Transmyocardial laser revascularization for management of refractory angina

INTRODUCTION — Despite the increasing success of conventional medical therapeutic approaches and the continued development and improvement of mechanical revascularization approaches (eg, drug-eluting stents), a significant number of patients with ischemic heart disease and angina pectoris cannot be successfully managed. (See "Chronic coronary syndrome: Overview of care" and "Chronic coronary syndrome: Indications for revascularization".)

In addition, a substantial proportion of patients undergoing percutaneous coronary intervention or coronary artery bypass surgery do not achieve complete revascularization and, despite maximal medical therapy, many of these patients continue to experience residual anginal symptoms or myocardial ischemia requiring hospitalization. The outcome with medical therapy is poor and one study of 59 such patients found that the one-year rate of myocardial infarction or death was 25.5 and 17 percent, respectively [1].

There are several novel therapeutic strategies that are currently being evaluated for treating patients with refractory angina [2]. In 2002, a report from the European Society of Cardiology reviewed these strategies, including transmyocardial and percutaneous laser revascularization, and summarized the strength of the evidence supporting their use (table 1) [3].

The role of transmyocardial laser revascularization will be found here. Other modalities, including medical therapies such as antagonism of endothelin-1 and chelation, and invasive modalities such as promotion of angiogenesis, spinal chord stimulation, and external balloon counterpulsation are discussed elsewhere. (See "Therapeutic angiogenesis for management of refractory angina" and "New therapies for angina pectoris".)

TMLR — Transmyocardial laser revascularization (TMLR) is a technique that uses laser ablation to create transmural channels in the ischemic myocardium in order to restore myocardial perfusion. It shows promise in patients who have angina that is refractory to medical therapy and who are not candidates for surgery or angioplasty. It has also been used as an adjunctive therapy with minimally invasive coronary artery bypass graft surgery to achieve more complete revascularization [4]. Animal studies have shown that TMLR reduces infarct size and preserves myocardial function after an infarction [5]. (See "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use".) However, despite United States Food and Drug Administration (FDA) approval of some of the laser devices for treatment of intractable angina, these techniques are in the early stages of their development; while they offer much promise, there is substantial risk associated with their use.

Mechanism of effect — The physiologic premise behind the application of TMLR is based upon the work of early investigators who were seeking to emulate reptilian circulation in the mammalian heart by creating direct conduits for blood flow from the left ventricular cavity into the myocardium (figure 1) [6]. A variety of techniques, including needle acupuncture, mechanical drilling of the left ventricular conduits, and insertion of T-tubes into the myocardium, were attempted with variable success. Development of the clinical high power CO2, holmium:yttrium-aluminum garnet, and excimer laser systems led to FDA approval of laser myocardial revascularization as a stand-alone therapy in patients with intractable angina. This decision was based upon the demonstration of significant reduction in anginal symptoms as assessed by angina class scale and improvement in exercise capacity. However, there has been little objective evidence of improvements in myocardial perfusion as assessed by nuclear perfusion imaging.

Further studies in large animal models have shown that the original premise of TMLR, passive myocardial perfusion of oxygenated blood via newly created channels, is almost certainly false. Essentially, all channels are closed by 24 hours, possibly within the first hour, and direct measurement of channel-supplied myocardial blood flow suggests that the increase in myocardial blood flow is minuscule [7-9]. The lack of improved blood flow has also been observed clinically. As an example, one study performed positron emission tomography prior to and at 7.5 and 34.6 weeks after TMLR in seven patients; despite a reduction in angina, there was no change in myocardial blood flow at rest and during dobutamine infusion or in coronary vasodilator reserve in lasered and unlasered regions [10]. Thus, the mechanism of the observed clinical benefit, ie, reduction in symptom intensity, following TMLR remains uncertain. A number of possibilities have been proposed to explain these results:

●Myocardial angiogenesis resulting from the upregulation and release of vascular endothelial growth factors and inflammatory mediators [11,12].

●Myocardial sympathetic denervation [6,13,14].

●Myocardial fibrosis that results in a tethering action to improve myocardial function and promote favorable remodeling.

Regardless of the mechanism, there is usually a delay in clinical benefit; improvement in anginal class is often not evident for at least three months postoperatively [15]. This situation places patients at high risk for perioperative morbidity and mortality.

