Comparison of Transmyocardial Revascularization with Medical Therapy in Patients with Refractory Angina
Keith B. Allen, M.D., Robert D. Dowling, M.D., Tommy L. Fudge, M.D., G. Phillip Schoettle, M.D., Samuel L. Selinger, M.D., Deepak M. Gangahar, M.D., William W. Angell, M.D., Michael R. Petracek, M.D., Carl J. Shaar, Ph.D., and William W. O'Neill, M.D.
Background Transmyocardial revascularization involves the creationof channels in the myocardium with a laser to relieve angina.We compared the safety and efficacy of transmyocardial revascularizationperformed with a holmium laser with those of medical therapyin patients with refractory class IV angina (according to thecriteria of the Canadian Cardiovascular Society).
Methods In a prospective study conducted between March 1996and July 1998 at 18 centers, 275 patients with medically refractoryclass IV angina and coronary disease that could not be treatedwith percutaneous or surgical revascularization were randomlyassigned to receive transmyocardial revascularization followedby continued medical therapy (132 patients) or medical therapyalone (143 patients).
Results After one year of follow-up, 76 percent of the patientswho had undergone transmyocardial revascularization had improvementin angina (a reduction of two or more classes), as comparedwith 32 percent of the patients who received medical therapyalone (P<0.001). Kaplan–Meier survival estimates atone year (based on an intention-to-treat analysis) were similarfor the patients assigned to undergo transmyocardial revascularizationand those assigned to receive medical therapy alone (84 percentand 89 percent, respectively; P=0.23). At one year, the patientsin the transmyocardial-revascularization group had a significantlyhigher rate of survival free of cardiac events (54 percent,vs. 31 percent in the medical-therapy group; P<0.001), asignificantly higher rate of freedom from treatment failure(73 percent vs. 47 percent, P<0.001), and a significantlyhigher rate of freedom from cardiac-related rehospitalization(61 percent vs. 33 percent, P<0.001). Exercise toleranceand quality-of-life scores were also significantly higher inthe transmyocardial-revascularization group than in the medical-therapygroup (exercise tolerance, 5.0 MET [metabolic equivalent] vs.3.9 MET; P=0.05; quality-of-life score, 21 vs. 12; P=0.003).However, there were no differences in myocardial perfusion betweenthe two groups, as assessed by thallium scanning.
Conclusions Patients with refractory angina who underwent transmyocardialrevascularization and received continued medical therapy, ascompared with similar patients who received medical therapyalone, had a significantly better outcome with respect to improvementin angina, survival free of cardiac events, freedom from treatmentfailure, and freedom from cardiac-related rehospitalization.
Despite the success of current medical and surgical managementof ischemic heart disease, a growing number of patients havediffuse obstructive coronary artery disease that is not amenableto coronary-artery bypass grafting or catheter-based interventions.This problem has stimulated interest in developing alternativetherapeutic approaches. Early attempts at indirect myocardialrevascularization had limited success. Beck's use of omentopexy,reported in 1935,1 and Vinberg's use of thoracic-artery implantation,reported in 1954,2 were attempts to provide direct myocardialperfusion and were based on the description by Wearn et al.,in 1933,3 of a sinusoidal network in the human heart. In 1965,Sen et al. proposed the creation of transmural channels in theleft ventricular wall to permit direct perfusion of ischemicmyocardium with oxygenated left ventricular blood.4 This conceptwas based on the model of the reptilian heart, in which theleft ventricle is directly perfused from endothelium-lined channelsthat radiate out from the left ventricular cavity. Mirhoseiniand associates5,6 advanced the concept by using laser energyrather than mechanical energy to create the transmural channels.Subsequent clinical trials using a carbon dioxide laser7,8,9,10,11,12,13or a holmium:yttrium–aluminum–garnet laser14,15,16(hereafter referred to as a holmium laser) demonstrated thattransmyocardial revascularization significantly improved anginain patients who were not candidates for conventional therapies.
