This article was originally published in French on Medscape.
WASHINGTON, DC — By giving Alain Cribier, MD, PhD, professor emeritus at Rouen University Hospital in Rouen, France, the Presidential Citation Award, the American College of Cardiology Congress (ACC 2022) paid homage to the interventional cardiologist who, through sheer determination, succeeded in devising the transcatheter aortic valve replacement (TAVR) procedure. It was just 20 years ago that the first valve was implanted at Rouen University Hospital in a man with inoperable aortic stenosis. We look back with Hélène Eltchaninoff, MD, head of cardiology at Rouen University Hospital, on those years of research and perseverance before the device became so widely used.
Multiple cardiac arrests, cardiogenic shock, limited heart function with a left ventricular ejection fraction of 12%, an inaccessible femoral approach, multiple comorbidities…the first patient to receive a TAVR to treat symptomatic aortic stenosis was far from having the ideal profile to guarantee the best chances of success. Yet the results surpassed expectations.
Recovery in 8 Days
On that day in April 2002, the 57-year-old patient, whose stenosis had been managed unsuccessfully with aortic dilatation, was admitted to Rouen University Hospital to undergo the first transcatheter aortic valve implantation, which until that point had only been tested in animals. Once the replacement valve had been inserted by catheter and deployed amid the aortic calcification, “the result was unbelievable, with an improvement in the aortic pressure gradient. Within 8 days, the patient had completely recovered,” said Cribier during a presentation on the history of TAVR at the last European Conference of the French Society of Cardiology.
“Percutaneous aortic dilatation proved insufficient to improve this patient’s condition. As far as Cribier was concerned, we couldn’t let this young patient die, when our prototype was ready after being tested on around a hundred sheep,” said Eltchaninoff — who was involved in the development of the device — in the French edition of Medscape. “The operation was very complicated, as the arteritis prevented us from going in via the femoral artery, as we’d initially planned. We instead had to opt for the transseptal approach [through the wall of the heart separating the two ventricles]. Once deployed, the valve remained in place, as we had come to expect from our experiments in animals. But what’s more, blood pressure immediately returned to normal.”
Every year, the American College of Cardiology (ACC) gives the Presidential Citation Award in recognition of an essential contribution in the field of cardiology. “This year, I’m proud to recognize Dr Cribier with this honor for his unwavering commitment to a seemingly impossible project that today is saving lives and giving hope to hundreds of thousands of patients worldwide,” declared Dipti Itchhaporia, MD, president of the ACC, during the conference and on the 20th anniversary of TAVR. Itchhaporia is a cardiologist at Newport Coast Cardiology in Newport Beach, California.
For the interventional cardiology team at Rouen University Hospital, then led by Cribier, this operation is the result of many years of research spent to find a way of saving the many patients with aortic stenosis who are not eligible for surgical valve replacement.
In the 1980s, “one third of patients with symptomatic aortic stenosis were not eligible for surgery,” Cribier recalled. Being older than 70 years, in particular, is considered a contraindication to heart surgery. Yet half of patients suffering from aortic stenosis are within this age group. Among patients who do not undergo surgery, the mortality rate at 2 years is 80%, leaving cardiology departments to face an “unacceptable loss of life.”
Shortly after his arrival at Rouen University Hospital as a resident in 1977, Cribier was sent to Cedars-Sinai Medical Center in Los Angeles, which specializes in cardiac catheterization. He would come back with “lots of technological innovations in mind.” With his team at the University Hospital, he was involved in the development of balloon aortic dilatation, which led to the first percutaneous valvuloplasty in 1985. “At the time, inserting a balloon into a calcified valve was considered impossible. It was thought that the maneuver would lead to the immediate death of the patient,” Cribier said.
At age 72 and with highly symptomatic stenosis, the first patient to undergo this procedure had been refused surgery, owing to her age and the presence of angina pectoris. After aortic dilatation obtained simply by inflating a balloon in the defective valve, she was able to resume a normal life without symptoms for 2 years.
