PACING
Managed ventricular pacing vs. conventional dual-chamber pacing for elective replacements: the PreFER MVP study: clinical background, rationale, and design
1 Department of Cardiology, Hospital General Universitario de Valencia, Avenida Tres Cruces s/n, Valencia 46014, Spain; 2 S. Anna Hospital, Como, Italy; 3 Klinikum der Justus-Liebig-Universitat Gießen, Gießen, Germany; 4 University Hospital Brno Bohunice, Czech Republic; 5 Landeskrankenhaus—Universitätsklinikum Graz, Graz, Austria; 6 Aarhus Universitetshospital, Skejby, Denmark; 7 Centre Cardiologique du Nord, Saint-Denis, France; 8 San Filippo Neri Hospital, Rome, Italy; 9 Johann-Gutenberg-Universität, Mainz, Germany; 10 Medtronic Bakken Research Center B.V., Maastricht, The Netherlands; 11 Cliniques Universitaires de Mont-Godinne, Yvoir, Belgium
Manuscript submitted 11 November 2007. Accepted after revision 19 January 2008.
* Corresponding author: C/Gongora 1, 26, Valencia 46015, Spain. Tel: +34 961 972 155; fax: +34 961 972 161. E-mail address: quesada_aur{at}gva.es
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Abstract |
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Aims: Several clinical studies have shown that, in patients with intact atrioventricular (AV) conduction, unnecessary chronic right ventricular (RV) pacing can be detrimental. The managed ventricular pacing (MVP) algorithm is designed to give preference to spontaneous AV conduction, thus minimizing RV pacing. The clinical outcomes of MVP are being studied in several ongoing trials in patients undergoing a first device implantation, but it is unknown to what extent MVP is beneficial in patients with a history of ventricular pacing. The purpose of the Prefer for Elective Replacement MVP (PreFER MVP) study is to assess the superiority of the MVP algorithm to conventional pacemaker and implantable cardioverter-defibrillator programming in terms of freedom from hospitalization for cardiovascular causes in a population of patients exposed to long periods of ventricular pacing.
Methods and results: PreFER MVP is a prospective, 1:1 parallel, randomized (MVP ON/MVP OFF), single-blinded multi-centre trial. The study population consists of patients with more than 40% ventricular pacing documented with their previous device. Approximately, 600 patients will be randomized and followed for at least 24 months. The primary endpoint comprises cardiovascular hospitalization.
Conclusion: The PreFER MVP trial is the first large prospective randomized clinical trial evaluating the effect of MVP in patients with a history of RV pacing.
Key Words: Right ventricular, Managed ventricular pacing, Congestive heart failure, Atrial fibrillation
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Introduction |
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Several clinical studies (Danish I,1
,2 Danish II,3,4 DAVID,5 MOST sub-analysis6) have shown that unnecessary chronic right ventricular (RV) pacing has detrimental effects such as atrial fibrillation (AF), left ventricular (LV) dysfunction, and congestive heart failure, even in patients with intact atrioventricular (AV) conduction.
Right ventricular apical (RVA) pacing produces an anomalous activation of the ventricles resulting in mechanical asynchrony, especially when conduction disturbances are present.7 It is known that this anomalous activation pattern results in a redistribution of the myocardial workload and perfusion and, after years, a remodelling of the LV with a redistribution of the myocardial wall mass.8,9 Together, these processes may result in LV dysfunction and reduced ejection fraction (EF). The clinical manifestations of these deleterious effects may appear early in patients with previously depressed LV function or in some predisposed individuals with no apparent significant structural heart disease previously. However, in patients with normal LV EF, the process is thought to develop as a slow, insidious pattern, which is dependent on the degree of RVA pacing.10,11
Devices with dual-chamber pacing and sensing capabilities (DDD/R) were developed to offer AV synchrony for patients with AV block, thus avoiding AV dissociation and retrograde ventriculoatrial (VA) conduction associated with the ventricular-inhibited (VVI) pacing mode. The criteria for physiological pacing were defined as pacing modes that restored both AV synchrony and adequate chronotropic function.12 Thus, adaptive rate atrial pacing (AAIR) (when no AV block is present) and rate modulated dual-chamber pacing (DDDR) fulfilled these criteria and both were considered physiological. With the Danish trial results,1,2 the superiority of AAIR vs. VVIR was extrapolated to the DDDR mode and its use expanded.
The importance of interventricular synchrony gained more relevance with the results of the MOST substudy13 and the DAVID study,14 which showed that the adverse effects of RVA pacing appeared independently of maintained AV synchrony. The need to define and quantify the consequences of RVA pacing increased and subsequently strategies to achieve low RV pacing percentages were developed.
