Ann Thorac Surg 2006;82:1704-1708
© 2006 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Spinal Cord Stimulation for Patients With Refractory Angina and Previous Coronary Surgery
Elisabetta Lapenna, MDa,*,
Dino Rapati, MDb,
Paola Cardano, MSc,
Michele De Bonis, MDa,
Francesca Lullo, MDb,
Alberto Zangrillo, MDb,
Ottavio Alfieri, MDa
a Department of Cardiac Surgery, San Raffaele University Hospital, Milan
b Department of Anaesthesiology, San Raffaele University Hospital, Milan
c Clinical Group, Medtronic, Italy
Accepted for publication May 18, 2006.
* Address correspondence to Dr Lapenna, Divisione di Cardiochirurgia, IRCCS Ospedale Universitario San Raffaele, Via Olgettina, 60, 20132 Milano, Italy (Email: lapenna.elisabetta{at}hsr.it).
| Drs Lapenna, Rapati, and De Bonis and Ms Cardano disclose that they have a financial relationship with Medtronic.
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Abstract
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BACKGROUND: Refractory angina pectoris is an exceptionally debilitating condition affecting patients who have typically failed multiple percutaneous and surgical revascularizations and optimal medical therapy and who are not amenable for further revascularization procedures. Spinal cord stimulation (SCS) has been adopted in this context at our institution and midterm mortality, anginal status, and quality of life have been evaluated.
METHODS: From 1998 to 2004, 51 patients with refractory class III-IV angina, who were not considered candidates for revascularization procedures, underwent SCS. All patients had already undergone previous surgical revascularization and a median of two percutaneous procedures. Transmyocardial laser revascularization had been previously performed in 8 cases (15.6%). Most of the patients (70.5%) had experienced a myocardial infarction. Mean ejection fraction was 0.42 ± 0.121, Canadian Cardiovascular Society class 3.5 ± 0.5, quality of life (Spitzer index) 4.5 ± 1.2, and the median frequency of weekly angina episodes was 10.
RESULTS: There were no SCS implantation-related complications. At follow-up (100% complete, mean 24 ± 18 months), a significant improvement of anginal symptoms (>50% reduction of weekly anginal episodes) occurred in 45 patients (88.2%). In those patients (Responders), the quality of life improved significantly (6.8 ± 1.5; p < 0.0001), CCS class decreased to 2 ± 0.7 (p < 0.0001), and the median frequency of weekly angina episodes to 3 (p < 0.0001). At 3 years, Responders' survival was 91.8 ± 4.6% and the freedom from cardiac events 72.6 ± 8.42%.
CONCLUSIONS: Spinal cord stimulation is a safe and effective procedure in truly no-option patients affected by refractory angina. A midterm sustained improvement of symptoms and quality of life have been documented with a satisfactory 3-year survival rate.
Percutaneous coronary revascularization (PTCA), coronary artery bypass graft surgery (CABG), and medical management are very effective in treating the majority of patients affected by angina pectoris. However, a growing number of patients develop a pattern of diffuse and severe coronary artery disease which is both refractory to maximal medical therapy and not amenable to further PTCA or CABG procedures. The epidemiology of refractory angina pectoris is not clearly defined, but estimation depicts that more than 100,000 patients may be diagnosed each year in the United States [1] and about 50,000 in Europe [2]. Spinal cord stimulation (SCS) has been claimed as a valuable therapeutic option for this difficult population of patients who suffer disabling severe angina. The aim of this study is to assess the midterm benefits of SCS in no-option patients affected by refractory angina after previous CABG.
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Material and Methods
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Patients
Between February 1998 and December 2004, 60 consecutive patients affected by medically refractory Canadian Cardiovascular Society (CCS) class III and IV angina pectoris underwent SCS implantation at San Raffaele University Hospital. For the purpose of this study, only those who had already received at least one previous CABG operation were selected. Therefore, 51 patients represent the final study population. Nine patients, who had not undergone previous coronary surgery, were excluded for a number of reasons. Some of them had angiographically normal coronary arteries despite severe angina, refractory to medical therapy (X Syndrome). The others, after several unsuccessful PTCA and stenting, were considered ineligible for coronary surgery because of severe comorbidities such as respiratory insufficiency, dialysis, extreme obesity, major cerebrovascular disease, end-stage metastatic cancer, or severely calcified aorta (often concomitantly present). Those patients, indeed, had a coronary anatomy still suitable for surgery but were not operated on because of their extremely high surgical risk. Therefore, they represented a specific subgroup rather different from the study population.