We conducted a prospective, randomized, multicenter trial tocompare the safety and efficacy of transmyocardial revascularization,performed with a holmium laser and followed by continued medicaltherapy, with the safety and efficacy of medical therapy alonein patients with refractory class IV angina (according to theclassification system of the Canadian Cardiovascular Society[CCS]). Eighteen centers in the United States participated inthe study.
Methods
Patients
Between March 1996 and July 1998, 275 patients with medicallyrefractory class IV angina and coronary artery disease thatcould not be treated with percutaneous or surgical revascularizationwere randomly assigned to undergo transmyocardial revascularizationand continued medical therapy (132 patients) or medical therapyalone (143 patients). Randomization was performed by each centeron a 1:1 basis, with a block size of six patients per center.The demographic and clinical characteristics of the patientsin the two treatment groups were similar (Table 1). A blinded,independent data and safety monitoring committee monitored thestudy. Study approval was obtained from the Food and Drug Administration(FDA) and the institutional review board of each participatingcenter. Informed consent was obtained from each patient beforeenrollment.
Table 1. Characteristics of the Patients and Cardiac Risk Factors.
The criteria for enrollment were refractory class IV anginathat was not amenable to coronary-artery bypass grafting orpercutaneous transluminal coronary angioplasty (as determinedby a surgeon and an interventional cardiologist at each center);reversible ischemia, as determined by myocardial perfusion scanning,within the distal two thirds of the left ventricle (i.e., thearea of the ventricle amenable to transmyocardial revascularization);and a left ventricular ejection fraction greater than 25 percent.Exclusion criteria were a contraindication to general anesthesia;severe chronic obstructive pulmonary disease (indicated by aforced expiratory volume in one second that was less than 55percent of the predicted value); the need for continued useof intravenous antiangina medications; an inability to undergodipyridamole–thallium stress scintigraphy; a non–Q-wavemyocardial infarction within the previous two weeks or a Q-wavemyocardial infarction within the previous three weeks; the needfor long-term anticoagulant therapy; the presence of a ventricularmural thrombus; severe arrhythmias; and decompensated congestiveheart failure.
Medically refractory angina was defined as CCS class IV anginathat was present despite maximal tolerated doses of multipleantianginal medications (nitrates, calcium-channel blockers,and beta-blockers). At the time of enrollment, 91 percent ofthe patients (250 of 275) were taking two or more antianginalmedications, and 31 percent (85 of 275) were taking analgesicsor narcotics.
Forty-six patients (32 percent) initially assigned to receivemedical therapy alone met the a priori criteria for treatmentfailure and could not be weaned from intravenous antianginalmedication on two attempts over a period of 48 hours. They werewithdrawn from the study and underwent transmyocardial revascularizationunder a parallel, FDA-approved protocol for patients who couldnot be weaned from intravenous antianginal medications. Thus,there were three groups of patients: those randomly assignedto undergo transmyocardial revascularization and to receivecontinued medical therapy (132 patients), those who receivedmedical therapy alone throughout the study (97), and those randomlyassigned to receive medical therapy alone who met the criteriafor treatment failure and underwent transmyocardial revascularizationas part of a separate protocol (46). The third group of patientsis hereafter referred to as the crossover group.
Operative Technique and Laser Procedure
The operative procedure has been described in detail elsewhere.14,15Cardiac exposure was accomplished through a limited left anteriorthoracotomy. The administration of intravenous fluids was minimizedto prevent fluid overload. A 20-W, pulsed holmium laser (EclipseSurgical Technologies, Sunnyvale, Calif.) was used to createtransmyocardial channels. The laser, which has been approvedby the FDA, was calibrated to deliver 6 to 8 W per pulse, andenergy was delivered at the rate of five pulses per second througha flexible 1-mm optical fiber. Energy application was not gatedto the cardiac cycle. Channels were placed every square centimeterthroughout the distal two thirds of the left ventricle. Threeto five channels were placed, followed by the application ofdigital pressure for two to three minutes to obtain hemostasisand allow for myocardial recovery. Mechanical manipulation ofthe heart was minimized. A mean (±SD) of 39±11channels were created per patient. The mean durations of surgeryand laser use were 99±43 and 25±13 minutes, respectively.
