Spinal Cord Stimulation for the Management of Refractory Angina Pectoris

Transcription

1 S36 Journal of Pain and Symptom Management Vol. 31 No. 4S April 2006 Special Article Spinal Cord Stimulation for the Management of Refractory Angina Pectoris Eric Buchser, MD, DEAA, Anne Durrer, CRNA, and Eric Albrecht, MD Anesthesia and Pain Management Services (E.B., A.D., E.A.), Center for Neuromodulation EHC, Hospital of Morges, Morges; and Anesthesia Department (E.B.), University Hospital, CHUV, Lausanne, Switzerland Abstract Despite sophisticated medical and surgical procedures, including percutaneous endovascular methods, a large number of patients suffer from chronic refractory angina pectoris. Improvement of pain relief in this category of patients requires the use of adjuvant therapies, of which spinal cord stimulation (SCS) seems to be the most promising. Controlled studies suggest that in patients with chronic refractory angina, SCS provides symptomatic relief that is equivalent to that provided by surgical or endovascular reperfusion procedures, but with a lower rate of complications and rehospitalization. Similarly, SCS proved cost effective compared to medical as well as surgical or endovascular approaches in a comparable group of patients. This technique is still met with reluctance by the medical community. Reasons for this disinclination may be related to incomplete understanding of the mechanism of action of SCS and the fact that SCS refers to the modulation of neuroendocrine parameters rather than to revascularization, which is currently the dominant treatment paradigm in coronary artery disease. J Pain Symptom Manage 2006;31:S36--S42. Ó 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Refractory angina, spinal cord stimulation, chronic pain Introduction Coronary artery disease (CAD) is still the major cause of death in the Western countries, although pharmacological and surgical strategies have significantly improved the quality of Dr. Eric Buchser is a consultant for Medtronic Europe Sàrl. Address reprint requests to: Eric Buchser, MD, DEAA, Ensemble Hospitalier de la Côte -- Hôpital de Morges, Anesthesia and Pain Management, Center for Neuromodulation, 1110 Morges, Switzerland. eric.buchser@hospvd.ch. Accepted for publication: November 15, Ó 2006 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. life and the life expectancy of CAD sufferers. However, as more patients survive primary and subsequent coronary events, the prevalence of chronic refractory angina is expected to increase. It has been estimated that 2.4 million patients suffer from refractory ischemia in the United States, 1 and this number is increasing by at least 100,000 every year. 2 The term refractory angina pectoris is used to describe patients with severe chest pain due to CAD that is not relieved by conventional treatment, i.e., pharmacological, surgical, or both. The European Society of Cardiology has acknowledged the importance of this particular condition by creating an ad hoc study group that has recently redefined this disorder as /06/$--see front matter doi: /j.jpainsymman

