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Atrial fibrillation (AF) remains the most common rhythm disturbance requiring treatment, and its incidence is increasing with the aging of the population. Optimal treatment strategies for AF continue to be investigated and debated vigorously. For instance, 4 recent clinical trials, including the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial, failed to demonstrate superiority of rhythm control (restoration of sinus rhythm) over rate control with regard to important clinical outcomes, including mortality and thromboembolic events. These findings lead us to believe that control of the ventricular rate is a primary treatment option in the management of patients with AF.
AF causes a ventricular rhythm that is both rapid and irregular. Although excessive heart rates during AF are easily recognized clinically, few studies provide firm guidelines regarding what is considered "good" or "optimal" rate control during AF. Control of the heart rate at rest does not ensure that the rate is well regulated during exercise. The AFFIRM trial used a target heart rate ≤ 80 beats/min at rest and ≤ 110 beats/min during a 6-min walk test or ≤ 100 beats/min on average during 24-hour Holter monitoring. However, this definition does not include consideration of regularization of the heart rate during AF or the adequacy of chronotropic competence during exercise.
An irregular ventricular rhythm has negative hemodynamic effects, independent of heart rate, and chronotropic incompetence is known to occur in up to 30% of patients with chronic AF. Finally, most rate control guidelines do not consider that the criteria for rate control may vary with patient age and/or associated medical conditions.
Pharmacologic Approach to Blocking Atrioventricular (AV) Nodal Pacing
One approach to rate control consists of medically blocking the AV nodal pacing of the ventricle; however, it is difficult to achieve satisfactory rate control in some patients this way.
Failure of the rate control treatment strategy can lead to poor quality of life and development of a tachycardia-induced cardiomyopathy. Difficulties with rate control in AF may be related to AV nodal blocking medication intolerance, side effects or inefficacy, or patient noncompliance with multidrug regimens. In addition, associated conditions including congestive heart failure (CHF), pulmonary disease, and sinus node dysfunction may limit pharmacologic options for rate control. For example, patients with reactive airway disease or markedly reduced pulmonary function may not tolerate beta blockers, especially at doses adequate to control ventricular rates. In patients with CHF, calcium channel blockers may adversely affect survival. A combination of drugs is often necessary to achieve rate control in AF patients in the acute and chronic settings. A patient may exhibit slow ventricular rates during sleep but an accelerated ventricular response during exercise. These wide swings in rate create therapeutic challenges. Therapy may require careful dose titration to prevent excessive bradycardia, especially in those with conduction system disease. Chronotropic incompetence may be caused or exacerbated by AV nodal blocking medications, resulting in worsening of symptoms or exercise intolerance.
A deficiency of all pharmacologic measures aimed at slowing the heart rate in AF is that they do not control the irregularity of the ventricular rhythm. Newer pharmacologic agents for control of the ventricular response are under clinical investigation. One such agent slows heart rate and impulse conduction through the AV node by stimulation of the A1 adenosine receptor.
Alternative to Pharmacologic Control: "Ablate and Pace" Therapy
Ablation of the AV node and permanent pacing ("ablate and pace") offers an alternative to pharmacologic control of heart rate in patients with AF. It has the theoretical advantages of perfect control and regularization of the ventricular rate. It also provides the ability to fine-tune the ventricular rate in AF at rest, during exercise, and with changing clinical conditions.
Monitoring the adequacy of rate control can be done continuously through the pacemaker over long-term follow-up. The benefits of this AF treatment strategy have been demonstrated in numerous uncontrolled trials, randomized controlled studies, and in a meta-analysis.
Ablate and pace improves measures of quality of life, cardiac function, exercise tolerance, and healthcare utilization. It is easy to perform and has a very low complication rate. However, ablate and pace has the disadvantage of being a palliative, not curative, procedure and does not obviate the need for long-term anticoagulation. Furthermore, ablation creates irreversible iatrogenic AV block with resultant pacemaker dependency in many patients. There has been some concern that ablate and pace may increase the risk of torsade de pointes and sudden death. However, 1 study found that there was no difference in mortality between patients undergoing this procedure and those who continued on medical therapy for AF.
