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Abstracts & Commentary
Synopsis: In patients with refractory angina who were not candidates for percutaneous or surgical revascularization, transmyocardial revascularization resulted in more relief of angina, increased freedom from cardiac events, and a better quality of life.
Sources: Frazier OH, et al. N Engl J Med 1999;341:1021-1028; Allen KB, et al. N Engl J Med 1999;341:1029-1036.
In the april 1999 Clinical Cardiology Alert, we reported the disappointing results of a randomized controlled trial of surgical transmyocardial revascularization (TMR) and speculated that perhaps catheter-based systems would be the answer (Schofield PM, et al. Lancet 1999;353:519-524). However, two studies were reported in a recent issue of the New England Journal of Medicine of successful results with surgical TMR. Of note, one study used carbon dioxide laser and one used holmium laser. Both were prospective randomized trials in refractory angina patients who were not candidates for percutaneous or surgical revascularization. Patients were randomized to surgical TMR or medical therapy. Both studies required documented ischemia and a left ventricular ejection fraction greater than 20%. Also, both studies allowed medically randomized patients who developed angina refractory to intravenous medications to cross over to TMR. End points in both studies included angina severity, exercise thallium imaging, and quality of life over 12 months.
The CO2 laser study (Frazier and colleagues) randomized 192 patients and 60 of 101 initially assigned to medical therapy crossed over to TMR. After one year, angina class was significantly improved in 72% of TMR patients and 13% of the medical patients, (P < 0.001) as was quality of life (38% vs 6%; P < 0.001). The number of thallium scan nonischemic segments increased 20% with TMR and fell 27% in medical patients (P = 0.002). Hospitalizations for unstable angina occurred in 2% of TMR patients in one year vs. 69% of medical patients (P < 0.001). Perioperative mortality was 3% with TMR. One-year survival was 85% in the TMR group and 79% in the medical patients (NS).
The holmium laser study (Allen and colleagues) randomized 275 patients and 46 of the 143 medical patients (32%) crossed over to TMR. Significant reductions in angina occurred in 76% of the TMR patients vs. 32% of the medical patients (P < 0.001). Although survival at one year was not different (84 vs 89%), survival free of cardiac events was better with TMR (54% vs 31%; P < 0.001). Exercise tolerance was better after TMR (5 MET vs 4 MET; P = 0.05), as was quality of life score (21 vs 12; P = 0.003). However, myocardial perfusion by thallium scintigraphy was not different between the two groups and perioperative mortality was 5%.
Both studies concluded that in patients with refractory angina who were not candidates for percutaneous or surgical revascularization, TMR resulted in more relief of angina, increased freedom from cardiac events, and a better quality of life. One study concluded that myocardial perfusion was also improved (CO2 laser study).
Comment by Michael H. Crawford, MD
These two studies represent a significant advance since the negative results of the previous controlled study (Lancet 1999). Also, they dispel the notion that CO2 laser is better than other types since their results were similar. The major difference between these studies and the Lancet study is that the patients were sicker in these studies: 70-100% were excluded in the Lancet study. Perhaps unstable patients stand to gain more from TMR. Although there was no difference in exercise tolerance at 12 months in the Lancet study, angina frequency, hospitalization, and use of medications decreased with TMR vs. medical therapy. Also, fixed defects on thallium scintigraphy remained stable after TMR but increased in the medical group, suggesting scarring of ischemic areas since there was no change in total defects. Thus, taken together, these three studies suggest benefit for highly selected patients for TMR.
The real concern is whether this is just another Vineberg operation and we are observing the placebo effect of cardiac surgery. This cannot be answered unless a sham operation control group is included in the next study, which is unlikely. This raises the issue of mechanism of any benefit. Originally it was thought that these channels would stay open and create a reptilian heart with sinusoids for perfusion of the myocardium, hence the idea that CO2 laser was better because the channels were cleaner with it. Now we know the channels close. So what is the benefit? Perhaps denervation is the mechanism. This would explain the decrease in angina, but not the reduction in fixed defects in one study and improved perfusion observed in another study. The most popular explanation now is that these laser channels stimulate angiogenesis.
Another concern is the initial mortality associated with surgery and the lack of survival gain in these small studies. In the CO2 laser study, it was noted that if surgery was delayed, two weeks mortality decreased from 3% to 1%. In the holmium laser study, it was noted that mortality for the last 100 patients decreased from 5% overall to 2%. Thus, careful management of these sick patients may make perioperative mortality acceptable.
Another limitation to these studies is the allowance of crossovers to TMR. Naturally it was high (30-60%) because the patient had to be medically refractory to be candidates for the studies. However, in both studies the crossover group did almost as well as the TMR groups and better than the medical group.
Morbidity was not inconsequential in the TMR groups: ventricular tachyarrhythmias in 8% of the CO2 laser patients and 12% of the holium laser patients; heart failure in 11% and 4%; and myocardial infarction in 7% and 6%, but does not appear excessive vs. bypass surgery. Complications were similar in the crossover groups despite their acuity.
What about the catheter-based approach, percutaneous myocardial revascularization (PMR)? Although still being studied, its development was hampered by difficulty in directing the laser beam by catheter in the beating heart. A new system has now been developed with better steering capabilities called directed myocardial revascularization (DMR). This field, like most, is a moving target. At this point, TMR appears more promising, PMR has faded, but DMR raises hopes for a percutaneous approach.
a. relief of angina.
b. reduced cardiac events.
c. better quality of life.
d. All of the above