Correspondence
Transmyocardial Laser Revascularization
N Engl J Med 2000; 342:436-438February 10, 2000
- Article
To the Editor:
The placebo effect of surgery for the treatment of angina that is mentioned by Lange and Hillis (Sept. 30 issue)1 in their editorial on transmyocardial laser revascularization deserves elaboration. In the era before direct coronary revascularization, internal-thoracic-artery ligation was touted as a method to increase myocardial blood flow and relieve anginal symptoms. Initial reports by Ellis et al.2 and Kitchell et al.3 indicated that 68 to 75 percent of patients had clinical improvement, including approximately 35 percent who had complete relief and 42 percent with objective improvements, as measured electrocardiographically. These investigators were honest and intelligent but not impartial observers. Double-blind studies conducted later by Cobb et al.4 and Dimond et al.5 demonstrated that a sham thoracotomy alone could decrease the need for nitroglycerin and increase exercise tolerance and that it produced subjective improvement in more than 35 percent of patients. These results are similar to the improvement among 34 percent of the patients in the British study of transmyocardial laser revascularization mentioned by Lange and Hillis.
When perfusion scans do not correlate in time or magnitude with the patient's clinical improvement, the more subjective data on improvement of symptoms must be approached with great skepticism. As was the case in earlier studies, the thoracotomy incision alone may have an important effect directly or indirectly on the patient's perception of pain. The fact that a patient has already undergone the surgical procedure of last resort has a high likelihood of affecting a physician's choice of treatment plans, and thus study outcome.
It may be completely correct that transmyocardial laser revascularization benefits patients with chronic angina. However, given the substantial morbidity and mortality (9 to 15 percent mortality among the patients who were crossed over to transmyocardial laser revascularization in the studies by Frazier et al.6 and Allen et al.7 discussed by Lange and Hillis), the potential for a placebo effect must always be remembered.
7 ReferencesStephen W. Downing, M.D.
University of Maryland School of Medicine, Baltimore, MD 212011
Lange RA ,Hillis LD . Transmyocardial laser revascularization. N Engl J Med 1999;341:1075-1076
Full Text | Web of Science | Medline2
Ellis LB ,Blumgart HL ,Harken DE ,Sise HS ,Stare FJ . Long-term management of patients with coronary artery disease. Circulation 1958;17:945-952
Web of Science | Medline3
Kitchell JR ,Glover RP ,Kyle RH . Bilateral internal mammary artery ligation for angina pectoris: preliminary clinical considerations. Am J Cardiol 1958;1:46-50
CrossRef | Web of Science | Medline4
Cobb LA ,Thomas GI ,Dillard DH ,Merendino KA ,Bruce RA . An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med 1959;260:1115-1118
Full Text | Web of Science | Medline5
Dimond EG, Kittle CF, Crockett JE. Evaluation of internal mammary artery ligation and sham procedure in angina pectoris. Circulation 1958;18:712-3. (abstract).
6
Frazier OH ,March RJ ,Horvath KA . Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999;341:1021-1028
Full Text | Web of Science | Medline7
Allen KB ,Dowling RD ,Fudge TL , et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med 1999;341:1029-1036
Full Text | Web of Science | Medline
To the Editor:
The studies by Frazier et al. and Allen et al. showed that transmyocardial laser revascularization significantly reduced angina scores and improved the quality of life of patients with refractory angina. The findings of these reports, along with those of the Angina Treatments — Lasers and Normal Therapies in Comparison (ATLANTIC) study,1 contrasted with the findings of a report by Schofield et al.2 Before assessing the effect of transmyocardial laser revascularization in clinical practice, it is important to consider what constitutes the ultimate goal of therapy. Transmyocardial laser revascularization, like other forms of revascularization, should aim to alleviate the symptoms of myocardial ischemia without compromising life expectancy or cardiac function. We are not convinced that the more recent randomized studies show that transmyocardial laser revascularization has achieved this goal.
There is no mention of the effect of transmyocardial laser revascularization on left ventricular function in the reports by Frazier et al. and Allen et al., and the effects reported in the ATLANTIC trial were worrisome.1 In the ATLANTIC study, echocardiography showed that 27 percent of patients undergoing transmyocardial laser revascularization (25 of 92) had a significant reduction in left ventricular function, as compared with 11 percent of those in the medically treated group (10 of 90, P<0.001). Even though there was no difference in mortality at 12 months, it is well recognized that the ejection fraction provides long-term prognostic information.3 In view of these findings, we think it is essential that Frazier et al. and Allen et al. provide data on the effects of transmyocardial laser revascularization on cardiac function.
