The astounding 19-year journey to a sea change for heart patients

When she was 9, in 1949, Brunhilde “Brunie” Seffens contracted scarlet fever. In postwar Germany, where she lived, antibiotics were not broadly used. Doctors told her she would probably develop heart problems when she was older.

Seffens grew up to become a computer engineer. She learned computer programming on an IBM mainframe in 1965, and met her husband, Marty, at Xerox, where both worked. She didn’t develop heart problems until 2014, when a doctor told her that the valve on her aorta, the blood vessel that brings blood from the heart to the rest of the body, was built up with calcium and not working properly. The solution? Open-heart surgery. She was terrified.

“Your heart is stopped, and they put you on a lung and heart machine,” Seffens said in an interview. “People go through excruciating pain and suffering and I was mainly very scared I would not survive this.”

But Seffens was about to run into one of the defining features of medical breakthroughs: They happen in slow motion, as clinical trials are conducted and regulators weigh factors like efficacy and safety. There was a procedure that would spare Seffens surgery. It had been developed by a California company called Edwards Lifesciences. Its transcatheter aortic valve replacement (TAVR) snakes a compressed valve up an artery into the heart, and expands it. But the Food and Drug Administration insisted that TAVR valves be used only in patients who were too sick for surgery until their benefits were proven. And Seffens was told she was not a candidate.

In May 2017, however, her condition started to plummet. Doctors kept telling her she needed open heart surgery, and she kept trying to avoid it. On July 3, 2017, she woke up and could barely breathe. Marty drove her three hours from their home in Palm Desert, Calif., to the emergency department at the University of California, Los Angeles. There, they offered her a 50 percent chance at TAVR: She could enter a clinical trial being run in patients at low surgical risk; as part of the trial, she might still be assigned to undergo surgery. She got lucky. She got the TAVR. The next day, she was walking up and down the hills and stairs of the J. Paul Getty Museum. “I’ve been feeling absolutely fantastic ever since,” she said.

She was not alone. Last weekend, at the annual meeting of the American College of Cardiology, researchers presented data from Brunie’s study, sponsored by Edwards, and from a second clinical trial sponsored by rival Medtronic. Both showed dramatic results: The heart valve procedure was not only safe for patients but effective. Janet Wyman, a doctor of nursing practice and administrator at Henry Ford Hospital in Detroit, said at a press conference that the paradigm had not just shifted, it had completely flipped.

“The conversations for our patients will be completely different,” she said. Instead of TAVR being an alternative to surgery, many experts said, surgery would be the rare alternative to TAVR.

But the shift didn’t happen in an instant, like the release of the personal computer or the iPhone. Instead, there were fits and starts. There were worries that patients were at risk and that doctors and entrepreneurs were getting rich improperly; there was a constant risk of failure. It took 19 years.

The story of TAVR starts not with a researcher or even a typical entrepreneur, but with a corporate lifer looking to climb to the top rung. Michael Mussallem was a 20-year veteran at Baxter Health. He’d become a chemical engineer because he heard they made a lot of money, and had originally gotten a job helping to make Prestone antifreeze at Union Carbide. He found it unfulfilling. “I saved a few engine blocks, but it’s not like saving lives,” he said recently.

In the 1980s, Baxter bought a health care business. At first, Mussallem worked on heart-lung machines, used to keep patients alive when their hearts are stopped during open-heart surgery. He liked knowing that there were patients being helped by the machines he worked on. He became one of the leaders of Baxter’s heart business, but it was one of the worst performing units there. The problem, he was convinced, was that Baxter wasn’t investing in innovation. The decision was made to spin off the cardiovascular division as its own company. He raised his hand to run it. On April 3, 2000, investors received one share of Edwards Lifesciences for every five shares they owned of Baxter.

Mussallem had wanted a name that went with the times, when dot-com stocks were booming and tech-sounding names were being put on everything from Accenture to Altria. But with every set of names that was tested with employees or customers, his team threw in “Edwards,” the name of a predecessor company, Edwards Laboratories, that had been founded in 1958. Lowell Edwards, a hydraulics engineer, had developed heart disease and wanted to develop an artificial heart. He met a young surgeon, Albert Starr, who convinced him to instead make the first surgical heart valve in the world. The name still resonated, and Mussallem’s team kept it.

