- Email: [email protected]
What Can We Expect from the ISSUE 3 Trial?
J Arrhythmia
Vol 27 No 2 2011
Review Article
What Can We Expect from the ISSUE 3 Trial? Richard Sutton DSc FRCP FACC FESC FAHA FHRS1 , Michele Brignole MD FESC2 1
Professor of Clinical Cardiology and Consultant Cardiologist, Imperial College and Imperial College Healthcare NHS Trust St Mary’s Hospital, London, United Kingdom 2 Head of Department of Cardiology, Ospedali del Tigullio, Servizio Sanitario Nazionale, Lavagna, Italy
The ISSUE 3 Trial is designed to demonstrate which patients with vasovagal syncope over the age of 40 years will benefit from pacing dual chamber with the rate drop response. The trial has completed its recruitment of 521 patients and 78 have now been randomized in Phase 2, which is the Pacing ON versus Pacing OFF comparison. During this Phase the end-points are recurrence of syncope or two years of follow-up without recurrence. It has been calculated that 27 early end-points will be sufficient to determine a significant difference between the groups. The background, details and design of the trial are explained. Some early findings are presented. Definitive results are expected by the end of 2011. (J Arrhythmia 2011; 27: 116–119)
Key words: Vasovagal syncope, Pacemakers, Randomized controlled trial, Implantable loop recorders
Introduction ISSUE 3 is an on-going trial, which is attempting to identify the patients with severe Reflex syncope that might benefit from permanent dual chamber pacing with a rate drop response algorithm. Patients are selected on the basis of age being >40 years and history of syncope suggestive of a Vasovagal cause with >3 episodes in the last 2 years and at least one in the last 6 months. Patients were then implanted with a Loop recorder (ILR) and time was allowed for a recurrence of syncope. The data from the ILR were analysed. Patients showing asystole or severe bradycardia entered the ISSUE 3 trial which is a double blind randomized controlled trial of pacing using the rate drop response (Pacing-ON) versus no pacing in
ODO mode (Pacing-OFF). The end-points of the trial are either recurrent syncope or follow-up for two years without syncope. Patients with an identified tachyarrhythmia, on the ILR recording, were treated according to need and those who had syncope but demonstrated sinus rhythm entered another trial called PC 2. This trial compares physical countermeasures with routine management and will be reported elsewhere. The study design of ISSUE 3 has been published.1) Sixty centres participated from all over Europe and Canada. No centre included more than 10% of the patients recruited. Details of ISSUE 3 Phase 1 of the trial attempted to identify patients who are suitable for study along the lines of the
Address for correspondence: Professor Richard Sutton, International Centre for Circulatory Health, 59-61 North Wharf Road, London, W2 1LA, United Kingdom. Telephone: +442079351011 E-mail: [email protected]
116
Sutton R
ISSUE 2 Registry.2) Patients, over 40 years of age, presenting with 3 or more episodes of syncope in the last two years and one in the last 6 months, clinically suspected of having VVS have been recruited and implanted with an ECG loop recorder (Medtronic Reveal DX, Medtronic Inc., Minneapolis, MN, USA). They have been followed closely until the first recurrence of syncope at which point the ECG recorded during the attack has been analysed. Patients then progress into one of three arms of the study. The most important of these is when asystole has occurred as these patients receive a dual chamber pacemaker (Medtronic Adapta. Advisa or Versa). Asystole should be >3 s and be symptomatic. It may be due to sino-atrial arrest without escape rhythm or to complete atrio-ventricular block. Patients with an asymptomatic or pre-syncope asystolic period of >6 s have also been included. Post-tachycardia pauses were not considered. As soon as the implant is successfully completed patients were centrally randomized to Pacing-ON or Pacing-OFF. This was Phase 2. In the Pacing-ON arm the rate drop response is activated according to the findings of the ISSUE 2 registry. If sinus rhythm is recorded during the index attack patients move into another study of counter-pressure manoeuvres in control of symptoms compared with standard measures such as increased fluids, salt, education, reassurance and avoidance of triggers and situations where syncope may occur (PC2 Trial — a sub-study of ISSUE 3) and if a pathological tachycardia is identified patients leave the trial and are treated according to the arrhythmia shown. This article will concentrate on those patients who are included in the pacing arm of ISSUE 3. Exclusions from the trial were designed, as far as possible, to focus on patients with VVS rather than those with paroxysmal atrio-ventricular block due to conduction tissue disease. Furthermore, choice of relatively frequent syncope, often with complicating features such as lack of warning of impending attack, abnormal movements or incontinence during attacks, serves to select patients for whom the medical profession and the patient and family all feel that something, some potentially definitive therapy, needs to be undertaken. Very frequent syncope and younger patients were avoided as in the former presentation there are often important psychological aspects and in the latter the prognosis in young people is usually good not justifying such drastic action as implanting a pacemaker. In contrast the older patient is likely to be presenting a poorer prognosis related to ageing of the autonomic control systems.3) Patients with orthostatic hypotension and
What can we expect from ISSUE 3?
