Efficacy of Spinal Cord Stimulation in patients with Refractory Angina Pectoris; a randomized controlled trial

In recent decades, evolution of medical therapy, coronary artery bypass
grafting (CABG) and percutaneous coronary interventions (PCI) significantly
reduced the morbidity and mortality in patients presenting with stable coronary
artery disease (CAD). Despite all treatment innovations, 5 - 10% of patients
with stable CAD remain symptomatic with optimal therapy referred to as
*refractory angina pectoris (RAP)*. This condition is defined as a *chronic
condition (> three months) characterized by diffuse coronary artery disease in
the presence of proven ischemia, which is not amendable to a combination of
medical therapy, angioplasty or coronary bypass surgery*. Patients with RAP are
severely restricted in performing daily activities due to debilitating angina
complaints, leading to decreased quality of life.
Spinal Cord Stimulation (SCS) is one of the treatment options for patients with
RAP. SCS is a device with a lead located in the epidural space that provides
neurostimulation. Transcutaneous Electrical Nerve Stimulation (TENS) has the
same effect as SCS but is used by applying two adhesive electrodes to the skin
(in the thoracic region) to provide neurostimulation. Four possible mechanisms
explaining the beneficial effects of SCS/TENS on RAP have been described;
reduction of pain perception, decreased sympathetic tone, reduced myocardial
oxygen demand, and improved coronary microcirculatory blood flow.
Research into the effect of SCS on RAP has mainly been observational studies.
Only four placebo-controlled randomized controlled trials have been performed
up to date comparing different settings of neurostimulation (normal,
subthreshold and sham), with differing results (3-6). Reduction of angina
pectoris attacks due to SCS was proven in all studies. But it is not clear if
there is a placebo effect as suggested by the study of Zipes et al. This study
showed no significant differences between the high and low stimulation groups
whereas the other two studies did show differences between the groups at
different levels of stimulation. The inclusion of patients was slow in these
studies, were underpowered and one study had to be terminated early, making the
interpretation of the results all the more difficult. The primary end point of
these studies was also based on frequency of angina pectoris, a soft endpoint.
The recently published ESC guideline *chronic coronary syndromes* mention
non-existing to promising levels of evidence with regard to treatment options
in patients with RAP and concludes that SCS may be considered (Class IIB; level
of evidence B). It concludes that, *Larger RCTs are required to define the role
of each treatment modality for specific subgroups, to decrease non-responder
rates and ascertain benefit beyond potential placebo effects*

The aim of this study is to determine whether treatment with spinal cord
stimulation in patients with refractory angina pectoris leads to a significant
reduction in myocardial ischemia. Other aims are to determine the effect of
this treatment on the frequency of angina pectoris attacks, the effect on
quality of life, use of short-acting nitrates, patient condition using the
6-minute walking test, clincical outcomes (hospitalizations, percutaneous
interventions, coronary artery bypass grafting), as well as possible
complications arsing from the spinal cord stimulator implantation (secondary
outcome measures).

It is a double-blind, cross-over, placebo-controlled, single centre randomized
controlled trail.

All patients who participate in this study will receive an implanted spinal
cord stimulator. The spinal cord stimulator that will be implanted consists of
one battery, one lead and a remote control. With the remote control the patient
can change the desired level of stimulation. The lead will be placed in the
epidural space at the cervico-thoracic level.

After implantation of the spinal cord stimulator an installation programmer
will be used by the dedicated pain nurse to input the mode of stimulation. When
the installation programmer is used the spinal cord stimulator will be
programmed to think that two leads are connected to the battery whilst only one
lead has been implanted and connected to the battery. When programming the
spinal cord stimulator it will be possible to a) stimulate the actual lead
located in the epidural space, b) stimulate the non-existent second lead. What
this means is that the patient can use the remote control to change the level
of stimulation in both situations, whilst no stimulation occurs if the
non-existent second lead has been programmed to stimulate.

The patient will be informed that during the study he will receive six months
of high-density neurostimulation, i.e. actual lead, and six months of no
neurostimulation. The high-density form of stimulation does not usually lead to
parasthesia. During the entire study period (both in the six months the SCS is
on and in the 6 months the SCS is off) the patient will be able to use the
remote control.

This study design is deemed safe because in this patient population there are
no more treatment options available and spinal cord stimulation is an
*additional* last resort* treatment option. All patients participating in this
study will receive optimized standard care which is the same as the treatment
all patients with refractory angina pectoris in the Netherlands receive.

For the randomisation procedure the online program Research Manager will be
used. After the spinal cord stimulator has been implanted randomisation will
take place into Group A starting with *Stimulation On - High-density* or Group
B starting with *Stimulation Off - No stimulation*;
- Stimulation On - High-density: The lead in the epidural space will be
stimulated using high-density stimulation and is referred to as *high-density
mode*. During this period the patient will not feel paraesthesia*s in the
thoracic region. This is the effective treatment option.
- Stimulation Off - No stimulation: The programmed second non-existent lead
will be programmed as active, whilst leading to no neurostimulation and is
referred to as *no stimulation*. Tthe patient will not feel paraesthesia*s
during this period but he will be able to change the level of stimulation. This
is the placebo treatment option. The lead in the epidural space will not be
used during this period.

After 6 months cross-over will take place, meaning that Group A is switched to
'Stimulation Off - No stimulation' and Group B is switched to 'Stimulation on -
High-density'. When the study has finished (after 12 months), the spinal cord
stimulator will be changed in all patients to the conventional stimulation
mode.

During this study the patient will have to come to the hospital a total of 7
times. The first visit is for screening purposes to determine whether the
patient can participate in the study (by performing the TENS-test using a
treadmill). If the patient is eligable, first a PET-scan will be performed
(rest and stress) to determine whether myocardial ischaemia is present (this
PET-scan is part of the regular care). If myocardial ischaemia is present, then
the patient is eligible to participate in the study.Two visits to the
out-patient clinic will be done to explain the study to the patient, answer
questions and, if the patient wants to participate, written informed consent.
At this time a six-minute walking test will be performed. Next the patient will
come to hospital for the duration of 1 day and night for the implantation of
the spinal cord stimulator and will receive intraveneous antibiotics for
prevention of an infection of the device and/or the surgical wounds.
After the implantation the patient will be seen at the outpatient clinic at 1,
3, 6 and 12 months. Prior to the 6 and 12 month visits the patients will be
asked to fill out two questionnaires at home (taking a maximum of 30 minutes)
and take these with them to the outpatient appointments. During the outpatient
visit at 6 and 12 months the 6-minute walking test will be repeated.
After the implantation the PET-scan will also repeated (stress only) at 6 and
12 months, this will take approximately 60 minutes and the patient will receive
instructions prior to the scan in preperation. Over a period of 12 months, the
patient will undergo 3 PET-scans, and the radiation exposure has been kept to a
minimum.
The overall burden and risks (mainly possible complications arising from the
implanted spinal cord stimulator) of this study are acceptable. These patients
have been diagnosed with refractory angina pectoris for which we know are no
further treatment options. From the literature we know treatment with spinal
cord stimulation leads to a reduction in the number of angina pectoris episodes
and an improved quality of life. This is why we conclude that the possible
benefits in this patient group outweigh the possible risks and burden
associated with this study.

With regard to the spinal cord stimulator; the device will remain in situ after
the study has been finished. The device will be set to conventional
stimulation.If the patient wants the device removed, this can be discussed with
the researchers and the spinal cord stimulator can be explanted. If an
infection of the spinal cord stimulator should occur, then (part of) the spinal
cord stimulator will have to be removed. it will be possible to place a new
spinal cord stimulator at a later date.