2 Vol. 31 No. 4S April 2006 SCS for the Management of Refractory Angina Pectoris S37 a chronic condition characterized by the presence of angina, caused by coronary insufficiency in the presence of coronary artery disease, which cannot be adequately controlled by a combination of medical therapy, angioplasty, and coronary artery surgery. The presence of reversible myocardial ischemia should be clinically established to be the cause of symptoms. 3 Treatment options that are available for this group of patients have recently been reviewed, 4 and spinal cord stimulation (SCS) appears to be the most promising. Ischemic Heart Disease The heart may only tolerate an oxygen debt within narrow limits, and coronary atherosclerosis, spasm, or a combination of both can produce an imbalance between the requirements and the delivery of oxygen that usually results in angina pectoris. The mechanism of the pain due to cardiac ischemia is not fully understood. It has long been acknowledged that episodes of clear myocardial ischemia can occur without symptoms (silent ischemia) and may be provoked by the same triggers as in symptomatic angina. 5 On the other hand, there are patients who suffer from angina pectoris but have normal coronary arteries. This condition has been labeled Syndrome X and is thought to be due to endothelial dysfunction involving abnormal distribution and function of adenosine receptors as well as estrogen deficiency. 6 The principle behind any conventional treatment of CAD is the restoration of the best possible balance between the cardiac oxygen demand and the actual oxygen delivery to the myocardium. Local ischemia can be reduced through modalities that are pharmacological, interventional, or both. SCS in Refractory Angina SCS has been used since the late 1960s to treat neurogenic pain, 7 and since 1976 a number of reports have been published on the efficacy of SCS in the treatment of ischemic pain in patients with peripheral artery disease. The clinical application of SCS to treat chronic refractory angina was first published by a group from Western Australia, 8 who reported a decrease in both anginal attacks and nitrate consumption. These favorable results were met with great skepticism that proved to be extremely tenacious, despite a large number of subsequent clinical trials and fundamental research that advocated neuromodulation as an effective treatment modality for patients with disabling chronic refractory angina pectoris Several reasons may explain the reluctance of the medical community to accept a role for SCS in this condition. These include a mechanism of action that is still only partially understood and the development of minimally invasive transluminal procedures that suited both the established paradigm of flow restoration and the skills of interventional cardiologists. The most common objection to neuromodulation treatments in angina pectoris is related to the fear that SCS would only treat pain without affecting myocardial ischemia, and, therefore, would mask a useful warning signal. Current data show convincingly that this is not the case. Mechanism of Action of SCS The mechanism of action of SCS is still unclear, and the discussion of the current hypothesis is beyond the scope of this paper (see Meyerson and Linderoth 16 for a recent review). Only the basic aspects will be mentioned here. The understanding of the effect of SCS is based on the Gate Control Theory, 17 according to which fast conducting A fibers modulate (or even block) the slower conducting C fibers that convey pain at the level of the dorsal horn of the spinal cord. The anti-ischemic effect of SCS is attributed, at least in part, to the modulation of the autonomic (sympathetic) nervous system. While the heart rate variability and norepinephrine metabolism remain unchanged during SCS, 18 the integrity of the sympathetic nervous supply to the heart is a prerequisite for SCS to be effective. 19 The increased sympathetic tone and noradrenaline spillover into the coronary sinus that may result from myocardial ischemia and/or pain can persist for a prolonged period of time, 20,21 despite adequate beta blocker therapy. 22 This may exacerbate the myocardial oxygen imbalance and result in

3 S38 Buchser et al. Vol. 31 No. 4S April 2006 a vicious cycle producing more ischemia and myocardial injury. 20,23 It has been shown that SCS significantly decreases both this reflex pathway and the noradrenaline spillover. 24 In addition, SCS has a significant impact on the neural modulation of myocardial function and blood flow. 25 The alleviation of pain related to stress is a key issue in the treatment of angina. 26 Theoretically, SCS can decrease myocardial ischemia by one (or a combination) of the following ways: increase of coronary blood flow, decrease of oxygen demand, and direct pain inhibition with a reduction of myocardial oxygen consumption as a secondary phenomenon. Although the mechanism of action of SCS is not fully elucidated, it appears that neuromodulation raises the anginal threshold, possibly through a redistribution of the coronary blood flow. Whether this redistribution is related to the recruitment of collaterals, 27 angiogenesis, 28 preconditioning, 29 or a combination of any of these is yet unknown. Effects of SCS Many publications from different centers indicate that the antianginal effect of SCS is paralleled by a reduction in myocardial ischemia. The anti-ischemic effect has been demonstrated using various tools including ECG during exercise stress testing 13, and ambulatory ECG monitoring. 9,13,15,32,33 Both open and randomized studies have shown that the reduction in anginal pain during SCS enables the patient to prolong the exercise without increasing myocardial ischemia. In addition, anginal pain was delayed and myocardial oxygen consumption was decreased by SCS at comparable heart rate induced by atrial pacing. 34 However, regardless of the efficacy of SCS, all patients eventually experience angina when the workload of the heart is increased to higher levels. The quality and distribution of the pain is similar to the original symptoms. The concern regarding the SCS-related deprivation of a warning signal of myocardial ischemia is clearly not rational. Although systematic studies are lacking, there is credible evidence that SCS does not influence heart rate variability, 14,35 and that it does not have an arrhythmogenic effect. 11 While it may be argued that patients with chronic refractory angina are at lower risk of malignant cardiac arrhythmias, the decrease of myocardial ischemia provided by SCS may potentially decrease the risk of rhythm disturbances. At the cardiac level, SCS is thought to stabilize the function of intracardiac neurons during ischemia 36 and may, therefore, have a beneficial effect on the occurrence of life-threatening arrhythmias, either autonomically induced or resulting from reperfusion. Proper use of SCS implies that the epidural electrode is inserted at a level (and stimulated in a way) that paresthesias are elicited over the area of anginal pain. Although this prevents adequate blinding of the therapy, several randomized controlled trials have convincingly established the clinical efficacy of SCS in chronic refractory angina pectoris. 15,32,37 Implantation Procedure The electrode implantation procedure for the treatment of refractory angina is similar to the method used for other SCS indications. Percutaneous puncture (usually between Th 4 and Th 8 ) and fluoroscopic guidance should be performed under local anesthesia to elicit the paresthesia in the appropriate area. The proper positioning of the electrode is essential to the success of SCS, and this procedure is the only way to verify that the segment of spinal cord that innervates the heart is being stimulated. In most cases, paresthesias that cover the area of anginal pain are obtained when the tip of the electrode is placed in the posterior epidural space at the level of Th 1 or Th 2, slightly left to the spinal midline. One of the most common causes of SCS failure is related to the incorrect positioning of the electrode. Comparison Between SCS and CABG Compared to coronary artery bypass grafting (CABG), SCS provided similar benefits in terms of pain control and quality of life improvement in patients with an increased risk of surgical complications and in whom the indication for CABG was based on symptoms rather than the prolongation of survival. 12 CABG significantly improved exercise capacity and decreased ST-segment depression, whereas

