Clinical trial NCT01477138: RV Septal Versus Minimized RV Pacing in Sick Sinus Syndrome
Official title: Comparison of Right Ventricular Septal Pacing to Minimized Right Ventricular Septal Stimulation in Patients With Sick Sinus Syndrome
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Sick Sinus Syndrome
Keywords: Sick Sinus Syndrome
Cardiac Pacing, Artificial
Cardiac Resynchronization Therapy
Pacemaker, Artificial
SSS
Lead sponsor: Klinikum Nürnberg
Sponsor class: OTHER
First posted: 2011-11-22
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adults with symptomathic sick sinus syndrome

Brief summary: Background:

* Potential negative effects of pacing in the RV-apex are well documented
* However, study results comparing septal / RVOT-pacing versus RV-apical pacing controversial.
* The optimal pacing mode in SSS (DDDR versus AAIR) is unclear, as the DDD (R) mode with an AV delay ≤ 220 ms should be the preferred pacing mode, according to the DANPACE trial \[DANPACE, ESC 2010, Stockholm\].

Aim:

- to evaluate chronic effects of proven right ventricular septal compared to minimized right ventricular septal pacing in patients with SSS

Inclusion criterion:

-Pacemaker indication according to current guidelines: sick sinus syndrome (SSS)

Exclusion criteria:

* Life expectancy \< 2 years
* Age \<18 years
* Noncompliance with regard to participation in the study
* Pregnancy
* AV block ° 2 and higher
* Permanent atrial fibrillation
* Heart failure NYHA III and IV, reduced LV-EF \<40%
* ICD indication
* Acute coronary syndrome. PCI or CABG \<3 months
* Heart transplant
* Placement of septal RV electrode is not possible

Study design:

* Prospective, monocentric, randomized, double-blinded
* Run-in phase: for weeks AAI \[R\]-DDD \[R\]
* Randomization: two groups A) septal right ventricular chamber pacing: mode DDD \[R\] versus B) Reduction of unnecessary ventricular pacing: AAI \[R\]-DDD \[R\].
* FU: 6 and 12-months

Primary endpoints:

-LV ejection fraction and end-systolic LV volume after 12 months.

Secondary endpoints:

-LV end-diastolic volume, TAPSE, parameters of dyssynchrony (SPWMD, LV-PEP, IVMD), AF-burden, % ventricular pacing, CPX: peak oxygen consumption (peak VO2), VO2 AT, VO2/HR, VE/VCO2 slope; QoL scores (SF-36) after 12 months.

Statistics/sample size estimation:

In order to detect a difference in LVEF of 5% and for LV-ESV of 5 mL between the 2 groups after 12 months:

* 90% power/alpha 5%: 84 patients per group
* 80% power/alpha 5%: 63 patients per group

  * 10% for compensation of drop-outs / patients lost of follow-up. Two-sided 5% type 1 error Analysis intention-to-treat and based on the finally programmed pacing mode.

Material

* PG: market released dual chamber pacemakers with the ability to pace AAI(R) -DDD(R)
* pacing leads: market-released standard active electrodes
* RV electrode: septal verified under multi-level screening (RAO/LAO) and ECG (LBBB narrow \<150 ms / inferior axis)

Detailed description: Background:

* Potential negative effects of pacing in the RV-apex are well documented
* Asynchronous ventricular activation
* reduction of systolic and diastolic LV function
* Experimental data: histological changes
* Asymmetric LV hypertrophy and thinning
* However, study results comparing septal / RVOT-pacing versus RV-apical pacing controversial:
* Acute versus chronic
* Small number of cases, uncontrolled, unblinded,
* Brief periods of observation in the cross-over design (3 months)
* "RVOT" often summarizes different stimulation sites: high RVOT, lateral, septal. Actually only limited data with proven septal stimulation
* No objective performance assessment (CPX)
* Assessment of alternative stimulation site previously RVOT versus RV-apex,
* ventricular pacing compared to ventricular pacing, then tested a potential harm to another
* The question of the optimal pacing mode of patients with SSS (DDDR versus AAIR) appears to be open again. While in Germany, two-chamber systems with AAI \[R\] mode with ventricular back-up are used, should the DDD (R) mode with an AV delay ≤ 220 ms be the preferred pacing mode, according to the results of the DANPACE trial for patients with SSS \[DANPACE, ESC 2010, Stockholm\].