those with transient loss of consciousness not due to syncope were specifically excluded. Finally but importantly, patients with Carotid Sinus syndrome were excluded after a positive Carotid Sinus massage as described in the recent European Society of Cardiology’s Task Force on Syncope.4) The study flow chart is shown in Figure 1. Background of ISSUE 3 The background of ISSUE 3 stems from the first ISSUE trial5) now referred to as ISSUE 1. In this study, one of the groups of patients examined had a history suggestive of Vasovagal Syncope but were tilt negative or were tilt positive without asystole or severe bradycardia. These patients underwent ILR implantation and recurrent syncope was frequently in both sub-groups due to asystole or severe bradycardia (16–21%). This study was the first to document the relative unreliability of tilt testing in defining the collapse pattern of the older patient with Vasovagal Syncope. These findings prompted the ISSUE 2 study,2) which hypothesized that the older patient with Vasovagal Syncope may be more precisely and earlier diagnosed by an ILR approach than using tilt testing. This study being only a registry allowed the caring physician to choose whether subsequent treatment after the ILR diagnosis would be according to the ILR findings or continue on conventional lines. An interpretable ECG was recorded during syncope in 30% of ILR implanted patients and in follow-up half of these were treated according to the ILR findings and the other half on conventional lines. Those with the ILR based therapy had much better results as most detected rhythms were asystole or severe bradycardia and those with ILR based therapy received a pacemaker. Recurrent episodes in those treated non-specifically were 0.83/patient/year whereas this figure was only 0.05 episodes in the paced group (p ¼ 0:001). Once these data were appreciated the next step was to test this finding in a randomized controlled trial prompting the design of the ISSUE 3 trial.1) Status of the ISSUE 3 trial Initial plans were to recruit 710 patients but during the recruitment phase it became clear that a lesser number would yield sufficient to permit the second goal of randomizing 120 patients that is 60 in the pacing-ON and 60 in the pacing-OFF arms. This sample size yields 80% power to discriminate between the groups within 95% confidence limits. It is anticipated that the study will be stopped when
117
J Arrhythmia
Vol 27 No 2 2011
Suspected NMS (screening phase)
Eligible patients ILR implantation Phase I FU (max 24 months) Phase I end-points Phase II
Suspected hypotensive NMS (type 2,3):brady, slight or no rhythm variations
Suspected asystolic NMS (type 1): •Asystolic syncope =3” or •Non-syncopal asystole =6”
Tachycardia (type 4)
R Physical counterpressure Manoeuvres (PC-2 study)
PM ON arm
PM OFF arm
Phase 2 FU
Phase 2 FU
ISSUE 3 trial
Figure 1 ISSUE 3 study flow chart NMS: neurally mediated syncope, ILR: implantable loop recorder, FU: follow-up. The Types referred to in the Figure are those in the Proposed electrocardiographic classification of spontaneous syncope.6)
27 randomized patients have sustained a recurrent syncope in Phase 2. Recruitment was closed at 521 patients, who received an ILR, at the end of November 2010. By mid-April 2011, 78 patients had been randomized with excellent quality ILR recorded ECGs, full data available and implantation of a dual chamber pacemaker according to protocol. It is anticipated that the desired total of 120 randomizations will be achieved within a few more months. At that point the study will give its first report. An interesting finding reproducing that made in ISSUE 22) was that approaching 30% of the index ECGs during attacks showed episodes of atrioventricular block as might be expected in patients with Stokes-Adams disease rather than the slowing of sinus rate associated ultimately with cessation of both sinus and ventricular activity or atrio-ventricular block with very slow sinus activity. These latter findings are those expected in classical Vasovagal Syncope. These two different ECG patterns are classified as 1C and 1A/1B respectively according to the criteria proposed in the interpretation of rhythm disturbances found during ILR recording of sponta-
118