Primary End Points
The primary end points were a change in angina symptoms, treatmentfailure, and a change in myocardial perfusion. Angina was evaluatedat 3, 6, and 12 months in all surviving patients who were notcrossed over to surgical treatment and who had reached the designatedfollow-up time (hereafter referred to as eligible patients):213 of 221 patients (96 percent) at 3 months, 172 of 183 (94percent) at 6 months, and 126 of 136 (93 percent) at 12 months.Improvement in angina was defined as a reduction of two or moreCCS angina classes from base line. An independent laboratory(at the Cleveland Clinic Foundation, Cleveland) conducted amasked assessment of angina and quality of life at 12 months.Angina was assessed with the use of a questionnaire designedto classify the symptoms of angina according to the CCS class(with class 0 indicating the absence of angina). The Duke ActivityStatus Index17 was used to assess the quality of life. The indexis based on a scale from 0 to 58, with higher scores indicatinggreater functional capacity. Among the first 160 patients enrolledin the study, these assessments were performed at 12 monthsin 112 of 132 eligible patients (85 percent).
Treatment failure in both the transmyocardial-revascularizationgroup and the medical-therapy group was defined a priori asdeath, Q-wave myocardial infarction, two cardiac-related hospitalizationswithin a 3-month period, three cardiac-related hospitalizationswithin a 12-month period, or an inability to withdraw intravenousantianginal medications on at least two attempts in a 48-hourperiod. Data on treatment failure were available at 12 monthsfor 273 of 275 patients (99 percent).
Myocardial perfusion was assessed with the use of dipyridamole–thalliumstress testing, with images obtained while the patient was atrest, under conditions of drug-induced stress, and after a four-hourdelay. Imaging was performed at base line in all patients andat 3, 6, and 12 months in the first 160 patients enrolled inthe study. Computerized quantification of ischemic changes,perfusion defects at rest, and delayed perfusion defects wasperformed in a masked manner by an independent laboratory (atBrigham and Women's Hospital, Boston), with the use of the validatedEmory/Cedars–Sinai software package, version 1.0. A changein perfusion was defined as a difference of more than 10 percentfrom the base-line value. The 46 patients in the crossover groupunderwent follow-up thallium scanning only at rest and wereexcluded from this analysis. Computer-quantified, paired scans(base-line and 12-month follow-up) were available for 61 of95 eligible patients (64 percent).
Secondary End Points
Secondary end points included freedom from cardiac-related rehospitalization,survival free of cardiac events, use of cardiac medications,performance on an exercise treadmill test, and quality-of-lifescore. Freedom from cardiac-related rehospitalization, occurrenceof Q-wave and non–Q-wave myocardial infarction, and survivalfree of cardiac events were evaluated at 3, 6, and 12 months.Survival free of cardiac events was defined as freedom fromdeath, Q-wave myocardial infarction, cardiac-related hospitalization,and subsequent coronary-artery bypass grafting or percutaneousangioplasty.
The rates of use of cardioactive medications (calcium-channelblockers, beta-blockers, and nitrates) and doses were determinedat base line and at 3, 6, and 12 months. The use of cardiacsuppressants (beta-blockers and calcium-channel blockers) wasavoided during the first 48 hours after surgery, but treatmentwith nitrates, angiotensin-converting–enzyme inhibitors,and diuretics was resumed after the operation. Cardioactivemedications that had been administered before surgery were continuedfor two months after surgery and then gradually withdrawn, astolerated, on the basis of the patient's anginal symptoms. Anindependent laboratory (at Stanford University Medical Center,Stanford, Calif.) performed a masked analysis of medicationuse at 12 months for the first 160 patients enrolled in thestudy. Data were available for 126 of the 132 eligible patients(95 percent).