4 Vol. 31 No. 4S April 2006 SCS for the Management of Refractory Angina Pectoris S39 SCS did not affect these variables. However, SCS was discontinued 24 hours before the exercise tests, which was not the case in the previous studies that unequivocally demonstrated a reproducible anti-ischemic effect, 13,33,34 indicating that SCS does not produce a longterm effect on myocardial ischemia. The mortality and the cerebrovascular morbidity were significantly higher in the CABG group, but there was no difference in the cardiac morbidity or in the long-term survival. 38,39 There is conceivably a significant placebo effect in the efficacy of SCS. However, the placebo effect is thought to decrease with time and is assumed to be negligible after a few months. In contrast, the effect of SCS lasts for years, suggesting that other mechanisms are involved. This is also supported by the fact that battery failure resulted in the recurrence of anginal attacks and self-reported impaired physical activity, albeit without rebound effect in myocardial ischemia. 15 Complications The complication rate of SCS for angina is very low. The combined rate of minor complication is 6.8%. 39,40 Minor complications include lead migration, most of which occur during the first year, 41 electrode fracture, early battery exhaustion as well as infection, usually of the pulse generator pocket, which does not necessarily require the explantation of the system. Although theoretically possible, permanent neurological damage was not described in conjunction with the implantation of an SCS electrode. The published rate of perioperative complication is 0% because no procedure-related myocardial infarction, stroke, death, paralysis, or sepsis was reported when SCS was used for the treatment of refractory angina. Device-related complications may occur more frequently with other indications for SCS, 42 presumably because of different electrode locations, previous spinal surgery, and more active patients. Lead migration is most frequently encountered and results in the loss of proper paresthesia coverage. In about two-thirds of the cases, reprogramming of the generator solves the problem. However, revision of the electrode is required when reprogramming fails or when the electrode breaks (2%). Cost Effectiveness of SCS The clinical outcome of patients with refractory angina is poor. Despite optimal medical treatment, these patients suffer a high annual rate of myocardial infarction (25.5%), rehospitalization (1.3 per patient per year), and mortality (16.9%). 43 Looking at the economic consequences of SCS (cost utility) in a group of patients suffering from refractory angina, a Danish study 44 showed that invasive tests were reduced, resulting in a 30% annual saving in medical costs in SCS-treated patients. Overall, this translated into a yearly saving of US$8,430. Merry et al. 45 calculated that the cost of implanting an SCS system can be recovered in 15 months, a result that is consistent with those of the other groups. 46 This compares favorably to the high cumulative costs of either bypass surgery 47 or percutaneous coronary stenting, which are greater than US$50,000 at 5 years. 48 The need for rehospitalization (per patient per year) after SCS compared to revascularization was decreased (P ¼ 0.002), 49 and the duration of the hospital stay was significantly shorter. When compared to CABG, SCS is significantly (P < 0.001) less expensive. 50 Conclusion In conclusion, the current treatment of CAD is essentially focused on the restoration of the aerobic balance, by providing reperfusion (CABG or percutaneous transluminal coronary angioplasty, PTCA), decreasing oxygen demand, or both. The approach is, therefore, concentrated on hemodynamic issues. Neuroendocrine mechanisms are, by and large, considered secondary. Yet, the data regarding efficacy and cost effectiveness of SCS compare very favorably to those regarding medical therapy, 44 bypass surgery, 47 or percutaneous coronary stenting. 48 Similarly, SCS is associated with a lower morbidity and mortality than either standard medical treatment 43 or revascularization procedures. 51,52 Compared to CABG there was no difference with regard to symptom relief, but the mortality and cerebrovascular morbidity were lower in the SCS group. 12 However, the therapy is still met with reluctance and disinclination by cardiologists and

