Heart and Metabolism

New therapeutic approaches: TMR, PMR, and SCS

Duncan C. McNab, Peter M. Schofield
Department of Cardiology, Papworth Hospital NHS Trust, Cambridge, UK

Correspondence: Dr Duncan C. McNab, Cardiac Studies Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridgeshire, UK. Tel: +44 1480 830541, fax: +44 1480 364356, e-mail: duncan.mcnab@papworth-tr.anglox.nhs.uk

Abstract
Many patients with symptomatic coronary artery disease can be effectively treated through a combination of medication and percutaneous or surgical revascularization. Unfortunately, some patients cannot be adequately managed by these conventional strategies and suffer severe angina. Three of the most promising therapies for these patients are transmyocardial laser revascularization (TMR), percutaneous myocardial laser revascularization (PMR), and spinal cord stimulation (SCS). Although the mechanisms of action for each of these modalities remain unclear, their use appears to confer symptomatic benefit to patients with chronic refractory angina. In this article we review and compare the clinical evidence for TMR, PMR, and SCS. n Heart Metabol. 2002;16:19–22.

Key words: Myocardial revascularization, therapies

Introduction
Ischemic heart disease (IHD) remains one of the greatest health burdens in developed countries [1]. Most patients suffering from IHD can be treated adequately through a combination of medication and revascularization strategies including CABG or angioplasty and stent implantation, but a subgroup has coronary artery disease that is not amenable to conventional therapies. Typically these patients either demonstrate diffuse coronary disease unsuitable for revascularization or have undergone previous revascularization, with a lack of graft options preventing a repeat procedure.
We review the clinical evidence for three of the most promising new therapeutic modalities for chronic refractory angina: transmyocardial laser revascularization (TMR), percutaneous myocardial laser revascularization (PMR), and spinal cord stimulation (SCS).

Transmyocardial laser revascularization (TMR)
In 1981, Mirhoseini and Cayton reported their experience with the use of lasers to create transmyocardial channels in animals [2]. Within 5 years TMR had been performed in humans [3]. During TMR, a laser is placed on the epicardial surface of the left ventricle via a left lateral thoracotomy and a variable number (10–50) of small transmural channels is created. The proposed potential mechanisms of action include direct flow of blood from the left ventricle into the ischemic myocardium via the laser-created channels, laser-induced angiogenesis, and laser-induced denervation.
Initial observational data were encouraging [4–6] and these stimulated the conduct of a number of trials comparing TMR with medical therapy. Five large trials of TMR and medical therapy have been published [7–11] and their results are summarized in Table I.

Table I. Results of randomized trials of TMR (12 months).

Unfortunately, two of these trials [8, 9] suffered from profound methodological deficiencies that have resulted in ongoing controversy about the validity of their results [12]. In both of these studies there was a high crossover rate from medical therapy to TMR and a significant loss to follow-up.
Three trials did not permit crossover and had more complete follow-up data [7, 10, 11]. All three studies demonstrated a significant improvement in angina status and quality of life, and in one, a significant improvement in exercise capacity [10]. However, none of these studies were able to show any improvement in survival, myocardial perfusion, or left ventricular ejection fraction. It is therefore difficult to exclude the possibility of a significant contribution from a placebo effect in the TMR trial results, particularly as none of the trials performed a sham procedure, eg, a thoracotomy incision, that would have enabled blinding of patient and assessor.
Finally, TMR is associated with significant procedural mortality and morbidity rates. In observational studies, the perioperative mortality was as high as 10% [5, 6], and although this was lower (1% to 5%) in trials in which patients were carefully selected [7–11], significant morbidity persisted. Combination of these perioperative mortality and morbidity data has led some observers to conclude that, despite the consistent demonstration of an improvement in anginal symptoms, the magnitude of the risks may outweigh the benefits [7].