Exercise treadmill testing was not part of the original studydesign. Following a recommendation by the FDA, however, we modifiedthe protocol after the first 160 patients had been enrolled,eliminating follow-up thallium scanning and substituting treadmilltesting according to the Naughton protocol at 12 months. Notreadmill tests were performed at base line. Analysis of totalexercise time included only the 81 patients who underwent Naughtontesting; the 9 patients who underwent other types of treadmilltesting were excluded. To determine the average workload, expressedas metabolic equivalents (MET), Naughton and non-Naughton testresults were combined. The 11 patients who were unable to exercisebecause of angina were assigned a score of 1 MET. Exercise treadmilltests were performed in 90 of 132 eligible patients (68 percent)at 12 months.
Statistical Analysis
Since 32 percent of the patients assigned to receive medicaltherapy alone met the predefined criteria for treatment failureand were withdrawn from this study to undergo transmyocardialrevascularization in a parallel, nonrandomized study, a modifiedapproach to the statistical analysis was required for certainend points. For definitive end points recorded before crossover(treatment failure, survival free of cardiac events, and cardiac-relatedrehospitalization), an intention-to-treat analysis was used.For end points measured at 12 months (improvement in angina,results of thallium scanning, myocardial-infarction rates, medicationuse, quality-of-life scores, and performance on an exercisetreadmill test), the patients who underwent transmyocardialrevascularization were compared with the patients who receivedmedical therapy alone throughout the study. Survival at oneyear was determined with the use of both types of analyses.
A central laboratory using Statgraphics Plus, version 2.1, performedall analyses of thallium scans. Base-line scans obtained atrest, under conditions of stress, and after a four-hour delaywere compared with follow-up scans. Mean changes were calculatedfor each variable, and Student's t-test was used to analyzeunpaired data.
Kaplan–Meier estimates were used to compare the treatmentgroups at one year with respect to mortality, survival freeof cardiac events, freedom from treatment failure, freedom fromcardiac-related hospitalization, and myocardial infarction.With the exception of the analysis of thallium scans, all analyseswere performed with the use of SAS software, versions 6.11 and6.12 (SAS Institute, Cary, N.C.). The chi-square test and Student'st-test were used to compare qualitative and continuous variables,respectively, and P values of 0.05 or lower on two-tailed testingwere considered to indicate statistical significance.
Results
Primary End Points
Angina improved in a significantly larger proportion of patientsin the transmyocardial-revascularization group than in the medical-therapygroup at 3, 6, and 12 months (P<0.001 for all three comparisons)(Figure 1). At 12 months, 76 percent of the patients in thetransmyocardial-revascularization group had improvement in angina(a reduction of two or more CCS classes), as compared with only32 percent of patients in the medical-therapy group (P<0.001).The proportion of patients in the crossover group who had improvementin angina at 12 months was similar to that in the transmyocardial-revascularizationgroup. The results of the masked assessment of angina were closelycorrelated with the study investigators' assessment and differedby no more than one CCS class 80 percent of the time.
Figure 1. Improvement in Angina at 3, 6, and 12 Months in Patients Randomly Assigned to Undergo Transmyocardial Revascularization (TMR), Patients Who Received Medical Therapy Alone Throughout the Study (MT), and Patients Assigned to Receive Medical Therapy Who Met the Criteria for Treatment Failure and Underwent Transmyocardial Revascularization (Crossover).
All patients had class IV angina at base line. The improvement in angina in the medical-therapy group at 12 months reflects the reduction in the number of patients in this group as the sicker patients were withdrawn so that they could undergo transmyocardial revascularization under a separate protocol. P<0.001 for the comparison between the transmyocardial-revascularization and medical-therapy groups at all three points in time. The numbers at the bottom of the graph are numbers of patients.
