SupplementaryAppendix

This appendix provides additional information about the MINERVA study.

Table of contents

  1. MINERVA study group
  2. Inclusion and exclusion criteria
  3. EnRhythm pacemaker
  4. AT/AF detection
  5. MVP feature
  6. Atrial ATP therapies
  7. Atrial preventive pacing algorithms
  8. Patient randomization
  9. Pacemaker programming
  10. Study Committees members
  1. MINERVA study group

A total of 63 centers enrolled patients in the Minerva trial, in particular 56 centers in European countries and 7 centers in Asian countries.

The list of MINERVA investigators and centersis reported in the following, in alphabetical order according to the country name and according to first investigator name .

AUSTRIA

W Kainz - HanuschKrankenhaus, Wien

M Nürnberg -Wilhelminenspital der Stadt Wien, Wien

H Pürerfellner - Krankenhaus der Elisabethinen Linz, Linz

FRANCE

A Pisapia - Hôpital Saint-Joseph, Marseille

GERMANY

T Lewalter, S Remerie - Rheinische Friedrich-Wilhelm-Universität Bonn, Bonn

G Mentz - St. Josefs Hospital, Wiesbaden

H Schäfer - PhilippusstiftKath. KH gGmbH, Essen (Borbeck)

P Schauerte - RWTH Aachen, Aachen

GREECE

N Fragkakis - G. Papanikolaou Hospital Thessaloniki,Thessaloniki

E Hatzinikolaou - Agios Loukas Hospital, Thessaloniki

AS Manolis - Evaggelismos Hospital, Athens

T Maounis - Onassis Cardiac Surgery Center Clinic A, Athens

G Theodorakis - Henry Dunant Hospital, Athens

V Voudris, AKostopoulou - Onassis Cardiac Surgery Center Clinic B, Athens

V Vassilikos - University Hospital AHEPA Thessaloniki, Thessaloniki

HONG KONG

Tse Hung-fat - Queen Mary Hospital, Hong Kong SAR

ISRAEL

A Glick, S Viskin - Tel-Aviv Sourasky Medical Center-Ichilov Hospital, Tel Aviv

A Katz, VHelmaizer - Barzilai Medical Center, Ashkelon

A Militianu - Carmel Medical Center, Haifa

S Rosenheck, A Weiss - Hadassah Medical Center, Jerusalem

ITALY

M Accogli - Azienda Ospedaliera Card. G. Panico, Tricase

M Bernasconi - Ospedale San Carlo Borromeo, Milano

G Boriani, M Biffi, I.Diemberger, C.Martignani, M Ziacchi- Policlinico Sant Orsola-Malpighi, Bologna

GL Botto, M Luzi,G Russo, B Mariconti- Ospedale S.Anna, Como

D Tarricone, G Bacchioni - Ospedale S. Paolo P.M., Milano

P Capogrosso, G Covino, M Volpicelli - Ospedale S. Giovanni Bosco, Napoli

M Gulizia, M Francese - Az.Osp. Garibaldi -Osp. Garibaldi Nesima, Catania

G Inama - Ospedale Maggiore di Crema, Crema

F Magliari, ECL Pisanò, G Milanese - Ospedale Vito Fazzi, Lecce

M Marini -P.O. di Trento P.O.S.Chiara, Trento

S Orazi - Ospedale San Camillo de Lellis, Rieti

L Padeletti - Azienda Ospedaliera Careggi, Firenze

L Pandolfo - Ospedale S. Spirito, Roma

GB Perego - Ist. Auxologico Italiano-Ospedale S.Luca,Milano

G Piccione - Ospedale Maggiore di Modica, Ragusa

LG Piraino, A Stabile - A.R.N.A.S. Ospedale Civico e Benfratelli, Palermo

A Proclemer, D Facchin - Az. Ospedaliera S.Maria della Misericordia, Udine

W Rauhe - Ospedale Regionale San Maurizio, Bolzano

F Romeo,L Santini, GB Forleo, D Sergi - A. O. Universitaria Policlinico Tor Vergata, Roma