All 51 patients enrolled in the study were on maximally tolerated medications and had a median of 2 PTCA (range 0 to 13). In 8 cases (15.6%) transmyocardial laser revascularization had also been performed. The presence of reversible myocardial ischemia, as the cause of the symptoms, was assessed in all patients by using an exercise treadmill test or stress imaging studies. All patients underwent a coronary angiography, which was reviewed by two cardiac surgeons and two interventional cardiologists not involved in the study. The SCS therapy was decided because all 51 cases were considered not suitable for further revascularization procedures due to very poor peripheral coronary artery anatomy. Baseline demographic and clinical data are listed in Table 1. Before SCS implantation the following clinical parameters were carefully collected: CCS angina class, weekly anginal episodes in the last month, number of sublingual nitroglycerin tablets (or equivalents) taken per week in the last month, hospital admissions because of angina during the previous 6 months. Quality of life (QOL) was assessed using the Spitzer test which consists of five multiple-choice questions which quantify physical limitation, disease perception, and patient mood. A 0 to 10 score was obtained, with higher values indicating a better QOL. All patients underwent a 4-week trial period, during which a temporary external device was utilized. Only patients with at least 50% reduction in the number of weekly anginal episodes (the so-called "Responders") received permanent pulse generator implantation. On the other hand, those who did not show significant clinical benefits during the trial period were considered as "Non-Responders" and were not implanted with the definitive SCS device, remaining on maximal medical therapy.
The Ethics Committee approved this study and waived the need for individual consent for the study. However, all patients signed the Informed Consent for the operation and for the treatment of their data in an anonymous way.
Implantation Procedure
The SCS device implantation was performed in two sessions, one for the lead insertion and one to implant the permanent pulse generator. In the first one, under local anesthesia and sterile conditions, a lead (Pisces Quad, Medtronic Inc, Minneapolis, MN) was inserted into the epidural space at the level of T6, through a Tuohy needle. The tip of the lead was advanced under X-ray control and positioned usually at the C6- T2 level in order to cover with the paraesthesia the area of the chest referred by the patient as the region of the anginal pain. Correct placement was confirmed by test-stimulation and interviewing the patient. The lead was then fixed to the paravertebral muscles and connected to a temporary, external portable neurostimulator. In the second surgical session, usually one month later, the lead was connected to an extension wire which was tunnelled subcutaneously below the left costal arch and connected to a permanent pulse generator (Itrel 3; Medtronic Inc) placed in a subcutaneous pocket in the lateral abdominal region. The neurostimulator was set to give, constantly, a continuous paresthesic stimulation at the minimal level perceived by the patient. Before discharge, an external programmer was given to the patient in order to increase the intensity of stimulation for 5 to 10 minutes in case of acute angina attack.
Follow-up
Follow-up ranged from 2 to 73 months (mean 24 ± 18, median 20) and was 100% complete. All patients were reviewed in our dedicated outpatient clinic, where a complete clinical assessment was performed. Deaths, acute myocardial infarction, PTCA, and transmyocardial laser revascularization procedures were systematically recorded as well as all the clinical parameters collected at baseline. All hospital admissions due to ischemic heart disease were reported and all patients were asked to fill the Spitzer test. Follow-up visits were scheduled at 1, 3, 6, and 12 months, and every 6 months thereafter.
Statistical Analysis
All data were prospectively entered into a dedicated database. Statistical data were expressed as percent or mean ± SD. A probability value of less than 0.05 was considered to be statistically significant. Calculations were performed using SPSS version 11.5 (SPSS Inc, Chicago, IL) for the Windows (Microsoft Corp, Redmond, WA) software package. Survival and freedom from cardiac events were analyzed with Kaplan-Meier actuarial methods. Outcomes were compared using the 
2 analysis for categoric data and the t test for continuous variables. Univariate analysis of risk factors was performed with Cox proportional hazards regression and with logistic regression, as indicated. Spinal cord stimulation was considered effective when there was a 50% or greater reduction in the number of weekly anginal episodes at follow-up, compared with the baseline. Analysis of variance with a repeated measure design was used to assess changes in clinical variables at the three time points considered (preimplant, 6 months, and last follow-up).
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Results
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Out of the 51 patients who received the temporary SCS device, 45 (88.2%) were considered as Responders and underwent permanent pulse generator implantation. The remaining 6 patients did not show significant clinical benefits during the trial period with the temporary external neurostimulator (Non-Responders) and, therefore, were not implanted with the definitive device.
Univariate analysis failed to identify any significant predictor for "being a Non-Responder," among the baseline clinical variables reported in Table 1. There were no deaths and no early complications related to temporary or permanent SCS device implantation.
