Design and rationale of the efficacy of spinal cord stimulation in patients with refractory angina pectoris (SCRAP) trial

Abstract Background The use of spinal cord stimulation (SCS) in patients with refractory angina pectoris (RAP) is still under debate. Studies up to date have shown a positive effect with an improvement in quality of life. However, no double blinded randomized controlled trials have been performed. Hypothesis & Methods The objective of this trial is to investigate if high density SCS leads to a significant reduction in the amount of myocardial ischemia in patients with RAP. Eligible patients must meet the criteria for RAP, have proven ischemia and a positive transcutaneous electrical nerve stimulator treadmill test. Patients who meet the inclusion criteria will receive an implanted spinal cord stimulator. Patients receive 6 months of high density SCS and 6 months of no stimulation using a cross‐over design. The order of the treatment options is determined using randomization. The primary endpoint is the effect of SCS measured by the change in percentage of myocardial ischemia using myocardial perfusion positron emission tomography scan. Key secondary endpoints are patient related outcome measures, major cardiac adverse events and safety endpoints. The follow‐up period is 1 year for the primary and key secondary endpoints. Results The SCRAP trial began enrollment on December 21, 2021 and is set to complete the primary assessments in June 2025. To date, January 2, 2023, 18 patients have been enrolled in the study and 3 patients have completed the 1‐year follow‐up. Conclusions The SCRAP trial is an investigator‐initiated, single‐center, double‐blind, placebo‐controlled, and cross‐over randomized controlled trial investigating the efficacy of SCS in patients with RAP. (ClinicalTrials. gov Identifier: NCT04915157)


| INTRODUCTION
Coronary artery disease (CAD) is one of the most prevalent diseases worldwide. Due to advancements in treatment options mortality and morbidity rates in this patient population have steadily declined.
However, up to 20% of patients with stable CAD have persisting angina symptoms. 1 It is estimated that 5%-10% of patients with stable CAD who remain symptomatic despite optimal treatment have "refractory angina pectoris" (RAP). 2 reduction of myocardial oxygen demand, reduction of pain perception, and a decrease in sympathetic tone and an improvement in the coronary microcirculatory blood flow. 5,6 The majority of research into the effect of SCS on RAP has been observational in nature. To date three placebo-controlled randomized controlled trials have been performed and one study compared SCS with usual care. [6][7][8][9] In the three placebo-controlled studies various settings of spinal cord stimulation (normal, subthreshold, and sham) have been compared with differing results. [7][8][9] Reduction in the number and severity of angina symptoms 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. 9 In this study two modes of stimulation; highconventional use of spinal cord stimulation, and low-spinal cord stimulation during 1 min each day, were compared with no significant differences between the two groups after 6 months of treatment. 9 Whilst the two other studies comparing different levels of spinal cord stimulation did find significant differences between the groups. 7,8 These conflicting results make interpretation difficult, especially taking into account that the studies were underpowered and had slow patient inclusion rates which led to early termination of the studies. Despite the limitations of these individual studies two systematic reviews confirm that there is a significant improvement in exercise duration, Canadian Cardiovascular Society (CCS) class, Visual Analog Scale (VAS) score, daily angina episodes, angina frequency, daily nitrate consumption, disease perception and treatment satisfaction in RAP patients with SCS. 10,11 Although the exact working mechanism of SCS in RAP has not been elucidated studies have repeatedly shown an improvement in the quality of life and a reduction in angina symptoms. [7][8][9][11][12][13] It is unclear if SCS leads to reduction in the amount of myocardial ischemia. One study by Diedrichs et al. determined the effect of SCS based on the amount of myocardial ischemia using Methoxyisobutylisonitrile single photon emission computed tomography (MIBI-SPECT). 14 All patients were treated with SCS and MIBI-SPECT was performed at baseline, 3 and 12 months. After 12 months, there was a significant reduction in the amount of myocardial ischemia that was not seen at 3 months. Because the reduction of myocardial ischemia was only seen at 12 months, the authors concluded that this effect might not have been a direct effect of SCS, but rather due to better coronary collateralization created by enhanced physical activity.
Thus, the question remains whether SCS actually reduces the amount of myocardial ischemia.
The recently published European Society of Cardiology (ESC) guideline "Chronic Coronary Syndromes" describes varying levels of evidence with regard to treatment options in patients with RAP. The ESC guideline concludes that SCS may be considered (Class of recommendation IIB; level of evidence B). 15 It summarizes that "Larger RCTs are required to define the role of each treatment modality for specific subgroups, to decrease nonresponder rates and ascertain benefit beyond potential placebo effects," confirming the need for additional studies. 15 The type of SCS traditionally used in patients with RAP is conventional stimulation. With this type of stimulation the patient will feel paresthesia at the target area. For this study a paresthesia free form of stimulation, high density (HD) stimulation, will be applied. Based on previous experience it is a viable treatment modality, it allows adequate blinding of patients because no paresthesia are felt and the patient can be fully informed about the fact that the spinal cord stimulator will be turned off for a period of 6 months. 16 This is in contrast to previous studies in which blinding of patients has been problematic due to the paresthesia felt by the patient. [6][7][8][9] The aim of this investigator-initiated, single-center, placebocontrolled, double-blind, cross-over, randomized controlled trial is to determine if high density spinal cord stimulation, a paresthesia free form of stimulation, leads to a significant reduction in the amount of myocardial ischemia in patients with RAP. The trial has been registered at ClinicalTrials.gov with NCT identifier NCT04915157.