F Ruffa - Ospedale Manzoni, Lecco

M Santini, R Ricci, C Pignalberi- Ospedale San Filippo Neri, Roma

P Serra,G Speca - Ospedale Civile G. Mazzini, Teramo

R Tomei, G. Morani, L. Tomasi - Ospedale Civile Maggiore di Borgo Trento, Verona

F Zerbo, F Zoppo -Ospedale Civile di Mirano,Mirano

KUWAIT

F Al Kandari - Chest Disease Hospital, Safat

PORTUGAL

J de Sousa, P Marques - Hospital de Santa Maria, Lisboa

L Duarte- Centro Hospitalar doBaixoAlentejo, Beja

V Martins - Hospital Distrital de Santarém, Santarém

H Reis - Hospital Geral de Santo António, Porto

RUSSIAN FEDERATION

SV Molodykh -MUZ Central Municipal Hospital No4Nizhniy Tagil,

IV Samoilenko,EV Pervova - Ctr of Surg. Treatm. ofArrh. & Card. Electrop., Moscow

SLOVAKIA

L Urban - NUSCH-Narodny ustav srdcovych a cievnych chorob, Bratislava,

SPAIN

N Calvo, I Garcia Bolao - Clinica Universitaria de Navarra, Pamplona

ML Fidalgo, R Garcia Calaboza, JM Gonzalez Rebollo, M Montes - Complejo Asistencial de Leon, Leon

JF Garcia-Sacristàn, R Ceres, J Enero - Complejo Hospitalario Universitario de de Albacete, Albacete

JL Mont, A Berruez, JM Tolosana - Hospital Clínic i Provincial de Barcelona, Barcelona

SWITZERLAND

H Sunthorn, H Burri - HôpitauxUniversitaires de Genève, Genève

TAIWAN

JL Lin - National Taiwan University Hospital, Taipei

THE NETHERLANDS

JH Ruiter - Medisch Centrum Alkmaar, Alkmaar

MG Scheffer, PC Smits – MaasstadZiekenhuis, Rotterdam

M Sedney- BronovoZiekenhuis, Den Haag

R Tukkie, B van Vlies- KennemerGasthuis, Haarlem

DJ van Doorn - SpaarneZiekenhuis, Hoofddorp

  1. Inclusion and exclusion criteria

Inclusion criteria were: standard Class I or II indications for permanent dual-chamber pacing and a history of atrial tachyarrhythmias, at least 1 episode of atrial fibrillation, flutter or tachycardia in the last 12 months documented by ECG or Holter.

Exclusion criteria were: permanent third-degree AV block or history of AV node ablation, history of permanent AF and candidacy for ICD or cardiac resynchronization therapy device implantation, anticipated major cardiac surgery during the course of this study, atrial fibrillation ablation or other cardiac surgery, uncontrolled hyperthyroidism, age less than 18 years, pregnancy, unwillingness or inability to give informed consent or to commit to follow-up schedule, medical conditions that preclude protocol-required testing or limit study participation, enrolment or intention to participate in another clinical trial during the course of this study and life expectancy less than 2 years.

  1. EnRhythm pacemaker

EnRhythm™ is a DDDR pacemaker with specific features for a) giving priority to intrinsic AV conduction by means of MVP (atrial pacing with ventricular backup pacing if AV-conduction fails); b) detecting AT/AF with high sensitivity and specificity; c) preventing the onset of AT/AF through three atrial preventive pacing algorithms and d) terminating AT/AF by means of Reactive ATP, with Ramp and Burst+ pacing being delivered at the onset of arrhythmia and during its dynamic changes toward rhythms which may differ in terms of rate and/or regularity.