AV node ablation and pacing is reserved primarily for a small minority of AF patients who are severely symptomatic and refractory to drug therapy. In the AFFIRM trial, radiofrequency ablation to modify or eliminate AV conduction was used in 5.2% of the patients in the rate-control group after failure of rate-control drugs. It is estimated that more than 30,000 ablate and pace procedures for AF were performed in the United States in 2003, which represents about 1% to 2% of the AF population. These numbers are expected to increase in coming years.
Effects of Right Ventricular (RV) Pacing
One of the recent concerns about the ablate and pace approach for rate control in AF is the increasing recognition of the potential for deleterious effects associated with chronic pacing from the RV apex. This was highlighted in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial in patients with underlying left ventricular (LV) dysfunction (LV ejection fraction [EF] ≤ 40%), in which RV pacing increased the risk of death or heart failure hospitalization. Likewise, in the Mode Selection Trial (MOST) in patients requiring permanent pacing for sinus node dysfunction, the cumulative percent ventricular pacing was a strong predictor of the need for heart failure hospitalization.
Thus, dyssynchronous ventricular activation during RV pacing can have detrimental long-term effects on clinical outcomes. Of note, in 3 recent prospective, randomized trials of ablate and pace therapy, the LVEF following AV nodal ablation showed only a modest improvement or no change in patients with LV dysfunction prior to the procedure. In addition, in some patients, RV apical pacing worsens mitral regurgitation. Thus, it may be that in some patients, part of the benefit of rate control and regularization provided by ablate and pace therapy is offset by nonphysiologic RV pacing-induced ventricular dyssynchrony.
The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT) showed no benefit to the ablate and pace approach compared with pharmacologic heart rate control in terms of ventricular systolic function or exercise duration in patients with well-preserved ventricular systolic function. Pacing from the RV outflow tract or dual-site RV pacing (from the outflow tract and apex, sequentially) does not result in superior clinical outcomes compared with permanent pacing from the RV apex alone.
In the Right Ventricular Outflow Versus Apical Pacing (ROVA) trial in patients with chronic AF, heart failure, and LV systolic dysfunction, there was no consistent incremental benefit associated with chronic RV outflow tract or dual site RV pacing either in patients following AV nodal ablation or in those receiving pharmacologic heart rate control.
Potential for Biventricular (BV) Pacing
There is increasing evidence for a favorable effect of BV pacing in patients with heart failure and intraventricular conduction delay. Thus far, cardiac resynchronization therapy (CRT) has been studied primarily in patients with advanced CHF that is refractory to medical therapy, LV dysfunction (EF < 35%), a wide intrinsic QRS duration (> 130 ms), and sinus rhythm. In these patients, BV pacing improves exercise capacity and quality of life, lessens mitral regurgitation, and results in favorable ventricular remodeling. Less well studied is the role of CRT in patients with permanent AF or in patients with milder degrees of CHF or LV dysfunction.
LV-Based Cardiac Stimulation Post-AV Nodal Ablation
The Left Ventricular-based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE), sponsored by St. Jude Medical (St. Paul, Minnesota), was a prospective, randomized study that evaluated BV pacing after AV nodal ablation in patients with permanent AF. Of particular interest, patients were enrolled regardless of LV systolic function, New York Heart Association (NYHA) functional class, or intrinsic QRS duration.
The primary endpoint of PAVE was exercise capacity measured by the distance walked during 6-minute walk testing. A total of 252 patients (mean age 69 years, about two thirds male) with chronic AF of at least 1 month's duration undergoing AV nodal ablation and permanent pacemaker implantation were enrolled. Study patients had a mean LVEF of 46% and were in NYHA classes I to III prior to enrollment. All patients underwent AV nodal ablation, followed by BV pacing in 146 and RV only pacing in 106. Implant success rate for the BV pacing system was 86%.
Results
Although exercise capacity improved in both groups, patients who had a successful BV pacing implant and completed the 6-month follow-up phase had a significantly greater improvement in 6-minute walk distance than those who received RV-only pacing (82 vs 56 meters, respectively; P = .03). In addition, there were significant improvements in peak VO2 and exercise duration during cardiopulmonary exercise testing within the BV group, but no significant change in these parameters within the RV group. Health-related quality of life improved in both groups with ablation and pacing.
