Supplementary Appendix

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 centers is reported in the following, in alphabetical

order according to the country name and according to first investigator name .

AUSTRIA

W Kainz - Hanusch Krankenhaus, 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 - Philippusstift Kath. 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, A Kostopoulou - 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, V Helmaizer - 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 do Baixo Alentejo, Beja

V Martins - Hospital Distrital de Santarém, Santarém

H Reis - Hospital Geral de Santo António, Porto 

RUSSIAN FEDERATION 

SV Molodykh - MUZ Central Municipal Hospital No4 Nizhniy Tagil,

IV Samoilenko, EV Pervova - Ctr of Surg. Treatm. of Arrh. & 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 - Hôpitaux Universitaires de Genève, Genève

TAIWAN

JL Lin - National Taiwan University Hospital, Taipei

THE NETHERLANDS 

JH Ruiter - Medisch Centrum Alkmaar, Alkmaar

MG Scheffer, PC Smits – Maasstad Ziekenhuis, Rotterdam

M Sedney - Bronovo Ziekenhuis, Den Haag

R Tukkie, B van Vlies - Kennemer Gasthuis, Haarlem

DJ van Doorn - Spaarne Ziekenhuis, Hoofddorp

2. 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.

3. 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.

4. 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.

5. 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.

6. 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 allows aATP

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:

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).

7. 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 pacing rate, 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.

8. 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%.

9. Pacemaker programming

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

PARAMETER Control DDDR DDDRP+MVP MVP

Run-in period

Mode DDDR or DDD DDDR or DDD DDDR or DDD

SAV Investigator discretion Investigator discretion Investigator discretion

PAV Investigator discretion Investigator discretion Investigator discretion

MVP mode ON ON ON

aATP therapies Off (nominal) Off (nominal) Off (nominal)

Atrial Rate Stabilization (ARS) Off (nominal) Off (nominal) Off (nominal)

Atrial Preference Pacing (APP) Off (nominal) Off (nominal) Off (nominal)

On randomization

Mode DDDR or DDD AAIR <=> DDDR nominal)

or AAI <=> DDD

AAIR <=> DDDR

(nominal) or AAI <=> DDD

SAV Investigator discretion Investigator discretion or

Optimized AV delay

Investigator discretion or

Optimized AV delay

PAV Investigator discretion Investigator discretion

or Optimized AV delay

Investigator discretion or

Optimized AV delayMVP mode OFF ON ON

Rate Adaptive AV Off (nominal) Off (nominal) Off (nominal)

Mode Switch On (nominal) On (nominal) On (nominal)

PVAB Method Partial (nominal) Partial (nominal) Partial (nominal)

Atrial tachyarrhythmias

Detection

Monitor (nominal) Monitor (nominal) Monitor (nominal)

aATP therapies Off (nominal) On Off (nominal)

Atrial Rate Stabilization (ARS) Off (nominal) On Off (nominal)

Atrial Preference Pacing (APP) Off (nominal) On Off (nominal)

APP and ARS Maximum Rate Off (nominal) 95 bpm Off (nominal)

10. Study Committees 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 pri-

mary endpoint and adverse event case report forms and of hospital discharge letters. The commit-

tee members were blind to the programming and randomization assignment of each subject; more-

over 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 Man-

agement: 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, Ospedale Sant´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, Ospedale

Careggi, Firenze, Italy; Pisapia A, Hopital Saint Joseph, Marseille, France; Puererfellner H, Elisa-

bethinen-Hospital, Linz; Tukkie R, Kennemer Gasthuis, Haarlem, The Netherlands.