Survival
The overall actuarial survival at 3 years was 90.6 ± 4.6. Late mortality was 7.8% (4 of 51). Three patients died in the Responders group (3 of 45, 6.6%) (two because of heart failure at 2 and 6 months after SCS implantation and one due to gastric hemorrhage) for a 1- and 3-year survival rate of 95.5 ± 3 % and 91.8 ± 4.6%, respectively (Fig 1). One death occurred at follow-up among the Non-Responders (1 of 6, 16.6%) due to myocardial infarction. The difference in late mortality was not statistically significant between the two groups (p = 0.9). Among the baseline clinical variables, only a better preimplant QOL was associated with a significantly lower late mortality (hazard ratio [HR] 0.3, 95% confidence interval [CI] 0.1 to 0.9; p = 0.03) on Cox proportional regression analysis.
Cardiac Events
Three-year freedom from cardiac events (cardiac deaths, myocardial infarction, PTCA, and transmyocardial laser revascularization) was 70.4 ± 8.2%. In the Responders group, two patients (4.4%) had a nonfatal acute myocardial infarction; respectively, 20 and 39 months after SCS implantation, treated with primary PTCA (the culprit vessel was not critically diseased at the time of SCS implantation). Six more patients underwent PTCA (from 10 to 50 months after SCS implantation) as a result of coronary artery disease progression or restenosis of previously intervened vessels. In particular, in two patients the PTCA was performed on venous grafts which were not significantly diseased at the time of SCS implantation. In another two patients the procedure was performed on the native coronary arteries due to the development of new critical stenoses. Finally, two patients underwent PTCA because of new intrastent restenosis. Therefore, freedom from cardiac events in the Responders group was 94.9 ± 3.5 and 72.6 ± 8.42% at 1 and 3 year follow-up, respectively (Fig 2). In the Non- Responders group, only one patient underwent percutaneous laser revascularization. No significant predictors of cardiac events were identified among the baseline clinical variables included in the model.
Clinical Features
In the 45 patients belonging to the Responders group, a significant improvement of all indicators of anginal status occurred at 6 months after SCS implantation and persisted through a follow-up of 3 years: CCS class decreased from 3.5 ± 0.5 to 2 ± 0.7 (p < 0.0001), the median frequency of weekly angina episodes from 10 to 3 (p < 0.0001), and the weekly short-acting nitrate consumption from 10 to 1 (p < 0.0001) (Table 2). Thirty of the 45 Responders (66%) experienced two or more CCS class improvements. Quality of life, assessed using the Spitzer index, increased from 4.5 ± 1.2 (range, 2 to 7) at baseline to 6.5 ± 1.5 (range, 4 to 10) at 6 months (p < 0.0001) and this result was consistent after 3 years (Table 2). Moreover, there was a significant reduction in the average rate of hospital admissions due to angina during the 6 months after the SCS implantation compared with the same period of time preceding the device implant (3.3 ± 4; median, 2.5; range, 0 to 20, vs 0.1 ± 0.3; median, 0; range, 0 to 1; p < 0.006). In the patients belonging to the Non-Responders group, no significant improvement of the clinical conditions could be demonstrated after temporary SCS implantation.
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Table 2. The CCS Functional Class, Number of Anginal Episodes, and Sublingual Nitrates per Week, at Baseline, at 6 Months, and at the Last Follow-up After SCS Implantation, in the Responders Group
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Complications
No life-threatening complications related to temporary and permanent SCS were observed. Among the 45 patients receiving the definitive device, electrode dislodgment requiring repositioning occurred in 4 cases (8.8%), skin pocket hematoma and infection in 1 (2.2%) and in 2 (4.4%), respectively. The stimulator had to be removed because of infection in one patient.
