Clinical and cost-effectiveness analysis of an open label, single-centre, randomised trial of spinal cord stimulation (SCS) versus percutaneous myocardial laser revascularisation (PMR) in patients with refractory angina pectoris: The SPiRiT trial
© Dyer et al; licensee BioMed Central Ltd. 2008
Received: 25 March 2008
Accepted: 30 June 2008
Published: 30 June 2008
Patients with refractory angina have significant morbidity. This study aimed to compare two of the treatment options, Spinal Cord Stimulation (SCS) and Percutaneous Myocardial Laser Revascularisation (PMR) in terms of clinical outcomes and cost-effectiveness.
Eligible patients were randomised to PMR or SCS and followed up for exercise tolerance time (ETT), Canadian Cardiovascular Society (CCS) classification and the quality of life measures SF-36, Seattle Angina Questionnaire and the EuroQoL at 3, 12 and 24 months. Utilities were calculated using the EQ-5D and these and costs were compared between groups. The incremental cost-effectiveness ratio (ICER) per QALY for SCS compared to PMR was also calculated.
At 24 months post-randomisation, patients that had SCS and PMR had similar ETT (mean difference 0.05, 95% CI -2.08, 2.18, p = 0.96) and there was no difference in CCS classification or quality of life outcomes. The difference in overall mean costs when comparing SCS to PMR was GBP5,520 (95% CI GBP1,966 to GBP8,613; p < 0.01) and the ICER of using SCS was GBP46,000 per QALY.
Outcomes after SCS did not differ appreciably from those after PMR, with the former procedure being less cost-effective as currently applied. Larger studies could clarify which patients would most benefit from SCS, potentially increasing cost-effectiveness.
Current Controlled Trials ISRCTN09648950
There are estimated to be 30,000–50,000 new patients with refractory angina pectoris per year in Europe, who are unsuitable for conventional revascularisation . Procedures aiming to improve quality of life in affected patients include transmyocardial laser revascularisation (TMR) and percutaneous myocardial laser revascularisation (PMR). TMR uses laser ablation to create transmural channels in ischaemic myocardium via a thoracotomy whilst the less invasive PMR, delivered via catheter, creates channels from the endocardium partially through the myocardium. Previous studies comparing TMR and optimal medical management have shown improved relief of angina offset by perioperative mortality and morbidity [2, 3]. One UK trial-based analysis concluded that the technology, with an incremental cost per quality-adjusted life year gained (QALY) over 12 months of over £200,000, was not cost-effective in comparison to optimal medical management . Published clinical evidence suggests that PMR is an attractive alternative to TMR due to significantly lower procedural mortality and morbidity [5, 6]. One UK trial-based analysis of PMR versus medical management produced an estimate over 12 months of over £50,000 per QALY , again above currently accepted UK thresholds.
Spinal cord stimulation (SCS) has been used for many years in the treatment of chronic pain and, since 1995, for the treatment of refractory angina pectoris. SCS is a surgically implanted device that produces a low voltage electrical impulse near the dorsal surface of the spinal cord, which blocks pain stimuli, leaving the patient with paraesthesia instead. Observational and randomized studies of SCS have found a reduction in angina frequency and an improvement in quality of life whilst not preventing nor concealing the symptoms of myocardial infarction [8–13]. Retrospective data from small, uncontrolled studies and one prospective study in patients with severe angina have shown that the higher costs of initial SCS treatment may be offset by fewer subsequent hospital admissions [13–18]. This study aims to assess the cost-effectiveness of SCS relative to PMR up to 24 months post-procedure using prospectively collected data from a randomised controlled trial in a UK setting.
Full details of the randomised trial, including detailed description of the two procedures, baseline characteristics, and outcome measures are reported elsewhere . Between December 2000 and December 2003, 68 patients in a tertiary referral centre for cardiovascular disease were randomised to either SCS with optimal medical therapy (n = 34) or PMR with optimal medical therapy (n = 34). Patients were followed up to endpoints at 3, 12 and 24 months. This report focuses on the 24 month results. Approval was obtained from the local research Ethics Committee prior to study commencement and informed consent was obtained.
The primary objective of the study was to compare the effect of SCS versus PMR on exercise treadmill time using a modified Bruce Protocol at 24 months post-treatment. Secondary measures of effectiveness included angina (as measured by the Canadian Cardiovascular Society classification), morbidity/mortality and quality of life, measured by the disease-specific Seattle Angina Questionnaire (SAQ) and the generic Short Form-36 (SF-36) and EuroQoL questionnaires. The SAQ measures functional status of patients with angina. SF-36 and EuroQoL are more general measures of health status. The SF-36 scores patients based on 8 broad health outcomes and allows for calculation of summary physical and mental health scores. EuroQoL scores mobility, self-care, usual activities, pain/discomfort and anxiety/depression and combines these with self-rated health status, to give a health status score. The EuroQoL is also used to generate a utility measure for use in cost-effectiveness analyses. The economic analysis was designed alongside the clinical study to estimate cost-effectiveness of SCS relative to PMR, up to 24 months.
