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Published at www.nejm.org November 15, 2009 (10.1056/NEJMoa0907555)

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ABSTRACT

Background Observational studies suggest that conventional right ventricular apical pacing may have a deleterious effect on left ventricular function. In this study, we examined whether biventricular pacing is superior to right ventricular apical pacing in preventing deterioration of left ventricular systolic function and cardiac remodeling in patients with bradycardia and a normal ejection fraction.

Methods In this prospective, double-blind, multicenter study, we randomly assigned 177 patients in whom a biventricular pacemaker had been successfully implanted to receive biventricular pacing (89 patients) or right ventricular apical pacing (88 patients). The primary end points were the left ventricular ejection fraction and left ventricular end-systolic volume at 12 months.

Results At 12 months, the mean left ventricular ejection fraction was significantly lower in the right-ventricular-pacing group than in the biventricular-pacing group (54.8±9.1% vs. 62.2±7.0%, P<0.001), with an absolute difference of 7.4 percentage points, whereas the left ventricular end-systolic volume was significantly higher in the right-ventricular-pacing group than in the biventricular-pacing group (35.7±16.3 ml vs. 27.6±10.4 ml, P<0.001), with a relative difference between the groups in the change from baseline of 25% (P<0.001). The deleterious effect of right ventricular apical pacing occurred in prespecified subgroups, including patients with and patients without preexisting left ventricular diastolic dysfunction. Eight patients in the right-ventricular-pacing group (9%) and one in the biventricular-pacing group (1%) had ejection fractions of less than 45% (P=0.02). There was one death in the right-ventricular-pacing group, and six patients in the right-ventricular-pacing group and five in the biventricular-pacing group were hospitalized for heart failure (P=0.74).

Conclusions In patients with normal systolic function, conventional right ventricular apical pacing resulted in adverse left ventricular remodeling and in a reduction in the left ventricular ejection fraction; these effects were prevented by biventricular pacing. (Centre for Clinical Trials number, CUHK_CCT00037.)

Preclinical data suggested that biventricular pacing might preserve myocardial performance better than right ventricular apical pacing in patients with atrioventricular block and normal systolic function.⁸ The underlying mechanism may be a reduction in left ventricular systolic dyssynchrony, as shown by advanced echocardiography.⁹ Furthermore, patients with preexisting left ventricular dysfunction and an indication for standard pacing have improved left ventricular systolic function, exercise capacity, and quality of life after biventricular pacing as compared with right ventricular apical pacing.¹⁰ This finding was corroborated in a study of acute hemodynamic responses in patients with a normal QRS complex and a left ventricular ejection fraction of more than 40%, which showed that biventricular pacing, but not right ventricular apical pacing, preserved left ventricular systolic function.¹¹ These results suggest that biventricular pacing may be a feasible option for permanent pacing in the majority of patients who have normal left ventricular systolic function and that it may attenuate the adverse effect of conventional right ventricular apical pacing on left ventricular systolic function.

Methods

Patients

The Pacing to Avoid Cardiac Enlargement (PACE) study was a prospective, double-blind, randomized, multicenter clinical trial. It was designed to test whether atrial-synchronized biventricular pacing is superior to right ventricular apical pacing in preserving left ventricular systolic function and avoiding adverse left ventricular remodeling in patients with a normal left ventricular ejection fraction (45%) and standard indications for pacing. These indications included sinus-node dysfunction and bradycardia due to advanced atrioventricular block. Patients were excluded from the study if they had persistent atrial fibrillation, unstable angina, or an acute coronary syndrome; if they had undergone percutaneous coronary intervention or coronary-artery bypass surgery within the previous 3 months; if they had a life expectancy of less than 6 months; if they had received a heart transplant; or if they were pregnant.¹² Patients who fulfilled the eligibility criteria but in whom implantation of a biventricular system was unsuccessful were also excluded. Attending physicians were encouraged to maintain the same doses of medications, especially neurohormonal blockers and antiarrhythmic drugs, throughout the study period.

Study Design

Patients who were enrolled in the study received an atrial-synchronized biventricular pacemaker capable of delivering right ventricular apical pacing or biventricular pacing, depending on the programming of the device (InSync III, Medtronic). In brief, the right atrial and right ventricular leads were positioned at the right atrial appendage and the right ventricular apex, respectively, through a transvenous route. The left ventricular lead was positioned preferentially at the posterolateral or lateral venous branches of the coronary sinus. Two days after successful implantation of the device, patients were stratified according to the presence of normal or abnormal left ventricular diastolic function, as assessed by standardized criteria of Doppler echocardiography (Figure 1).¹³ Patients who had a mechanical mitral valve or high-grade atrioventricular block and in whom left ventricular diastolic function could therefore not be determined were counted as part of the group with abnormal left ventricular diastolic function.

