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Dual chamber pacing may have no benefit over ventricular backup pacing in people without indications for anti-bradycardia pacing
TREATMENT
Dual chamber pacing may have no benefit over ventricular backup pacing in people without indications for anti-bradycardia pacing Abstracted from: DAVID 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.
BACKGROUND Implantable cardioverter de¢brillators (ICD) are associated with increased survival in people with a history of life-threatening ventricular arrhythmias. Most ICD devices provide dual-chamber pacing therapy in the event of inadequate ventricular activity. OBJECTIVE To assess the e⁄cacy of dual-chamber pacing compared with backup ventricular pacing in people without indications for anti-bradycardia pacing. SETTING Thirty-seven centres in the United States; enrolment October 2000 to September 2002.
second or third degree AV block; atrial ¢brillation of unknown or less than 6 months duration; life expectancy less than 1 year, and frequent uncontrolled atrial tachyarrhythmia. INTERVENTION An ICD with dual-chamber, rate-responsive pacing capability was implanted in all participants. ICDs were then randomly programmed to ventricular backup pacing at 40/min or dualchamber rate responsive pacing at 70/min. All participants were prescribed maximal tolerated medical therapy for left ventricular dysfunction, including ACE inhibitors and beta blockers. Median follow-up was 8.4 months (range 0 to 23.6 months).
METHOD Single-blind randomised trial. PARTICIPANTS Five hundred and six people with indications for ICD therapy. All had an index arrhythmia unrelated to transient or correctable causes, left ventricular ejection fraction of 40% or less, no indication for anti-bradycardia pacemaker therapy and no persistent atrial arrhythmia. Mean age 66 years;17% women. Exclusion criteria were pre-existing endocardial pacing leads; pacemaker; planned arrhythmia surgery; symptomatic bradycardia or
OUTCOMES Composite end-point of death or hospitalisation for congestive heart failure. MAIN RESULTS Severe outcomes within 30 days of implantation were similar between groups. Late complications were rare. At 1 year, 83.9% of the ventricular backup pacing group were alive without hospitalisation for congestive heart failure compared with 73.3% of the dual chamber pacing group (relative hazard 1.61; 95% CI 1.06 to 2.44,Table 1).
Table 1 One-year outcomes for people receiving ventricular backup pacing or dual chamber pacing Dual chamber pacing % (n = 250)
Ventricular backup pacing % (n = 256)
Number needed to treat with dual chamber to harm one (95% CI)
Absolute risk increase % (95% CI)
Relative risk increase % (95% CI)
Death or hospitalisation for congestive heart failure Mortality
26.7
16.1
10.1
6.5
9 (6 to 29) Not signi¢cant
Hospitalisation for congestive heart failure
22.6
13.3
11 (4 to 18) 4 (1% ARR to 8% ARI) 9 (3 to 16)
66 (8 to 123) 55 (37% RRR to 148% RRI) 70 (4 to 135)
11 (6 to 38)
Note: ARR/ARI=absolute risk reduction/increase, RRR/RRI=relative risk reduction/increase.
1361-2611/03/$ - see front matter & 2003 Published by Elsevier Science Ltd. doi:10.1016/S1361-2611(03)00031-9
Evidence-based Cardiovascular Medicine (2003) 7, 89^91
89
AUTHORS’ CONCLUSIONS Dual-chamber pacing has no clinical advantage over ventricular backup pacing for people with standard indications for ICD therapy, no indication for cardiac pacing and a left ventricular ejection fraction of 40% or less.
Sources offunding: St Jude Corporation, California. Correspondenceto: BWilko¡, Cleveland Clinic Foundation, Ohio, USA. Email: [email protected] Abstract provided by Bazian Ltd, London.
NOTE The study was stopped prematurely after interim analysis.
