The PACE NOW Trial: A Prospective, rAndomized Comparison of tEmporary transvenous pacing and leadless paciNg therapy in pOst-TAVI patients With conduction abnormalities

In 6-28% of patients undergoing transcatheter aortic valve implantation , there
is a need for temporary and subsequent permanent pacing therapy, and it is
difficult to predict which patients will develop this need. Patients requiring
transvenous temporary pacing (TV-TP) are mandated bed rest and therefore at
risk for infections, cardiac perforation, lead malfunction, delirium,
re-intervention and prolonged hospitalization. In up to 67% of these patients
who received TV-TP the pacing need persists, hence requiring a second
procedure, the implantation of a permanent pacemaker (PPM). TV-TP therapy
complications can be reduced by replacing it with leadless pacemaker (LP)
therapy, a recently introduced technology aimed to reduce complications related
to conventional PPM therapy. Patients can be treated in one procedure, and
potentially be mobilized and discharged earlier compared to standard of care.
It is expected that LP may provide an additional treatment benefit for the
elderly population by reducing re-operations and hospital stay.

The primary objective of the study is to outline the advantages of LP
implantation in TAVI patients who require temporary, and possibly permanent
pacing compared to the Standard of Care using TV-TP therapy. We will study
whether placement of a LP system following TAVI procedure is superior to TV-TP
therapy with respect to intervention-related complications. Secondary
objectives are the evaluation of: all-cause mortality, major adverse cardiac
event, stroke, NYHA functional classification, left ventricular systolic
function, duration of hospitalization, time to mobilization, recurrent
hospitalization due to cardiovascular event, Health Related Quality of Life,
cost-effectiveness, percentage patients requiring PPM following TV-TP,
percentage need for pacing therapy in all PM patients, determine conduction
disorder progression, and patient satisfaction.

This will be a prospective, randomized, multicenter, interventional two-arm
trial to claim superiority of an intervention (LP) over a SOC strategy (TV-TP)
in selected TAVI patients on intervention-related complications. Patients will
be randomized in two arms on a 1:1 basis (block randomization):

1) Interventional arm: implant of LP therapy in TAVI-patients who are indicated
for temporary pacing therapy post-TAVI implantation.
2) Control arm: standard TV-TP therapy in TAVI-patients who are indicated for
temporary pacing therapy post-TAVI implantation, and subsequent conventional
transvenous PPM therapy if applicable.

We will select up to 10 centers, 6 from The Netherlands (including University
and Non-University Hospitals) and 4 from European countries with similar health
care systems. There are additional requirements for site selection. In section
4.1 the site selection requirements are reported.

This study will include 210 patients with a follow-up of 12 months. With 2 x
105 (including 5% attrition) randomized patients the trial has 90% power to
claim superiority of the interventional arm (LP) with respect to the primary
endpoint of difference in intervention-related complications in comparison to
the conventional arm (TV-TP therapy) at 12 months from randomization. The
complete sample size calculation is discussed in 4.4.

Pilot/ First phase interim analysis
We will start with the pilot, a prospective, randomized, monocenter,
interventional two-arm trial, including 20 patients (2x10 patients per
treatment arm) with a follow-up of 30 days. This pilot will be executed in the
Academic Medical Center to determine feasibility and logistics of the study
design. If deemed necessary in additional Dutch medical centers will be asked
to participate. These 20 patients will be included in the total study
population of the subsequent international multicenter study.

The patients who are allocated to the interventional arm are implanted with a
leadless pacemaker, preferably within the same procedure as the TAVI, but must
be implanted with a leadless pacemaker within 12 hours after randomization.
These patients will receive standard care for leadless pacemaker implantation.
The LP will be implanted under fluoroscopic guidance, using a percutaneous,
transfemoral approach with a 18F introducer sheath (Nanostim LP) or 27F
introducer sheath (Micra TPS). The LP will be implanted in the right
ventricular apicoseptal region. After electrical testing, the LP will be
released, and the delivery catheter will be removed from the groin. The
expected fluoroscopy time will be expected to be less than 5 minutes (3.5-4.0
mSv). The implant procedure of the LP is described in section 6 of the study
protocol in more detail.
The patient has to undergo one procedure when radomised in the interventional
arm in comparison to two procedures with standard of care. There are two types
of leadless pacemakers: the Micra (Medtronic) and the Nanostim (Abbott). The
choise for leadless pacemaker will be based on availability and patients/
implanting physicians.

In TAVI patients who develop a need for pacing due to conduction abnormalities
secondary to the TAVI implant, transvenous temporary pacing (TV-TP) therapy is
provided as a bridge to PPM. In some patients the need for pacing is only
temporary. Guidelines recommend to implant a PPM within 7 days if the
conduction abnormalities persist. TV-TP therapy requires monitoring, often in
the cardiac care unit, resulting in prolonged hospital stay providing a
significant economical and logistic burden. To attain deeper knowledge on TV-TP
our research group performed a scoping review in order to give an up-to-date
overview on complications, need for subsequent PPM of all available studies
until December 2016. In 17 out of 31 studies the need for PPM placement
following TV-TP was documented. In 57.4% of patients subsequent PPM was
required after TV-TP therapy.

