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Ann Thorac Surg 2004;77:1228-1234
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Transmyocardial revascularization: 5-year follow-up of a prospective, randomized multicenter trial

^a Department of Cardiothoracic Surgery, Indiana Heart Institute, Indianapolis, Indiana, USA
^b Department of Cardiothoracic Surgery, University of Louisville, Jewish Heart and Lung Institute, Louisville, Kentucky, USA
^c Department of Cardiothoracic Surgery, Tampa General Hospital, Tampa, Florida, USA
^d Department of Cardiothoracic Surgery, Nebraska Heart Hospital, Nebraska Heart Institute, Lincoln, Nebraska, USA
^e Department of Cardiothoracic Surgery, Cardiovascular Institute of South-Surgery, Houma, Louisiana, USA
^f Department of Cardiothoracic Surgery, University of Iowa Hospital, Iowa City, Iowa, USA
^g Department of Cardiothoracic Surgery, Sacred Heart Hospital, Spokane, Washington, USA
^h Department of Cardiothoracic Surgery, St. Thomas Heart Institute, Nashville, Tennessee, USA
ⁱ St. Joseph's Hospital, Atlanta, Georgia, USA

Accepted for publication January 22, 2004.

^* Address reprint requests to Dr Allen, 10590 N Meridian St, Indianapolis, IN 46260, USA
e-mail: kallen2340{at}aol.com

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
BACKGROUND: In prospective randomized trials at 1 year, transmyocardial revascularization (TMR) provided superior relief of angina, decreased rehospitalizations, and improved exercise times. We evaluated 5-year mortality and angina class in "no-option" patients with diffuse coronary artery disease randomized to TMR or continued medical management.

METHODS: Two hundred twelve patients with refractory class IV angina who were not candidates for conventional therapy were randomized to receive holmium:yttrium-aluminum-garnet TMR (n = 100) or continued medical management (n = 112) at nine centers. Follow-up included all-cause mortality along with angina class assessment by blinded evaluators. Mean follow-up was 5.7 ± 0.8 years.

RESULTS: Mean angina scores for TMR patients were 4.0 ± 0.0 at baseline, 1.5 ± 1.4 at 1 year, and 1.2 ± 1.1 at a mean of 5 years (p < 0.001). After an average of 5 years, a significantly greater proportion of TMR than medical management patients experienced two or more class improvement in angina (88% versus 44%; p < 0.001). Kaplan-Meier intention-to-treat survival at 5 years was 65% versus 52% (TMR versus medical management; p = 0.05). Cumulative hazard curves demonstrated a significantly reduced risk of late death for TMR patients; average annual mortality beyond 1 year was 8% versus 13% (TMR versus medical management; p = 0.03).

CONCLUSIONS: Five-year follow-up of prospectively randomized, no-option class IV angina patients demonstrated significantly increased Kaplan-Meier survival in patients randomized to TMR. The significant angina relief observed 12 months after sole therapy TMR was sustained long term and continued to be superior to that observed for patients maintained on continued medical management alone.

	Introduction

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A majority of patients with angina related to coronary artery disease respond appropriately to medical management, percutaneous coronary interventions (PCI), or coronary artery bypass grafting (CABG). Despite these modalities, however, a growing number of patients develop a pattern of diffuse coronary artery disease that is both refractory to medical therapy and not amenable to PCI or CABG [1]. Transmyocardial revascularization (TMR) is a surgical option intended for this difficult patient population who suffer disabling, medically refractory, severe angina as assessed using the Canadian Cardiovascular Society (CCS) scale [2]. Five prospective randomized trials with 1-year follow-up have evaluated the safety and efficacy of TMR compared with continued maximal medical management in "no-option" patients [3–7]. Among these trials, TMR has provided superior angina relief, improved exercise tolerance, decreased rehospitalizations, and improved event-free survival compared with continued medical management. To determine the long-term benefits of TMR, we collected 5-year follow-up on no-option CCS class IV angina patients prospectively randomized to TMR or continued medical management and report on their angina class and all-cause mortality.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patients and follow-up
From 1996 to 1998, a cohort of patients with medically refractory CCS class IV angina who were not candidates for traditional methods of revascularization were randomized to receive TMR using a holmium:yttrium-aluminum-garnet (holmium:YAG) laser (CardioGenesis Corporation, Foothill Ranch, CA) or continued maximal medical management. Trial approval and 1-year follow-up was obtained from the institutional review board of each participating center and the US Food and Drug Administration (FDA) under an investigational device exemption. Informed consent was obtained from each patient before enrollment. Important enrollment criteria included (1) medically refractory class IV angina that could not be treated with CABG or PCI; (2) evidence of reversible ischemia; (3) ejection fraction more than 0.25; (4) no requirement for intravenous antianginal medication; and (5) absence of decompensated congestive heart failure. Patients randomized to medical therapy who met the a priori criteria for treatment failure (hospitalized and unweanable from intravenous antianginal drugs on two attempts > 48 hours) were allowed to cross over to a parallel, US Food and Drug Administration–approved study within the first year after randomization and receive TMR while unstable. Details of enrollment and 1-year follow-up were previously reported [3].