Patients randomized to BV pacing maintained a mean LVEF of 46% over the 6-month follow-up period, whereas those who received RV pacing experienced a deterioration of LV systolic function with a decline in LVEF from 45% prior to implant to 41% at 6 months. Thus, the PAVE trial demonstrates that in patients with chronic AF treated with AV nodal ablation, BV pacing produces a significant incremental improvement in functional capacity and prevents deterioration in LV systolic function associated with RV pacing.
Comment
Several comments and notes of caution in interpreting the results of PAVE are warranted. First, the results presented by Rahul Doshi, MD, Sunrise Hospital and Medical Center (Las Vegas, Nevada), at the American College of Cardiology (ACC) Annual Scientific Session 2004 Late Breaking Clinical Trials session included only the "analyzable population," which represented an on-treatment analysis of BV pacing in this population (ie, patients who had a successful implant and completed the 6-month follow-up). As such, endpoint data from only 70% of patients randomized to BV pacing (102 of 146 patients) and 77% of those randomized to RV pacing (82 of 106 patients) were presented. BV device implantation was reported as unsuccessful in 21 patients (14.4%) compared with none in the RV group, and 21 patients (14 [9.6%] in the BV and 7 in the RV group) had < 6 months of follow-up. Two patients (1 in each group) required system explantation.
An intention-to-treat analysis encompassing all patients in the group randomized to BV pacing, whether or not they were implanted successfully, would be of interest to more fully understand the potential impact and limitations of this therapy. A previous randomized study of ablate and pace in heart failure patients with chronic AF did not show any statistically significant difference in clinical end points between BV and RV pacing when an intention-to-treat analysis was performed. Complication rates (eg, coronary sinus dissection, lead dislodgement, phrenic nerve stimulation, and high pacing thresholds) also were not provided during the ACC presentation.
The implant success rate for the LV lead in PAVE was comparable to that reported with other new BV pacing systems. Over-the-wire lead technology for the LV lead was not utilized in the PAVE trial, which may have limited lead implantation in small or tortuous coronary veins.
Although the PAVE investigators are to be congratulated on their study, it must be recognized that this represents a small number of patients with only limited follow-up. As such, it cannot answer all the questions that naturally arise from such a study. It would have been of interest to know whether the benefits of BV pacing observed at 6 months were maintained or more likely amplified during long-term follow-up. Some studies suggest that the deleterious effects of RV apical pacing are not observed until at least 6 months after implantation. Finally, the question arises as to whether one needs to pace the right ventricle at all.
The ongoing European Optimal Pacing Site (OPSITE) study is comparing RV and LV pacing in patients with permanent AF undergoing ablation and pacing therapy. This study, however, will not answer the question of whether BV is preferred to LV only pacing.
Implications of PAVE
What, then, are the implications of the PAVE trial, especially in the context of AF management? First, the data reconfirm the benefits of ablate and pace therapy with regard to improvements in functional capacity, exercise tolerance, and quality of life with RV or BV pacing, but raise once again a concern regarding the potential deleterious effects of RV pacing even in patients with well-preserved ventricular function. The incremental benefits of BV pacing over RV pacing in PAVE were modest, and although statistical significance was achieved, one has to ask whether these benefits are clinically meaningful, especially in a population with well-preserved ventricular function of whom almost two thirds were in NYHA class I or II. The modest degree of benefit is not surprising if we consider that a significant improvement was achieved by AV junction ablation alone, which reduces the potential additional benefits to be gained. The magnitude of benefit in exercise capacity in the PAVE trial was similar to that found in a previous randomized crossover study in heart failure patients with AF in which the mean distance walked increased significantly by 9.3% and peak oxygen uptake increased by 13% during BV pacing compared with RV pacing.
To put the question of benefit in clinical context, is it worth the extra effort and expense of implanting a BV system, so that a patient can walk on average 26 meters further on a 6-minute walk test (beyond the 56-meter improvement seen with ablation and RV pacing alone) or 22 seconds longer on an exercise test?