In the DDD/R mode, fixed extension of AV interval, and several types of hysteresis functions were considered to be solutions to decrease unnecessary RVA pacing.15 The efficacy of this strategy is, however, limited, with only modest reductions in the amount of RV pacing achieved with cumulative pacing percentages of 15–23%.16–20 Prolonging the AV interval may, moreover, lead to endless loop tachycardias15,21 and create timing cycle conflicts restricting the upper rate limit or the detection of atrial tachyarrhythmias.22,23 These limitations are further complicated in implantable cardioverter-defibrillator (ICD) patients where extended AV intervals should be avoided to prevent under-detection of ventricular tachyarrhythmias.
AAI pacing preserves normal ventricular activation sequences and requires stable long-term AV conduction; otherwise there is a potential risk of syncope and asystole.24
Several manufacturers have developed pacing modalities to give preference to intrinsic cardiac conduction and minimized RV pacing. One of these algorithms, managed ventricular pacing (MVP, Medtronic Inc., MN, USA) automatically switches between AAI/R and DDD/R pacing mode. Several ongoing trials compare the DDD vs. MVP impact on clinical endpoints in first implant patients.25–27 The question remains to what extent MVP is beneficial in patients with a history of ventricular pacing and whether the resulting deleterious effect can be reversed. No large prospective study has evaluated the effects of MVP in patients with chronic RVA pacing without apparent effects in their clinical status. The prefer for elective replacement MVP (PreFer MVP) study is designed to assess whether a reduction in the amount of unnecessary RV pacing by the MVP pacing mode can alter the detrimental effects of long-term ventricular apical pacing on heart function and therefore clinical outcome.
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Study objectives
The primary objective of the PreFER MVP study is to demonstrate that MVP is superior to conventional implantable pulse generator and ICD programming in terms of freedom from hospitalization for cardiovascular causes. The outcome measure is cardiovascular hospitalization evaluated over a two-year follow-up. As cardiovascular hospitalization has been shown to be a surrogate endpoint for mortality in this patient population,28
–31 it was chosen to be the primary endpoint. Most important secondary objectives are to compare AF burden, LVEF, NYHA class, cardiovascular medication, ventricular pacing percentage, development of class 1 pacemaker indications (in ICD recipients), and quality of life among patients randomized to MVP ‘ON’ or MVP ‘OFF’.
Study design
This study is a prospective, 1:1 parallel randomized, single-blinded multi-centre trial (Figure 1). A parallel instead of a crossover design was chosen because of potential long-term effects of ventricular pacing on the cardiovascular status of the patient. Randomization is between MVP programmed ON and MVP programmed OFF.
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To evaluate the primary objective, a minimum of 600 patients will be enrolled with a follow-up duration of 24 months for each patient. All patients are followed at 1, 12, and 24-month post-implant visits. The study enrolment phase is expected to take 36 months, which will result in total study duration of 60 months.
Approximately 80 institutions in Europe, the Middle East, Canada, and Australia will participate. Documented approval from the Ethics Committee affiliated with the study centres is required before starting the study.
Patient eligibility criteria
Patient inclusion and exclusion criteria are presented in Table 1. Patients eligible for the study are patients with a dual-chamber device (including VDD programming) implanted for a minimal duration of 2 years and planned for device replacement. Patients should have a documented average percentage of ventricular pacing greater than 40% with their previous device for a period of at least 4 weeks before randomization. This pacing percentage should not be related to backup VVI mode caused by battery depletion. Patients should have no need for a change in pacing mode or AV interval programming at the time of planned replacement.
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The 40% limit is mainly based on the MOST substudy,6
which showed that percentages above this cut-off point correlated with increased risks of hospitalization. Patients are excluded if they have an indication for cardiac resynchronization therapy, have permanent AF, or permanent AV block, have neurocardiogenic syncope as primary pacemaker indication or if a cardiovascular intervention is planned. Exclusion will extend to patients unable to complete follow-up visits or included in another trial that will affect the objectives of this study or who cannot give informed consent.
Medical treatment
Heart failure (HF) patients should receive the optimal medical therapy available as presently documented in the ‘Guidelines for the diagnosis and treatment of chronic heart failure’.32
Sample size estimation
The primary endpoint, time to cardiovascular hospitalization, is chosen as a surrogate endpoint for mortality to achieve a realistic sample size and an acceptable follow-up period.28–31
The sample size calculations reflect considerations from Sweeney et al.6 who showed that the event-free percentage of HF hospitalization was 91.5% at 2 years in the group with cumulative ventricular pacing >40%. This was reduced by 65% after 2 years for the group with 
40% ventricular pacing. Absolute reduction was 5.5% after 2 years and 10% after 4 years. The same relative effect on cardiovascular hospitalization is expected in PreFER MVP.