Analysis was by intention to treat for subjects for whom follow-up data were available. Survival was summarized and compared using Kaplan-Meier methods and the log-rank test. Adverse events were compared using Poisson regression. Total exercise time was summarised using the mean and standard error. Analysis of variance was used to assess the difference in exercise time between the two groups adjusting for baseline time. Similar models were used to assess the difference in health-related quality of life scales. Since not all patients experienced angina on the treadmill, the mean time to angina was estimated from the area under a Kaplan-Meier curve, with angina-free patients censored at the total exercise time. The change in angina-free exercise time was calculated from the estimated means and standard errors, accounting for the correlation between baseline and follow up estimated from those patients who were not censored. The comparison between groups in angina-free exercise time used Student t-tests based on these Kaplan-Meier summaries. CCS class was compared between groups using the Mantel-Haenszel test for ordered categorical variables. Fisher's exact test was used to assess differences in the proportion of patients having a decrease of 2 or more CCS classes (considered clinically significant), medication usage and proportion of patients free from angina during exercise. Differences were considered significant if p < 0.05.
An NHS perspective was adopted. Resources included were those associated with the procedures, cardiac-related medication, and cardiac or non-cardiac-related inpatient or outpatient admissions, up to 24 months after procedure. Resources consumed solely as a result of the research element of the trial protocol were excluded. All resources were valued at 2005/06 costs.
SCS and PMR procedures
Main resource use and cost categories
Cardiac Ward Bed day
Papworth NHS Trust
SCS Equipment – Electrode/IPG
Papworth NHS Trust
PMR Equipment – (Laser/Catheter)
Papworth NHS Trust
SCS Procedure (HRG: A08)
Papworth NHS Trust
SCS Procedure (HRG: R11)
Papworth NHS Trust
PMR Procedure – Catheter Lab
Papworth NHS Trust
Pathology/Radiology Tests (Both procedures)
Papworth NHS Trust
Cardiac-related medication (cost per month):
Calcium Antagonists -Atenolol (50 mg)
Long-Acting nitrates – Imdur (60 mg)
Short-Acting nitrates – GTN spray (1200 mcg)
ACE Inhibitors – Lisinopril (10 mg)
Diuretics – Frusemide (40 mg)
Statins – Simvastatin (20 mg)
Use of major cardiac-related medication were recorded for all patients. Since information on dosage was not available, an average dosage based on clinical opinion was applied and a monthly cost was calculated (see Table 1). If a patient stopped taking a drug between follow up visits, it was assumed that cessation occurred at the mid-point between the visits. Costing to 24-months was carried out using the British National Formulary .
Inpatient and outpatient episodes
Length of stay and diagnosis were recorded for all inpatient episodes. For cardiac-related inpatient episodes, the mean national cost of the relevant HRG finished consultant episode was applied, adjusted for actual length of stay . Papworth hospital costs of overnight admissions for cardiac-related investigations were adjusted to a national level by the National Reference Cost Index. Cardiac-related inpatient episodes for crossover patients (two SCS and four PMR) during the 12 – 24 month follow-up period were included. The mean national cost of the relevant HRG finished consultant episode was applied for non-cardiac-related inpatient episodes.
Patient Utility and QALYs
At baseline, and 3, 12 and 24 months post-procedure, patients completed the EuroQol questionnaire. Each patient's self-reported classification was valued according to the tariff of UK population values by Dolan et al. . Assuming a linear change in values between time points, patient specific utilities up to 24 months from randomisation were calculated. For missing EQ-5D data, values were interpolated between adjacent visits. Where 24-month data were missing, the value from the last visit was carried forward. A utility value of zero was applied to patients who died.
The QALYs to 24 months from randomisation were calculated as the area under the utility curve to 24 months or time of death. General linear modelling was used to adjust follow-up utility values for baseline. To estimate confidence intervals, without assuming any parametric form for cost and QALY distributions, bootstrapping was used (1000 samples) . Costs and utilities incurred between 12 and 24 months were discounted at an annual rate of 3.5% based on the latest NICE guidance . As a small number of patients in both treatment groups were censored prior to 24-month follow-up, published methods to deal with censored data were applied to the cost and QALY estimates . The Incremental Cost-Effectiveness Ratio (ICER) was calculated as the difference in mean cost divided by the difference in mean QALY. Uncertainty due to parameter estimation was demonstrated by calculation of the cost-effectiveness acceptability curve. This curve plots the probability that SCS is cost-effective, compared with PMR, against the maximum societal willingness to pay for 1 QALY gain.