Interestingly, health-related quality of life was not consistently different between the groups. Of note, there was a trend toward worsening heart failure episodes and mortality in the RV compared with the BV group. Whether this was related to the small decrease in LVEF seen with RV pacing would have required a much larger cohort of patients with longer follow-up to demonstrate that RV pacing results in worsened clinical outcomes (heart failure hospitalization or death). This finding, however, is entirely consistent with what has come to be increasingly recognized with respect to the deleterious effects of RV pacing.
The PAVE trial data will likely reinforce the recent trend away from RV pacing and toward more physiologic pacing for patients who require ventricular pacing because of bradycardia.
In conclusion, the increased awareness of the importance of rate control in AF will undoubtedly continue to promote the need for ablate and pace therapy. The most appropriate patients for this therapy remain those who are symptomatic, with poor rate control despite drug therapy, and who are not candidates for curative procedures. Concerns regarding the iatrogenic creation of AV block and ventricular dyssynchrony from RV pacing may be mitigated by the benefits of CRT in this patient population. Thus, the PAVE trial has highlighted a new treatment option for symptomatic patients with permanent AF and may help to change the way we pace the ventricle in other patients.
References
Atrial fibrillation (AF) remains the most common rhythm disturbance requiring treatment, and its incidence is increasing with the aging of the population. Optimal treatment strategies for AF continue to be investigated and debated vigorously. For instance, 4 recent clinical trials, including the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial, failed to demonstrate superiority of rhythm control (restoration of sinus rhythm) over rate control with regard to important clinical outcomes, including mortality and thromboembolic events. These findings lead us to believe that control of the ventricular rate is a primary treatment option in the management of patients with AF.
AF causes a ventricular rhythm that is both rapid and irregular. Although excessive heart rates during AF are easily recognized clinically, few studies provide firm guidelines regarding what is considered "good" or "optimal" rate control during AF. Control of the heart rate at rest does not ensure that the rate is well regulated during exercise. The AFFIRM trial used a target heart rate ≤ 80 beats/min at rest and ≤ 110 beats/min during a 6-min walk test or ≤ 100 beats/min on average during 24-hour Holter monitoring. However, this definition does not include consideration of regularization of the heart rate during AF or the adequacy of chronotropic competence during exercise.
An irregular ventricular rhythm has negative hemodynamic effects, independent of heart rate, and chronotropic incompetence is known to occur in up to 30% of patients with chronic AF. Finally, most rate control guidelines do not consider that the criteria for rate control may vary with patient age and/or associated medical conditions.
Pharmacologic Approach to Blocking Atrioventricular (AV) Nodal Pacing
One approach to rate control consists of medically blocking the AV nodal pacing of the ventricle; however, it is difficult to achieve satisfactory rate control in some patients this way.
Failure of the rate control treatment strategy can lead to poor quality of life and development of a tachycardia-induced cardiomyopathy. Difficulties with rate control in AF may be related to AV nodal blocking medication intolerance, side effects or inefficacy, or patient noncompliance with multidrug regimens. In addition, associated conditions including congestive heart failure (CHF), pulmonary disease, and sinus node dysfunction may limit pharmacologic options for rate control. For example, patients with reactive airway disease or markedly reduced pulmonary function may not tolerate beta blockers, especially at doses adequate to control ventricular rates. In patients with CHF, calcium channel blockers may adversely affect survival. A combination of drugs is often necessary to achieve rate control in AF patients in the acute and chronic settings. A patient may exhibit slow ventricular rates during sleep but an accelerated ventricular response during exercise. These wide swings in rate create therapeutic challenges. Therapy may require careful dose titration to prevent excessive bradycardia, especially in those with conduction system disease. Chronotropic incompetence may be caused or exacerbated by AV nodal blocking medications, resulting in worsening of symptoms or exercise intolerance.
A deficiency of all pharmacologic measures aimed at slowing the heart rate in AF is that they do not control the irregularity of the ventricular rhythm. Newer pharmacologic agents for control of the ventricular response are under clinical investigation. One such agent slows heart rate and impulse conduction through the AV node by stimulation of the A1 adenosine receptor.