The absolute values reported, however, could be higher in view of the extended reporting of hospitalization which also will collect all cardiovascular causes, emergency room visits, office visits for acute treatment of worsened cardiac condition, and cardioversions. As they require a device replacement, enrolled patients are expected to be older which is also associated with higher hospitalizations rates. There are, however, contradictory factors such as improved patient management and difference in baseline characteristics. These factors taken together were estimated to cancel out, yielding no additional primary endpoints.
The study is thus designed to detect an absolute difference in freedom from event after 2 years of 5.5%, going from 91.5 to 97%. Using the Medstat statistical software package, log-rank non-parametric method, there are 572 required patients needed to detect this difference with a two-sided alpha of 0.05, 80% power, and 1:1 randomization. Twenty-eight additional patients will be enrolled to correct for lost to follow-up. The rounded target number of patients will be 600.
The managed ventricular pacing mode
All pacemaker/ICD devices included in this study are equipped with MVP, an atrial-based dual-chamber pacing mode that combines functional AAI(R) pacing with ventricular monitoring and backup DDD(R) pacing, as needed, in order to preserve intrinsic conduction whenever possible.33 The nominal MVP setting is AAI(R) 
DDD(R). This mode selection causes the device to perform beat-to-beat conduction checks after every atrial event (paced or sensed). It allows for an occasional dropped ventricular beat and if at least two out of four atrial intervals have no ventricular sensed event, the device automatically switches to the DDD(R) operating mode. Periodic conduction checks are performed to allow the device to return to functional AAI(R) pacing when the patient's intrinsic conduction is restored.
Devices with this feature and allowed in this trial are the IntrinsicTM, EnTrustTM, VirtuosoTM, EnRhythmTM, and AdaptaTM models (Medtronic Inc., MN, USA).
In the PreFER MVP study, patients will be randomized MVP ON vs. MVP OFF. Additional programming requirements are listed in Table 2. Once a patient is enrolled and randomized, the programming recommendations hold until the study exit.
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Randomization and data collection
Data are collected through an internet-based data system (TrialXS, ClinSource NV, Belgium). This system allows online data entry. Data inconsistencies will result in a query or an obvious data modification sent to the responsible centre. TrialXS also generates queries whenever data are entered outside given limits (automatic queries).
The randomization assignment is done automatically by the TrialXS database system upon enrolment of the patients, balancing the sample size of the two arms over the different sites. The randomization will be stratified by LV EFs (40 or >40) and by pacemaker vs. ICD.
Clinical data (adverse events, arrhythmia episodes, cardiovascular medication, etc.) and a device interrogation saved to disk will be collected at every patient follow-up. At 12 and 24 months follow-up, quality of life, ECG, and echocardiographic measurements will be obtained.
The daily ventricular pacing percentage, a crucial parameter, will be taken from the device and a per patient average over the total follow-up period will be calculated. As a limitation of the currently available pacing counters of the devices it is important to realize that this ventricular pacing percentage includes both complete paced, fusions, and pseudofusion beats.
Adverse Event Advisory Committee
The Adverse Event Advisory Committee (AEAC) will conduct a medical review of adverse events and deaths for all study patients. This committee is responsible for adjudicating all reported adverse events, hospitalizations, emergency room, and office visits. The AEAC consists of physicians with study relevant backgrounds who are independent of the study and the study sponsor. The committee will be blinded to the programming and randomization assignment of each patient (in the case of deaths, the committee may need to review the programming). The members of the AEAC will report their interpretation of death and cardiovascular hospitalization data to the Data Monitoring Committee (DMC) for their review.
Data Monitoring Committee
The DMC is responsible for safeguarding the interests of trial subjects and for monitoring the overall conduct of the clinical trial. The DMC will assess the accumulating data on safety and efficacy during the trial. The DMC may provide recommendations about early termination of the trial. To enhance the integrity of the trial, the DMC may also formulate recommendations related to the selection, recruitment and retention of subjects, improvement of adherence to protocol-specified regimens, and procedures for data management and quality control.
The DMC will review interim data of the primary endpoint unblinded to randomization assignment. Also, data on programming changes or non-compliant programming will be reviewed in order to assess the impact of these deviations on the primary objective.
Data analyses
The primary analysis will be performed according to the intention-to-treat principle. The principal objective is to evaluate if MVP is superior to common clinical pacemaker and ICD programming in terms of freedom from hospitalization for cardiovascular causes.