neous syncope.6) The 1C type of ECG must raise the inevitable question of why this occurs and how is it caused bearing in mind that all the patients were thought clinically to have Vasovagal Syncope. A possible explanation is that those with the 1C collapse pattern are reflecting disease of the conduction system in parallel with Vasovagal Syncope or that this is simply a manifestation of an ageing process in autonomic control of the heart. This finding will be further studied in the ISSUE 3 patients and will also be a focus of further research work. What Can We Expect from ISSUE 3? The first results can be expected late in 2011. If the trial reaches a statistically significant difference between those with pacing-ON compared with those with the pacing-OFF in terms of syncope recurrence we will have the evidence of efficacy of pacing in VVS and a clear indication for pacing in this group of patients. Hitherto, the literature has been contradictory and unable to provide clarity in direction.
Sutton R
The early studies suggested benefit for those paced7–9) but the comparison was between surgery for pacemaker implantation and no surgery. These trials were criticised and two subsequent studies,10,11) which probably, in retrospect, failed to select the patients at greatest possibility of benefit, too young10) and insufficiently bradycardiac.11) There followed ISSUE 2,2) which raised the likelihood that a group of patients can benefit from pacing if they are selected on the basis of age and clearly documented bradycardia. ISSUE 3 also may throw more light on the pathophysiology of the vasovagal patient. There will be available for analysis more comparative data on tilt testing versus ILR recording and more data concerning the choice of programming characteristics of the rate-drop response algorithm so as to achieve the best effect on the control of symptoms.
What can we expect from ISSUE 3?
5)
6)
7)
8)
References 1) The Steering Committee of the ISSUE 3 study. [Sutton R]. International study on syncope of uncertain aetiology 3 [ISSUE 3]: pacemaker therapy for patients with asystolic neurally mediated syncope: rationale and study design. Europace 2007; 9: 25–30 2) Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, Andresen D, Benditt DG, Vardas P for the International Study on Syncope of Uncertain Etiology [ISSUE 2] Group: Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006; 27: 1085–1092 3) Alboni P, Brignole M, degli Uberti EC: Is vasovagal syncope a disease? Europace 2007; 9: 83–87 4) Moya A, Sutton R, Ammirati F, Blanc J-J, Brignole M, Dahm JB, De Haro J-C, Gajek J, Gjesdal K, Krahn A,
9)
10)
11)
Massin M, Pepi M, Pezawas T, Granell R, Sarasin F, Ungar A, van Dijk J, Walma EP, Wieling W: Guidelines for the diagnosis and treatment of syncope (version 2009). Eur Heart J 2009; 30: 2631–2671 Moya A, Brignole M, Menozzi C, Garcia-Civera R, Tognarini S, Mont L, Botto G, Giada F, Cornacchia D: Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation 2001; 104: 1261–1267 Brignole M, Moya A, Menozzi C, Sutton R: Proposed electrocardiographic classification of spontaneous syncope documented by an implantable loop recorder. Europace 2005; 7: 14–18 Connolly SJ, Sheldon R, Roberts RS, Gent M: The North American vasovagal pacemaker study (VPS). A randomized controlled trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 1999; 33: 16–20 Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya A: Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope: Pacemaker versus no therapy: a multicenter randomized study. The Vasovagal Syncope International Study (VASIS) Investigators. Circulation 2000; 102: 294–249 Ammirati F, Colivicchi F, Santini M: Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. Circulation 2001; 104: 52–57 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, Morillo C, Gent M for the VPS II Investigators: Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: second vasovagal pacemaker study (VPS II). JAMA 2003; 289: 2224–2229 Raviele A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R: The vasovagal syncope and pacing trial [SYNPACE]. A randomised, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. Eur Heart J 2004; 25: 1741–1748
119
Vol 27 No 2 2011
Review Article
What Can We Expect from the ISSUE 3 Trial? Richard Sutton DSc FRCP FACC FESC FAHA FHRS1 , Michele Brignole MD FESC2 1
Professor of Clinical Cardiology and Consultant Cardiologist, Imperial College and Imperial College Healthcare NHS Trust St Mary’s Hospital, London, United Kingdom 2 Head of Department of Cardiology, Ospedali del Tigullio, Servizio Sanitario Nazionale, Lavagna, Italy
The ISSUE 3 Trial is designed to demonstrate which patients with vasovagal syncope over the age of 40 years will benefit from pacing dual chamber with the rate drop response. The trial has completed its recruitment of 521 patients and 78 have now been randomized in Phase 2, which is the Pacing ON versus Pacing OFF comparison. During this Phase the end-points are recurrence of syncope or two years of follow-up without recurrence. It has been calculated that 27 early end-points will be sufficient to determine a significant difference between the groups. The background, details and design of the trial are explained. Some early findings are presented. Definitive results are expected by the end of 2011. (J Arrhythmia 2011; 27: 116–119)