Alternative to Pharmacologic Control: "Ablate and Pace" Therapy
Ablation of the AV node and permanent pacing ("ablate and pace") offers an alternative to pharmacologic control of heart rate in patients with AF. It has the theoretical advantages of perfect control and regularization of the ventricular rate. It also provides the ability to fine-tune the ventricular rate in AF at rest, during exercise, and with changing clinical conditions.
Monitoring the adequacy of rate control can be done continuously through the pacemaker over long-term follow-up. The benefits of this AF treatment strategy have been demonstrated in numerous uncontrolled trials, randomized controlled studies, and in a meta-analysis.
Ablate and pace improves measures of quality of life, cardiac function, exercise tolerance, and healthcare utilization. It is easy to perform and has a very low complication rate. However, ablate and pace has the disadvantage of being a palliative, not curative, procedure and does not obviate the need for long-term anticoagulation. Furthermore, ablation creates irreversible iatrogenic AV block with resultant pacemaker dependency in many patients. There has been some concern that ablate and pace may increase the risk of torsade de pointes and sudden death. However, 1 study found that there was no difference in mortality between patients undergoing this procedure and those who continued on medical therapy for AF.
AV node ablation and pacing is reserved primarily for a small minority of AF patients who are severely symptomatic and refractory to drug therapy. In the AFFIRM trial, radiofrequency ablation to modify or eliminate AV conduction was used in 5.2% of the patients in the rate-control group after failure of rate-control drugs. It is estimated that more than 30,000 ablate and pace procedures for AF were performed in the United States in 2003, which represents about 1% to 2% of the AF population. These numbers are expected to increase in coming years.
Effects of Right Ventricular (RV) Pacing
One of the recent concerns about the ablate and pace approach for rate control in AF is the increasing recognition of the potential for deleterious effects associated with chronic pacing from the RV apex. This was highlighted in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial in patients with underlying left ventricular (LV) dysfunction (LV ejection fraction [EF] ≤ 40%), in which RV pacing increased the risk of death or heart failure hospitalization. Likewise, in the Mode Selection Trial (MOST) in patients requiring permanent pacing for sinus node dysfunction, the cumulative percent ventricular pacing was a strong predictor of the need for heart failure hospitalization.
Thus, dyssynchronous ventricular activation during RV pacing can have detrimental long-term effects on clinical outcomes. Of note, in 3 recent prospective, randomized trials of ablate and pace therapy, the LVEF following AV nodal ablation showed only a modest improvement or no change in patients with LV dysfunction prior to the procedure. In addition, in some patients, RV apical pacing worsens mitral regurgitation. Thus, it may be that in some patients, part of the benefit of rate control and regularization provided by ablate and pace therapy is offset by nonphysiologic RV pacing-induced ventricular dyssynchrony.
The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT) showed no benefit to the ablate and pace approach compared with pharmacologic heart rate control in terms of ventricular systolic function or exercise duration in patients with well-preserved ventricular systolic function. Pacing from the RV outflow tract or dual-site RV pacing (from the outflow tract and apex, sequentially) does not result in superior clinical outcomes compared with permanent pacing from the RV apex alone.
In the Right Ventricular Outflow Versus Apical Pacing (ROVA) trial in patients with chronic AF, heart failure, and LV systolic dysfunction, there was no consistent incremental benefit associated with chronic RV outflow tract or dual site RV pacing either in patients following AV nodal ablation or in those receiving pharmacologic heart rate control.
Potential for Biventricular (BV) Pacing
There is increasing evidence for a favorable effect of BV pacing in patients with heart failure and intraventricular conduction delay. Thus far, cardiac resynchronization therapy (CRT) has been studied primarily in patients with advanced CHF that is refractory to medical therapy, LV dysfunction (EF < 35%), a wide intrinsic QRS duration (> 130 ms), and sinus rhythm. In these patients, BV pacing improves exercise capacity and quality of life, lessens mitral regurgitation, and results in favorable ventricular remodeling. Less well studied is the role of CRT in patients with permanent AF or in patients with milder degrees of CHF or LV dysfunction.