Time from randomization to onset of event, consisting of a hospitalization for cardiovascular causes and adjudicated by the AEAC, will be analysed using the log-rank test. The analysis will be supported by a Kaplan–Meier calculation of the two groups, with the number of patients at risk per 6 months period indicated. Additional evaluation including the second and third event could be done.
An interim analysis will also be performed after the 450th enrolment. Based on this data, the required study size may be adjusted.
Enrolment status and protocol amendments
The PreFER MVP study was launched in October 2005. Over 240 patients have been enrolled in more than 50 activated centres. The enrolment rate is below expectation because fewer patients than expected meet the eligibility criteria. This can partly be explained by a change in routine care which results in active and more dedicated reprogramming of the AV interval in order to avoid unnecessary ventricular pacing.
In the initial version 1.2 of the clinical investigation plan, the primary endpoint was defined as a combination of time to first event defined as all-cause mortality or cardiovascular hospitalization. Since the mortality rates between the two arms were not expected to differ, however, in view of the data from CTOPP34 (annual death rate 6.6% for VVI and 6.3% for DDD pacing) and the control arm of the DAVID trial5 with VVI back-up pacing (annual death rate 6.5%), a cumulative total mortality of around 13% after 2 years in both arms was expected. Because the enrolment rate after a 2-year period was below expectation, and because using a combined endpoint of mortality and cardiovascular hospitalization required a larger sample size, the Steering Committee, in consultation with the DMC decided to switch from a combined endpoint of mortality and CV hospitalization to hospitalization only.
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Discussion |
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RVA pacing results in an altered LV electrical activation sequence that resembles left-bundle branch block. Pacing-induced ventricular desynchronization has been shown to induce AF, ventricular arrhythmias, and heart failure in several trials.1
–6 As a result, minimizing RVA is becoming the standard of care.
The majority of patients who receive pacemakers for standard bradycardia indications do not experience HF that can be attributed to RVA pacing, even at high pacing rates.35 This questions the usefulness of MVP in chronically paced patient.
A possible explanation is that patients are not aware of the progressive deterioration of their LV function and simply accept a reduction of their physical well-being as shown in several studies.36,37 Thackray et al.36 observed that HF owing to LV systolic dysfunction was common in pacemaker recipients. In Europe, the SHAPE study37 showed that community awareness of HF is low, with 34% of the participants believing that HF is a normal consequence of ageing. Such patients are unlikely to consult health-care providers for appropriate measures.
Another possible explanation is that specific patient groups, for instance those patients with low EF or a previous myocardial infarction (MI), are more vulnerable to the detrimental effects of RVA pacing. In a recent study by Sweeney and Hellkamp,35 data from the MOST study were used to investigate which patients had the highest risk of HF hospitalization. These authors suggested that HF, during cardiac pacing, can be explained by complex interactions between a so-called substrate (such as atrial rhythm, AV conduction, ventricular conduction, ventricular function, and symptomatic HF and MI) and promoters. The promoters of HF would be specific to the implementation of cardiac pacing and they contain two constituents: ventricular desynchronization (paced QRSd and cumulative %VP) and AV desynchronization (pacing mode). It was concluded that management of RVA pacing was especially important in patients with reduced ventricular function and HF symptoms.
Finally, the lack of correlation between the percentage RVA pacing and adverse clinical events in certain patient groups is arguably related to short follow-up. Importantly, our current cumulative ventricular pacing percentage measurement is only an estimation, because so far we cannot subtract fusion and pseudofusion percentage from the total ventricular pacing. This is inherent to the currently available technology. In this sense, the limit of 40% must be contemplated as an approximation better than an absolute value.
While all of these explanations may hold true, the effects of decreasing RVA pacing in a population of patients with a history of ventricular pacing are not known and needs further investigation. Studying a replacement population offers a unique opportunity to evaluate the effects of a significant decrease in RVA pacing in patients who have had a high cumulative percentage RVA pacing in their past. Until now, the reversibility of the detrimental effects caused by ventricular pacing had only been initially investigated in small patient populations with short pacing-periods in AAI.3,38 The PreFER MVP trial is the first large randomized clinical trial evaluating the efficacy of an algorithm which avoids unnecessary ventricular pacing in patients with a history of RV pacing.
If the hypothesis confirms that MVP is superior to conventional programming in terms of cardiovascular hospitalization, this study will contribute to the arguments for reducing ventricular pacing, even in a patient population that declares no apparent detrimental effects related to their RV pacing.