Commentary It has happened again.The f|eld of clinical cardiac electrophysiology has been upended by a clinical trial with results contrary to standard practice. We should anticipate this by now. The CAST trial suggested that certain anti-arrhythmic agents are more often harmful than helpful.1 EMIAT and CAMIAT found that amiodarone is associated with a neutral effect, at best.2,3 Amiodarone prevents some sudden deaths, but this benef|t is offset by an increase in non-cardiac deaths. MADIT taught us that certain asymptomatic patients do better with an ICD than empiric drug therapy.4 This was extended in MADIT II to people who never had a documented arrhythmia.5 MUSTT found that electrophysiological studies have little value in predicting response to anti-arrhythmic drug therapy.6 A recent substudy from MADIT II also suggested that inducibility of ventricular function predicts a lower likelihood of developing ventricular f|brillation. This study’s contribution The DAVID trial may catch electrophysiologists off guard again. The use of dual-chamber ICDs increased dramatically after their approval in 1997. About 65% of all non-resynchronisation ICDs are dual chamber.The DAVID trial questions this logic.The investigators found a signif|cant increase in heart failure hospitalisation and total mortality among people receiving dual chamber devices over single chamber devices. Our f|rst response may be to distrust the results. Perhaps the increased dual chamber mortality rate was due to an increased operative risk? Not so, because all participants received a dualchamber device, with half randomised to single chamber programming. Perhaps the devices were incorrectly programmed? For most of the dual chamber devices, the mode was DDDR at rate of 70 with an AV interval of 180 milliseconds ^ standard practice at many centres. Perhaps the trial placed dual-chamber devices in patients who would best benefit from a triple-chamber biventricular resynchronization defibrillator (CRT-D)? Only 12% of participants were NYHA functional class III^IVand only about 30% had a QRS duration over130 milliseconds.Thus, only an estimated 4% of the participants would receive a CRT-D device based on current evidence-based practice. Cardiac resynchronisation therapy is the key to understanding the DAVID trial results. People with an intrinsic intraventricular block, whether due to left or right bundle branch block, or a nonspecific conduction delay appear to benefit from biventricular pacing.7 Clinical parameters of heart failure are improved by resynchronising ventricular contraction. The unpublished
90
Evidence-based Cardiovascular Medicine (2003) 7, 89^91
COMPANION trial found that mortality improved 20% over conventional therapy with a CRT device and 40% when cardiac resynchronisation pacing was coupled with a defibrillator. The DAVID investigators speculate that the mechanism for increased mortality with dual-chamber pacing is artificial ‘desynchronisation’ created with RV apex pacing. This hypothesis is supported by the finding that increased use of the dual chamber pacing was associated with greater risk (75.9% event-free rate at 12 months with pacing 41% to 100% of the time v 86.9% free from death or heart failure exacerbation when pacing was used 40% of the time or less). Clinical implications These f|ndings do not suggest that dual-chamber pacing is without merit. Adding an atrial lead may help with arrhythmia discrimination, avoid atrial f|brillation and provide an important symptomatic benef|t in people who need bradycardia support. Nevertheless, in those who do not need bradycardia support, the DAVID trial suggests that programming changes are needed. Patients should have the AV interval (AVI) extended to the point where ventricular capture is a rare event, generally requiring an AVI of 200 milliseconds or greater. Based on this f|nding, it seems reasonable to reprogram dual chamber devices in most existing patients who meet these criteria to an extended AVI. So if dual-chamber pacing is potentially harmful, what are we to do with new patients? In people without a bradycardia indication who are unlikely to use the advantages of a dual-chamber device, it seems reasonable to prescribe a less expensive singlechamber ICD. Until more data are available, the remaining challenge centres on the new implant patient with symptomatic heart failure. Those with a bradycardia indication may benef|t from a biventricular device.This may also include those with a prolonged intrinsic PR interval (4200 ms) as diminished atrial contribution becomes signif|cant. Programming the AV delay to values over 200 milliseconds may preventright ventricular pacing, but can result in a diminished atrial f|lling period.Thus, if a patient is likely to need ventricular pacing and they meet other criteria for resynchronisation therapy (NYHA III-IVdespite optimum pharmacologic therapy), a biventricular device may be recommended. The expense and clinical benef|t of this expanded use requires further study. Steven L Higgins, MD Regional Cardiac Arrhythmia Center Scripps Memorial Hospital La Jolla, California, USA
Literature cited 1. Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med 1991; 324: 781^788. 2. Julian DG, Camm AJ, Frangin G et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349: 667^ 674. 3. Cairns JA,Connolly SJ, Roberts R,Gent M.Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction ArrhythmiaTrial Investigators. Lancet 1997; 349: 675^ 682. 4. Moss AJ, Hall WJ, Cannom DS et al. Improved survival with an implanted def|brillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996; 335: 1933^1940. 5. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a def|brillator in patients with myocardial infarction and reduced ejection fraction; the multicenter automatic def|brillator implantation trial II (MADIT II). N Engl J Med 2002; 346: 877^ 883. 6. Buxton AE, Lee KL, Fisher JD et al. A randomized study for the prevention of sudden death in patients with coronary artery disease. N Engl J Med1999; 341: 1882^1890.
