Refractory angina (RA) is defined by a European Society of Cardiology taskforce as a “clinical diagnosis based on the presence of symptoms of stable angina, thought to be caused by ischemia due to advanced coronary disease and which are not controllable by a combination of maximal medical therapy, bypass surgery and percutaneous intervention” . Others have proposed that RA is an indication in which patients are refractory to drug therapy but also unsuitable for revascularization. The United Kingdom (UK) national chronic RA guideline group defines RA as “chronic stable angina that persists despite optimal medication and when revascularization is unfeasible or where the risks are unjustified” . The most frequent reasons that patients are unsuitable for revascularization include unfavorable coronary anatomy, multiple previous revascularization procedures (both percutaneous and surgical), the lack of suitable bypass graft targets or conduits, and significant extra-cardiac co-morbidities . It is estimated that in Europe the incidence of RA is 100,000 new cases per year . RA patients experience severe chest pain, which can result in multiple hospitalizations and low levels of health-related quality of life . A number of therapies have been recommended for the treatment of RA following optimization of their cardiovascular drug therapy, that is, beta blockers, nitrates, potassium agonists and newer generation drugs (for example, ranolazine) [1, 3]. These additional therapies include sympathectomy, analgesics (usually opiate-based), angina management programs, stimulation induced analgesia, stellate ganglion block, epidural blocks, spinal cord stimulation (SCS), enhanced external counterpulsation and percutaneous laser myocardial revascularization [4, 5].
The use of spinal cord stimulation (SCS) for angina was first described in 1987. SCS is a reversible procedure in which electrodes are implanted in the epidural space to stimulate the dorsal columns of the spinal cord . The technique has been described in detail elsewhere . SCS has been successfully used to relieve pain in a number of chronic conditions, including neuropathic pain and pain due to peripheral vascular disease .
The mechanism of action of SCS in neuropathic pain is well documented. For ischemic pain there are a number of proposed mechanisms. It is believed to have its effects by a combination of modulation of pain pathways within the central nervous system and anti-ischemic mechanisms. SCS modulates the autonomic nervous system, suppresses intrinsic cardiac nerve activity independent of beta sympathetic nervous system activity and is cardio-protective [9, 10].
Systematic review and meta-analysis
To summarize the current evidence for the use of SCS for RA, we updated a recent systematic review . We searched a number of electronic databases including Medline, Embase and Cochrane Library up to April 2011 (with a further search in October 2012) to identify randomized controlled trials (RCTs) of SCS in RA. The reference lists of included studies were checked for potential additional studies. The search strategy, inclusion and exclusion criteria, study selection, data extraction and risk of bias assessment are detailed elsewhere .
We identified eight RCTs that included a total of 322 RA patients (see Additional file 1: Table S1) [12–19]. Five studies compared SCS stimulation (‘SCS ON’) to either sub-threshold or no SCS stimulation (‘SCS OFF’) [13, 16–19], one study compared SCS to usual care , and two studies compared SCS with an alternative therapy (that is, coronary artery bypass graft  and percutaneous myocardial laser vascularization ). The risk of bias of five trials was judged to be high (that is, met two out of five criteria) and three trials to be low to moderate (that is, met three or more out of five criteria) (see Additional file 1: Table S2).
Findings are presented according to the two broad categories of control group, that is, SCS versus active intervention and active SCS versus no or sub-threshold SCS. The between group differences of active SCS (‘SCS ON’) versus no or inactive SCS (‘SCS OFF’) trials were quantitatively pooled using a conservative Der Simonian random effects meta-analysis model to take account of the potential heterogeneity (both clinical and methodological) across trials . Given the variety of exercise capacity, consumption of nitrate medication and health-related quality of life outcomes were reported, results were expressed as a standardized mean difference (SMD). SMD is a summary statistic used when trials assess the same outcome, but measure it in a variety of ways . The SMD expresses the size of the treatment effect in each trial relative to the study variance or standard deviation observed in the trial. All analyses were performed using RevMan, version 5.0 (http://www.cc-ims.net/RevMan).