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Comment
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The main finding of this prospective study is that SCS provides significant and long-lasting improvement of daily-life anginal symptoms and QOL in patients with disabling refractory angina after previous CABG operation and percutaneous procedures. Recurrence of symptoms, several years after bypass surgery, is commonly due to progression of disease in the native coronary arteries and to the development of graft atherosclerosis. Both conditions often lead to successive rounds of revascularization therapies that eventually result in an end-stage coronary anatomy unsuitable for further revascularization (distal stenoses, diffuse coronary artery disease, small coronary arteries). If symptoms still persist despite maximal medical therapy, treatment options are rather limited and the management of these patients becomes challenging [3]. Spinal cord stimulation could represent an alternative option for this growing population of patients who are refractory to conventional antianginal drugs. The American College of Cardiology/American Heart Association has formally recognized the value of this therapy as recommendation of class IIb in the 2002 Consensus Guidelines for the management of refractory chronic stable angina pectoris [4]. The SCS might have a beneficial effect on anginal pain by modulating pain transmission through a selective stimulation of the inhibitory neurons in the posterior horns of the spinal cord [5]. Moreover, it could play a relevant antiischemic role [6, 7] by decreasing myocardial oxygen consumption, reducing the sympathetic tone, changing the beta-endorphin cardiac metabolism, and redistributing the coronary blood flow from nonischemic to ischemic areas [2]. The pain relief provided by spinal cord stimulation seems to last beyond the period of stimulation itself ("carry-over" effect) [8]. This beneficial effect, however, does not increase the risk of silent ischemic events and does not deprive the patient of the warning signal [9]. The symptoms of acute myocardial infarction are not masked [9] and the incidence of ventricular arrhythmias is not increased [10, 11]. Several studies on SCS based on exercise electrocardiogram [ECG], Holter monitoring, and positron emission tomography, have shown, although in small figures, an improvement in the functional status, an increase in the exercise tolerance, and in the time to ECG signs of ischemia, and, finally, an improved perfusion of the ischemic areas [5, 12–14]. Our data, prospectively collected, provide further evidence of the beneficial effects of SCS on anginal symptoms and QOL. The peculiarity of our population, compared with those of previous studies, is represented by the fact that all patients enrolled in our series were truly "no other options" patients. Indeed, all of them had already been submitted to previous surgical revascularization and, in many cases, to repeated percutaneous procedures as well. More than one CABG operation had been performed in 31% of the cases and laser revascularization had been tried in 15% of the patients. Moreover, 68% had a still patent left internal mammary artery to left anterior descending anastomosis with a very small and diseased distal vessel leading to an extremely poor run-off. Eight patients, considered unsuitable for PTCA at enrollment, underwent percutaneous revascularization after SCS implantation. For those specific cases, we would like to emphasize that such PTCA procedures were absolutely not indicated before spinal chord therapy and became necessary at follow-up to treat new intrastent, native coronary arteries or venous graft stenosis which were absent or not critical at the time of SCS implantation. Taking into account the really unhealthy patients included in the study, our clinical results should be considered of outmost importance. The actuarial 1- and 3-year survival in the Responders group was 95% and 91% and the freedom from cardiac events 95% and 72%, respectively. Previous trials, involving similar patients affected by refractory angina treated either with maximal medical therapy alone or with transmyocardial laser revascularization (TMLR), reported a 1-year survival rate ranging from 79% to 89% in the former group and from 84% to 89% in the TMLR one. The annual mortality rate was 13% and 8%, respectively, with a significantly lower 5-year survival in the medical therapy compared with the TMLR group [15–18]. The cardiac event-free survival at 1 year ranged from 11% to 31% in the medically treated group and from 54% to 66% in the TMLR group [15–18].
As far as the anginal status is concerned, clinical follow-up showed that at 3 years about 88% of our population (Responders) enjoyed lasting symptom relief with significant improvement of CCS class, reduced frequency of angina attacks, and lower consumption of short-acting nitroglycerin. Hospital admission rate decreased after SCS implantation and QOL significantly improved. Unfortunately, we were unable to identify distinctive features for the patients who did not respond (Non-Responders) to the SCS therapy. Finally, because a proper balance of procedural risks and benefits remains the most important principle for any therapeutic intervention, it is mandatory to emphasize that SCS implantation represents a minor surgical procedure, with negligible perioperative mortality and morbidity. No major complications occurred in our series and the follow-up rate of lead migration, subcutaneous infections, and hematoma was rather low as well. On the other hand, TMLR carries a perioperative mortality rate of 3% to 5% and a significant risk of in-hospital morbidity (acute myocardial infarction, congestive heart failure, ventricular arrhythmia) [16, 17].
In conclusion, the present results demonstrate a consistent efficacy of SCS, through a mean follow-up of 3 years, whether assessed by CCS class, number of anginal attacks, nitroglycerin consumption, hospitalization rate, or QOL. This therapy is simple and safe and should be considered an effective and valuable treatment for truly no-option patients affected by refractory angina pectoris.
Limitations
This study has several important limitations. Although the data were prospectively collected, the number of patients enrolled is rather small and a control group has not been included. Indeed, we were unable to attain a consistent number of non-SCS patients with comparable degrees of angina because most of them are referred to our unit specifically for device implantation. As far as a placebo control group is concerned, this is almost impossible to obtain due to the need to induce chest paraesthesia to verify the presence of active neurostimulation. Therefore, a placebo effect of treatment cannot be completely ruled out. However, since such an effect is mostly believed to decrease with time, the sustained relief of symptoms over 3 years in our series seems to contradict the placebo effect as the main cause of clinical improvement. Another limitation is the lack of serial quantitative exercise testing to obtain objective demonstration of improvement of the ischemia threshold and exercise capacity after SCS implantation. Finally, the number of patients reported in our experience, although relatively small, remains considerable when compared with other single centers or even multicenter studies reported in the literature.
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References
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Abstract
Introduction