7. Auricchio A, Stellbrink C, Block M et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999; 99: 2993^3001.
Author’s Response There may be a diff|culty with programming extended AV intervals. Data from the trial suggest a mode of VVI and 40 bpm. Slightly enhanced programming of DDI at 40 bpm may be benef|cial, but DDD with a long AV interval may be problematic. All of the ICDs currently implanted use ventricularly based timing. Sensing the QRS before the end of the AV interval will artif|cially increase the base rate of pacing. DDI at 40 bpm with a long AV interval would be good programming, consistent with the results of the trial, while programming DDDR with a long AV interval could create very rapid pacing and frequent RV pacing. In our study, participants that had 40% or more of the heart beats ventricularly paced had increased mortality and CHF hospitalisation. Bruce L.Wilkoff, MD The Cleveland Clinic Foundation Cleveland, Ohio, USA
Evidence-based Cardiovascular Medicine (2003) 6, 89^91
91
Dual chamber pacing may have no benefit over ventricular backup pacing in people without indications for anti-bradycardia pacing Abstracted from: DAVID 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.
BACKGROUND Implantable cardioverter de¢brillators (ICD) are associated with increased survival in people with a history of life-threatening ventricular arrhythmias. Most ICD devices provide dual-chamber pacing therapy in the event of inadequate ventricular activity. OBJECTIVE To assess the e⁄cacy of dual-chamber pacing compared with backup ventricular pacing in people without indications for anti-bradycardia pacing. SETTING Thirty-seven centres in the United States; enrolment October 2000 to September 2002.
second or third degree AV block; atrial ¢brillation of unknown or less than 6 months duration; life expectancy less than 1 year, and frequent uncontrolled atrial tachyarrhythmia. INTERVENTION An ICD with dual-chamber, rate-responsive pacing capability was implanted in all participants. ICDs were then randomly programmed to ventricular backup pacing at 40/min or dualchamber rate responsive pacing at 70/min. All participants were prescribed maximal tolerated medical therapy for left ventricular dysfunction, including ACE inhibitors and beta blockers. Median follow-up was 8.4 months (range 0 to 23.6 months).
METHOD Single-blind randomised trial. PARTICIPANTS Five hundred and six people with indications for ICD therapy. All had an index arrhythmia unrelated to transient or correctable causes, left ventricular ejection fraction of 40% or less, no indication for anti-bradycardia pacemaker therapy and no persistent atrial arrhythmia. Mean age 66 years;17% women. Exclusion criteria were pre-existing endocardial pacing leads; pacemaker; planned arrhythmia surgery; symptomatic bradycardia or
OUTCOMES Composite end-point of death or hospitalisation for congestive heart failure. MAIN RESULTS Severe outcomes within 30 days of implantation were similar between groups. Late complications were rare. At 1 year, 83.9% of the ventricular backup pacing group were alive without hospitalisation for congestive heart failure compared with 73.3% of the dual chamber pacing group (relative hazard 1.61; 95% CI 1.06 to 2.44,Table 1).
