St. Jude facing safety questions regarding tiny new pacemaker

St. Jude Medical's tiniest pacemaker is supposed to eliminate complications sometimes seen in older versions of the device. The Little Canada-based medical technology company called it one of the most important advances in heart-pacing technology after acquiring the technology in 2013.

Since then, St. Jude has twice halted implants of its Nanostim pacemaker in Europe, and the company is now examining a report that a patient had one of the devices break free and get stuck in the artery that leads to the lungs. That incident followed a letter sent to European doctors earlier this year disclosing statistics on eight other incidents in which the device came dislodged, including six in the United States.

The company says a small number of such events are to be expected. But physicians, and some stock analysts, are closely watching the safety profile of tiny novel pacemakers like the Nano­stim in ongoing studies. Advanced versions of the pen-cap sized devices may one day revolutionize cardiac pacemaking, but only if they're at least as safe as traditional pacemakers.

"The trial is ongoing, so we will be getting more information. But everything I have seen would suggest that the leadless pacemaker meets that high bar as being as safe as a traditional pacemaker," said Dr. Paul Friedman, the Mayo Clinic principal investigator in St. Jude's ongoing national safety study. "In my heart of hearts, I wouldn't offer this to patients if I didn't think it was an important advance."

Last year, in the wake of the news that two early patients in the European Nanostim study died after implants, Friedman said the company narrowed the eligible study population there. Since then St. Jude has been rewriting its training manuals for European doctors while consulting with U.S. regulators about plans to seek full commercial approval from the Food and Drug Administration later this year, according to statements from the company and analysts.

"St. Jude Medical is confident in the safety profile of Nanostim," spokeswoman Kate Stoltenberg wrote in an e-mail. "We've analyzed data from our worldwide studies, and what we're seeing are outcomes that meet or exceed the current safety profiles of traditional pacemaker technologies."

Traditional pacemakers sit under the skin near the shoulder, requiring a chest incision to implant the device and its wires, called leads, that deliver low-power electric stimulation to fix a slow heart beat. While rare, the most common complications are infection in the pocket of tissue around the device, and leads moving out of place.

The new pacemakers like Nanostim require neither a pocket nor leads. They're small enough to fit entirely inside the right ventricle of the heart, placed there using a long, thin tube guided into the heart from a small puncture in the groin.

Nanostim was the first device of its kind. St. Jude got approval to sell it in Europe in 2013, and did the first U.S. implant in February 2014 in the ongoing clinical trial. Stoltenberg said more than 700 devices have been implanted worldwide.

Medtronic PLC, which is based in Dublin, Ireland, but has its cardiac rhythm unit headquarters in Mounds View, earlier this year got European approval to sell an even smaller leadless pacemaker called the Micra. Medtronic has started a large-scale trial in the U.S.

Massachusetts-based Boston Scientific, whose cardiac-rhythm division is located in the Twin Cities, is developing a leadless pacemaker so new it doesn't yet have a name.

Since the device sits inside the heart, attention has focused on the best ways to securely attach the devices without damaging the heart tissue. St. Jude's device screws into the tissue, while Medtronic's uses flexible metal hooks called tines for fixation. Boston Scientific executives said their design makes use of tines as well.

In the first four months of 2014, St. Jude analyzed 147 patients as part of a post-approval follow-up study and found six cases in which the device appeared to perforate small holes in the patients' heart muscles or cause fluid buildup, and two more cases in which the device came dislodged, according to data in a European "Dear Doctor" letter dated Feb. 20, 2015, which was obtained by the Star Tribune.

According to a research note from Glenn Novarro at RBC Capital Markets, St. Jude executives said the deaths were related to physicians' implant techniques and patient-selection criteria, not flaws with the device. The European study was restarted in June 2014, and as of January had seen two more incidents of swelling at the attachment site, but no further dislodgments.

However, the European study was halted a second time, and will not restart without approval from regulators there. The February letter to European doctors said the pause was declared "as a precautionary matter" to evaluate new cases of abnormal fluid buildup, known as pericardial effusion, in the tissue surrounding the heart.

The same letter disclosed "serious adverse device effects" in the ongoing U.S. trial: five incidents of perforation or effusion, and six cases of dislodgment, among a study population of 322 patients. Those data only include events through January. A company spokeswoman said newer data is not available.

"Perforations and dislodgments are anticipated adverse events with traditional pacemakers as well as the Nano­stim leadless pacemaker," St. Jude's Stoltenberg wrote. "The perforation and dislodgment rates for Nanostim are in-line with rates reported in literature from traditional pacemaker technologies."

The Mayo's Dr. Friedman cautioned against drawing conclusions about safety from early reports. For example, he was told that one of the European patients who died had two other procedures the week before — confounding factors that would have eliminated that person from eligibility in any of the 56 U.S. hospitals in the study, and would now exclude that person under the revamped criteria overseas.

On March 26, an unidentified hospital reported to the Food and Drug Administration that a Nanostim dislodged and got stuck in the patient's pulmonary artery. After initial attempts to fish it out failed, the patient was admitted to intensive care and had a successful procedure to remove it the next day, according to the public adverse-event report on file with the FDA. The report classified the issue as a problem with the product.

Asked about the report, Stoltenberg noted that the FDA's adverse-event reporting system doesn't have a thorough review of events. "It would be premature to indicate the final disposition of the event," she wrote.

All medical devices carry risks. A St. Jude website on Nanostim cites peer-reviewed clinical research to estimate that 4 percent of traditional pacemakers come with complications, including 1 percent in which the pacemaker's pocket becomes infected and another 3 percent in which the leads become displaced.

Among the first 322 U.S. Nanostim patients through Jan. 5, all the serious adverse events taken together — 20 of various types, in total — amount to a 6 percent rate of complications. Dislodgments happened in 1.9 percent of the patients, and perforation or effusion happened in 1.6 percent. No infections were reported.

Medtronic, meanwhile, reported safety data for its Micra at an industry conference in Boston earlier this month. A company news release declared all 140 of its first Micra patients on three continents had "a successful implant procedure."

But the data say eight of the patients — nearly 6 percent of the study population — had serious adverse events, including two that required prolonged hospitalization. "This rate is in line with rates observed in studies of traditional pacemakers," the Medtronic announcement says.

Over at Boston Scientific, where engineers are still designing their leadless pacemaker, executives said their slower approach to designing such a device is partly a calculated decision based on the goal of achieving the highest safety statistics possible.

"Nothing is 100 percent," Dr. Kenneth Stein, chief medical officer of Boston Scientific's heart-rhythm management division, said in an interview. "Everyone in this business understands that. I think patients understand that. But we want to make sure that when you bring out a new technology that it is at least as safe as the one it is replacing."

Mayo Clinic's Friedman said he's glad multiple leadless technologies are under development, because some designs might be better for certain patients than others, and competition drives companies to improve their devices.

"One of the things I worry a little bit about, frankly, is that sometimes when there are competitors in a space, they make what I'll call provocative comments to suggest that one is better than the other," Friedman said. "The reality is, we don't have long-term data on any of the devices."

Joe Carlson • 612-673-4779

Twitter: @_JoeCarlson