LV-Based Cardiac Stimulation Post-AV Nodal Ablation
The Left Ventricular-based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE), sponsored by St. Jude Medical (St. Paul, Minnesota), was a prospective, randomized study that evaluated BV pacing after AV nodal ablation in patients with permanent AF. Of particular interest, patients were enrolled regardless of LV systolic function, New York Heart Association (NYHA) functional class, or intrinsic QRS duration.
The primary endpoint of PAVE was exercise capacity measured by the distance walked during 6-minute walk testing. A total of 252 patients (mean age 69 years, about two thirds male) with chronic AF of at least 1 month's duration undergoing AV nodal ablation and permanent pacemaker implantation were enrolled. Study patients had a mean LVEF of 46% and were in NYHA classes I to III prior to enrollment. All patients underwent AV nodal ablation, followed by BV pacing in 146 and RV only pacing in 106. Implant success rate for the BV pacing system was 86%.
Results
Although exercise capacity improved in both groups, patients who had a successful BV pacing implant and completed the 6-month follow-up phase had a significantly greater improvement in 6-minute walk distance than those who received RV-only pacing (82 vs 56 meters, respectively; P = .03). In addition, there were significant improvements in peak VO2 and exercise duration during cardiopulmonary exercise testing within the BV group, but no significant change in these parameters within the RV group. Health-related quality of life improved in both groups with ablation and pacing.
Patients randomized to BV pacing maintained a mean LVEF of 46% over the 6-month follow-up period, whereas those who received RV pacing experienced a deterioration of LV systolic function with a decline in LVEF from 45% prior to implant to 41% at 6 months. Thus, the PAVE trial demonstrates that in patients with chronic AF treated with AV nodal ablation, BV pacing produces a significant incremental improvement in functional capacity and prevents deterioration in LV systolic function associated with RV pacing.
Comment
Several comments and notes of caution in interpreting the results of PAVE are warranted. First, the results presented by Rahul Doshi, MD, Sunrise Hospital and Medical Center (Las Vegas, Nevada), at the American College of Cardiology (ACC) Annual Scientific Session 2004 Late Breaking Clinical Trials session included only the "analyzable population," which represented an on-treatment analysis of BV pacing in this population (ie, patients who had a successful implant and completed the 6-month follow-up). As such, endpoint data from only 70% of patients randomized to BV pacing (102 of 146 patients) and 77% of those randomized to RV pacing (82 of 106 patients) were presented. BV device implantation was reported as unsuccessful in 21 patients (14.4%) compared with none in the RV group, and 21 patients (14 [9.6%] in the BV and 7 in the RV group) had < 6 months of follow-up. Two patients (1 in each group) required system explantation.
An intention-to-treat analysis encompassing all patients in the group randomized to BV pacing, whether or not they were implanted successfully, would be of interest to more fully understand the potential impact and limitations of this therapy. A previous randomized study of ablate and pace in heart failure patients with chronic AF did not show any statistically significant difference in clinical end points between BV and RV pacing when an intention-to-treat analysis was performed. Complication rates (eg, coronary sinus dissection, lead dislodgement, phrenic nerve stimulation, and high pacing thresholds) also were not provided during the ACC presentation.
The implant success rate for the LV lead in PAVE was comparable to that reported with other new BV pacing systems. Over-the-wire lead technology for the LV lead was not utilized in the PAVE trial, which may have limited lead implantation in small or tortuous coronary veins.
Although the PAVE investigators are to be congratulated on their study, it must be recognized that this represents a small number of patients with only limited follow-up. As such, it cannot answer all the questions that naturally arise from such a study. It would have been of interest to know whether the benefits of BV pacing observed at 6 months were maintained or more likely amplified during long-term follow-up. Some studies suggest that the deleterious effects of RV apical pacing are not observed until at least 6 months after implantation. Finally, the question arises as to whether one needs to pace the right ventricle at all.
The ongoing European Optimal Pacing Site (OPSITE) study is comparing RV and LV pacing in patients with permanent AF undergoing ablation and pacing therapy. This study, however, will not answer the question of whether BV is preferred to LV only pacing.