View larger version (20K): [in this window] [in a new window]   Figure 1. Screening, Enrollment, Random Assignment, and Follow-up. BiV denotes biventricular, and RVA right ventricular apical.

 
Patients in each of the groups that were stratified according to left ventricular diastolic function were randomly assigned to receive biventricular pacing or right ventricular apical pacing, and their pacemakers were programmed accordingly. Patients were randomly assigned in a ratio of 1:1 by a computer-generated list at a central location. We used a permuted-block randomization procedure, with each block containing four assignments, two for each pacing group. All the devices were programmed to an atrial-synchronized DDDR mode, with a lower rate of 60 beats per minute and an upper tracking rate of 140 beats per minute. For patients with heart block, the paced and sensed atrioventricular intervals were programmed to 130 msec and 100 msec, respectively. For patients with sinus-node dysfunction, the atrioventricular intervals were programmed to be 20 msec shorter than the intrinsic atrioventricular interval. The pacing settings were kept unchanged throughout the study period.

Baseline assessments included echocardiography, measurement of the distance covered on a 6-minute walk, quality-of-life assessment with the use of the 36-Item Short-Form General Health Survey (SF-36), and electrocardiography. All patients had follow-up visits at 1, 3, 6, 9, and 12 months, and the assessments were repeated at those times. The echocardiographic images were stored and sent to the core laboratory for analysis by echocardiographic specialists who were unaware of the assigned treatment.

The study protocol was approved by the local ethics committee at each participating institution and complies with the provisions of the Declaration of Helsinki. Written informed consent was obtained from all patients.

The study, which was sponsored by Medtronic, was an investigator-initiated clinical trial, and the protocol was designed and written by investigators who were members of the steering committee (see the Appendix). Data were gathered by the investigators. The publication committee consisted of physicians on the steering committee and investigators from the top-enrolling centers. Data analysis was performed by two of the investigators. The manuscript was written by the principal investigator, and the accuracy of the data reported was confirmed by the publication committee, whose members had full access to the data; no restrictions or limitations were imposed by the sponsor. The sponsor had no involvement in the design of the study, the analysis of the data, or the preparation or editing of the manuscript.

Study End Points

The two primary end points were the left ventricular ejection fraction (as an assessment of left ventricular systolic function) and left ventricular end-systolic volume (as an assessment of left ventricular remodeling) at 12 months. They were evaluated primarily with the use of real-time three-dimensional echocardiography. The secondary end points included the distance covered in a 6-minute walk, quality of life as assessed with the use of the SF-36, and hospitalization for heart failure.

Echocardiographic Assessments

Standard echocardiography (with the Vivid 7 system, General Electric) was performed to assess left ventricular function. To assess left ventricular volume and ejection fraction, real-time three-dimensional echocardiography (with the iE33 system, Philips) was preferred and was used in 90% of the patients, whereas the biplane Simpson's method was used in the other 10%. For three-dimensional echocardiography, optimized images of full left ventricular volume were obtained in the apical four-chamber view with the use of a matrix-array transducer (X3-1, 1.9/3.8 MHz; Philips), while the patient held his or her breath. Image optimization and quality requirements have been described previously.¹⁴ The images were stored digitally and transferred to the work station for blinded offline analysis.

Echocardiographic images were analyzed offline for the treatment effect in the echocardiography core laboratory with the use of dedicated software (QLAB 7.0, Philips). Images from different time points were arranged in random order and were then analyzed by experienced readers in a blinded fashion. An automatic left ventricular border detection algorithm was used, and a virtual left ventricular cast was constructed that measured left ventricular volume, ejection fraction, and systolic dyssynchrony.^14,15 Interobserver and intraobserver variability for the measurement of left ventricular ejection fraction, left ventricular volume, and dyssynchrony index (the standard deviation of the time to minimal systolic volume among the 16 left ventricular segments) were assessed in 30 randomly selected patients; the rates of interobserver and intraobserver variability were 3.9% and 4.2%, respectively, for measurement of left ventricular ejection, 6.7% and 6.5% for measurement of left ventricular volume, and 8.8% and 7.4% for dyssynchrony index.