Even if he didn’t get his high-tech name, Mussallem said, he steeped himself in the ideas of that time. He was fascinated by the work of Harvard professor Clayton Christensen, who coined the word “disruption” and posited that companies either had to replace their own innovations, or be see themselves replaced by outsiders. “We had to be willing to disrupt ourselves,” Mussallem recalled recently. He set his engineers on the task of creating a heart valve that could be implanted with a catheter.

They were convinced they had a solid approach, but they became aware of a small competitor, Percutaneous Valve Technologies (PVT), in 2002. Then PVT went into human trials first. Faced with a choice as to whether to be first or best, Mussallem decided on both, and convinced his board to purchase PVT for $125 million in 2004, borrowing money to do the deal and working hard to retain PVT’s team. “I was a real believer for sure,” Mussallem said. “We did it. We borrowed money and bought that company, we retained those employees and it was the beginning of this journey.”

The journey was not easy. At the opening session of the 2004 Transcatheter Therapeutics meeting, one of the biggest for interventional cardiologists, a specialist in Italy was implanting Edwards’ experimental valve — as the procedure was broadcast live to the conference. He made a mistake, and damaged another heart valve in the process. The patient went into shock and later died.

The Food and Drug Administration stopped an early trial testing the feasibility of the device, leading Barron’s to run an article warning investors away. Mussallem still has a copy of that story, headlined, “Headed for Heartache?” Even after the Edwards valve, called SAPIEN, was launched in Europe, the FDA insisted on more rigorous clinical trials. It was not approved in the U.S. until 2011.

Edwards was also drawn into a debate over conflicts of interest. Senators wanted to know about $6.9 million that had been paid to Columbia University researcher Dr. Martin B. Leon for his role in starting PVT. Businessweek and The New York Times ran stories painting Leon as symbolic of a larger problem of doctors who work too closely with industry. At the conference last weekend, it was Leon, who played a key role in running clinical trials for the Edwards valve, who presented the results that left physicians so excited.

“It’s a very difficult topic,” Leon told STAT, when asked about the earlier controversy. “We worked very hard to develop new technologies, in order to develop new technologies, we need to have partners that are in industry. We view them as collaborators and partners.” He described his current relationship with Edwards as “hands off” and said that he had no economic relationship with the company aside from the funding of the clinical trial he conducted.

Worries about the device, seen through the prism of the knowledge that the treatment worked in the end, might seem overdone. But they are not. It was once hoped that the first major catheter-based intervention, percutaneous coronary intervention or PCI, would prove as good as heart bypass surgery for treating patients with severe chest pain. But studies have shown that for patients who need bypass surgery, stents don’t have the same survival benefit. In 2010, Medtronic spent $800 million on a technology that lowered blood pressure by permanently deadening nerves in the kidney. The technology failed in a large clinical trial, though Medtronic is still pursuing it.

For Mussallem and his team, the two-decade journey has been astounding. And the result is a technical marvel.

The width of the device that must be threaded up an artery has shrunk from 8 millimeters to a little more than 5 millimeters. Many thought the procedure would push debris from the arteries into the bloodstream, leading to strokes. In the Edwards trial presented on Sunday in New Orleans, there was a 1 percent rate of stroke in the patients who received TAVR, compared to 3 percent of those who underwent surgery. Mussallem also argues that, overall, the device is cost-saving because it keeps people out of the hospital.

For the hospitals that conduct it, though, it can actually be less profitable because the TAVR valves sold by Edwards and Medtronic cost $30,000, compared to about $6,000 for a surgical valve. But they receive similar reimbursement from the Centers for Medicare and Medicaid Services.

That won’t keep sales from growing. Analysts at Jefferies estimate that the global TAVR market will grow from $3.8 billion last year to $6 billion in 2021. The bank estimates Edwards will maintain a 50 percent market share, despite the competition from Medtronic. The stock price has risen 2,000 percent since the company was spun out of Baxter.

Mussallem has done well, too. The company’s definitive proxy from last March shows that he has control over shares worth $150 million, and he appears to have sold more than $250 million worth of shares since 2014. He also owns more than 1.6 million stock options and restricted stock units. Edwards emphasizes that the company has a pay-for-performance philosophy, and that most of its CEO’s payment has been in stock.

The long grind is a sharp contrast to the rapid rise — and rapid wealth accumulation — associated with tech companies like Facebook or Snapchat. The same meeting Edwards presented at opened with a new study about using the Apple Watch to detect a heart arrhythmia, atrial fibrillation.

Experts noted it was cool technology, but not a medical-grade device. You want to create one of those and get it adopted? It’s going to take a long time.