Treatment of refractory angina pectoris

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).

Conclusion:

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.