| Study design
The primary objective of this study is to determine the effect of SCS in patients with RAP on the percentage of myocardial ischemia measured using a myocardial perfusion positron emission tomography (PET) scan. Patients with RAP referred to our hospital (Catharina hospital, Eindhoven, the Netherlands) will be screened for eligibility to participate in the study. The inclusion criteria must be met,   • No revascularization (PCI and/or CABG) performed between ischemia testing and study inclusion.
T A B L E 2 Exclusion criteria.
• Acute coronary syndrome during the 3-month period before screening.
• Life expectancy less than 12 months.
• Inability to perform a 6-min walking test.
• Inability to give informed consent.
• Spinal cord disease which could prevent correct positioning of the lead in the epidural space; to be determined by the anesthesiologist performing the implantation.
• Anticoagulation therapy that cannot be stopped/bridged before spinal cord stimulator implantation.
• Inadequate paresthesia coverage, during implantation, of the thoracic region where angina complaints are localized.
• Mild Cognitive Impairment or dementia.
• Concomitant symptomatic valvular heart disease including severe aortic stenosis and/or regurgitation, severe mitral valve stenosis and/or regurgitation or severe tricuspid valve regurgitation. setting for a duration of 2 weeks. After this period the effect of TENS will be re-evaluated by the same team to determine whether the effect was positive or negative (a dubious test result is not possible).
If the effect is positive the patient is eligible and a myocardial perfusion PET scan will be performed 1 month after termination of TENS treatment (washout period to prevent possible lingering effects of the TENS treatment) (Figure 1).
If myocardial ischemia is proven, with myocardial perfusion PET scanning, the patient is included. All participating patients will receive an implanted spinal cord stimulator. The total duration of the study is 12 months during which patients will receive 6 months of HD SCS, a paresthesia free form of SCS, and 6 months of no stimulation using a cross-over design. To determine the order of the treatment options randomization using the online program Research Manager will be performed ( Figure 2). The randomization is done by the study nurse. The study nurse will be the only person of research team that knows to which arm the patient has been randomized. This same study nurse is also responsible for inputting the correct programming of the SCS based on the randomization. The patient and the remaining members of the research team are blinded to the randomization process. During the study period of one year the patient will have use of the patient programmer. To ensure blinding of the patient remains intact, during the "SCS OFF" or placebo period, a non-existent second lead will be programmed as being active, whilst leading to no actual SCS. This enables the use of the patient programmer during the "SCS OFF" or placebo period and also keeps the blinding of the patient intact.

