Punching Holes in the Heart: Not Quite a Knockout
ABSTRACT & COMMENTARY
Synopsis: The adoption of the transmyocardial laser revascularization procedure cannot be advocated. Further research will help to find out whether any subgroup of patients will benefit.
Source: Schofield PM, et al. Lancet 1999;353:519-524.
Abritish trial of transmyocardial laser revascularization (TMLR) has recently been reported, which is the first randomized study of this technology compared to conventional medical therapy. A total of 188 patients with severe chronic stable angina who were poor or noncandidates for coronary bypass surgery or angioplasty were randomized to optimal anginal therapy or TMLR plus anti-anginal therapy; patients were enrolled between 1993 and 1997. Follow-up was for at least one year; no crossovers occurred. The primary outcome was exercise test duration at 12 months. A variety of secondary outcomes were assessed, including physician and patient angina class assessment; a 12-minute walk test; hospitalization for unstable angina; cardiovascular death; ejection fraction; and exercise methoxyisobutyl isonitrile (MIBI) radionuclear scans. All end points were assessed at 12 months. A priori improvement on stress testing was defined as a 50% increase in maximum exercise time. All patients had chronic angina (all with inducible ischemia), relatively normal LV function, and were unsuitable for conventional revascularization. TMLR was carried out with a carbon dioxide laser (PLC Medical Systems) through a small anterolateral thoracotomy adjacent to the area of reversible ischemia as identified on nuclear stress testing. Approximately 30 channels were made per patient (range, 6-75), each approximately 1 mm in diameter, with a distribution of approximately 1 per cm2. An independent data monitoring committee met on two occasions and chose to continue the trial until 190 patients were recruited. The patient population was predominantly male, approximately 60 years of age, with Canadian Class III angina (73%) or Class IV (27%) angina. Ejection fraction was approximately 50%. Three-fourths had had a prior myocardial infarction and almost all had had prior coronary bypass grafting. Twenty-five percent had had a PTCA. Almost 20% were diabetic. Medical therapy consisted of conventional anti-anginal medications. Calcium antagonists were used in more than 90% at baseline, declining to 85% at 12 months in the TMLR subjects, and 100% of medically treated patients at one year. Nitrate use declined in the TMLR patients as opposed to the medical group.
The main results are not impressive. Survival was not different—89% in the TMLR cohort and 96% in the medical cohort at 12 months. Perioperative mortality for TMLR patients was 5%. Mean hospital stay was 10-11 days; there was significant morbidity in the TMLR group, with one-third having some type of infection. Exercise time was approximately 40 seconds shorter in the TMLR group, at each testing interval (3, 6, 12 months, none statistically significant). Patients stopped more frequently for angina in the medical cohort, and more for dyspnea or fatigue in the TMLR patients. TMLR patients did not walk greater distances on the 12-minute walk test at 12 months, but these patients did walk farther at three and six months. More TMLR subjects achieved a reduction in Canadian angina class as assessed by physicians; however, on an angina scale recorded by patients, there was less difference in chest pain frequency. TMLR patients had fewer unstable angina admissions at 12 months. Both groups demonstrated a decrease in segments with reversible ischemia and an increase in irreversible ischemic myocardial segments. Ejection fraction was essentially unchanged. Schofield and colleagues conclude that "there were no clinically important differences between groups in treadmill exercise time or 12-minute walking distance." There was a modest improvement in angina in TMLR patients. TMLR carried a significant burden of morbidity and mortality, particularly in the early postoperative period. Schofield et al strike a cautionary note about the procedure as well as the costs of new technologies in countries with limited resources. They also stressed the lack of industry funding for trials with devices and the possible selection of patients away from clinical trials to institutions who offer as yet unproven technology. They conclude, "The adoption of the TMLR procedure cannot be advocated. Further research will help to find out whether any subgroup of patients will benefit."
Comment by Jonathan Abrams, MD
This is a sobering report of significance to those who were hoping that laser revascularization would represent a boon for patients with angina pectoris who are not candidates for further revascularization procedures. Nevertheless, the case is not necessarily closed, in that there are now a number of trials under way assessing catheter-based laser revascularization. The first reports of TMLR in a cardiac surgery setting appeared in 1995. Several nonrandomized studies have been reported, most of which were quite promising, but none were truly randomized to include a cohort of medically treated subjects. In addition to the high-energy carbon dioxide laser, Homian Yag laser systems are currently under investigation. The Food and Drug Administration (FDA) has approved the CO2 PCL laser and the Eclipse Homian Yag unit for surgical use only. Data from two large studies with catheter-based systems (Eclipse, CardioGenesis) will be submitted to the FDA in the future. If this new concept of treatment of coronary artery disease using state-of-the-art technology is to be successful, it makes sense to use a percutaneous catheter-based system. Considerable experience is being accrued in the United States in randomized trials. While there is some morbidity, mortality does not appear to be a problem. Patients can be discharged from the hospital within 48 hours. At the recent American College of Cardiology meeting (March 8, 1999), the PACIFIC Trial was reported at a late-breaking trial session (S. Oesterle, MD), demonstrating favorable results with a non-FDA-approved Homian Yag catheter system (CardioGenesis). Two hundred twenty three patients were randomized to the laser or medical therapy. At six months, there was a significant improvement in angina status and exercise duration in the TMLR group compared to medical treatment. Other unpublished data are promising with catheter-based Homian Yag lasers. The use of fiber optic delivery catheters using fluoroscopic guidance by experienced interventionalists may have promise, particularly as the morbidity and mortality associated with surgical-based TMLR is not a factor.
We do not know how or why laser revascularization might be effective. The original premise that intramyocardial channels would remain open appears not to be valid. Angiogenesis and/or collateral development is a possibility, as is cardiac denervation. All cardiologists have patients in their practice who have undergone one or more revascularizations, often many, who have severe refractory stable angina, relatively preserved left ventricular function, and who are deemed to be nonrevascularizable. These individuals lead lives of quiet desperation. While TMLR does not appear to be a panacea to these patients, it may be that selected use of this procedure, particularly if catheter-based techniques turn out to be safe and effective, may provide important palliative improvement for such individuals, in whom a modest enhancement in exercise time and a decrease in angina frequency, even without complete elimination of ischemic symptoms, would be a real advance. If this can be done with a reasonable safety and cost profile, this truly would be an advance for this unfortunate group of patients. At the present time, the British trial dampens the enthusiasm for this approach, at least with laser energy delivered through a thoracotomy, while the just released PACIFIC Trial (catheter-based TMLR) is encouraging.