5 S40 Buchser et al. Vol. 31 No. 4S April 2006 general practitioners. This eventually results in the underprescribing of a potentially cheaper alternative and increases the burden on already overstretched institutions that end up managing these patients with iterative invasive modalities, potentially at a higher cost and complication rate but similar symptomatic relief and comparable survival rates. References 1. Holmes DR Jr. Treatment options for angina pectoris and the future role of enhanced external counterpulsation. Clin Cardiol 2002;25: Mukherjee D, Bhatt DL, Roe MT, Patel V, Ellis SG. Direct myocardial revascularization and angiogenesisdhow many patients might be eligible? Am J Cardiol 1999;84: A8. 3. Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina. Report from the ESC Joint Study Group on the treatment of refractory angina. Eur Heart J 2002;23: Svorkdal N. Pro: anesthesiologists role in treating refractory angina: spinal cord stimulators, thoracic epidurals, therapeutic angiogenesis, and other emerging options. J Cardiothorac Vasc Anesth 2003;17: Deanfield JE, Shea M, Kensett M, et al. Silent myocardial ischaemia due to mental stress. Lancet 1984;2: Panza JA. Myocardial ischemia and the pains of the heart. N Engl J Med 2002;346: Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg 1967;46: Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 1987;28: Eliasson T, Jern S, Augustinsson LE, Mannheimer C. Safety aspects of spinal cord stimulation in severe angina pectoris. Coron Artery Dis 1994;5: Augustinsson LE, Eliasson T, Mannheimer C. Spinal cord stimulation in severe angina pectoris. Stereotact Funct Neurosurg 1995;65: Eliasson T, Augustinsson LE, Mannheimer C. Spinal cord stimulation in severe angina pectorisdpresentation of current studies, indications and clinical experience. Pain 1996;65: Mannheimer C, Eliasson T, Augustinsson LE, et al. Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 1998;97: de Jongste MJ, Haaksma J, Hautvast RW, et al. Effects of spinal cord stimulation on myocardial ischaemia during daily life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study [see comments]. Br Heart J 1994;71: Hautvast RW, Brouwer J, DeJongste MJ, Lie KI. Effect of spinal cord stimulation on heart rate variability and myocardial ischemia in patients with chronic intractable angina pectorisda prospective ambulatory electrocardiographic study. Clin Cardiol 1998;21: Jessurun GA, DeJongste MJ, Hautvast RW, et al. Clinical follow-up after cessation of chronic electrical neuromodulation in patients with severe coronary artery disease: a prospective randomized controlled study on putative involvement of sympathetic activity. Pacing Clin Electrophysiol 1999;22: Meyerson B, Linderoth B. Spinal cord stimulation: mechanisms of action in neuropathic and ischaemic pain. In: Simpson BA, ed. Electrical stimulation and the relief of pain. Amsterdam: Elsevier Science B.V., 2003: Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150: de Jongste MJL, Nagelkerke D, Hooyschuur CM, et al. Stimulation characteristics, complications, and efficacy of spinal cord stimulation systems in patients with refractory angina: a prospective feasibility study. Pacing Clin Electrophysiol 1994;17: Armour JA, Linderoth B, Arora RC, et al. Long-- term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischaemic hearts. Auton Neurosci 2002;95: Heusch G, Deussen A, Thamer V. Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 1985;13: Neri Serneri GG, Boddi M, Arata L, et al. Silent ischemia in unstable angina is related to an altered cardiac norepinephrine handling. Circulation 1993; 87: McCance AJ, Thompson PA, Forfar JC. Increased cardiac sympathetic nervous activity in patients with unstable coronary heart disease. Eur Heart J 1993;14: Chierchia S, Muiesan L, Davies A, et al. Role of the sympathetic nervous system in the pathogenesis of chronic stable angina. Implications for the mechanism of action of beta-blockers. Circulation 1990; 82: Norrsell H, Eliasson T, Mannheimer C, et al. Effects of pacing-induced myocardial stress and spinal cord stimulation on whole body and cardiac norepinephrine spillover. Eur Heart J 1997;18: Kingma JG Jr, Armour JA, Rouleau JR. Chemical modulation of in situ intrinsic cardiac neurones

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