In 1996, physicians told Pat Gibbs, a 67-year-old cardiac patient from Alabama with severe angina, that nothing could be done for her. Refusing to give up, Gibbs underwent transmyocardial laser revascularization (TMR) therapy and today, lives pain-free. Some cardiologists say TMR’s benefit is merely a placebo effect, others say it is real. A growing market for the procedure, however, could muzzle the naysayers.
TMR is a surgical revascularization procedure that may be performed through either a minimally invasive or an open surgical approach. During the procedure, a cardiac surgeon utilizes a laser to create approximately 15 to 40 millimeter-sized channels through the myocardium to promote increased blood flow.
Experts have debated the mechanisms of relief and have dismissed the patent channel theory and the placebo effect as significant contributors. “The mechanism is likely multifactorial with denervation responsible for the acute benefits and angiogenesis responsible for the long-term benefits,” according to Allen et al (Anesthesiology Clin 2008;26:501–519).
The FDA in the late 1990s approved two TMR laser systems: the holmium:yttrium-aluminum-garnet (Ho:YAG) system (Cardiogenesis) and the CO2 Heart Laser (PLC Medical Systems). Gibbs was treated with the CO2 laser at the Washington Hospital Center in Washington, D.C., after she was rejected for a heart transplant because of her age.
In 2004, the Society of Thoracic Surgeons (STS) published guidelines that gave TMR a Class I/Level A recommendation as the sole therapy for patients with an ejection fraction greater than 30 percent and Class III or IV angina that is refractory to maximal medical therapy (Ann Thorac Surg 2004 Apr;77:1494-502). Five randomized trials showed a significant improvement in angina but none of the trials demostrated a significant survival benefit. In their 2008 analysis of the evidence, Allen et al cited a five-year follow-up that showed a significantly increased survival for patients randomized to Ho:YAG TMR compared with medical therapy (65 percent vs. 52 percent).
“It’s difficult to believe the placebo effect works for five years,” says Mark Tauscher, president and CEO of PLC Medical Systems.
The STS guidelines also support TMR as an adjunct to CABG, albeit with weaker evidence (Class IIa/Level B). Both TMR alone or in conjunction with CABG are reimbursable procedures. The guidelines do not consider percutaneous myocardial revascularization (PMR), which is not an approved technique in the U.S.
In 2005, Martin Leon, MD, and colleagues from Columbia University published results from a randomized, placebo-controlled trial with patients treated with a percutaneous approach they called direct myocardial revascularization (DMR). They concluded that treatment with DMR “provides no benefit beyond that of a similar sham procedure in patients blinded to their treatment.” But they went further to declare that the benefits from surgical TMR also could be attributed to a placebo effect (J Am Coll Cardiol 2005;46:1812-1819).
Keith A. Horvath, MD, director of the Cardiothoracic Research Program at the National Heart, Lung and Blood Institute, took Leon et al to task for extrapolating their findings from PMR to TMR. He wrote that at the time when Leon’s study was actually conducted (1999-2000), the PMR devices created a “3- to 4-mm endocardial laser divot” as opposed to the TMR devices, which create “channels through the full thickness of the myocardium.” Horvath also said that while the degree of pain relief might be subjective, objective imaging data show improved perfusion following TMR (J Am Coll Cardiol 2006;48:2354-55).
Leon responded, in the same issue of JACC, saying that he and his colleagues believed that their study “accurately highlights the potent placebo effects in this patient population. As such, this causes us to doubt the clinical benefits referenced in the surgical TMR literature.” He also said that most studies showed no quantitative perfusion improvements after surgical TMR and that even TMR plus CABG has no proven benefit over CABG alone. Leon did not respond to a request for a comment.
Allen et al cited several studies that used PET imaging and echocardiography to demonstrate an improved myocardial blood flow in lased regions. In those studies, there also was no perfusion improvements “following a sham thoracotomy or the use of a non-injury-producing laser.” Horvath says that he has conducted preclinical studies with MRI and echocardiography that show an improved perfusion and regional wall motion after therapy with the CO2 laser but not with the Ho:YAG device. Horvath has yet to find a publisher for the studies.
Richard P. Lanigan, president of Cardiogenesis, says that the Ho:YAG laser device used by Leon relied on a single pulse delivered to the endocardial surface of the left ventricle to an average of 20 locations, compared to an average of 35 full-thickness channels performed in surgical TMR. “From a dosage perspective, Dr. Leon’s laser system delivered approximately 5 percent the amount of directed laser energy to the targeted heart muscle compared to surgical TMR,” Lanigan says. The Cardiogenesis percutaneous system that uses a multiple-pulse Ho:YAG device has shown a good response rate, he says, adding that Leon’s conclusions should be applicable only to the specific system he used.
Percutaneous or not
In 1998, Cardiogenesis received the CE Mark for its Axcis PMR system. Study results showed the device contributed to a 50 percent reduction in mean angina class and a significant improvement in exercise tolerance. Lanigan says the company has continued to work with the FDA towards approval of its percutaneous delivery devices, but that his main focus is on advancing the company’s TMR technology.
In 2007, the FDA approved a minimally invasive robotic hand piece delivery system, the PEARL 5.0, from Cardiogenesis, that works in conjunction with Intuitive Surgical’s da Vinci robotic system. Lanigan says that studies show a procedure time similar to traditional thoracotomy approach, which “is enlightening because critics of robotics in cardiac surgery complain that it is cumbersome.” In 2006, the company gained CE Mark for the Phoenix, which combines the delivery of a therapeutic biologic with TMR laser therapy. The company is working with several European centers in the initial clinical application of the device.
PLC Medical, on the other hand, has no plans to develop PMR devices, according to Tauscher. PLC continues to educate cardiologists and referring physicians about the risk versus benefits of TMR. “Within the context of a surgical intervention for a relatively sick group of patients, TMR has a 2 to 3 percent risk, consistent with CABG procedures. I think many patients would be willing to take on that risk, but they can’t if their physicians don’t know about or understand TMR,” he says.
Tauscher is encouraged because PLC’s second quarter revenues rose over first quarter sales this year. In March 2007, Novadaq Technologies acquired the rights to sell and market PLC’s CO2 TMR laser device domestically. Tauscher says the partnership could prove fruitful, given Novadaq’s intraoperative imaging technology, which could “influence the application of TMR.”
Perhaps the best outreach effort would be to trot out Gibbs, who was told 12 years ago “to go home and pray.” Prior to her TMR treatment, she had received a variety of therapies including numerous medications, several interventions and two coronary bypass surgeries. “Many more patients can be given an option to live pain-free through TMR if only their cardiologists and referring physicians know about the technique,” Tauscher says.