Previously reported complication rates are high with a mean of 26.5%, but
ranging from 10-60%. These complications are often related to the temporary
pacing lead (i.e. dislodgement, malfunction, perforation, infection) or to the
venous access (i.e. pneumothorax, venous thrombosis, access site bleeding,
hematomas). Since the reported complication rates were so high and varied
widely we evaluated this problem in our scoping review. We observed a total
complication rate ranging from 0.8% to 80.5%. The weighted mean complication
rate of all included studies was 30.7%.

Patients who receive TV-TP are required to remain bed rested in order to
minimize risk of lead dislocation or perforation. Not only is this not
comfortable for the patients, especially the elderly TAVI population is at high
risk for development of muscle atrophy, hospital acquired pneumonia , and
delirium (in 10-40%) which is often associated with adverse short- and
long-term health implications.

Recently, LP therapy has been introduced aimed to reduce complications related
to conventional PPM therapy (e.g. lead fractures, pocket infection, pacemaker
endocarditis, pneumothorax).There are currently two LP available an used in
clinical practice: 1) The nanostim LP (15) and 2) the Micra transcatheter
pacing system (TPS). First studies showed safety and efficacy of these devices.
For the Nanostim LP, complication rates ranged from 4-6% and were almost all
related to the implant procedure (i.e. perforation, dislocation, venous access
site bleeding). Major device-related complications occurred in 25 (3.4%) of the
725 patients following Micra TPS. No reports of infection of the both devices
have been reported in the patient cohort with the longest follow-up of 12
months. Outside of the investigational setting, recent results of the acute
performance of the Micra TPS from a worldwide Post-Approval Registry were
presented at EHRA Cardiostim Congress June 2017 in Vienna. The device was
successfully implanted in 792 of 795 registry patients (99.6%) by 149
implanters at 96 centers in 20 countries. Through 30 days post implant, a total
of 13 major complications occurred in 12 patients, for a major complication
rate of 1.51% (95% confidence interval, 0.78%-2.62%). Major Early pacing
capture thresholds were low and stable.

Patients will be randomised to either routine therapy with (temporary)
tranvenous pacing therapy, or to treatment with a leadless pacemaker. Patients
in the leadless pacemaker arm will be subjected to additional follow-up visits
compared to routine therapy. However, this is standard care following leadless
pacemaker implantation, and not be considered additional burden.Patient with
leadless pacemaker implantation in whom the pacing indication disappears, are
subjected to an extra procedure, namely the leadless pacemaker implant.
However, results from our scoping review showed that in 56%, patients will
develop a permanent pacing indication. In patients who do not require the need
for pacing, it is recommended to leave the LP implanted and program the
pacemaker to a lower rate of 30 BPM VVI to prevent against SCD or/and treat
future progression of conduction disorders.

There are risk associated with both therapies which are:

Potential device and procedure related risks for both leadless pacemakers
include:
-Cardiac perforation
*Pericardial effusion and cardiac tamponade
*Vascular complication
-Bleeding
*Arteriovenous fistula
*Pseudoaneurysm
*Failure of vascular closure device requiring intervention
-Arrhythmia during device implantation
*Asystole
*Ventricular tachycardia or ventricular fibrillation
-Cardiopulmonary arrest during implantation procedure
-Device dislodgement
-Device migration during implantation owing to inadequate fixation
-Pacing threshold elevation with retrieval and implantation of new device
-Other
Hemothorax
Angina pectoris
Pericarditis
Acute confusion and expressive aphasia
Dysarthria and lethargy after implantation
Contrast-induced nephropathy
Orthostatic hypotension with weakness
Left-leg weakness during implantation
Probable pulmonary embolism
Ischemic stroke

Transvenous Pacing Therapy
An overview of potential risks following transvenous pacing therapy is
listed below:
-Traumatic complications
* Perforation of cardiac structure
* Pneumo(hemo)thorax
* Pericardial effusion
-Lead related complications
*Lead fractrure
*Lead dislocation or disconnection
*Insulation problem
*Infection (ie, lead endocarditis
*Stimulation threshold problem
* Diaphragm or pocket stimulation
-Pocket complications
*Hematoma
*Difficult to control bleeding
*Infection
*Discomfort due to pocket or pacemaker
*Skin erosion
-Pulse generator problems
*Problem with connection screw
*Manufacturer recall
*Reset to default settings
*Device cannot be programmed
*Pacemaker tachycardia
* Malfunction of software algorithm