Recruitment and follow-up
There were eight deaths to the end of September 2005, five in the SCS group and three in the PMR group (one patient had previously withdrawn). Causes of death (days post procedure) were ischaemic heart disease (18), metastatic squamous cell carcinoma (442), presumed malignancy (630) and two acute MI (589 and 660) in the SCS group and stomach carcinoma (430), ischaemic heart disease/MI (490) and unknown (683) in the PMR group. Survival was 85% at 24 months in the SCS group and 94% at 24 months in the PMR group (p = 0.46).
Adverse events *
Months 0–12 post-
Months 13–24 post-
Loss of pain relief/angina worse
Total disease related
SCS related: Infection of SCS system
Undesirable change in stimulation
Pain at neurostimulator site
PMR related: Femoral pseudoaneurysm
Total excluding SCS/PMR related
Exercise Tolerance Tests and CCS class
Comparisons between SCS and PMR in mean exercise tolerance and CCS at 24 months
for baseline 95%CI
Exercise test at 24 months
(n = 22)
(n = 21)
Mean (SEM) exercise time
0.05 (-2.08, 2.18)
Mean* (SEM) time to angina
0.91 (-2.67, 4.49)
No angina during exercise
CCS class at 24 months
(n = 22)
(n = 21)
Change in CCS >= 2 classes
At 24 months there was no significant difference between the treatment groups in CCS class. A greater number of SCS patients had a decrease of two or more CCS classes, although this result was not statistically significant.
Health-related quality of life
As at baseline, all patients were being treated with maximally tolerated anti-anginal medication at 24 months. Among the patients who completed the exercise test, there were no significant differences between SCS and PMR groups in use of Beta Blockers (91% vs. 81%), Calcium Antagonists (68% vs. 71%), ACE Inhibitors (46% vs. 57%), long acting Nitrates (77% vs. 91%) short acting Nitrates (100% vs. 86%) Aspirin (77% vs. 86%) or Nicorandil (77% vs. 91%) (all p ≥ 0.11).
Resource use and costs
Mean costs and QALYs to 24 months post-randomisation
SCS (n = 34)
Mean cost per patient (95% CI)
PMR (n = 34)
Mean cost per patient (95% CI)
Mean cost difference
£4,353 (£4,046 to £4,397)
£326 (£307 to £353)
£756 (£685 to £872)
£812 (£695 to £988)
Total SCS/PMR procedure cost
£13,350 (£13,112 to £13,491)
£6,892 (£6,757 to £7,087)
£6,459 (£6,196 to £6,642) †
£957 (£839 to £1,088)
£1,025 (£891 to £1,147)
£3,294 (£2,076 to £5,844)
£3,645 (£1,638 to £7,537)
Cardiac inpatient episodes
£97 (£22 to £281)
£146 (£18 to £492)
Non-cardiac inpatient episodes
£4,350 (£3,064 to £6,873)
£4,811 (£2,750 to £8,633)
Total non-procedural costs
-£461 (-£4,399 to £1,964) ‡
Overall treatment costs at 24 months**
£17,736 (£16,398 to £19,202)
£12,215 (£9,603 to £15,448)
£5,520 (£1,966 to £8,613)†
SCS (n = 34)
PMR (n = 34)
Mean QALY per patient (95% CI)
Mean QALY per patient (95% CI)
QALYs up to 24 months**
1.19 (1.040 to 1.319)
1.07 (0.960 to 1.178)
0.12 (-0.04 to 0.30)‡
Initial Procedure Costs
The mean cost per patient of the PMR (laser equipment and catheter) and SCS (implantable pulse generator, electrode) equipment was £5,755 and £8,239 respectively. Other resources used during the procedure (staff time, overheads, catheter lab, theatre time etc) were much greater for SCS (£4,353 versus £326), mainly because it was a longer procedure (two to three hours on average) which takes place in theatre (based on British Pain Society recommendations for best clinical practice ) whilst the shorter PMR procedure (90 minutes) takes place in the catheter lab. Length of hospital inpatient stay (and therefore cost of stay) was similar: mean 2.9 days for PMR and 2.7 days for SCS. The mean total procedure cost was £6,892 (95% CI £6,757 to £7,087) for PMR and £13,350 (95% CI £13,112 to £13,491) for SCS.
The costs of cardiac-related medication and cardiac and non-cardiac inpatient episodes, including subsequent SCS/PMR procedures, were similar (Table 4). The mean overall difference between the two groups for non-procedural costs favoured SCS but was not significant at -£461 (95%CI -£4,399 to £1,964).
Overall costs SCS vs. PMR
The difference in overall mean costs to 24 months of £5,520 (95% CI £1,966 to £8,613; p < 0.01) indicates that the additional cost of the SCS procedure was not offset by the small reduction in non-procedure costs over two years.