Key words: Vasovagal syncope, Pacemakers, Randomized controlled trial, Implantable loop recorders
Introduction ISSUE 3 is an on-going trial, which is attempting to identify the patients with severe Reflex syncope that might benefit from permanent dual chamber pacing with a rate drop response algorithm. Patients are selected on the basis of age being >40 years and history of syncope suggestive of a Vasovagal cause with >3 episodes in the last 2 years and at least one in the last 6 months. Patients were then implanted with a Loop recorder (ILR) and time was allowed for a recurrence of syncope. The data from the ILR were analysed. Patients showing asystole or severe bradycardia entered the ISSUE 3 trial which is a double blind randomized controlled trial of pacing using the rate drop response (Pacing-ON) versus no pacing in
ODO mode (Pacing-OFF). The end-points of the trial are either recurrent syncope or follow-up for two years without syncope. Patients with an identified tachyarrhythmia, on the ILR recording, were treated according to need and those who had syncope but demonstrated sinus rhythm entered another trial called PC 2. This trial compares physical countermeasures with routine management and will be reported elsewhere. The study design of ISSUE 3 has been published.1) Sixty centres participated from all over Europe and Canada. No centre included more than 10% of the patients recruited. Details of ISSUE 3 Phase 1 of the trial attempted to identify patients who are suitable for study along the lines of the
Address for correspondence: Professor Richard Sutton, International Centre for Circulatory Health, 59-61 North Wharf Road, London, W2 1LA, United Kingdom. Telephone: +442079351011 E-mail: [email protected]
116
Sutton R
ISSUE 2 Registry.2) Patients, over 40 years of age, presenting with 3 or more episodes of syncope in the last two years and one in the last 6 months, clinically suspected of having VVS have been recruited and implanted with an ECG loop recorder (Medtronic Reveal DX, Medtronic Inc., Minneapolis, MN, USA). They have been followed closely until the first recurrence of syncope at which point the ECG recorded during the attack has been analysed. Patients then progress into one of three arms of the study. The most important of these is when asystole has occurred as these patients receive a dual chamber pacemaker (Medtronic Adapta. Advisa or Versa). Asystole should be >3 s and be symptomatic. It may be due to sino-atrial arrest without escape rhythm or to complete atrio-ventricular block. Patients with an asymptomatic or pre-syncope asystolic period of >6 s have also been included. Post-tachycardia pauses were not considered. As soon as the implant is successfully completed patients were centrally randomized to Pacing-ON or Pacing-OFF. This was Phase 2. In the Pacing-ON arm the rate drop response is activated according to the findings of the ISSUE 2 registry. If sinus rhythm is recorded during the index attack patients move into another study of counter-pressure manoeuvres in control of symptoms compared with standard measures such as increased fluids, salt, education, reassurance and avoidance of triggers and situations where syncope may occur (PC2 Trial — a sub-study of ISSUE 3) and if a pathological tachycardia is identified patients leave the trial and are treated according to the arrhythmia shown. This article will concentrate on those patients who are included in the pacing arm of ISSUE 3. Exclusions from the trial were designed, as far as possible, to focus on patients with VVS rather than those with paroxysmal atrio-ventricular block due to conduction tissue disease. Furthermore, choice of relatively frequent syncope, often with complicating features such as lack of warning of impending attack, abnormal movements or incontinence during attacks, serves to select patients for whom the medical profession and the patient and family all feel that something, some potentially definitive therapy, needs to be undertaken. Very frequent syncope and younger patients were avoided as in the former presentation there are often important psychological aspects and in the latter the prognosis in young people is usually good not justifying such drastic action as implanting a pacemaker. In contrast the older patient is likely to be presenting a poorer prognosis related to ageing of the autonomic control systems.3) Patients with orthostatic hypotension and
What can we expect from ISSUE 3?