In the intention-to-treat analysis, the rate of freedom fromtreatment failure at one year was significantly higher in thetransmyocardial-revascularization group than in the medical-therapygroup (73 percent vs. 47 percent, P<0.001) (Figure 2). Patientsrandomly assigned to receive medical therapy alone were twiceas likely to meet the a priori criteria for treatment failureat 12 months as patients randomly assigned to undergo transmyocardialrevascularization.
Figure 2. Kaplan–Meier Estimates of Freedom from Treatment Failure at One Year for the 132 Patients Randomly Assigned to Undergo Transmyocardial Revascularization (TMR) and the 143 Patients Assigned to Receive Medical Therapy Alone (MT) in the Intention-to-Treat Analysis.
The difference between the groups was significant (P<0.001 by the log-rank test).
Computer-quantified changes in perfusion between base line and12 months are shown in Figure 3. There were no significant differencesbetween the transmyocardial-revascularization group and themedical-therapy group with respect to changes in ischemia, defectsin perfusion at rest, or delayed defects. Furthermore, no correlationwas noted between improvement in angina and the results of thalliumscanning. Since laser energy ablates myocardial tissue, therewas concern that transmyocardial revascularization might improveangina by creating zones of infarction; however, no differencesin fixed defects were noted.
Figure 3. Changes from Base Line to 12 Months in Ischemia, Perfusion Defects at Rest, and Delayed Defects.
TMR denotes transmyocardial revascularization, and MT medical therapy.
Perioperative Morbidity and Mortality
The rate of perioperative (in-hospital or 30-day) mortalityafter transmyocardial revascularization was 5 percent (7 ofthe 132 patients died), which included 1 patient who died afterrandomization but before undergoing transmyocardial revascularization.Five patients (4 percent) died from cardiac causes: two fromleft ventricular dysfunction and three from ventricular fibrillation.Two patients died from noncardiac causes: one each from respiratoryinsufficiency and multisystem organ failure. The perioperativemortality rate among the last 100 consecutively enrolled patientswas 2 percent. Perioperative adverse events in the transmyocardial-revascularizationgroup are shown in Table 2. The perioperative mortality ratein the crossover group was 9 percent (4 of the 46 patients died).Two of the 97 patients (2 percent) who received medical therapyalone throughout the study died within 30 days after enrollment;both deaths resulted from myocardial infarctions. The mortalityrates at 30 days in the transmyocardial-revascularization, medical-therapy,and crossover groups did not differ significantly (P=0.07).
Table 2. Perioperative (In-Hospital or 30-Day) Mortality and Complications among the 132 Patients Randomly Assigned to Undergo Transmyocardial Revascularization.
In the intention-to-treat analysis, Kaplan–Meier survivalestimates at one year for the transmyocardial-revascularizationand medical-therapy groups did not differ significantly (84percent and 89 percent, respectively; P=0.23) (Figure 4). Whenthe crossover patients were considered separately, there werealso no significant differences in survival at one year (transmyocardial-revascularizationgroup, 84 percent; medical-therapy group, 88 percent; and crossovergroup, 91 percent; P=0.47) (Figure 5).
Figure 5. Kaplan–Meier Estimates of Survival at One Year for the 132 Patients Randomly Assigned to Undergo Transmyocardial Revascularization (TMR), the 97 Patients Who Received Medical Treatment Alone Throughout the Study (MT), and the 46 Patients Assigned to Receive Medical Therapy Who Met the Criteria for Treatment Failure and Underwent Transmyocardial Revascularization (Crossover).
The differences in survival were not significant.
Secondary End Points
In the intention-to-treat analysis, the Kaplan–Meier estimateof survival free of cardiac events at one year was significantlyhigher in the transmyocardial-revascularization group than inthe medical-therapy group (54 percent vs. 31 percent, P<0.001).The rate of freedom from cardiac-related rehospitalization wasalso significantly higher in the transmyocardial-revascularizationgroup (61 percent vs. 33 percent, P<0.001) (Figure 6). Thetransmyocardial-revascularization group and the medical-therapygroup did not differ significantly with respect to freedom fromQ-wave infarction (98 percent and 96 percent, respectively;P=0.56) or freedom from non–Q-wave infarction (88 percentand 93 percent, respectively; P=0.17).
