Spinal cord stimulator trial underway for patients with refractory angina

In the STARTSTIM trial, neurostimulation is being studied as a therapy for patients who cannot be revascularized.

Implantable spinal cord stimulation devices may someday become an additive therapy for patients with end-stage coronary disease who are not able to be revascularized and have recurrent angina.

“For reasons that are unknown at the present time, this approach has been a significant advance in treating several groups of patients,” said Douglas P. Zipes, MD, distinguished professor of medicine at the Indiana University School of Medicine.

One such group are patients who have intractable back pain for whom neurostimulation has already been shown to provide significant relief. “A second group are those who have severe angina and who have reached the point where they cannot be revascularized and are continuing to have angina despite optimal medical management,” Zipes told Cardiology Today. He is the editor of Cardiology Today’s Electrophysiology and Arrhythmia Disorders section.

In Europe, approximately 3,500 neurostimulation devices have been implanted. This approach has provided patients with significant pain relief from angina, according to Zipes.

Pacemaker-like device

Spinal cord stimulation involves placing an electrode in the epidural space alongside the spinal cord, usually at the T1 or T2 level in the upper thoracic region. The electrode is connected to a “pacemaker-like” device. This device delivers stimuli directly to the electrode, which is then transmitted to the spinal cord. The entire system is implanted subcutaneously.

Douglas Zipes

The mechanism by which neurostimulation works is not yet clear. “It has been suggested that the stimulation may actually block neural impulses going to the brain that would signify a patient is having chest pain. It has also been suggested that perhaps it creates the release of endorphins,” Zipes said.

Zipes and his colleagues have researched a different mechanism in angina relief using the neurostimulation approach, however. “We have demonstrated in dogs that spinal cord stimulation actually increases vagal activity and decreases sympathetic activity to the heart; that might be the mechanism by which angina is relieved.

“We’ve also shown that it decreases ventricular arrhythmia associated with acute myocardial ischemia, so conceivably it could be an antiarrhythmic as well as an antianginal approach.” The manuscript of this particular research is currently under review, Zipes noted.

Clinical trial underway

Aside from research on the mechanisms of neurostimulation, Zipes is the primary investigator of the Stimulation Therapy for Angina Refractory to Standard Treatment, Interventions and Medication trial, or STARTSTIM.

STARTSTIM is a multicenter trial being conducted on a spinal cord stimulator developed by Medtronic, called the Itrel 3. The trial, sponsored by the company, is currently enrolling patients at 20 to 30 centers in the United States and Canada. Patients being randomized for inclusion in the trial have end-stage, nonrevascularizable coronary disease and recurrent angina.

The Intrel 3 is a "pacemaker-like" neurostimulation device that may provide relief from recurrent angina.

All patients will receive the device, but one group will receive low levels of stimulation while the second group will receive higher levels of stimulation. “We’re attempting to demonstrate — in a prospective, randomized, controlled fashion — that indeed this therapy is beneficial in patients with angina,” Zipes said.

The trial has so far randomized a significant number of patients en route to its goal enrollment of about 230 patients. Because the trial is blinded, Zipes could not yet comment on any early trial findings. He noted, however, that in several centers patients have already been treated with neurostimulation outside of the STARTSTIM study.

“Since this is an approved therapy for chronic back pain, it is usable off-label for patients similar to those enrolled in our study, and they’ve shown a significant reduction in anginal episodes. I’m convinced that the approach does work,” he said.

Additive therapy

Zipes sees spinal cord stimulation as comparable to biventricular pacing for heart failure, because spinal cord stimulation is additive to maximal beneficial medical therapy. “For the patient who is still symptomatic despite the optimal medical management of their coronary disease, then this can be considered as an alternative therapy,” Zipes said. “Certainly, all of the customary and usual noninvasive therapeutic approaches need to be considered first.”

Device implantation in STARTSTIM is being performed by electrophysiologists in concert with either anesthesiologists or neurosurgeons. “The reason anesthesiologists get involved is because they are often approached for nerve-blocking therapies in patients with refractory pain, as well as for the fact that they commonly do epidural anesthesia in patients,” he said.

The implantation technique is simple, according to Zipes, and it is “far less complex than biventricular pacing implants, which electrophysiologists do routinely,” he said.

“If this approach is ultimately as efficacious as I think it will be, it will fall to interventional cardiologists to be the implanters, the same way pacemakers started in the hands of surgeons and cardiologists have taken over.”

Population, costs, other therapies

Zipes estimated that 10% of the population of people with coronary disease would fit into the category of non-revascularizable with recurrent angina despite optimal medical management.

The cost of neurostimulation is considerably lower than implantable cardioverter defibrillators. The company plans to offer the complete spinal cord stimulator system for less than $10,000.

As far as other therapies for this population of patients, Zipes said that only counterpulsation is an alternative. While people who use it find it does improve angina, “it is also a significant time commitment,” Zipes said.

“Once we demonstrate the effectiveness of spinal cord stimulation in a well-done scientific trial, there should be reasonable acceptance of it, with interventional cardiologists working with neurosurgeons or anesthesiologists,” he said.

“If you think back to 1980, the requirements for receiving a defibrillator were to have survived two cardiac arrests. See where we are 25 years later? Acceptance of this may be slow, but ultimately if it indeed is as efficacious as preliminary data show, it will be accepted rapidly.” – by Evan Young

Dr. Zipes is a consultant for Medtronic and is the primary investigator of STARTSTIM.