Statistical Analysis

The sample size was estimated on the basis of the postulated difference in left ventricular ejection fraction of 5 percentage points between the two pacing groups at 12 months (PASS 2000 software, NCSS). We estimated that with 85 patients in each group, the study would have 90% power to detect a difference of 5 percentage points between the null hypothesis that both groups would have a mean ejection fraction of 60% and the alternative hypothesis that the mean ejection fraction in the right-ventricular-pacing group would be 55%, with a standard deviation of 10% and a two-sided 5% type 1 error. Thus, the estimated sample size for the study was 170 patients. With this sample size, we estimated that the study would also have at least 90% power to detect a difference of 5 ml in left ventricular end-systolic volume.

The primary analysis was performed on the basis of the intention-to-treat principle, and patients with a minimum of 3 months of follow-up were included. An analysis was also performed on the basis of final pacing sites. A two-sided Student's t-test was used to test for a difference in prespecified end points between the right-ventricular-pacing group and the biventricular-pacing group at baseline and at the 12-month visit. In the analysis, when the assumption of normality was violated, a nonparametric test (Mann–Whitney test or Wilcoxon signed-rank test) was performed. A subgroup analysis was performed with the use of a general linear model to look for potential interactions between clinical factors and primary end points. Prespecified subgroups were defined according to the presence or absence of preexisting left ventricular diastolic dysfunction, age (<70 or 70 years), sex, indication for pacing (sinus-node dysfunction or heart block), and presence or absence of diabetes mellitus, hypertension, and coronary heart disease. A subgroup analysis that was not prespecified was performed for QRS duration (<110 or 110 msec). All reported P values are two-sided and have not been adjusted for multiple analyses.

Results

Patients

From March 2005 through July 2008, a total of 251 patients were screened at four centers (Figure 1). Fifty-eight patients were excluded from the study because of echocardiographic images that were of poor quality (7 patients), ejection fractions that were less than 45% (6), or the patients' refusal to join the study (45). Among 193 patients who underwent implantation of the study device, 14 had a high left ventricular lead pacing threshold (>5 V) and 2 had dissection of the coronary sinus without clinical complications. These 16 patients received conventional dual-chamber pacing and did not undergo randomization. The remaining 177 patients were randomly assigned to biventricular pacing (89) or right ventricular apical pacing (88). The majority of the left ventricular leads (95%) were placed in a lateral or posterolateral position, with 33% at the posterolateral vein, 31% at the lateral vein, and 31% at the posterior vein. At 12 months, the average percentage of ventricular pacing was 98% in the biventricular-pacing group and 97% in the right-ventricular-pacing group (P=0.95). The baseline clinical characteristics were similar between the two treatment groups, and medications were similar at 12 months (Table 1).

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients in the Right-Ventricular-Pacing and Biventricular-Pacing Groups.

 
Compliance with Therapy

At 12 months, data from 87 patients in the biventricular-pacing group and 86 patients in the right-ventricular-pacing group were available for analyses of the primary end point. Four patients who had undergone randomization were not included in the analysis: two patients declined the 12-month visit (one from each group, both of whom remained well clinically at 12 months), one patient died, and the echocardiographic images for one patient were of inadequate quality for analysis. Diaphragmatic stimulation occurred in two patients in the biventricular-pacing group, and the two patients were crossed over to the right-ventricular-pacing group (one at 1 month and one at 7 months); the analyses were performed according to the intention-to-treat principle. There was no crossover from right ventricular apical pacing to biventricular pacing.

Assessment of the Primary End Points

At 12 months, the right-ventricular-pacing group had a significantly lower mean left ventricular ejection fraction than did the biventricular-pacing group (54.8±9.1% vs. 62.2±7.0%, P<0.001), with an absolute difference of 7.4 percentage points (P<0.001) (Table 2 and Figure 2A). The absolute reduction in the ejection fraction from baseline to 12 months in the right-ventricular-pacing group was 6.7 percentage points, but there was no change in the ejection fraction in the biventricular-pacing group.

View this table: [in this window] [in a new window]   Table 2. End-Point Measures According to Treatment Group.

 

View larger version (16K): [in this window] [in a new window]   Figure 2. Comparison of Primary End Points at 12 Months between Patients Who Received Biventricular Pacing and Those Who Received Right Ventricular Apical Pacing. The values shown are means. Among patients who received right ventricular apical (RVA) pacing, there was a significant decrease in the left ventricular ejection fraction (Panel A), whereas the left ventricular end-systolic volume was increased (Panel B). I bars indicate 95% confidence intervals. BiV denotes biventricular, and LV left ventricular.