Figure 6. Kaplan–Meier Estimates of Freedom from Cardiac-Related Rehospitalization at One Year in the Intention-to-Treat Analysis.
The difference between the groups was significant (P<0.001 by the log-rank test). TMR denotes transmyocardial revascularization, and MT medical therapy.
The rate of use of calcium-channel blockers at 12 months waslower in the group of patients who underwent transmyocardialrevascularization (44 percent [26 of 59 patients]) than in thegroup that received medical therapy alone (76 percent [32 of42], P=0.002). Similarly, the use of beta-blockers was reducedor discontinued in 39 percent of the transmyocardial-revascularizationgroup (28 of 72 patients), as compared with 17 percent of themedical-therapy group (7 of 42, P=0.02). Although the percentageof patients who decreased or discontinued their use of nitrateswas greater in the transmyocardial-revascularization group thanin the medical-therapy group, the difference was not significant(P=0.12).
The higher rates of improvement in angina and freedom from treatmentfailure and the reduced rates of cardiac-related rehospitalizationand use of cardioactive medications among the patients treatedwith transmyocardial revascularization, as compared with thosereceiving medical therapy alone, were reflected in the surgicalgroup's greater tolerance of exercise (5.0± 0.7 vs. 3.9±0.8MET, P=0.05) and higher quality-of-life score (21±14vs. 12±11, P= 0.003) at 12 months.
Discussion
Direct surgical or percutaneous revascularization remains themainstay of treatment for angina. Unfortunately, a subgroupof patients with medically refractory angina have small or diffuselydiseased distal vessels that are not amenable to conventionalrevascularization therapies. Transmyocardial revascularizationhas been introduced to supplement medical management of thisdifficult condition.
The perioperative mortality rate after transmyocardial revascularizationperformed with a carbon dioxide laser in patients with stableangina ranges from 1 to 20 percent.8,9,13 We performed transmyocardialrevascularization with a holmium laser in patients with medicallyrefractory class IV angina. The perioperative mortality ratein this group of patients was 5 percent (7 of 132 patients died);5 of the 7 deaths occurred during the first three months inwhich the study was conducted. The perioperative mortality ratein the last 100 consecutively enrolled patients was 2 percent,which was the same as the rate in the group of patients whoreceived medical therapy alone. The rate of perioperative complicationswas low in view of the coexisting conditions in this patientpopulation.
In one study, transmyocardial revascularization with a carbondioxide laser resulted in a higher perioperative mortality ratein patients with unstable angina than in those with stable angina(27 percent vs. 1 percent).13 In a study of transmyocardialrevascularization with a holmium laser in 85 patients who couldnot be weaned from intravenous antianginal medications, Dowlingand associates reported an operative mortality rate of 12 percent(10 of 85 patients died).15 In our study, the crossover group(patients in the medical-therapy group who could not be weanedfrom intravenous antianginal medications and underwent transmyocardialrevascularization as part of a separate protocol) and the transmyocardial-revascularizationgroup had similar rates of perioperative mortality (9 percentand 5 percent, respectively; P=0.48), survival in the Kaplan–Meieranalysis (91 percent and 84 percent, respectively; P=0.53),and improvement in angina at one year. These results suggestthat transmyocardial revascularization with a holmium lasershould be performed, when possible, in patients with stableangina but that those with unstable angina should not be deniedthis procedure.