those with transient loss of consciousness not due to syncope were specifically excluded. Finally but importantly, patients with Carotid Sinus syndrome were excluded after a positive Carotid Sinus massage as described in the recent European Society of Cardiology’s Task Force on Syncope.4) The study flow chart is shown in Figure 1. Background of ISSUE 3 The background of ISSUE 3 stems from the first ISSUE trial5) now referred to as ISSUE 1. In this study, one of the groups of patients examined had a history suggestive of Vasovagal Syncope but were tilt negative or were tilt positive without asystole or severe bradycardia. These patients underwent ILR implantation and recurrent syncope was frequently in both sub-groups due to asystole or severe bradycardia (16–21%). This study was the first to document the relative unreliability of tilt testing in defining the collapse pattern of the older patient with Vasovagal Syncope. These findings prompted the ISSUE 2 study,2) which hypothesized that the older patient with Vasovagal Syncope may be more precisely and earlier diagnosed by an ILR approach than using tilt testing. This study being only a registry allowed the caring physician to choose whether subsequent treatment after the ILR diagnosis would be according to the ILR findings or continue on conventional lines. An interpretable ECG was recorded during syncope in 30% of ILR implanted patients and in follow-up half of these were treated according to the ILR findings and the other half on conventional lines. Those with the ILR based therapy had much better results as most detected rhythms were asystole or severe bradycardia and those with ILR based therapy received a pacemaker. Recurrent episodes in those treated non-specifically were 0.83/patient/year whereas this figure was only 0.05 episodes in the paced group (p ¼ 0:001). Once these data were appreciated the next step was to test this finding in a randomized controlled trial prompting the design of the ISSUE 3 trial.1) Status of the ISSUE 3 trial Initial plans were to recruit 710 patients but during the recruitment phase it became clear that a lesser number would yield sufficient to permit the second goal of randomizing 120 patients that is 60 in the pacing-ON and 60 in the pacing-OFF arms. This sample size yields 80% power to discriminate between the groups within 95% confidence limits. It is anticipated that the study will be stopped when
117
J Arrhythmia
Vol 27 No 2 2011
Suspected NMS (screening phase)
Eligible patients ILR implantation Phase I FU (max 24 months) Phase I end-points Phase II
Suspected hypotensive NMS (type 2,3):brady, slight or no rhythm variations
Suspected asystolic NMS (type 1): •Asystolic syncope =3” or •Non-syncopal asystole =6”
Tachycardia (type 4)
R Physical counterpressure Manoeuvres (PC-2 study)
PM ON arm
PM OFF arm
Phase 2 FU
Phase 2 FU
ISSUE 3 trial
Figure 1 ISSUE 3 study flow chart NMS: neurally mediated syncope, ILR: implantable loop recorder, FU: follow-up. The Types referred to in the Figure are those in the Proposed electrocardiographic classification of spontaneous syncope.6)
27 randomized patients have sustained a recurrent syncope in Phase 2. Recruitment was closed at 521 patients, who received an ILR, at the end of November 2010. By mid-April 2011, 78 patients had been randomized with excellent quality ILR recorded ECGs, full data available and implantation of a dual chamber pacemaker according to protocol. It is anticipated that the desired total of 120 randomizations will be achieved within a few more months. At that point the study will give its first report. An interesting finding reproducing that made in ISSUE 22) was that approaching 30% of the index ECGs during attacks showed episodes of atrioventricular block as might be expected in patients with Stokes-Adams disease rather than the slowing of sinus rate associated ultimately with cessation of both sinus and ventricular activity or atrio-ventricular block with very slow sinus activity. These latter findings are those expected in classical Vasovagal Syncope. These two different ECG patterns are classified as 1C and 1A/1B respectively according to the criteria proposed in the interpretation of rhythm disturbances found during ILR recording of sponta-
118
neous syncope.6) The 1C type of ECG must raise the inevitable question of why this occurs and how is it caused bearing in mind that all the patients were thought clinically to have Vasovagal Syncope. A possible explanation is that those with the 1C collapse pattern are reflecting disease of the conduction system in parallel with Vasovagal Syncope or that this is simply a manifestation of an ageing process in autonomic control of the heart. This finding will be further studied in the ISSUE 3 patients and will also be a focus of further research work. What Can We Expect from ISSUE 3? The first results can be expected late in 2011. If the trial reaches a statistically significant difference between those with pacing-ON compared with those with the pacing-OFF in terms of syncope recurrence we will have the evidence of efficacy of pacing in VVS and a clear indication for pacing in this group of patients. Hitherto, the literature has been contradictory and unable to provide clarity in direction.