Conflict of interest: A.Q. is currently conducting research sponsored by Medtronic and has served as a paid consultant for Medtronic Inc. and Boston Scientific. R.R. is currently conducting research sponsored by Medtronic Inc. and is a member of the speakers' bureau. D.B., G.W., and L.D.R. are all also employees of Medtronic Inc.
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This work is supported by an unrestricted grant from Medtronic Inc (Minneapolis, USA).
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APPENDIX |
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PreFER MVP participating primary investigators and centres as per 1 November 2007: Dr Bru, La Rochelle, France; Dr Camous, Nice, France; Dr Durand, St Laurent du Var, France; Dr Galley, Albi, France; Dr Piot, St Denis, France; Dr Koistinen, Turku, Finland; Dr Hartikainen, Kuopio, Finland; Dr Moller, Odense, Denmark; Dr Engby, Vejle, Denmark; Dr Friis, Haderslev, Denmark; Dr Nielsen, Esbjerg, Denmark; Dr Simonsen, Hillerød, Denmark; Dr Cosedis Nielsen, Aarhus, Denmark; Dr Dahl Christensen, Viborg, Denmark; Dr De Roy, Yvoir, Belgium; Dr Friart, La Louvière, Belgium; Dr Evrard, Liège, Belgium; Dr Ebinger, Badour, Belgium; Dr Vandekerckhove, Brugge, Belgium; Dr van Gelder, Groningen, The Netherlands; Dr Botto, Como, Italy; Dr Mantovani, Desio, Italy; Dr Ciconte, Catanzaro, Italy; Dr Fedele, Rome, Italy; Dr Padeletti, Firenze, Italy; Dr Puntrello, Trapani, Italy; Dr Lisi, Catania, Italy; Dr Santini, Rome, Italy; Dr Delise, Conegliano, Italy; Dr Vaccari, Montebelluna, Italy; Dr Magliari, Lecce, Italy; Dr Quaglione, Rome, Italy; Dr Herreros, Valladolid, Spain; Dr Quesada, Valencia, Spain; Dr Balaguer, Guadalajara, Spain; Dr Mont, Barcelona, Spain; Dr Diago Torrent, Castellon, Spain; Dr Sotillo, Valencia, Spain; Dr Kaltofen, Chemnitz, Germany; Dr Meisel, Dresden, Germany; Dr Schade, Berlin, Germany; Dr Spencker, Berlin, Germany; Dr Götze, Berlin, Germany; Dr Will, Berlin, Germany; Dr Meltendorf, Magdeburg, Germany; Dr Hobrack, Wolmirstedt, Germany; Dr Kloppe, Lüdenscheid, Germany; Dr Hoppert, Schwedt, Germany; Dr Lewalter, Bonn, Germany; Dr Osswald, Basel, Switzerland; Dr Strohmer, Salzburg, Austria; Dr Al Kandari, Safat, Kuwait; Dr Kozak, Brno, Czech Republic; Dr Parizek, Hradec Kralove, Czech Republic; Dr Kaliská, Banská Bystrica, Slovakia; Dr
des, Debrecen, Hungary; Dr Katz, Ashkelon, Israel; Dr Strasberg, Petah Tikva, Israel; Dr Militianu, Haifa, Israel; Dr Rosenheck, Jerusalem, Israel; Dr Glick, Tel-Aviv, Israel; Dr Luriya, Tel Hashomer, Israel; Dr Apostolopoulos, Marousi, Greece; Dr Katritsis, Athens, Greece; Dr Basta, Halifax, Canada; Dr Crystal, Toronto, Canada; Dr Pantano, Edmonton, Canada; Dr Paredes, Sherbrooke, Canada; Dr Mond, Parkville, Australia; Dr Mabin, Cape Town, South Africa; Dr Chan, Hong Kong; Dr Kim, Seoul, South-Korea. PreFER MVP Steering Committee: Dr G. Botto, Como, Italy; Dr Cosedis Nielsen, Aarhus, Denmark; Prof. L. De Roy, Yvoir, Belgium; Dr A. Erdogan, Gießen, Germany; Dr M. Kozak, Brno Bohunice, Czech Republic; Dr P. Lercher, Graz, Austria; Dr O. Piot, Saint-Denis, France; Dr A. Quesada, Valencia, Spain; Dr R. Ricci, Rome, Italy; Dr C. Weiss, Mainz, Germany.
PreFER MVP Data Monitoring Committee: Prof. N. Freemantle, Birmingham, UK; Prof. J. Morgan, Southampton, UK; Dr A Pietersen, Copenhagen, Denmark.
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Footnotes |
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ClinicalTrials.gov identifier NCT00293241
[ClinicalTrials.gov]
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