There were no significant differences in overall utility at 24 months between groups after adjustment for baseline (Table 4). There was a mean QALY difference favouring SCS of 0.12 (95% CI: -0.04 to 0.30; p > 0.1). This difference equates to approximately 6 weeks in perfect health gained from the use of SCS over PMR (95% CI: -2 weeks to 16 weeks).
the effect of lower capital cost of the SCS equipment or more intensive use (i.e. higher patient throughput) by halving SCS equipment costs to £4,120 per case. This resulted in a smaller difference in mean costs (£2,340) and a lower ICER of £19,500 per QALY.
the effect of carrying out SCS in the catheter lab instead of in theatre, reducing total cost of the procedure by approximately £2,500. Similarly, this results in a lower difference in mean cost (£2,262) and a lower ICER of £18,850 per QALY.
combining (i) and (ii) resulted in SCS being cheaper than the PMR strategy (by approximately £1,700) and more effective.
sensitivity of the results to deaths was explored. Omission of these deaths (5 SCS; 2 PMR) results in a slightly higher mean QALY difference in favour of SCS of 0.19 reducing the ICER to approximately £30,000 per QALY.
the SF-36 allows calculation of an alternative utility measure (SF-6D) [28, 29], resulting in mean QALY difference favouring SCS of 0.011 (95% CI: -0.12 to 0.13; p > 0.1), and a much higher incremental cost per QALY of approximately £500,000.
This study compared two treatments for refractory angina and reported the results of follow-up at 24 months. SCS patients had greater time to angina and lower CCS class at 3 months, but these differences were not maintained at 12 months , nor at 24 months, as shown here. It was thought that differences between SCS and PMR groups might increase over time as follow up continued, but the differences between the groups were smaller at 24 months (0.05 minutes in exercise time and 0.91 minutes to angina versus 0.59 and 1.23 at 12 months).
Past studies have shown PMR to be a safer and more cost-effective option than TMR. It was thought that the increased costs of SCS might be offset by decreased morbidity and hospital admission costs compared to PMR. Patients did have non-significant improvements in exercise and quality of life outcomes with SCS over PMR, but these were small and not statistically significant, and costs were higher for SCS patients. In addition, while SCS is less invasive than TMR, it is more invasive than PMR.
The additional NHS cost of using SCS versus PMR was estimated to be £5,520. When combined with the small health benefits observed, the mean incremental cost per QALY was £46,000. Since this is based on early experience within a specialist tertiary centre, results may well improve with greater experience over time. Exploring the cost-effectiveness of SCS versus PMR in the first and second half of the study suggested there was an improvement over time, which could be indicative of a learning curve effect. For patients recruited during 2000/01, the ICER was estimated at £230,000 per QALY (95% CI: -£2,670,000 to £590,000) whereas for 2002/03, the ICER was estimated at £18,000 per QALY (95% CI: -£21,000 to £51,000). This improvement can largely be explained by better outcomes, in terms of survival and QoL, experienced by SCS patients in the second half of the study. Outcomes may not, however, be as good in a non-specialist centre.
A limitation is that the small sample size in this study resulted in low precision, in particular in the case of the QALY estimates, which showed no significant difference between the two groups. Given that we did not observe a difference, there is no a priori reason to assume that the relative cost-effectiveness of the two procedures would change if observed over a longer period.
Even if the (most optimistic) ICER estimate of £30,000 per QALY is the most appropriate, the issue of how SCS fits in to the overall picture in terms of cost-effectiveness of interventions for treatment of refractory angina is not clear. In this study, SCS was compared to PMR as the next best treatment to estimate cost-effectiveness. In a previous cost-effectiveness analysis, PMR was compared against optimal medical management producing an ICER over 12 months of over £50,000 per QALY , a figure well above the current maximum thresholds in the UK. Here, SCS was compared to PMR rather than optimal medical management thus raising the question of whether SCS was compared with the next best alternative treatment, at least from the cost-effectiveness perspective. Given that neither TMR nor PMR were cost-effective over 12 months in comparison with optimal medical management, one might presume that SCS is unlikely to prove cost-effective against medical management. This should be confirmed by comparing SCS with medical management either directly within a randomised controlled trial, or indirectly via economic modelling. In addition, we saw lower clinical effectiveness here than has been seen in other studies, however, this is likely due to over-estimation of the effectiveness of treatments in observational studies due to selection bias.
The results suggest that there is little difference between SCS and PMR with respect to clinical and patient outcomes. Larger studies of SCS are needed to determine which patients benefit most from SCS; targeting the treatment to these patients could make SCS more cost-effective.
The authors would like to acknowledge the patients who participated in this study and the Departments of Cardiology, Cardiac Technology, Radiology and Research and Development, Papworth Hospital. This study was funded by Medtronic SA. The sponsor had no role in study design, data collection and interpretation, or in the decision to submit the manuscript for publication.
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