Non-invasive programmed stimulation to identify high-risk patients with implanted cardioverter defibrillator (the NIPS-ICD study): study protocol for a randomized controlled trial

The study protocol was approved by the Ethics Committee of Regional Medical Chamber
in Rzeszów and is in full compliance with the Declaration of Helsinki. Approval Number:
77/2013/B.

The aim of the study

The aim of the study is to evaluate the usefulness of NIPS in determining the likelihood
of life-threatening arrhythmic events in patients with ICD.

Methodology/Design

The study group

The study will include 150 consecutive patients with an ICD implanted both for primary
and secondary prevention, regardless of etiology, who are followed in the outpatient
clinic of our center and do not meet the following exclusion criteria:

1. lack of consent for NIPS

2. decompensated heart failure

3. unstable angina

4. persistent/long standing AF without effective anticoagulation (risk of sinus rhythm
return during NIPS)

5. thrombus in the left ventricle

6. appropriate device interventions during the 40 days prior to planned NIPS

7. pacing/sensing problems

After selecting a patient to undergo NIPS, the following parameters will be analyzed:
etiology, age, sex, and anthropometric measurements (weight, height, and waist), echocardiogram
performed within 3 months after enrollment (including LVEF and end-diastolic dimension
of LV), NYHA class, presence of AF, state of renal function, width of native and paced
QRS complex, occurrence of ventricular arrhythmias (detected on ECG or EGM), previously
performed cardiac surgery and/or coronary angioplasty, occurrence of ICD interventions
in the past, and current drug therapy.

NIPS methodology

On admission, the patient will be fasting. After interviewing and physical examination,
the patient will be informed about the manner and purpose of the NIPS, and written
consent will be obtained. The ECG will be recorded, and access to the venous system
will be obtained. The patient will be transferred to the EP room. Throughout the duration
of the NIPS, surface 12-lead ECG from an electrophysiological system will be recorded.
ICD will be interrogated, and a review of the available events and interventions in
memory ICD will be performed. The parameters of the detection of VT/VF and therapy
parameters will be set out, as well as the parameters of stimulation and sensing:
the low and high voltage impedance, the signal from the defibrillation lead, and the
pacing threshold.

Next, a 12-step St. George’s Hospital NIPS protocol using ICD will be performed 27], 28], which consists of introduction of a single and double extrastimuli from the pacing
lead during sinus rhythm (or atrial fibrillation if present) and after eight-beat
extrastimulus drive trains at paced cycle lengths of 600, 500, and 400 ms. If a sustained
arrhythmia will not be inducible, the procedure will be repeated using triple extrastimuli,
wherein in step 12 the three premature impulses after the eight-beat drive at cycle
length of 400 ms are delivered.

The endpoint is to induce sustained ventricular arrhythmia (VT lasting more than 30 seconds
or hemodynamically unstable VT/VF) or the end of the protocol. In case of ventricular
arrhythmias induction, the following parameters will be defined:

1. arrhythmia-induction protocol (stage of NIPS at which arrhythmia was induced)

2. the type of arrhythmia (single extrasystoles, couplets, nonsustained VT (nsVT),
sustained VT (sVT), or VF)

3. In the case of VT/VF occurrence:

a. mean tachycardia cycle length calculated from the first 10 QRS complexes

b. effectiveness of ATP in terminating arrhythmia

c. in the case of ineffectiveness of ATP – efficacy of internal cardioversion/defibrillation.

In case of serious and/or hemodynamically unstable heart rhythm disorders resistant
to treatment with a low-energy ATP, the patient receives a short-term intravenous
general anesthesia, and internal or external defibrillation is performed.

If the test induces sustained ventricular arrhythmia, after the sinus rhythm has been
restored, the patient will be transferred to the intensive care room, where at the
time of his stay, continuous ECG and blood pressure will be performed.