Ventricular arrhythmia was an early concern with the use oflasers that were not gated to the cardiac cycle. The perioperativerate of ventricular arrhythmia in our trial was 12 percent,which is similar to the 10 percent rate in clinical trials usinga gated carbon dioxide laser.18
Transmyocardial revascularization performed with a holmium laserresulted in a significant improvement in angina at one yearin 76 percent of the patients in our study who underwent theprocedure, as compared with 32 percent of the patients who receivedmedical therapy alone. The subjective nature of angina assessmentintroduces the possibility of bias. Unlike previous studies,7,8,9,10,11,12,13,19ours included an independent, masked evaluation of angina. Therewas a strong correlation between the independent evaluationand that performed by the investigators, with a discrepancyof no more than one CCS class 80 percent of the time. The proportionof patients who reduced or ceased their use of cardioactivemedications was significantly larger in the transmyocardial-revascularizationgroup than in the medical-therapy group. Our findings are inagreement with those reported by other investigators8,9,13 andsupport the suggestion that relief of angina in patients treatedwith transmyocardial revascularization is not due to increaseduse of antianginal medications. Relief of angina for up to fouryears has been reported in patients who underwent transmyocardialrevascularization with a carbon dioxide laser.20 Although thebenefit of transmyocardial revascularization in our patientsmay have been due in part to a placebo effect, sustained reliefof angina and widely divergent Kaplan–Meier curves atone year (P<0.001) for freedom from treatment failure helprefute the argument that a placebo effect is an important mechanismfor the favorable results of transmyocardial revascularization.
The success of transmyocardial revascularization is thoughtto be due to improved regional blood flow to ischemic myocardium,but the precise mechanisms of its effects remain unclear. Althoughin our study the patients treated with transmyocardial revascularizationhad higher rates of improvement in angina, freedom from treatmentfailure, and freedom from cardiac-related rehospitalization,as well as better exercise tolerance and higher quality-of-lifescores at 12 months, than the patients treated with medicaltherapy alone, no significant differences in computer-quantifiedreversible or fixed perfusion defects were noted between thetwo groups.
Horvath and associates9 reported a small improvement in perfusionafter transmyocardial revascularization performed with a carbondioxide laser. These results seemingly supported the hypothesisthat transmyocardial revascularization improved myocardial perfusion.However, the follow-up was incomplete, the analysis was notcomputer-quantified, and improved perfusion was poorly correlatedwith relief of angina.21 In a prospective, randomized trialinvolving primarily patients with class III angina, Schofieldand associates19 compared transmyocardial revascularization(performed with a carbon dioxide laser) with medical therapyalone and were unable to demonstrate improved perfusion on thalliumscans obtained after transmyocardial revascularization. Althoughthe proportion of patients with improvement in angina was significantlylarger in the transmyocardial-revascularization group, it waslower than that reported in previous studies.9,16 The lowerrate of improvement in angina may reflect the enrollment ofpatients with class III angina rather than class IV angina.The failure to demonstrate improved perfusion after transmyocardialrevascularization may be due to the low sensitivity of thalliumscanning rather than to the absence of an effect. Using positron-emissiontomography, Frazier and associates7 demonstrated an improvementin subendocardial blood flow in 11 patients treated with transmyocardialrevascularization.
Angiogenesis22,23,24 and sympathetic denervation25,26,27 areplausible mechanisms for the clinical results achieved withtransmyocardial revascularization. Inflammatory cells recruitedin response to laser-induced myocardial injury may release angiogenicgrowth factors, and the actions of these growth factors mayresult in neovascularization and improved regional collateralflow. Sympathetic denervation may relieve angina without influencingmyocardial perfusion; this would explain the immediate reliefexperienced by some patients. The possibility that denervationmay lead to silent ischemia or infarction after transmyocardialrevascularization is less likely, since there was no increasein fixed perfusion defects in our transmyocardial-revascularizationgroup. The mechanism of action of transmyocardial revascularizationis probably multifactorial, with angiogenesis and denervationoccurring concurrently.