Meta-analysis results are shown in Additional file 1: Figure S1. Outcomes of SCS were similar when directly compared to either coronary artery bypass grafting or percutaneous myocardial laser revascularization. Compared to a ‘no stimulation’ control, there was some evidence of improvement in all outcomes following SCS implantation with gains observed in pooled exercise capacity (SMD: 0.62, 0.03 to 1.21, Additional file 1: Figure S1a), short acting nitrate consumption (SMD: -0.65, 95%, -1.34 to 0.05, Additional file 1: Figure S1b), and health-related quality of life (SMD: 0.61, 95% CI: 0.13 to 1.09, Additional file 1: Figure S1c).
SCS-related complications were reported in five trials [12–14, 16, 18] and included infections (1 out of 104 patients, 1%) and lead migrations or fractures (10 out of 128 patients, 8%). Relatively few fatal and non-fatal events were reported and in no studies was there a statistically significant difference in events between SCS and the comparator [12, 13, 19].
UK survey of current RA management
In designing a pragmatic trial of SCS for RA, it is important to determine what would constitute usual medical management and how this care might vary across centers in the UK.
It is likely that the management of patients with RA varies considerably. We were aware of only one UK specialist center for RA - the National Refractory Angina Centre in Liverpool. Outside of this center, the management of RA probably varies considerably by locality; some RA patients being managed within a cardiology unit, and others by a specialist pain team or a combination of the two. Furthermore, in the absence of authoritative evidence-based clinical guidelines for the management of RA, clinicians and centers may be recommending different therapies.
To assess current UK RA management and to quantify the potential variation in this practice, we undertook a national survey. Contact details were obtained for all UK pain centers (from the Dr Foster database) and cardiac centers (from the central cardiac audit database). After a number of rounds of drafting, we finalized a two-page questionnaire. A questionnaire and pre-paid return envelope were posted to all pain and cardiac units in April 2011. A follow-up questionnaire was posted to non-responding units in July 2011.
A total of 552 questionnaires was sent out and 215 replies were received (41%). Of these, 94 (44%) were from pain units, 49 (23%) were from cardiology units and the remainder (34%) did not indicate their specialty. The vast majority used either the European Society of Cardiology RA definition  (41%) or the UK National RA group definition  (54%) in their practice, the remainder (5%) stated that they used a different definition. Only 11 (5%) centers replied that they used a protocol or guideline for the management of their RA patients with RA. The drug therapies offered to patients with RA in addition to their cardiovascular drugs varied greatly with a total of 16 differing therapies identified. The most common treatments included regular slow release opiates (N = 122 units, 56%), instant release opiates as on demand prescriptions (101, 47%), transcutanous nerve stimulation (TENS) (116, 54%), exercise programs (84, 39%), cognitive behavioral therapy (72, 33%) and education (61, 28%). A total of 35 units (16%) used SCS. The complete list of RA treatments offered by units is summarized in Additional file 1: Figure S2.
Of the 192 (89%) centers who responded to the statement that ‘SCS was a suitable therapy for patients with RA’, 10% ‘strongly agreed’, 42% ‘agreed’, 42% were ‘unsure’, 5% ‘disagreed’ and 1% ‘strongly disagreed’. Of those who were unsure or disagreed, reasons given were that they did not know where to refer patients for SCS (26%), considered the clinical current evidence for SCS to be poor (46%), regarded SCS as too expensive (15%), did not understand how SCS worked (5%), were concerned that SCS may mask serious disease or felt RA did not require analgesia (1%). A total of 75 centers (44%) stated that they would be interested in participating in a multicenter trial involving patients with RA.
Pilot study objectives
It is hypothesized that the addition of SCS to usual care will have superior clinical effectiveness and cost-effectiveness compared to usual care alone in patients with RA. The RASCAL (Refractory Angina Spinal Cord stimulation and usuAL care) pilot study seeks to assess the feasibility of a definitive trial to address this hypothesis. RA patients will be randomized to SCS plus usual care (‘SCS group’) or usual care alone (‘UC group’).
The objectives of this study are to:
To assess recruitment, uptake and retention of patients in both groups.
To assess the feasibility and acceptability of SCS treatment from the point of view of patients and referring physicians.
To assess the feasibility and acceptability of standardizing usual care from the point of view of patients and referring physicians.
To test the feasibility and acceptability of the proposed trial outcome measures in both groups.
The results from this pilot study will inform the design and power for a definitive multicenter RCT.