  1. AT/AF detection

The device detects atrial tachyarrhythmias by examining the atrial rate and the relationship between atrial and ventricular events. When the median of the 12 most recent atrial intervals is less than the atrial tachyarrhythmias detection interval – which in MINERVA was set at 350 ms (171 bpm) – and the atrial tachyarrhythmias evidence counter has counted at least three ventricular events in which the A:V pattern shows evidence of an atrial tachyarrhythmia, the device detects the onset of an atrial tachyarrhythmia episode. If Mode Switch is enabled, the device starts mode switch operations when atrial tachyarrhythmia onset is detected. Atrial tachyarrhythmias detection is confirmed when the median atrial interval is less than the atrial tachyarrhythmias detection interval and the atrial tachyarrhythmias evidence counter has counted a given number - 32 in MINERVA settings – of ventricular events in which the A:V pattern shows evidence of an atrial tachyarrhythmia. After confirmation of detection, the atrial tachyarrhythmia episode is considered to be sustained; thereafter the device monitors the cardiac rhythm for changes or episode termination and can respond to detected episodes by delivering tachyarrhythmia therapies. Once the device detects an atrial tachyarrhythmia, the episode is considered to be ongoing until episode termination. The device classifies an atrial tachyarrhythmia episode as terminated when five consecutive beats exhibit the A:V pattern of sinus rhythm or if the rhythm remains unclassified for three minutes because the median atrial interval is greater than the atrial tachyarrhythmias detection interval or the atrial tachyarrhythmias evidence count is less than 27.

  1. MVP feature

The EnRhythm™ IPG is a modern dual-chamber pacemaker with a new pacing algorithm, Managed Ventricular Pacing (MVP), that giving priority to intrinsic AV conduction reduces unnecessary ventricular pacing. During intact AV conduction the device provides true atrial pacing (AAI/R) with immediate ventricular backup pacing if AV-conduction fails. If loss of AV-conduction is detected for at least two out of four atrial depolarizations the device switches to the DDD/R mode. Periodic AV-conduction checks are carried out, and the device switches back to AAI/R when intrinsic AV-conduction has been restored.

  1. Atrial ATP therapies

The device can respond to an atrial tachyarrhythmia episode by delivering aATP therapy. aATP therapies are designed to interrupt the re-entrant activation pattern of an atrial arrhythmia by means of pacing stimuli, thereby restoring the patient’s normal sinus rhythm.

The device can be programmed – as in the MINERVA trial - to deliver several sequences of up to three aATP therapies in the atrial tachyarrhythmias detection sub-zones.

aATP therapies become available when the duration of sustained atrial tachyarrhythmias exceeds the programmed value of episode duration before aATP delivery - that in the MINERVA trial was set at 1 minute.

The EnRhythm pacemaker has a specific aATP algorithm called Reactive ATP. This allowsaATP therapies to re-arm in the event of changes in atrial tachycardia cycle length or changes in the regularity of atrial tachyarrhythmia episodes or in the event of long atrial tachyarrhythmia episodes. These cases are managed by two specific features of the Reactive ATP algorithm, the Rhythm Change feature and the Time Interval feature, which can be programmed separately. In the MINERVA trial the Rhythm Change was enabled to allow the device to detect changes in the atrial arrhythmia on the basis of both regularity and cycle length. The atrial tachyarrhythmias zone is subdivided into a series of narrower sub-zones: specifically the atrial tachyarrhythmia Interval for regular rhythms is divided into 5 sub-zones of 50 ms length from 100 ms to 350 ms and the atrial tachyarrhythmias Interval for irregular rhythms is divided into 3 sub-zones, the first from 100 ms to 200 ms, the second from 200 ms to 300 ms and the third from 300 ms to 350 ms. Each sub-zone is supplied with a separate set of the atrial ATP therapies enabled for atrial tachyarrhythmia episodes, as shown in the following figure.

If the rhythm shifts into a different sub-zone because of a change in cycle length or regularity, the device delivers therapies from those available in the new sub-zone. The Time Interval feature of Reactive ATP allows treatment of atrial arrhythmias that may have changed during the course of an atrial episode. In the MINERVA trial the Reactive ATP Time Interval allow to re-arm a-ATP sequences when the Sustained Duration value reaches a multiple of 7 hours. In the MINERVA trial the Reactive ATP Time Interval was programmed with the Sustained Duration value equal to 7 hours, but only in a minority of patients. In the MINERVA trial the EnRhythm device was programmed to suspend all atrial therapies if an atrial episode exceeded the Duration to Stop parameter which was programmed at 48 hours.