Centers that participated in the original trial and which still had an existing research infrastructure participated in this longitudinal long-term follow-up. This represented 77% (212 of 275) of the original study cohort. Two hundred twelve patients were originally randomized: 47% (100 of 212) were randomly assigned to receive TMR, and 53% (112 of 212) were randomly assigned to continued medical management. Baseline demographic and clinical characteristics of the two treatment groups were similar (Table 1) and reflected the demographics of the original trial cohort. After meeting the a priori criteria for treatment failure, 26% (29 of 112) of patients initially assigned to receive continued medical management crossed over and received TMR while unstable. Approval for long-term follow-up was obtained in accordance with each center's institutional review board requirements, and informed consent was obtained from participating patients. The operative technique for holmium:YAG TMR has been previously described [8–10]. Transmyocardial revascularization–treated patients received an average of 40 ± 8 channels. Mean follow-up was 5.7 ± 0.8 years (range, 3.8 to 7.1 years). Follow-up was obtained through telephone interviews and self-administered worksheets and was complemented with hospital and physician medical records. Mortality follow-up was 100% and included querying of the Social Security Death Index. Canadian Cardiovascular Society angina class assessment was determined by blinded coordinators independent of study investigators and was completed in all consenting survivors.

Baseline continuous and qualitative variables were compared using the two-sample Student's t test and Fisher's exact test, respectively. Proportions of patients with mortality or angina improvement were compared using Fisher's exact test. Covariate analyses of angina improvement were performed using logistic regression; the Wald p values are presented. Kaplan-Meier survival estimates were used to analyze mortality rates through the current follow-up, with standard errors computed using Greenwood's algorithm. Groups are compared using the log-rank statistic. Patients at risk are those at the exact time point. Long-term survival covariate analyses are performed using Cox proportional hazards regression considering baseline variables (treatment arm; age; sex; ejection fraction; history of diabetes, hypercholesterolemia, and hypertension; prior myocardial infarction; prior CABG; and prior PCI). Additionally, two or more CCS class improvement and freedom from angina at 3 and 12 months after randomization were used in outcome covariate analyses. Statistical significance was considered for p values less than 0.05. All statistical analyses were performed using SAS software version 8.2 (SAS Institute, Inc, Cary, NC).

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Canadian Cardiovascular Society angina class
Transmyocardial revascularization provided significant and sustained angina relief in no-option class IV angina patients through a mean follow-up of 5 years (Fig 1). A significant reduction in mean CCS angina class from baseline (4.0 ± 0.0) was observed in surviving patients at 3 months (1.4 ± 1.3; p < 0.0001), 6 months (1.3 ± 1.2; p < 0.0001), 1 year (1.5 ± 1.4; p = 0.0001), and 5 years (1.2 ± 1.1; p < 0.0001) after sole therapy with TMR. There were no significant differences between groups in overall usage of ß-adrenergic blockers, antianginal drugs, diuretics, or angiotensin-converting enzyme inhibitors at follow-up. As a result of the advancements that have occurred in medications since the original trial (eg, new combination drugs, brands, and alternative dosage forms), a detailed dose-related analysis of medication usage was not appropriate.