Percutaneous myocardial laser revascularization (PMR)
PMR differs from TMR in both the site of delivery of the laser energy and the depth of the channels created. During PMR, the laser is directed against the endocardial surface of the left ventricle via a guiding catheter inserted via the femoral artery and positioned in the left ventricular cavity.
An intuitive attraction of PMR was the potential to achieve the symptomatic benefits of TMR with a lower associated mortality and morbidity. Initial observational data were promising [13] and have been supported by the results of the first randomized trial of PMR and medical therapy, the PACIFIC trial [14]. The results of this trial are presented in Table II.

Table II. Results of a randomized trial of PMR.

The results were similar to the TMR trials: an improvement in anginal symptoms and exercise time, but, once again, no improvement in myocardial perfusion, left ventricular function, or survival. In marked contrast to the TMR trials, however, there were no procedural deaths and morbidity was low.
Two blinded trials of PMR have been conducted: the DIRECT trial [15] and the BELIEF trial (presented at the 2001 American College of Cardiology conference). The results of these two studies have not yet been published in full, but preliminary results are conflicting, possibly as a result of different laser technologies employed in each trial. The DIRECT trial did not show any significant difference in angina relief between PMR plus medical therapy and placebo PMR plus medical therapy. The BELIEF trial reported that at 6 months, 41% of the PMR-treated patients had an improvement in two angina classes compared with 13% of those who received the sham PMR (J.E. Nordrehaug, personal communication, March 2001).

Spinal cord stimulation (SCS)
SCS involves placement of a quadripolar lead into the epidural space, sited so that when activated, SCS results in paresthesia in the dermatomes corresponding to the patient’s anginal symptoms.
Observational studies have shown that SCS use improves NYHA functional angina class [16], exercise duration [16–19], time to angina [17–19] on treadmill testing, angina severity (frequency, duration, and severity of episodes) [16–18, 20], medication use (nitrates and opiates) [16–19], and hospital admissions (frequency and duration of stay) [20]. Hautvast and colleagues [21] conducted a small, randomized study with 25 patients in which SCS was implanted in all subjects, but was inactivated in the control group for 6 weeks after implantation. The SCS group enjoyed signifi-
cant improvements in symptoms, exercise time, and ischemic changes on a 48-h ambulatory ECG, which did not occur in the control group. In another trial, the ESBY study, 104 patients with chronic angina but no prognostic indications for surgery were randomized to either SCS or CABG [22]. Both interventions relieved angina to a comparable and significant degree (83.7% and 79.5%, respectively), although cardiac mortality was significantly lower in the SCS group (1.9% vs. 13.7%, P = 0.02). However, compared with SCS, the CABG group had an increase in exercise capacity (P = 0.02) and less ST-segment depression on maximum workload (P = 0.0003).
Early concerns about the potential for adverse outcomes resulting from the masking of ischemic symptoms have not been substantiated. SCS does not conceal the symptoms of myocardial ischemia [19], including those of myocardial infarction [23], and, despite the increased activity of patients as a consequence of better symptom control, is not associated with an increase in ischemic burden or arrhythmia [24].
The possibility of a placebo effect with SCS has been suggested. Several factors argue against this as the sole mode of benefit, for, in addition to relieving symptoms of angina, SCS also improves markers of myocardial ischemia. These include a decrease in the degree of ST-segment depression during both exercise and atrial pacing [17, 18, 21], an improvement in myocardial lactate metabolism with SCS use during pacing [19], and a decrease in the frequency and duration of ischemic ECG abnormalities during 24-h ambulatory ECG monitoring [16, 21].

Conclusion
There appears to be reasonably robust clinical evidence that each of these new therapies improves anginal symptoms in patients with chronic refractory angina to a degree that is both statistically and clinically significant. The mechanisms of action of these modalities remain unclear. TMR may be best employed during CABG for regions of the myocardium that cannot be sufficiently revascularized by grafting, as use in this setting would avoid the additional mortality and morbidity associated with thoracotomy. For other patients, both PMR and SCS are attractive options. Which of these procedures, if either, is more effective, is not known. We are currently conducting a randomized trial at our institution to address this issue. Until the results of this trial are known, practical issues including patient and physician preference and the availability of each procedure are likely strongly to influence the choice of therapy.

REFERENCES
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2: J Microsurg 1981 Jun;2(4):253-60