There is still controversy over the supposed mechanism of action of transmyocardial laser revascularization that is responsible for relief of anginal symptoms. Frazier et al. assume that the mechanism is due to enhancement of myocardial perfusion, although they concede that the degree of symptomatic improvement is not necessarily matched by the improvements in perfusion. In the 30 days after transmyocardial laser revascularization in the study by Frazier et al., 6 patients (7 percent) had an acute myocardial infarction and congestive cardiac failure developed in 10 (11 percent). In the study by Allen et al., 5 percent of the patients who underwent transmyocardial laser revascularization went on to have an acute myocardial infarction and 4 percent had congestive cardiac failure. There is no mention of creatine kinase levels after revascularization in either of these studies. Among the patients who received transmyocardial laser revascularization, as compared with those who received medication only, the ATLANTIC investigators found a greater incidence of myocardial infarction (15 percent vs. 9 percent), heart failure (27 percent vs. 11 percent), and elevated serum creatine kinase levels (>1095 U per liter in 50 percent of patients). These findings suggest that important myocardial damage has occurred, which may have long-term implications.
On the basis of these unresolved issues, we believe that the application of transmyocardial laser revascularization in clinical practice must await more convincing data that show true benefits.
3 ReferencesSimon G. Williams, M.R.C.P.
David J. Wright, M.R.C.P.
Lip Bun Tan, D.Phil., F.R.C.P.
Leeds General Infirmary, West Yorkshire LS1 3EX, United Kingdom1
Burkhoff D ,Schmidt S ,Schulman SP , et al. Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. Lancet 1999;354:885-890
CrossRef | Web of Science | Medline2
Schofield PM ,Sharples LD ,Caine N , et al. Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial. Lancet 1999;353:519-524
CrossRef | Web of Science | Medline3
Cohn JN ,Johnson GR ,Shabetai R , et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87:Suppl:V-15
Author/Editor Response
The authors reply:
To the Editor: We appreciate Downing's concern regarding the placebo effect, which can occur after any surgical procedure, including transmyocardial laser revascularization. The studies of internal-thoracic-artery ligation he mentions were conducted in small numbers of patients with short follow-up and clearly showed that no patients had significant relief of angina for more than nine months. A lack of objective data and a short duration of benefits are classic signs of the placebo effect.
This finding highlights the main difference between internal thoracic artery ligation and transmyocardial laser revascularization with a carbon dioxide laser. In our study, perfusion scans showed significantly less ischemia without increases in infarction only in laser-treated patients. As we discussed, long-term follow-up had shown that clinical improvement lasts for three or more years in similar cohorts.1 Because of initial concern about the placebo effect, the senior author of our study required demonstration of improved perfusion as well as relief of angina before proceeding with more formal studies. Positron-emission tomographic studies showed improved subendocardial perfusion after transmyocardial laser revascularization and relief of angina in a preliminary trial.2
In the letter by Williams et al., trials in which different types of lasers were used in dissimilar patient populations are, unfortunately, combined. In patients treated with carbon dioxide lasers, regional left ventricular function improves.3 In our trial, global left ventricular function did not change significantly. Because most patients had a reasonably well preserved left ventricular ejection fraction at base line (50±11 percent), further improvement owing to any therapy would have been unlikely. The fact that 27 percent of the patients in the ATLANTIC trial4 had significant reductions in left ventricular function, meanwhile, is not surprising given the considerably more traumatic nature of treatment with the holmium:yttrium–aluminum–garnet laser as compared with treatment with the carbon dioxide laser.
We did not report creatine kinase levels, because they are generally unreliable after any surgical-revascularization procedure, particularly those involving thoracotomy and laser myocardial ablation. We observed no significant increase in the number of scars on myocardial perfusion scans, which would indicate no serious laser-induced infarction. More important, the incidence of recorded infarctions was 11 percent (10 of 91) in the laser group, as compared with 20 percent (8 of 41) in the control group. This finding indicates that infarction is not due to “important myocardial damage” by the laser, as Williams et al. suggest, but, rather, is a direct consequence of the high morbidity expected in this cohort. Incidentally, the high mortality figures associated with transmyocardial laser revascularization quoted by Downing refer to patients with unstable angina. The mortality rate is ≤1 percent among patients with chronic stable angina.
4 ReferencesO.H. Frazier, M.D.
Texas Heart Institute, Houston, TX 77225-0345Robert J. March, M.D.
Rush–Presbyterian–St. Luke's Medical Center, Chicago, IL 60612Keith A. Horvath, M.D.