Outpatient follow-up

The follow-up will be conducted at the outpatient clinic for patients with ICD located
in our center. Analysis of records of registered memory device classified as VT/VF
episodes will be collected in printed and electronic versions for further investigation
by the study team. Medical history will be taken, and a physical examination will
be carried out. In case of endpoint VT/VF occurrence during follow-up, the time from
NIPS test to ICD episode detection/therapy will be measured. The follow-up will last
one year and will be conducted every 3 months; thus, each patient will have four visits
– one at 3, 6, 9 and 12 months after performing NIPS. The following parameters will
be collected:

1. The patient’s clinical status will be determined on the basis of a physical examination,
NYHA class, changes in medication, hospitalizations, cardiac events such as syncope,
ICD discharges, palpitations and other, which occurred after the previous visit.

2. The ICD memory will be examined, and all events will be analyzed. All ICD interventions
will be analyzed and classified as appropriate or inappropriate. The type of cardiac
rhythm (VF, VT, or other) and the cycle length and duration will be also measured.

3. All follow-up visits and data collection will be performed by the principal investigator
(PF). If necessary, drug therapy will be modified during follow-up, but the result
of the NIPS will not be taken into account when changes in the antiarrhythmic drug
therapy are considered. Changes in ICD programming will be possible; however, these
will be based on arrhythmic events occurring during follow-up and not based on the
results of the NIPS.

Expected results

During the NIPS the following clinical situations are expected to occur:

1. lack of induction of arrhythmia (negative result)

2. induction of ventricular extrasystoles (negative result)

3. induction of hemodynamically stable nsVT (negative result)

4. induction of hemodynamically unstable nsVT (positive result)

5. sVT induction (positive result)

6. VF induction (positive result).

It is expected that appropriate ICD interventions during follow-up will occur more
often in patients who had sustained ventricular arrhythmias induced during NIPS (positive
result). The primary endpoint of the follow-up will be appropriate intervention of
ICD or sudden cardiac (arrhythmic) death; the secondary, appropriate ICD intervention
or death from cardiovascular causes; and the tertiary, appropriate ICD intervention,
death or hospitalization for cardiovascular causes. Because all patients will remain
under the study follow-up for 1 year, the degree of exposure to arrhythmia recurrence
(arrhythmia burden) will be determined defined as the number of relevant interventions
during the year of observation.

Appropriate ICD intervention is defined as the high or low energy treatment due to
the occurrence and detection of VT/VF.

For death from cardiovascular causes, it is considered death due to VF, extensive
myocardial infarction, end-stage heart failure, or electromechanical dissociation
or asystole due to presumed cardiovascular cause.

For sudden cardiac (arrhythmic) death, death due to sVT/VF or, in the absence of available
documentation, death that occurred within 1 hour of the onset of symptoms 29] may be considered. Every effort will be made to interrogate ICD postmortem in order
to establish the mode of death.

Statistical methods

The principal analysis will examine the relationship between positive NIPS result
and the follow-up outcome. Further subanalyses will also take into account the protocol
stage at which arrhythmia was induced as well as the tachycardia cycle length and
duration. At the first stage, groups of patients will be extracted by the occurrence
of arrhythmic events during NIPS,- as in section 4. Afterwards, these groups will
be compared according to the data collected during the follow-up (endpoints). The
group, in which the endpoints occurred, will be compared with a group of patients
without endpoints according to the NIPS result using Kaplan–Meier survival curves
and tested with a log-rank test. A P value of 0.05 will be considered statistically
significant for all analyses.

Next, with Multivariate Cox Proportional Hazards Model the presence or absence of
the NIPS result correlation will be determined with other risk factors affecting the
possibility of developing adequate ICD interventions that have been previously described
in the available literature and widely accepted, that is, echocardiogram result, NYHA
class, the presence of atrial fibrillation, renal function, width of native QRS complexes.
The sensitivity, specificity, positive, and negative predictive value in predicting
the occurrence of NIPS endpoints also will be calculated using Student’s t test or
the Mann–Whitney test for continuous variables, where appropriate.

With the chi-square test, 150 patients have been estimated as needed for inclusion
in the study. This assumption is based on the calculation that primary endpoints will
occur in 6.7 % patients, and the result of NIPS will be abnormal in 30 % of those
patients and in 7.9 % of patients without VT/VF recurrences 2], 30], 31]. This number of patients will be sufficient to demonstrate significant difference
(P??0.05) between the groups.