock options in Medtronic. Dr. St. John Sutton has received consulting fees from Medtronic and BioContro Medical.
- Abbreviations and Acronyms
- cardiac resynchronization therapy
- cardiac resynchronization therapy defibrillator
- cardiac resynchronization therapy pacemaker
- last observation carried forward
- left ventricular ejection fraction
- New York Heart Association
- posterior probability
- quality of life
- right ventricular
- Received September 17, 2015.
- Revision received February 18, 2016.
- Accepted February 23, 2016.
- 2016 American College of Cardiology Foundation
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