View larger version (10K): [in this window] [in a new window]   Fig 1. Mean Canadian Cardiovascular Society angina class in surviving patients after transmyocardial revascularization.

View larger version (34K): [in this window] [in a new window]   Fig 2. Improvement in Canadian Cardiovascular Society angina class at 3 months, 1 year, and a mean of 5 years. *Comparison between transmyocardial revascularization (TMR) and medical therapy. (Crossover = patients randomized to medical therapy who met the criteria for treatment failure and underwent transmyocardial revascularization while unstable; Medical Therapy = patients randomized to medical therapy excluding crossovers; TMR = patients randomized to transmyocardial revascularization.)

Survival
The operative mortality rate for patients randomly assigned to TMR was 3%. In crossover patients, who received TMR while unstable, the operative mortality rate was 7%. At 5 years, Kaplan-Meier intention-to-treat survival was increased for patients assigned to receive TMR compared with patients assigned to medical management (65% versus 52%; p = 0.05; Fig 3). Cumulative hazard analysis (depicting the instantaneous risk of death using a negative logarithmic transformation of the Kaplan-Meier analysis) indicates a decreased risk of late death beyond 1 year for TMR versus medically managed patients (annualized mortality rate 8% versus 13%; p = 0.03; Fig 4). In the three-group analysis (Fig 5), 5-year Kaplan-Meier survival estimates were 65%, 53%, and 48%, respectively, for randomly assigned TMR patients, medically managed patients excluding crossovers, and crossover patients (p = 0.16). When a cause of death was known, 87% were cardiac related.

View larger version (13K): [in this window] [in a new window]   Fig 3. Kaplan-Meier intention-to-treat survival estimates. (MMM = continued maximal medical management; TMR = transmyocardial revascularization.)

View larger version (10K): [in this window] [in a new window]   Fig 4. Cumulative hazard (CH) intention-to-treat analysis. (MMM = continued maximal medical management; TMR = transmyocardial revascularization.)

View larger version (16K): [in this window] [in a new window]   Fig 5. Kaplan-Meier 5-year survival estimates. (Crossover = patients randomized to medical therapy who met the criteria for treatment failure and underwent transmyocardial revascularization while unstable; Medical Therapy = patients randomized to medical therapy excluding crossovers; TMR = patients randomized to transmyocardial revascularization.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

This is the first long-term follow-up of prospectively randomized patients reported with holmium:YAG TMR. Our multicenter results demonstrate that the substantial angina improvement seen at 1 year after TMR persists through 5 years, and that a survival benefit is afforded to patients originally assigned to receive TMR. These results address the concern raised in small, single-center series involving nonrandomized patients, reporting that the robust angina relief observed at 1 year with holmium:YAG TMR, although still significantly improved over baseline status, may begin to wane beyond 2 years [12, 13]. The angina relief demonstrated in this 5-year follow-up is even more compelling considering the rigor of the intention-to-treat methodology used to analyze CCS class, whereby crossover patients, who showed substantial improvement at both 1 and 5 years, were retained in the medical therapy arm for analysis.

Our primary analysis for CCS class improvement included patients who received additional reintervention procedures during follow-up. Such interventions occurred in both groups after randomization; however, patients randomly assigned to receive continued medical management were significantly more likely to require a reintervention procedure. An intention-to-treat analysis of CCS class improvement including additional interventions is reflective of current practice patterns and is not biased against either treatment arm. Not surprisingly, an angina improvement analysis that excludes patients who fail their randomized therapy and receive a subsequent intervention demonstrates even greater long-term angina relief after TMR compared with medical therapy alone. This latter subanalysis, as reported in the 5-year follow-up of carbon dioxide TMR patients [14], can be criticized because it eliminates the sickest patients and presents results strongly favoring TMR.

The risk–benefit equation for TMR must include not only quality-of-life variables such as angina relief but also the long-term mortality risk associated with TMR compared with continued medical therapy alone. Although at 1 year there was no survival difference between groups [3], at this 5-year follow-up there was a significant survival advantage noted with primary TMR compared with medical therapy. This long-term benefit is primarily because of a significantly decreased risk of late death beyond 1 year in randomized TMR patients.