Table 1 One-year outcomes for people receiving ventricular backup pacing or dual chamber pacing Dual chamber pacing % (n = 250)
Ventricular backup pacing % (n = 256)
Number needed to treat with dual chamber to harm one (95% CI)
Absolute risk increase % (95% CI)
Relative risk increase % (95% CI)
Death or hospitalisation for congestive heart failure Mortality
26.7
16.1
10.1
6.5
9 (6 to 29) Not signi¢cant
Hospitalisation for congestive heart failure
22.6
13.3
11 (4 to 18) 4 (1% ARR to 8% ARI) 9 (3 to 16)
66 (8 to 123) 55 (37% RRR to 148% RRI) 70 (4 to 135)
11 (6 to 38)
Note: ARR/ARI=absolute risk reduction/increase, RRR/RRI=relative risk reduction/increase.
1361-2611/03/$ - see front matter & 2003 Published by Elsevier Science Ltd. doi:10.1016/S1361-2611(03)00031-9
Evidence-based Cardiovascular Medicine (2003) 7, 89^91
89
AUTHORS’ CONCLUSIONS Dual-chamber pacing has no clinical advantage over ventricular backup pacing for people with standard indications for ICD therapy, no indication for cardiac pacing and a left ventricular ejection fraction of 40% or less.
Sources offunding: St Jude Corporation, California. Correspondenceto: BWilko¡, Cleveland Clinic Foundation, Ohio, USA. Email: [email protected] Abstract provided by Bazian Ltd, London.
NOTE The study was stopped prematurely after interim analysis.
Commentary It has happened again.The f|eld of clinical cardiac electrophysiology has been upended by a clinical trial with results contrary to standard practice. We should anticipate this by now. The CAST trial suggested that certain anti-arrhythmic agents are more often harmful than helpful.1 EMIAT and CAMIAT found that amiodarone is associated with a neutral effect, at best.2,3 Amiodarone prevents some sudden deaths, but this benef|t is offset by an increase in non-cardiac deaths. MADIT taught us that certain asymptomatic patients do better with an ICD than empiric drug therapy.4 This was extended in MADIT II to people who never had a documented arrhythmia.5 MUSTT found that electrophysiological studies have little value in predicting response to anti-arrhythmic drug therapy.6 A recent substudy from MADIT II also suggested that inducibility of ventricular function predicts a lower likelihood of developing ventricular f|brillation. This study’s contribution The DAVID trial may catch electrophysiologists off guard again. The use of dual-chamber ICDs increased dramatically after their approval in 1997. About 65% of all non-resynchronisation ICDs are dual chamber.The DAVID trial questions this logic.The investigators found a signif|cant increase in heart failure hospitalisation and total mortality among people receiving dual chamber devices over single chamber devices. Our f|rst response may be to distrust the results. Perhaps the increased dual chamber mortality rate was due to an increased operative risk? Not so, because all participants received a dualchamber device, with half randomised to single chamber programming. Perhaps the devices were incorrectly programmed? For most of the dual chamber devices, the mode was DDDR at rate of 70 with an AV interval of 180 milliseconds ^ standard practice at many centres. Perhaps the trial placed dual-chamber devices in patients who would best benefit from a triple-chamber biventricular resynchronization defibrillator (CRT-D)? Only 12% of participants were NYHA functional class III^IVand only about 30% had a QRS duration over130 milliseconds.Thus, only an estimated 4% of the participants would receive a CRT-D device based on current evidence-based practice. Cardiac resynchronisation therapy is the key to understanding the DAVID trial results. People with an intrinsic intraventricular block, whether due to left or right bundle branch block, or a nonspecific conduction delay appear to benefit from biventricular pacing.7 Clinical parameters of heart failure are improved by resynchronising ventricular contraction. The unpublished
90
Evidence-based Cardiovascular Medicine (2003) 7, 89^91