The aATP therapies which can be delivered by the EnRhythm pacemaker are Burst+ or Ramp. Burst+ therapy sequences consist of a programmed number of AOO pulses followed by two premature stimuli that are delivered at shorter intervals. Ramp therapy sequences consist of a programmable number of AOO pulses delivered at decreasing intervals.

The Burst+ and Ramp pacing intervals are rate-adaptive, as they are percentages of the median of the last 12 P-P intervals prior to therapy delivery. The first pulse of each aATP sequence is delivered at a chosen percentage of the current atrial tachyarrhythmia cycle length. Subsequent pulses are delivered at progressively shorter intervals. Burst+ and Ramp pulses are never delivered at less than the programmed A-A Minimum Pacing Interval. This minimum pacing interval is the same for all Burst+ and Ramp therapies. If some calculated intervals are shorter than the programmed minimum, the pulses are delivered at the programmed minimum interval. If the median of the last 12 A-A intervals is shorter than the programmed minimum, the device will not deliver Burst+ or Ramp therapies until the atrial rate slows.

Reactive ATP programming is described below:

Therapy sequence / Rx1 / Rx2 / Rx3
Therapy / Ramp / Burst+ / Ramp
Initial pulse N° / 13 / 11 / 13
A-S1 / 91% / 84% / 81%
S1S2 / 81%
S2S3 / 20 ms
Dec Interval / 10 ms / 10 ms / 10 ms
Sequence N° / 10 / 10 / 10

Parameters for Burst+ therapy were the Number of S1 pulses in each burst sequence (11), the Pacing interval of the S1 burst pulses, as a percentage of the pre-therapy atrial cycle length (84%), the Pacing interval of the S2 stimulus following the burst as a percentage of the pre-therapy atrial cycle length (81%), the S2-S3 interval equals the S1-S2 interval minus this decrement value (20 ms), the Pacing interval decrement per sequence (10 ms), the Number of sequences in the Burst+ therapy (10).The Parameters for Ramp therapy were Number of pulses in the first Ramp sequence (13), the Pacing interval of the first Ramp pulse as a percentage of the pre-therapy atrial cycle length (91% in Rx1 and 81% in Rx3), the Pacing interval decrement per pulse for the remaining Ramp pulses in each sequence (10 ms), the number of sequences in the Ramp therapy (10).

  1. Atrial preventive pacing algorithms

The device includes three atrial preventive pacing algorithms designed to eliminate some of the onset mechanisms of atrial tachyarrhythmias and to reduce the incidence of atrial tachyarrhythmias. These atrial pacing features comprise the atrial pacing preference algorithm, for maintenance of a pacing rate just above the intrinsic rate, the atrial rate stabilization algorithm, designed to avoid short-long intervals following a premature atrial contraction, and the post-mode switching overdrive pacing algorithm designed to inhibit early re-initiation of atrial tachyarrhythmia following a mode switching episode.

The atrial pacing preference algorithm is available when the device is operating in the DDDR, DDD, AAIR, AAI modes. If it is enabled, the device responds to spontaneous rhythm higher than the current atrial paced rate by accelerating its pacing rate until a steady paced rhythm, slightly faster than the intrinsic rate, is obtained. The Interval Decrement in Minerva trial was set at 50 ms so that the pacing interval was decreased by 50 ms in response to an atrial sensed event to accelerate the pacing rate. After 10 Search Beats, i.e. consecutive atrial paces at the current atrial preference pacingrate, the pacing rate interval was increased by 20 ms to decelerate the pacing rate. The Maximum Rate induced by atrial preference pacing was set at 95 bpm.