In the only other published long-term follow-up of a randomized TMR trial [15], the authors reported significant angina relief 3 to 5 years after TMR using a carbon dioxide laser. Although there appeared to be an increased incidence of heart failure treatment after carbon dioxide TMR, no differences in ejection fraction or mortality were observed in randomized groups during follow-up. As an indirect measure of heart failure, our 5-year assessment showed no increase in diuretic usage above baseline; a more direct measure, such as ejection fraction, showed no change from baseline in either group within 1 year. The persistent improvement in angina observed by Aaberge and colleagues [15] is supported by a long-term follow-up of a series of 78 patients who received carbon dioxide TMR [14]. Although 5-year survival after carbon dioxide TMR was only 49%, surviving patients enjoyed improved quality of life and a significant reduction in angina from baseline.

In this series, crossover patients who failed medical therapy and received TMR while unstable not only showed substantial angina improvement but also had 1-year survival comparable to that observed for patients originally assigned to receive TMR. This finding has been noted previously by others [3, 9, 16] who reported similar angina improvement and 1-year survival in unstable versus stable patients undergoing TMR. Considering these findings, it has not been uncommon for cardiologists to delay referral of stable no-option patients for TMR until they become unstable, often treating CCS class IV patients with nonsurgical alternatives such as enhanced external counterpulsation or investigational gene or drug therapies, which are perceived as less risky. At 5-year follow-up, although similar angina relief persisted in both crossover and originally randomized TMR patients, survival curves diverged for these two groups (Fig 5). At 5 years, Kaplan-Meier survival rates for TMR patients, medically managed patients who did not crossover, and crossover patients were 65%, 53%, and 48%, respectively. This reduced long-term survival in crossover patients raises a serious question as to whether TMR treatment should be delayed once a no-option patient with stable CCS class IV angina is identified. Only prior myocardial infarction and PCI were found to be significant predictors of crossover; however, they were not found to be predictive of mortality. This suggests that in terms of long-term survival, randomization to the original TMR group is superior to crossing over to receive TMR after becoming unstable. Whereas TMR has a defined operative risk, delaying TMR in identified stable candidates is not recommended because of the potential for increased operative mortality and reduced long-term survival in unstable patients.

The long-term, persistent benefit of surgical TMR observed in this randomized study provides important insight on the potential contribution of placebo effect to the clinical results observed after this therapy. Whereas a placebo effect likely influences early outcomes in any clinical trial involving innovative technology, its persistence is diminished in late follow-up and much less plausible in the long term, particularly in light of the substantial survival benefit. These results comparing both arms of the original pivotal trial assuages the concern that placebo effect is a primary mechanism explaining the long-term survival and clinical benefits of TMR.

Although several of the original low-enrolling sites could not participate because of a lack of a research infrastructure, the baseline demographics of the patients in this study were well matched between groups and reflect the baseline demographics of the original study population. As a longitudinal follow-up of a prospectively conducted 1-year trial, our study is limited to assessments that could be made in a high proportion of patients with a high degree of confidence: blinded angina assessment independent of study investigators and survival. Because the original trial did not assess exercise at baseline, it was not possible to conduct a long-term paired assessment. Further elucidation of potential mechanism(s) explaining the clinical benefits after TMR is not addressed by this study. Nonetheless, as research continues in the treatment of advanced coronary artery disease, these data further support the aggressive use of TMR in no-option patients with medically refractory angina.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank William N. Anderson, PhD, for statistical analysis of the data and CardioGenesis Corporation for reimbursement of study expenses.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Keith B. Allen Robert D. Dowling William W. Angell Deepak M. Gangahar Tommy L. Fudge Wayne Richenbacher Samuel L. Selinger Michael R. Petracek Douglas Murphy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Allen, K. B. Articles by Murphy, D. Search for Related Content PubMed PubMed Citation Articles by Allen, K. B. Articles by Murphy, D. Related Collections Coronary disease