Sutton R
The early studies suggested benefit for those paced7–9) but the comparison was between surgery for pacemaker implantation and no surgery. These trials were criticised and two subsequent studies,10,11) which probably, in retrospect, failed to select the patients at greatest possibility of benefit, too young10) and insufficiently bradycardiac.11) There followed ISSUE 2,2) which raised the likelihood that a group of patients can benefit from pacing if they are selected on the basis of age and clearly documented bradycardia. ISSUE 3 also may throw more light on the pathophysiology of the vasovagal patient. There will be available for analysis more comparative data on tilt testing versus ILR recording and more data concerning the choice of programming characteristics of the rate-drop response algorithm so as to achieve the best effect on the control of symptoms.
What can we expect from ISSUE 3?
5)
6)
7)
8)
References 1) The Steering Committee of the ISSUE 3 study. [Sutton R]. International study on syncope of uncertain aetiology 3 [ISSUE 3]: pacemaker therapy for patients with asystolic neurally mediated syncope: rationale and study design. Europace 2007; 9: 25–30 2) Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, Andresen D, Benditt DG, Vardas P for the International Study on Syncope of Uncertain Etiology [ISSUE 2] Group: Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006; 27: 1085–1092 3) Alboni P, Brignole M, degli Uberti EC: Is vasovagal syncope a disease? Europace 2007; 9: 83–87 4) Moya A, Sutton R, Ammirati F, Blanc J-J, Brignole M, Dahm JB, De Haro J-C, Gajek J, Gjesdal K, Krahn A,
9)
10)
11)
Massin M, Pepi M, Pezawas T, Granell R, Sarasin F, Ungar A, van Dijk J, Walma EP, Wieling W: Guidelines for the diagnosis and treatment of syncope (version 2009). Eur Heart J 2009; 30: 2631–2671 Moya A, Brignole M, Menozzi C, Garcia-Civera R, Tognarini S, Mont L, Botto G, Giada F, Cornacchia D: Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation 2001; 104: 1261–1267 Brignole M, Moya A, Menozzi C, Sutton R: Proposed electrocardiographic classification of spontaneous syncope documented by an implantable loop recorder. Europace 2005; 7: 14–18 Connolly SJ, Sheldon R, Roberts RS, Gent M: The North American vasovagal pacemaker study (VPS). A randomized controlled trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 1999; 33: 16–20 Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya A: Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope: Pacemaker versus no therapy: a multicenter randomized study. The Vasovagal Syncope International Study (VASIS) Investigators. Circulation 2000; 102: 294–249 Ammirati F, Colivicchi F, Santini M: Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. Circulation 2001; 104: 52–57 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, Morillo C, Gent M for the VPS II Investigators: Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: second vasovagal pacemaker study (VPS II). JAMA 2003; 289: 2224–2229 Raviele A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R: The vasovagal syncope and pacing trial [SYNPACE]. A randomised, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. Eur Heart J 2004; 25: 1741–1748
119