| Spinal cord stimulator implantation
The spinal cord stimulator system consists of an implantable pulse

| Primary endpoint objective
The primary objective of this study is the effect of SCS in patients with RAP measured by the change in the percentage of myocardial ischemia (% of the left ventricular myocardium) using myocardial perfusion PET scan at the end of the six-month period of treatment with SCS compared with baseline.

| Secondary endpoint objectives
An overview of the secondary objectives is given in Table 3

| Follow-up
At baseline the SAQ, RAND-36, NRS-scale, and CCS class will be completed when the patient is seen for the initial standardized TENS treadmill test. The baseline 6-MWT will be performed after the baseline myocardial perfusion PET scan has shown myocardial after confirmation of complete data, the spinal cord stimulator settings will be set to conventional spinal cord stimulation by the study nurse in the same manner as the 6 month appointment. In addition the patient will be asked during which period of the study, the first or second 6 months, it was thought that the spinal cord stimulator was turned on.
For the duration of the study patients are asked to contact our center to inform us if visits to the emergency room, admissions to hospital and/or the undergoing of a PCI and/or CABG have occurred.
If complications arise related to the implanted spinal cord stimulator (i.e., signs of infection, battery dislocation, lead dislocation, and/or lead fracture) patients will be asked to contact the outpatient clinic of the department of anesthesiology to determine the appropriate course of action.
After completion of the study patients will be invited to the outpatient clinic each year for a total duration of 5 years for long-term follow-up. At each outpatient clinic appointment patients will be asked to complete the SAQ, RAND-36, NRS-scale, CCS class, and 6-MWT. Due to the study design using cross-over, it is theoretically possible that a carry-over and/or period effect could occur. We will apply the two-stage approach as proposed by Grizzle et al to assess the carry-over and period effect. 20 To assess the carry-over effect we will first determine the summed effect over the two periods and compare these between the two groups (A and B). In the same way we will assess the period effect by determining the summed effect over the two groups and compare these between the periods. When analyses show that the carry-over effect as well as the period effect are negligible, we will use a paired, two-tailed Students' T test for the main outcome parameter. If a significant carry-over effect is found, only data from the first period will be analyzed. Due to the long study period of 6 months before performing the PET scan after cross-over has taken place, the assumption is that there will not be a carry-over effect.

| Organization and ethical concerns
This is a single-center, investigator-initiated study. The study protocol has been approved by the local ethics committee. All T A B L E 3 Secondary objectives.
• Changes in absolute quantification of myocardial blood flow using myocardial perfusion PET scan including myocardial blood flow & myocardial flow reserve regionally and globally.

| DISCUSSION
The SCRAP trial will be conducted in a large specialized hospital in the and 7.8% of patients with lead migration or fracture (10 out of 128 patients). 25 As is true for all interventional therapies operator experience will lead to a reduction of the number of adverse events over time. Our center has been implanting spinal cord stimulators for the indication RAP since 2009 and a recent observational study carried out in our center showed a low percentage of adverse events over a follow-up period of one year (2.3%; 2 out of 87 patients), 13 showing that the risk of adverse events is low in patients with RAP receiving a spinal cord stimulator. The risk of a complication related to the spinal cord stimulator implantation has been taken into consideration in the design of the SCRAP trial in two ways. First, the drop-out rate of 10% was imbedded into the sample size calculation and secondly in the SCRAP trial adverse events related to the spinal cord stimulator implantation have been added as safety end points (Table 3) and will be reported at the end of the study period.

| LIMITATIONS
There are a number of limitations with regard to the SCRAP trial. One limitation is the difference in myocardial ischemia on which the sample size calculation is based. The power of the study is based on a relative reduction in myocardial ischemia of 25% after treatment with VERVAAT ET AL.
| 695 SCS, in absolute numbers a reduction from 10% to 7.5% of myocardial ischemia. Whilst this is a relatively modest difference, it is deemed clinically relevant. Patients with more than 10% myocardial ischemia have a worse prognosis in comparison to patients with less than 10% myocardial ischemia, 15

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author, FEV, upon reasonable request.