 
The left ventricular end-systolic volume was significantly larger at 12 months in the right-ventricular-pacing group than in the biventricular-pacing group (P<0.001), with an absolute difference of 8.1 ml (a relative difference between the groups in the change from baseline of 25%, P<0.001) (Table 2 and Figure 2B). The left ventricular end-systolic volume increased by 7.1 ml (a relative increase of 26%) from baseline to 12 months in the right-ventricular-pacing group but remained unchanged in the biventricular-pacing group. At 12 months, eight patients in the right-ventricular-pacing group (9%) and one patient in the biventricular-pacing group (1%) had a left ventricular ejection fraction that had decreased to less than 45% (P=0.02).

Assessment of Secondary End Points and Subgroup Analyses

In the assessment of distance covered in a 6-minute walk, although both pacing groups had an increase of more than 30 m at 12 months, there was no significant difference between the groups (Table 2). In the assessment of quality of life, the domain of physical role was improved at 12 months in both pacing groups, although there was no significant difference between the groups in any of the domains (Table 2). There was no significant difference between the two groups in the rate of hospitalization for heart failure.

For the subgroups shown in Figure 3 and Figure 4, no significant interaction was seen between biventricular pacing and left ventricular ejection fraction or left ventricular end-systolic volume at 12 months.

View larger version (32K): [in this window] [in a new window]   Figure 3. Subgroup Analyses of the Primary End Point of Left Ventricular Ejection Fraction at 12 Months. Differences in the left ventricular (LV) ejection fraction between patients who received biventricular (BiV) pacing and those who received right ventricular apical (RVA) pacing are shown for each subgroup. P values for interaction are shown. The bars indicate 95% confidence intervals.

 

View larger version (32K): [in this window] [in a new window]   Figure 4. Subgroup Analyses of the Primary End Point of Left Ventricular End-Systolic Volume at 12 Months. Differences in left ventricular (LV) end-systolic volume between patients who received biventricular (BiV) pacing and those who received right ventricular apical (RVA) pacing are shown for each subgroup. P values for interaction are shown. The bars indicate 95% confidence intervals.

 
Events and Adverse Events

There were no periprocedural deaths. One patient in the right-ventricular-pacing group died before the 12-month visit as a result of a urinary tract infection and septicemia. Of the 177 patients who underwent randomization, 11 were hospitalized for heart failure (6%): 6 in the right-ventricular-pacing group (7%) and 5 in the biventricular-pacing group (6%) (P=0.74). Among these 11 patients, only 2, both of whom were in the right-ventricular-pacing group, had a left ventricular ejection fraction of less than 45% at 12 months. Furthermore, three patients in the right-ventricular-pacing group (3%) were hospitalized for an acute coronary syndrome, and two in the biventricular-pacing group (2%) were hospitalized for stroke. Seven patients in the biventricular-pacing group had diaphragmatic pacing. In the case of five of these patients, the condition was managed by reprogramming of the device, and there were no further problems; the other two patients crossed over to the right-ventricular-pacing group.

Discussion

This study shows that right ventricular apical pacing has a detrimental effect on left ventricular systolic function in patients with a normal ejection fraction and indications for pacing owing to bradycardia. The adverse cardiac remodeling can be prevented by biventricular pacing.

Despite the use of right ventricular apical pacing for decades, its association with the development of heart failure and even death has been recognized only in the past 7 years with the publication of the results of various large-scale trials of pacemakers and implantable cardioverter–defibrillators.^2,3,16,17 The adverse clinical events seem to be related to a high cumulative percentage of right ventricular apical pacing.^2,3,4,5,6,7 Such pacing causes an abnormal left ventricular electrical-activation sequence, which is manifested on an electrocardiogram as left bundle-branch block^18,19; this abnormal sequence leads to an electromechanical delay in contraction (or systolic dyssynchrony) and, subsequently, to asymmetric hypertrophy, increased mitral regurgitation, and a decreased ejection fraction.^{4,20,21,22,23,24,25,26} Several pacing algorithms have been developed in an attempt to reduce the percentage of right ventricular apical pacing in patients with sinus-node dysfunction.^27,28,29 However, even a relatively low cumulative percentage of right ventricular apical pacing may result in impaired cardiac function, especially in elderly patients with underlying risk factors for heart failure.¹⁶

The PACE study showed that the mean (±SD) left ventricular ejection fraction declined by almost 7 percentage points (from 61.5±6.6 to 54.8±9.1) in the first year of right ventricular apical pacing in patients with a normal ejection fraction. A previous observational study involving patients with mildly reduced systolic function who received right ventricular apical pacing suggested that the left ventricular ejection fraction was reduced by 5 percentage points after a follow-up period of 3 years.³⁰ Since three-dimensional echocardiography has been shown to be highly accurate in measuring left ventricular volume and ejection fraction when validated against cardiac magnetic resonance imaging and computed tomography,³¹ our results suggest that adverse left ventricular remodeling caused by right ventricular apical pacing might have developed more rapidly than previously anticipated. The results of our study suggest that in patients who require a high percentage of ventricular pacing — especially patients with atrioventricular block — a biventricular-pacing strategy is preferable to right ventricular apical pacing.