Northwestern University Medical School, Chicago, IL 606111
Horvath KA ,Cohn LH ,Cooley DA , et al. Functional improvement, long term survival and angina relief after transmyocardial revascularization with a CO2 laser. Circulation 1998;98:Suppl I:I-217 abstract.2
Frazier OH ,Cooley DA ,Kadipasaoglu KA , et al. Myocardial revascularization with laser: preliminary findings. Circulation 1995;92:Suppl II:II-583
March RJ ,Macioch JE ,Donoghue J , et al. Transmyocardial laser revascularization preserves segmental left ventricular contractile reserve: a blinded echocardiographic evaluation. Circulation 1997;96:Suppl I:I-585 abstract.4
Burkhoff D ,Schmidt S ,Schulman SP , et al. Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. Lancet 1999;354:885-890
CrossRef | Web of Science | Medline
Author/Editor Response
In three prospective, randomized trials, patients with refractory angina who underwent transmyocardial laser revascularization had significantly better outcomes than patients who received medical management with respect to improvements in anginal symptoms, survival free of cardiac events, freedom from treatment failure, and freedom from cardiac-related rehospitalization.1-3 After one year of follow-up, patients who underwent transmyocardial laser revascularization had significant improvements in anginal symptoms and quality of life and were using less antianginal medication. Furthermore, Burkhoff et al.3 reported that exercise tolerance increased significantly after transmyocardial laser revascularization, whereas it decreased in the group that received continued medical management. All results were achieved without significant differences between the groups in one-year survival.
Downing and Williams et al. suggest that the clinical benefits observed after transmyocardial laser revascularization in these studies might have been the result of a placebo effect, since none of the studies included a sham-surgery control group. They cite as proof historical, poorly controlled studies that only suggested that there was a placebo effect after sham thoracotomy. Limited numbers of patients, lack of a control group, and variable follow-up reduce the relevance of these citations. Positive results after transmyocardial laser revascularization were sustained and constant at one year.1-3
In two additional multicenter, prospective, randomized, blinded trials, my colleagues and I4 and Frazier et al.5 compared coronary-artery bypass grafting combined with transmyocardial laser revascularization to coronary-artery bypass grafting alone in patients who otherwise would have received incomplete revascularization by conventional coronary-artery bypass grafting. In both studies, perioperative mortality and the need for postoperative left ventricular support were reduced after coronary-artery bypass grafting plus transmyocardial laser revascularization.4,5 In addition, my colleagues and I4 reported improved one-year survival after the combined procedure. Since the patients in both groups underwent sternotomy and were unaware of which treatment they had received, the beneficial effects of adjunctive transmyocardial laser revascularization could not have been the result of a placebo effect.
We1 noted no increase in fixed perfusion defects after therapy with transmyocardial laser revascularization alone and observed no difference in rates of myocardial infarction between the patients who underwent transmyocardial laser revascularization and those who received medical management. Although the data were not reported, there were no significant differences in ejection fraction at one year between the patients who underwent transmyocardial laser revascularization and those who received medical management, and neither group had a net change in ejection fraction from base line. The benefits of transmyocardial laser revascularization must be weighed against the reported operative mortality of 1 to 5 percent.1-3 As reported, with increased experience and improved patient selection and postoperative care, the mortality associated with the procedure has decreased from 5 percent to 2 percent.
On the basis of closely audited data from these studies, the Food and Drug Administration approved transmyocardial laser revascularization with the holmium laser (Eclipse Surgical Technologies, Sunnyvale, Calif.)1 and the carbon dioxide laser (PLC Medical Systems, Franklin, Mass.)2 for the treatment of medically refractory angina in patients who are not candidates for conventional revascularization.
5 ReferencesKeith B. Allen, M.D.
Indiana Heart Institute, Indianapolis, IN 462601
Allen KB ,Dowling RD ,Fudge TL , et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med 1999;341:1029-1036
Full Text | Web of Science | Medline2
Frazier OH ,March RJ ,Horvath KA . Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999;341:1021-1028
Full Text | Web of Science | Medline3
Burkhoff D ,Schmidt S ,Schulman SP , et al. Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. Lancet 1999;354:885-890
CrossRef | Web of Science | Medline4
Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser revascularization combined with coronary artery bypass grafting: a multi-center, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg (in press).
5
Frazier OH ,Boyce SW ,Griffith BP , et al. Transmyocardial revascularization using a synchronized CO2 laser as adjunct to coronary artery bypass grafting: results of a prospective, randomized, multi-center trial with 12-month follow-up. Circulation 1999;100:Suppl:I-240 abstract.
Author/Editor Response
As noted by Downing, double-blind studies of the efficacy of bilateral internal-thoracic-artery ligation in patients with angina pectoris showed that those who underwent a sham operation (bilateral parasternal skin incisions) often had resolution or improvement of symptoms, which persisted 15 to 18 months postoperatively. It has been suggested that the symptomatic relief associated with transmyocardial laser revascularization is unlikely to be due to a placebo effect, since such relief persisted for 12 months. The studies cited by Downing remind us that a placebo effect may, in fact, be long-lived. The duration of symptomatic relief does not allow one to distinguish between a placebo and a “real” effect.
Richard A. Lange, M.D.
L. David Hillis, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235- Citing Articles (2)
Citing Articles
1
Eduardo Briones, Juan Ramon Lacalle, Ignacio Marin, Eduardo Briones. 2009. Transmyocardial laser revascularization versus medical therapy for refractory angina. .
CrossRef2
E Briones, JR Lacalle, I Marin, Eduardo Briones. 2002. Transmyocardial laser revascularization versus medical therapy for refractory angina. .
CrossRef