The atrial rate stabilization algorithm is available when the device is operating in the DDDR, DDD, AAIR, AAI modes. When it is enabled, at each atrial event, for example a premature atrial contraction (PAC), the device calculates a new pacing interval, which is equal to the current pacing interval increased by the Interval Percentage Increment, and if this interval ends before the device senses an atrial event, the device delivers an atrial pace and recalculates its interval using the current atrial interval. After a PAC, the calculated escape interval stabilizes the atrial rate and gradually slows it to the intrinsic rate, sensor indicated rate or lower rate. This prevents the ‘short/long’ sequences of atrial cycle lengths that have been observed to precede the onset of some spontaneous atrial tachyarrhythmias. The Interval Percentage Increment, i.e. the pacing interval increment per beat, measured as a percentage of the preceding interval was set at 25% in our study. The Maximum Rate induced by atrial rate stabilization algorithm was set at 95 bpm.

The post-mode switching overdrive pacing algorithm is available when the device is operating in the DDDR or DDD modes. When it is enabled, at the termination of a mode switch, i.e. an atrial tachyarrhythmia episode, post-mode switching overdrive pacing causes the device to continue to pace in DDIR mode at the higher of the programmable Overdrive Rate or sensor-activated rate for a programmable Overdrive Duration. In the MINERVA trial the Overdrive Rate was set at 80 beats per minute and the Overdrive Duration was required to be ≤ 5 minutes.

  1. Patient randomization

The requirements for patient randomization were compliance with eligibility criteria, sinus rhythm at the time of the randomization visit and non-dependency on ventricular stimulation (patients with ventricular pacing ≥ 95% on device check were excluded). The method used to generate the random allocation sequence was simple random sample inside each randomization block. Each patient assignment was concealed on the study web site and was not revealed until all baseline data had been collected and the patient had been deemed eligible for randomization. Investigators accessed patient randomization through the study web site and assigned the randomization to participants, who remained blind to their treatment arm. Block randomization was performed to balance out the presence/absence of AV-block and left ventricular ejection fraction (LVEF) < 40 or ≥ 40%.

  1. Pacemaker programming

The following table summarizes the pacemaker programming in the MINERVA trial.

  1. StudyCommittees members

Adverse Event and Endpoint Committee: M Brignole (Lavagna, Italy), A Meijer (Eindhoven, The Netherlands), X Viñolas (Barcelona, Spain), P Ioannidis (Athens, Greece) and F Frattini (Milano, Italy), who are cardiologists with relevant study backgrounds, have served as Adverse Event and Endpoint Committee and adjudicated all primary endpoints and adverse events on the basis of primary endpoint and adverse event case report forms and of hospital discharge letters. The committee members were blind to the programming and randomization assignment of each subject; moreover identifiers of clinical sites and subjects were removed from all documentation.

Independent Statistical Center: L’Altrastatistica S.r.l. (Rome, Italy)

Sponsor Clinical Operations: General Study Management Federica Gavazza; Country Study Management: Austria, Christian Eppacher; France, Marc Mainardis; Germany, Klaudia Pokrajcic ; Greece, Maria Petraki; Hong Kong, Macrina Wong, Grace Wong;

Israel Meirav Hirsh Kovacs; Shirley Schoen; Italy, Federica Gavazza; Kuwait, Dania Choucair, Wael Chaar; Portugal, Carlos Santos; Russia Ekaterina Ostern; Saudi Arabia, Dania Choucair, Wael Chaar; Slovakia Petra Klosková; Spain Natalie Garcia Heil; Switzerland Ray Moser; Taiwan, Macrina Wong, Grace Wong; The Netherlands Eva Korthagen;

Study Steering Committee: Boriani G, OspedaleSant´Orsola, Bologna, Italy; Funck RC, Philipps University Marburg, Marburg, Germany; Grammatico A, Medtronic Clinical Research Institute, Rome, Italy; Israel CW, J. W. Goethe University Hospital, Frankfurt; Manolis AS, Evagelismos Hospital, Athens, Greece; Mont L, Hospital Clinic, Barcelona, Spain; Padeletti L, OspedaleCareggi, Firenze, Italy; Pisapia A, Hopital Saint Joseph, Marseille, France; Puererfellner H, Elisabethinen-Hospital, Linz; Tukkie R, KennemerGasthuis, Haarlem, The Netherlands.