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Prof. Filippo Crea ,
Prof. Gaetano A. Lanza
Refractory angina pectoris has become an increasingly challenging problem in clinical practice. Several forms of treatment have been tried, but results emerging from clinical studies suggest that spinal cord stimulation and enhanced external counterpulsation present the most favourable risk/cost to benefit profile.
Refractory angina pectoris (RAP) is defined as the occurrence of frequent angina attacks uncontrolled by optimal drug therapy, significantly limiting the patients’ daily activities, and with the presence of coronary artery disease rendering percutaneous coronary intervention or bypass surgery unsuitable (CABG) (1). The prevalence of RAP will probably increase in the next years, due to the progressively longer life expectancy of patients with complex or diffuse coronary artery disease. Several alternative forms of therapy have been proposed for RAP, but only a few of them have given rise to sufficient published data (1).
Transmyocardial laser revascularisation (TMLR) has been investigated in several randomised trials using the epicardial surgical approach or the endocardial percutaneous approach (2). Compared to maximal medical therapy, the studies reported overall improvement of symptoms by TMLR. However, no effect on mortality was observed and the only “sham”-controlled study conducted failed to show any improvement of angina symptoms in patients treated with percutaneous TMLR, compared to the control group (3). An important limitation of TMLR is the rather high risk of perioperative complications, including death (4-5%), myocardial infarction (10%) and lung infections (5-30%) (2).
Angiogenic therapy has been assessed in clinical trials through intracoronary or intramyocardial administration of growth factors or through gene therapy. The few controlled randomised trials however have delivered disappointing results, showing no effects on symptoms or marginal effects on symptoms and myocardial ischemia (4,5). Furthermore, an unresolved issue is the risk of extracardiac complications following the use of angiogenic factors or genic material.
Spinal cord stimulation (SCS) has been used for RAP for about 20 years. Several studies have reported beneficial effects on angina symptoms, quality of life and hospital re-admissions for angina (1). In particular, SCS was found to have similar effects as CABG regarding symptoms and quality of life at the 6-month and the 5-year follow-ups, with long-term survival being 75.5% and 68.6% in SCS and in CABG patients, respectively (p=NS) (6). In the prospective Italian registry, a significant improvement of symptoms was observed at the 13-month follow-up in 73% of 104 patients and was associated with a consistent reduction in the hospital admission rate for recurrent angina (7). No life-threatening complications related to the therapy have been reported with SCS, while local infectious complications or catheter dislodgment requiring re-implant did occur in a minority of patients.
Enhanced external counterpulsation (EECP) in population registries has been shown to improve the CCS angina class of RAP patients in 70-80% of cases (8) and a slight increase of time -to 1 mm ST segment depression on exercise stress tests- was also observed in a randomised “sham”-controlled study (9). EECP has not been associated with life-threatening complications; however, some bothering side effects may occur during treatment, including leg or back pain, skin abrasion or edema, headache, diziness, epistaxis and respiratory discomfort. Furthermore, some co-morbidities, including significantly reduced left ventricular function, uncontrolled hypertension, aortic aneurysm/dissection, significant valvular aortic regurgitation, peripheral venous disease and anticoagulant therapy, are contra-indications to EECP (8).
To conclude, although several forms of therapy have been investigated for RAP, early randomised trials seem to favour SCS or EECP. Indeed, although data should be interpreted with caution because the number of patients studied was limited and true placebo groups lacking, these forms of therapy seem to present the most favourable risk/cost to benefit ratios, thus justifying their use in RAP.
References 1. 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: 355-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11846493
2. Saririan M, Eisenberg MJ. Myocardial laser revascularization for the treatment of end-stage coronary artery disease. J Am Coll Cardiol 2003;41:173-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12535804
3. Stone JW, Teirstein PS, Rubenstein R, et al. A prospective multicenter randomized trial of a percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusion. J Am Coll Cardiol 2002;39:1581-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12020483
4. Henry TD, Annex BH, McKendall GR, The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003;107:1359-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12642354
5. Grines CL, Watkins MW, Helmer G, Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002;105:1291-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11901038
6. Ekre O, Norsell H, Währborg P, Eliasson T, Mannheimer C. Spinal cord stimulation and coronary artery bypass grafting provide equal improvement in quality of life. Data from the ESBY study. Eur Heart J 2002; 23: 1938-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12473256
7. Di Pede F, Lanza GA, Zuin G, et al. Immediate and long-term clinical outcome after spinal cord stimulation for for refractory angina pectoris patients. Am J Cardiol 2003; 91: 951-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12686334
8. Sinvhal RM, Gawda RM, Khan IA. Enhanced external counterpulsation for refractory angina pectoris. Heart 2003;89:830-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12860848
9. Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999;33:1833-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10362181
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