COMPANION trial found that mortality improved 20% over conventional therapy with a CRT device and 40% when cardiac resynchronisation pacing was coupled with a defibrillator. The DAVID investigators speculate that the mechanism for increased mortality with dual-chamber pacing is artificial ‘desynchronisation’ created with RV apex pacing. This hypothesis is supported by the finding that increased use of the dual chamber pacing was associated with greater risk (75.9% event-free rate at 12 months with pacing 41% to 100% of the time v 86.9% free from death or heart failure exacerbation when pacing was used 40% of the time or less). Clinical implications These f|ndings do not suggest that dual-chamber pacing is without merit. Adding an atrial lead may help with arrhythmia discrimination, avoid atrial f|brillation and provide an important symptomatic benef|t in people who need bradycardia support. Nevertheless, in those who do not need bradycardia support, the DAVID trial suggests that programming changes are needed. Patients should have the AV interval (AVI) extended to the point where ventricular capture is a rare event, generally requiring an AVI of 200 milliseconds or greater. Based on this f|nding, it seems reasonable to reprogram dual chamber devices in most existing patients who meet these criteria to an extended AVI. So if dual-chamber pacing is potentially harmful, what are we to do with new patients? In people without a bradycardia indication who are unlikely to use the advantages of a dual-chamber device, it seems reasonable to prescribe a less expensive singlechamber ICD. Until more data are available, the remaining challenge centres on the new implant patient with symptomatic heart failure. Those with a bradycardia indication may benef|t from a biventricular device.This may also include those with a prolonged intrinsic PR interval (4200 ms) as diminished atrial contribution becomes signif|cant. Programming the AV delay to values over 200 milliseconds may preventright ventricular pacing, but can result in a diminished atrial f|lling period.Thus, if a patient is likely to need ventricular pacing and they meet other criteria for resynchronisation therapy (NYHA III-IVdespite optimum pharmacologic therapy), a biventricular device may be recommended. The expense and clinical benef|t of this expanded use requires further study. Steven L Higgins, MD Regional Cardiac Arrhythmia Center Scripps Memorial Hospital La Jolla, California, USA
Literature cited 1. Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med 1991; 324: 781^788. 2. Julian DG, Camm AJ, Frangin G et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349: 667^ 674. 3. Cairns JA,Connolly SJ, Roberts R,Gent M.Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction ArrhythmiaTrial Investigators. Lancet 1997; 349: 675^ 682. 4. Moss AJ, Hall WJ, Cannom DS et al. Improved survival with an implanted def|brillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996; 335: 1933^1940. 5. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a def|brillator in patients with myocardial infarction and reduced ejection fraction; the multicenter automatic def|brillator implantation trial II (MADIT II). N Engl J Med 2002; 346: 877^ 883. 6. Buxton AE, Lee KL, Fisher JD et al. A randomized study for the prevention of sudden death in patients with coronary artery disease. N Engl J Med1999; 341: 1882^1890.
7. Auricchio A, Stellbrink C, Block M et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999; 99: 2993^3001.
Author’s Response There may be a diff|culty with programming extended AV intervals. Data from the trial suggest a mode of VVI and 40 bpm. Slightly enhanced programming of DDI at 40 bpm may be benef|cial, but DDD with a long AV interval may be problematic. All of the ICDs currently implanted use ventricularly based timing. Sensing the QRS before the end of the AV interval will artif|cially increase the base rate of pacing. DDI at 40 bpm with a long AV interval would be good programming, consistent with the results of the trial, while programming DDDR with a long AV interval could create very rapid pacing and frequent RV pacing. In our study, participants that had 40% or more of the heart beats ventricularly paced had increased mortality and CHF hospitalisation. Bruce L.Wilkoff, MD The Cleveland Clinic Foundation Cleveland, Ohio, USA
Evidence-based Cardiovascular Medicine (2003) 6, 89^91
91