One relevant observation in the PACE study was that of the nine patients in whom the left ventricular ejection fraction decreased to less than 45% at 12 months, eight (89%) were in the right-ventricular-pacing group. This suggests that the ejection fraction could decrease rapidly in vulnerable patients and that these patients might benefit even more from biventricular pacing. Patients with normal left ventricular diastolic function and those with abnormal left ventricular diastolic function benefited from biventricular pacing. Since systolic and diastolic function are closely coupled,³² the randomization scheme of the PACE study should have avoided any confounding effect of preexisting left ventricular diastolic dysfunction on the ejection fraction. Furthermore, the superiority of biventricular pacing over right ventricular apical pacing was consistently observed in all the prespecified subgroups.

We did not observe any significant difference between the two pacing groups in the results of the 6-minute walk test or the quality of life assessment at the 12-month visit. Symptoms related to chronotropic incompetence might have been alleviated by the rate-responsive support afforded by the devices in both groups. Also, a difference in these end points may be detected with extended follow-up if more heart-failure events occur.

There are several limitations of this study. The sample was small, and the study was not powered to detect significant differences in clinical events. However, the study was designed with adequate power to test for the expected differences between the two pacing groups with respect to left ventricular systolic function and left ventricular volume. The success rate for implantation of the biventricular-pacing system was 92%, which is lower than that for conventional dual-chamber pacing but similar to that for pacemakers that are implanted in patients with heart failure. Advances in the techniques used to implant left ventricular leads would be expected to improve the success rate even further and reduce device-related complications. The increased cost and complications associated with biventricular pacemakers are potential concerns. Randomized trials with longer follow-up periods, larger samples, and sufficient power to evaluate clinical outcomes between these two pacing strategies are warranted.

Supported by Medtronic.

Dr. Yu reports receiving consulting fees from Philips, lecture fees from GE, St. Jude Medical, Philips, Medtronic, and Boston Scientific, and research grants from Sanofi-Aventis Hong Kong and Philips; and Drs. Omar, Yip, and Hussin, receiving lecture fees from Medtronic. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong (C.-M.Y., J.Y.-S.C., Q.Z., G.W.-K.Y., F.F., J.W.-H.F.); the Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China (Q.Z.); the Department of Cardiology, National Heart Institute, Kuala Lumpur, Malaysia (R.O., A.H., K.H.L.); the Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong (H.C.-K.C.); and the Department of Medicine, North District Hospital, Hong Kong (J.W.-H.F.).

This article (10.1056/NEJMoa0907555) was published on November 15, 2009, at NEJM.org.

Address reprint requests to Dr. Yu at the Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital and Institute of Vascular Medicine and Li Ka Shing Institute of Health and Sciences, Chinese University of Hong Kong, Hong Kong, or at cmyu{at}cuhk.edu.hk.

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Steering Committee: C.-M. Yu, G.W.-K. Yip, Q. Zhang, J.Y.-S. Chan, Chinese University of Hong Kong; J.W.-H. Fung, North District Hospital; O. Razali, H. Azlan; National Heart Institute. Echocardiographic Core Laboratory: G.W.-K. Yip, C.-M. Yu, Q. Zhang, F. Fang, Chinese University of Hong Kong. Clinical Event Committee: W. Chan, A. Chan, Chinese University of Hong Kong; W.L Chan, Alice Ho Miu Ling Nethersole Hospital. Publication Committee: C.-M. Yu, J.W.-H. Fung, G.W.-K. Yip, Q. Zhang, J.Y.-S. Chan, Chinese University of Hong Kong; O. Razali, H. Azlan, National Heart Institute. Other investigators and institutions that participated in the PACE study: Alice Ho Miu Ling Nethersole Hospital, Hong Kong — H.C.-K. Chan, W.L. Chan; Prince of Wales Hospital, Chinese University of Hong Kong — J.Y.-S. Chan, C.-M. Yu, G.W.-K. Yip, A.K.Y. Chan; G.C.P. Chan; National Heart Institute, Kuala Lumpur — O. Razali, H. Azlan, K.H. Lam; North District Hospital, Hong Kong — J.W.-H. Fung, K.H. Yiu.

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