Aim:

- to evaluate chronic effects of proven right ventricular septal compared to minimized right ventricular septal pacing in patients with SSS

Inclusion criterion:

-Pacemaker indication according to current guidelines: sick sinus syndrome (SSS)

Exclusion criteria:

* Life expectancy \< 2 years
* Age \<18 years
* Noncompliance with regard to participation in the study
* Pregnancy
* AV block ° 2 and higher
* Permanent atrial fibrillation
* Heart failure NYHA III and IV, reduced LV-EF \<40%
* ICD indication
* Acute coronary syndrome. PCI or CABG \<3 months
* Heart transplant
* Placement of septal RV electrode is not possible

Study design:

* Prospective, monocentric, randomized, double-blinded
* Run-in phase: 4 weeks AAI \[R\]-DDD \[R\]
* ECG, PM-interrogation, echocardiography, performance diagnostics, CPX, QoL questionnaire
* Randomization: two groups 4 weeks (between 3 to 6 weeks) after implant A) septal right ventricular chamber pacing: mode DDD \[R\] versus B) Reduction of unnecessary ventricular pacing: AAI \[R\]-DDD \[R\].
* FU: 6 and 12-months
* ECG, Holter-ECG, PM-interrogation, echocardiography, performance diagnostics, CPX, QoL questionnaire
* Extension of follow-up if possible

Primary endpoints:

-LV ejection fraction and end-systolic LV volume after 12 months.

Secondary endpoints:

-LV end-diastolic volume, TAPSE, parameters of dyssynchrony (SPWMD, LV-PEP, IVMD), AF-burden, % ventricular pacing, CPX: peak oxygen consumption (peak VO2), VO2 AT, VO2/HR, VE/VCO2 slope; QoL scores (SF-36) after 12 months.

Blinding:

* Patient compared to the pacing mode
* Physician: offline analysis of echo and CPX blinded to the pacing mode

Statistics/sample size estimation:

In order to detect a difference in LVEF of 5% and for LV-ESV of 5 mL between the 2 groups after 12 months:

* 90% power/alpha 5%: 84 patients per group
* 80% power/alpha 5%: 63 patients per group

  * 10% for compensation of drop-outs / patients lost of follow-up. Two-sided 5% type 1 error Analysis intention-to-treat and based on the finally programmed pacing mode.

Material

* PG: market released dual chamber pacemakers with the ability to pace AAI(R) -DDD(R)
* pacing leads: market-released standard active electrodes (eg. BSCI FineLine 4470 and 4471) Implantation
* Transvenously
* RA-electrode: if possible, short atrial conduction time
* RV electrode: septal verified under multi-level screening (RAO/LAO) and ECG (LBBB narrow \<150 ms / inferior axis)

Eligibility criteria: Inclusion Criteria:

* Pacemaker indication according to current guidelines: sick sinus syndrome (SSS)

Exclusion Criteria:

* Life expectancy \<2 years
* Age \< 18 years
* Noncompliance with regard to participation in the study
* Pregnancy
* AV block ° 2 and higher
* Permanent atrial fibrillation
* Heart failure NYHA III and IV, reduced LV-EF \< 40%
* ICD indication
* Acute coronary syndrome. PCI or CABG \< 3 months
* Heart transplant
* Placement of septal RV electrode is not possible