In this prospective, randomized, multicenter trial, patientswith medically refractory class IV angina who underwent transmyocardialrevascularization and continued medical therapy had significantlyhigher rates of improvement in angina, survival free of cardiacevents, freedom from treatment failure, and freedom from cardiac-relatedrehospitalization than patients who received medical therapyalone. Mortality did not differ significantly between the twogroups. Although its mechanism of action is unknown, transmyocardialrevascularization is a treatment option for patients with medicallyrefractory angina who are not candidates for conventional revascularization.
Supported by a grant from Eclipse Surgical Technologies, Sunnyvale,California.
Source Information
From the Department of Cardiothoracic Surgery, St. Vincent Hospital and Indiana Heart Institute, Indianapolis (K.B.A., C.J.S.); the Department of Cardiothoracic Surgery, University of Louisville and Jewish Heart and Lung Institute, Louisville, Ky. (R.D.D.); the Department of Cardiothoracic Surgery, Terrebonne Hospital, Houma, La. (T.L.F.); the Department of Cardiothoracic Surgery, Methodist Hospital, Memphis, Tenn. (G.P.S.); the Department of Cardiothoracic Surgery, Sacred Heart Medical Center, Spokane, Wash. (S.L.S.); the Department of Cardiothoracic Surgery, Bryan Memorial Hospital, Lincoln, Nebr. (D.M.G.); the Department of Cardiothoracic Surgery, Tampa General Hospital, Tampa, Fla. (W.W.A.); St. Thomas Heart Institute, Nashville (M.R.P.); and the Division of Cardiology, William Beaumont Hospital, Royal Oak, Mich. (W.W.O.). Presented at the American Heart Association's 71st Scientific Session, Dallas, November 7–10, 1998.The centers and investigators participating in the study are listed in the Appendix.
Address reprint requests to Dr. Allen at 8333 Naab Rd., Suite 300, Indianapolis, IN 46260, or at cvsurgeon{at}iquest.net.
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Appendix
The following centers and investigators participated in thestudy; the number of patients enrolled at each center is shownin parentheses: Albany Hospital, Albany, N.Y. — J.M. Luber,Jr., and J.M. Kelley (3); Audubon Hospital, Louisville, Ky.— T. Matthew (8); Brook Army Hospital, Fort Sam Houston,Tex. — D. Cohen (1); Bryan Memorial Hospital, Lincoln,Nebr. — D.M. Gangahar (15); University of Louisville,Jewish Heart and Lung Institute, Louisville, Ky. — R.D.Dowling, A. Lansing, and A.D. Slater (31); Memorial Hospital,Springfield, Ill. — J.A. Schneider (11); Methodist Hospital,Memphis, Tenn. — G.P. Schoettle (25); Ochsner Hospital,New Orleans — J.L. Ochsner (2); Sacred Heart Hospital,Spokane, Wash. — S.L. Selinger, S.M. Cattaneo, and D.Sandler (21); St. John Hospital, Detroit — A. Kafi andT. Schreiber (5); St. Joseph's Hospital, Atlanta — D.Murphy and J.A. Wolfe (8); St. Thomas Heart Institute, Nashville— M.R. Petracek (14); St. Vincent Hospital and IndianaHeart Institute, Indianapolis — K.B. Allen, D.A. Heimansohn,and J.J. Schier (64); Tampa General Hospital, Tampa, Fla. —W.W. Angell, F. Matar, P.P. Mckeown, and N.J. Sears (15); TerrebonneGeneral Medical Center, Houma, La. — T.L. Fudge (32);University of Colorado Hospital, Denver — R.K. Brown (3);University of Iowa Hospital, Iowa City — W.E. Richenbacher(12); and William Beaumont Hospital, Royal Oak, Mich. —J.S. Basset (5).
Transmyocardial Laser Revascularization
Downing S. W., Williams S. G., Wright D. J., Tan L. B., Frazier O.H., March R. J., Horvath K. A., Allen K. B., Lange R. A., Hillis L. D.
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N Engl J Med 2000;
342:436-438, Feb 10, 2000.
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