Clinical trials — Several clinical trials have reported encouraging results following TMLR in patients with refractory angina who had lesions not amenable to revascularization or who were at high risk for revascularization [16-23]. The following reports illustrate the major findings:

●One trial involved 192 patients with refractory angina and left ventricular free-wall ischemia that was not amenable to direct coronary revascularization [16]. After a one-year follow-up, more patients undergoing TMLR improved by at least two Canadian Cardiovascular Society (CCS) classes (72 versus 13 percent for continued medical therapy) (table 2) and more had a significant improvement in quality of life. Myocardial perfusion, as assessed by thallium scanning, improved by 20 percent in the TMLR group compared to a 27 percent worsening in the medical group (figure 2). Overall survival at one year was the same in the two groups (85 versus 79 percent) but there was a marked reduction in hospitalization for unstable angina with TMLR (figure 3).

●Similar findings were noted in a trial of 275 patients with refractory angina [17]. At one year, more patients undergoing TMLR had an improvement in angina (76 versus 32 percent with medical therapy) (figure 4), a higher rate of survival free of cardiac events that was primarily due to freedom from cardiac related hospitalizations (61 versus 31 percent) (figure 5), and higher exercise tolerance and quality-of-life scores. There was no difference in myocardial perfusion with thallium imaging or in one-year survival (84 versus 89 percent).

At five years, patients treated with TMLR continued to have more frequent improvement in angina than those treated medically (88 versus 44 percent improved by two or more angina classes) (table 2) [24]. The survival rate was also significantly higher for patients initially assigned to TMLR; however, this difference disappeared when patients crossing over were analyzed separately.

●In a long-term follow-up of a Norwegian trial of 100 patients, anginal symptoms and hospitalization for unstable angina were still significantly reduced at 43 months [23]. There were no differences in the number of myocardial infarctions or mortality (22 versus 24 percent).

These benefits have not been confirmed in all trials [25,26]. One trial randomly assigned 188 patients with refractory angina due to severe coronary disease not amenable to revascularization with TMLR plus usual medication or to medical management only [25]. The perioperative mortality was 5 percent. After a one-year follow-up, patients who underwent TMLR had better relief of angina than the medically treated patients, but there was no difference in exercise capacity as assessed with treadmill exercise testing and a nonsignificant trend toward reduced survival (89 versus 96 percent in the medically treated patients).

Limitations — A limitation to these observations is that the surgical trials were not blinded, thereby permitting a possible placebo effect. The DIRECT trial, which is the only major blinded study of laser myocardial revascularization, failed to show any benefit compared to continued medical therapy [27]. (See 'DIRECT trial' below.)

Complications — Complications after TMLR are almost exclusively cardiac-related and include myocardial infarction, left ventricular failure, atrial fibrillation, and ventricular arrhythmias. Risk factors for an adverse event include CCS class IV status, unprotected left main stenosis, and diabetes mellitus [28].

The reported perioperative mortality has ranged from 3 to 5 percent in most reports [16,25,29], but rates as high as 12 percent have been described [26,30]. As noted above, however, the increase in short-term mortality does not appear to result in reduced survival at follow-up at one to four years [16,17,23,25].

The perioperative mortality may be related to acute adverse effects of TMLR on the myocardium that might lead to reduced myocardial blood flow, regional ischemia, and diastolic dysfunction, a result of an increase in regional myocardial edema [31]. In addition, the risk of both perioperative and long-term mortality may be reduced in patients with good blood flow to at least one region of the heart through a native artery or a patent vascular graft (5 versus 25 percent postoperative mortality in patients who did not have adequate blood flow to any region, a benefit that persisted at one year) (figure 6) [30].

Use in refractory unstable angina — Patients with unstable angina that is refractory to medical therapy are at high risk for myocardial infarction and death. Although such patients are usually referred for revascularization by either angioplasty or bypass surgery, there are patients in whom revascularization is not feasible, including those with failed prior procedures, diffuse coronary artery disease, distal stenosis, or small coronary arteries. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization" and "Percutaneous coronary intervention of specific coronary lesions", section on 'Long lesions or diffuse disease' and "Percutaneous coronary intervention of specific coronary lesions", section on 'Small coronary arteries'.)

The role of TMLR as an alternative approach for treatment of such patients was evaluated by a series of 76 patients with unstable angina of seven days duration who had three failed attempts at weaning from intravenous antianginal drugs; the outcome of these patients was compared to 91 patients with chronic stable angina who underwent TMLR [32]. The intensive care unit and hospital stay after TMLR was the same in both groups. Although perioperative mortality (≤30 days post-TMLR) was higher in the unstable angina group (16 versus 3 percent), the late mortality (up to one year after TMLR) was the same (13 versus 11 percent). Among the survivors, 82 percent had a reduction of angina by two or more classes at one year, which was similar to the outcome in patients with chronic stable angina.