Primary outcomes:
measure: end-systolic LV volume
timeFrame: at randomisation and after 12 months
measure: left ventricular ejection fraction (LV-EF)
timeFrame: at randomisation and after 12 months
Secondary outcomes:
measure: TAPSE
timeFrame: at randomisation and after 12 months
measure: echocardiographic parameter of dyssynchrony
timeFrame: at randomisation and after 12 months
measure: peak VO2, VO2 AT, VO2/HR, VE/VCO2 slope
timeFrame: at randomisation and after 12 months
measure: quality of life-scores
timeFrame: at randomisation and after 12 months
measure: AF burden
timeFrame: at randomisation and after 12 months
measure: % ventricular pacing
timeFrame: at randomisation and after 12 months
measure: LV end diastolic volume
timeFrame: at randomisation and after 12 months
Other outcomes:
Locations:
city: Nuernberg
country: Germany
facility: Klinikum Nuernberg South
state: Bavaria
Study officials:
affiliation: Klinikum Nuernberg South/ Cardiology
name: Matthias Pauschinger, Prof.Dr.med.
role: STUDY_CHAIR
affiliation: Klinikum Nuernberg
name: Dirk Bastian, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schwaab B, Frohlig G, Alexander C, Kindermann M, Hellwig N, Schwerdt H, Kirsch CM, Schieffer H. Influence of right ventricular stimulation site on left ventricular function in atrial synchronous ventricular pacing. J Am Coll Cardiol. 1999 Feb;33(2):317-23. doi: 10.1016/s0735-1097(98)00562-2.
citation: Tse HF, Yu C, Wong KK, Tsang V, Leung YL, Ho WY, Lau CP. Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation. J Am Coll Cardiol. 2002 Oct 16;40(8):1451-8. doi: 10.1016/s0735-1097(02)02169-1.
citation: Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, Lamas GA; MOde Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003 Jun 17;107(23):2932-7. doi: 10.1161/01.CIR.0000072769.17295.B1. Epub 2003 Jun 2.
citation: Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002 Dec 25;288(24):3115-23. doi: 10.1001/jama.288.24.3115.
citation: Stambler BS, Ellenbogen K, Zhang X, Porter TR, Xie F, Malik R, Small R, Burke M, Kaplan A, Nair L, Belz M, Fuenzalida C, Gold M, Love C, Sharma A, Silverman R, Sogade F, Van Natta B, Wilkoff BL; ROVA Investigators. Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation. J Cardiovasc Electrophysiol. 2003 Nov;14(11):1180-6. doi: 10.1046/j.1540-8167.2003.03216.x.
citation: Giudici MC, Thornburg GA, Buck DL, Coyne EP, Walton MC, Paul DL, Sutton J. Comparison of right ventricular outflow tract and apical lead permanent pacing on cardiac output. Am J Cardiol. 1997 Jan 15;79(2):209-12. doi: 10.1016/s0002-9149(96)00718-7.
citation: de Cock CC, Meyer A, Kamp O, Visser CA. Hemodynamic benefits of right ventricular outflow tract pacing: comparison with right ventricular apex pacing. Pacing Clin Electrophysiol. 1998 Mar;21(3):536-41. doi: 10.1111/j.1540-8159.1998.tb00095.x.
citation: Alboni P, Scarfo S, Fuca G, Mele D, Dinelli M, Paparella N. Short-term hemodynamic effects of DDD pacing from ventricular apex, right ventricular outflow tract and proximal septum. G Ital Cardiol. 1998 Mar;28(3):237-41.
citation: Yu CM, Chan JY, Zhang Q, Omar R, Yip GW, Hussin A, Fang F, Lam KH, Chan HC, Fung JW. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med. 2009 Nov 26;361(22):2123-34. doi: 10.1056/NEJMoa0907555. Epub 2009 Nov 15.
citation: Nielsen, Jens Cosedis - Blomstrom-Lundqvist, Carina. DANPACE: The Danish multicenter randomised trial on single lead atrial versus dual chamber pacing in sick sinus syndrome. ESC Kongress 2010, Stockholm, Session number: 708001 - 70800.