Implications of PAVE
What, then, are the implications of the PAVE trial, especially in the context of AF management? First, the data reconfirm the benefits of ablate and pace therapy with regard to improvements in functional capacity, exercise tolerance, and quality of life with RV or BV pacing, but raise once again a concern regarding the potential deleterious effects of RV pacing even in patients with well-preserved ventricular function. The incremental benefits of BV pacing over RV pacing in PAVE were modest, and although statistical significance was achieved, one has to ask whether these benefits are clinically meaningful, especially in a population with well-preserved ventricular function of whom almost two thirds were in NYHA class I or II. The modest degree of benefit is not surprising if we consider that a significant improvement was achieved by AV junction ablation alone, which reduces the potential additional benefits to be gained. The magnitude of benefit in exercise capacity in the PAVE trial was similar to that found in a previous randomized crossover study in heart failure patients with AF in which the mean distance walked increased significantly by 9.3% and peak oxygen uptake increased by 13% during BV pacing compared with RV pacing.
To put the question of benefit in clinical context, is it worth the extra effort and expense of implanting a BV system, so that a patient can walk on average 26 meters further on a 6-minute walk test (beyond the 56-meter improvement seen with ablation and RV pacing alone) or 22 seconds longer on an exercise test?
Interestingly, health-related quality of life was not consistently different between the groups. Of note, there was a trend toward worsening heart failure episodes and mortality in the RV compared with the BV group. Whether this was related to the small decrease in LVEF seen with RV pacing would have required a much larger cohort of patients with longer follow-up to demonstrate that RV pacing results in worsened clinical outcomes (heart failure hospitalization or death). This finding, however, is entirely consistent with what has come to be increasingly recognized with respect to the deleterious effects of RV pacing.
The PAVE trial data will likely reinforce the recent trend away from RV pacing and toward more physiologic pacing for patients who require ventricular pacing because of bradycardia.
In conclusion, the increased awareness of the importance of rate control in AF will undoubtedly continue to promote the need for ablate and pace therapy. The most appropriate patients for this therapy remain those who are symptomatic, with poor rate control despite drug therapy, and who are not candidates for curative procedures. Concerns regarding the iatrogenic creation of AV block and ventricular dyssynchrony from RV pacing may be mitigated by the benefits of CRT in this patient population. Thus, the PAVE trial has highlighted a new treatment option for symptomatic patients with permanent AF and may help to change the way we pace the ventricle in other patients.
References
Wyse DG, Waldo AL, DiMarco JP ; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
Ozcan C, Jahangir A, Friedman PA, et al. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med. 2001;344:1043-1051.
Wilkoff BL, Cook JR, Epstein AE, et al; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115-3123.
Sweeney MO, Hellkamp AS, Ellenbogen KA; MOde Selection Trial Investigators. 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. Circulation. 2003;107:2932-2937.
Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study. Circulation. 1998;98:953-960.
Ueng KC, Tsai TP, Tsai CF, et al. Acute and long-term effects of atrioventricular junction ablation and VVIR pacemaker in symptomatic patients with chronic lone atrial fibrillation and normal ventricular response. J Cardiovasc Electrophysiol. 2001;12:303-309.
Weerasooriya R, Davis M, Powell A, et al. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol. 2003;41:1697-1702.
Stambler BS, Ellenbogen K, Zhang X; ROVA Investigators. Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation. J Cardiovasc Electrophysiol. 2003;14:1180-1186.
Rahul D, Emile D, Christopher F, Kyong T, Aurelio D, Mohamed H. The PAVE Trial: The First Prospective, Randomized Study Evaluating BV Pacing After Ablate and Pace Therapy. Program and abstracts from the American College of Cardiology 53rd Annual Scientific Session; March 7-10, 2004; New Orleans, Louisiana. Late Breaking Clinical Trials, Mar 8, 2004.
Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J. 2002;23:1780-1787.
Brignole M, Gammage M. An assessment of the optimal ventricular pacing site in patients undergoing "ablate and pace" therapy for permanent atrial fibrillation. Europace. 2001;3:153-156.
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