Combined TMLR and CABG — The safety and efficacy of TMLR combined with coronary artery bypass grafting in patients with coronary disease not amenable to complete revascularization with bypass surgery was evaluated in a study of 263 patients [33]. Patients were randomly assigned to bypass grafting of suitable vessels plus TMLR of areas not graftable or bypass surgery alone, with nongraftable areas left unrevascularized.

The operative mortality was lower with the combined approach (1.5 versus 7.6 percent for bypass surgery alone) and the need for inotropic support or use of an intra-aortic balloon pump was less after surgery [33]. At thirty days, freedom from major adverse cardiac events (death or myocardial infarction) was significantly greater with TMLR (97 versus 91 percent), but this difference was no longer significant at one year. There was also no significant difference in relief of angina at one year.

At five years, patients treated with TMLR had significantly greater relief of angina by several measures [34]. However, survival at this time was not significantly different between the two groups.

PERCUTANEOUS TMLR — In order to reduce the perioperative mortality associated with surgical transmyocardial laser revascularization (TMLR), percutaneous TMLR has been performed in the catheterization laboratory using a holmium:yttrium-aluminum garnet laser, which can channel energy through flexible fibers, unlike the CO2 laser, creating channels in the presence of blood [35,36]. Preliminary phase I and open label phase II studies of percutaneous TMLR found similar results to those seen with the open chest CO2 TMLR studies: an improvement in angina class and exercise capacity with minimal or no change in nuclear perfusion scans [37,38].

The PACIFIC trial randomly assigned 221 patients with refractory angina (Canadian Cardiovascular Society class III or IV) (table 2) to percutaneous TMLR or conventional medical therapy [39]. At 12 months, those undergoing percutaneous TMLR had a greater median increase in exercise tolerance (89 versus 12.5 seconds [14.4 versus 5.5 percent]) and the angina was more likely to be class II or lower (34 versus 13 percent of patients). There was no difference in survival or the combined end point of death, myocardial infarction, or hospital admission between the two groups.

However, neither symptomatic nor survival benefits from percutaneous TMLR were noted in a trial of 141 patients with class III or IV angina (table 2) due to one or more chronically occluded coronary arteries who had failed previous percutaneous coronary intervention [40] or in the DIRECT trial.

DIRECT trial — The DIRECT trial is the only major blinded study of laser myocardial revascularization [27]. In this trial, 298 patients with refractory angina who were suboptimal candidates for coronary artery bypass graft surgery or percutaneous coronary intervention (PCI) were randomly assigned to low- or high-dose laser channels or no laser channels, blinded as a sham procedure. There was no benefit of TMLR compared to continued medical therapy in terms of patient survival, angina class, quality-of-life assessment, exercise duration, or nuclear perfusion imaging.

These findings raise doubt about previous positive studies, since they underscore the powerful placebo effect in patients with end-stage cardiac disease that can lead to physiologic benefits as well as improved symptoms. The placebo effect can persist for 30 months or more [41].

Combined with PCI — The safety and efficacy of PCI, including angioplasty, stenting, and/or atherectomy, combined with percutaneous TMLR performed in the same myocardial territory served by the treated vessel was addressed in a pilot study of 26 patients with class III/IV angina [42]. Major periprocedural adverse events, due to subacute vessel closure or tamponade, occurred in 11.5 percent. At six months, 19 percent of patients required repeat PCI for restenosis, 12 percent had class III/IV angina, and the mortality was 19 percent.

SUMMARY AND RECOMMENDATIONS — With the availability of drug-eluting stents and novel devices for chronic total occlusion, the number of patients who are truly not amenable to coronary artery bypass graft surgery or percutaneous coronary intervention is shrinking. (See "Percutaneous coronary intervention of specific coronary lesions", section on 'Chronic total occlusion'.)

We agree with the National Institute for Health and Clinical Excellence in the United Kingdom, which concluded that neither transmyocardial laser revascularization (TMLR) nor percutaneous TMLR should be used [43]. This is based on evidence of an absence of benefit (no significant improvement in myocardial function or survival) and the presence of safety concerns (both may be associated with an increase in periprocedural complications).