Bolstered by this initial success, the interventional cardiology team at Rouen University Hospital went on to treat several other patients deemed to be inoperable before publishing the results, which had a significant international impact. While the technique gave the team at Rouen University Hospital a certain renown, it had one major drawback: the stenosis forms again after the procedure.
“In these patients, restenosis was almost inevitable after aortic dilatation,” said Eltchaninoff. “It reappears after 3 months to 1 year. At 2 years, the rate of restenosis is 80%.” At the start of the 1990s, Cribier proposed a new concept as a solution to this drawback: “implanting a beating heart valve within the calcified aortic stenosis, using standard catheterization techniques and under local anesthesia.” At the time, surgeons deemed the idea “completely farfetched” and considered the procedure “technically impossible” and “extremely dangerous,” Cribier recalled. The fear was that the device would obstruct the entry of the coronary arteries, damage the mitral valve, or even crush the septum, thus putting the patient’s life at risk.
Decisive Resistance Tests
Rising to the challenge, the interventional cardiology team remained united around its leader. “We had some difficulty understanding how it would be possible to introduce a 2- to 3-cm-wide valve through the femoral artery, but we had faith in Professor Cribier’s innovative mind,” said Eltchaninoff. To prove the concept, the team experimented with implanting 23-mm-diameter stents in the stenotic aortic valves of deceased patients using an inflated balloon.
“These tests were decisive,” said Eltchaninoff. “They showed for the first time that the deployed stents resisted and stayed open after resolving the aortic calcification, all while remaining at a sufficient distance from the coronary arteries and the mitral valve.” All that remained was to finalize the model by inserting an expandable replacement valve within the stent so that, once compressed in the catheter, it did not exceed the 8-mm-diameter limit for it to pass through the femoral artery.
For 5 fruitless years after patenting his invention, Cribier tried to obtain support from manufacturers. He was once again met with the same arguments regarding the risk of complications. Still determined, the cardiologist managed to convince two engineers. In 1999, they founded the start-up Percutaneous Valve Technologies (PVT), the company behind the first TAVR tricuspid valve models, first using polymer, then bovine pericardium. After 3 years of testing in the laboratory and in animal models, the device was finally ready to be tested in humans.
The unexpected results obtained with the first patient were discussed in an article in Circulation that was met with great enthusiasm within the interventional cardiology community. It would be another year after publication of this article before the French National Authority for Health approved the compassionate use of this treatment for patients with life expectancies of less than 2 weeks.
Setbacks for French Research
Following this approval, the team operated on a series of 38 patients with severe conditions by transseptal approach and validated the technique by achieving an 80% success rate and excellent hemodynamic improvement. However, aortic regurgitation remained severe in 25% of cases, owing to the 23-mm diameter of the TAVR valve, which proved insufficient.
The exceptional improvement seen in the patients’ health was pivotal for finally convincing skeptics of the value of the device. One of the patients was 83 years of age and in cardiogenic shock. She was considered to be beyond help before the operation but was able to travel to the United States 1 year after surgery, where she attended the Transcatheter Cardiovascular Therapeutics Congress in Washington to recount her recovery. “Who could have anticipated such an outcome, when she was considered terminal?” asked Cribier. The technique began to take off internationally. In 2005, around 100 TAVR valves were implanted by transseptal approach worldwide.
It was at this time that the manufacturer Edwards — which had always refused to be involved in the development of this innovation — acquired the start-up PVT and developed a series of models, including the Sapien valve, which went on to become the reference model for implantation by femoral approach. This approach was used for the first time in Canada, much to the dismay of the French team that had initially envisaged it, who saw their invention escaping them. In France, for unclear reasons (related to surgeons’ reluctance, according Eltchaninoff), the health authorities were slow to give the green light.
The device was finally approved and given reimbursement status in France in 2009, as was the CoreValve prosthesis, a so-called self-expandable competitor TAVR valve.
Initial Concept Adopted
Gradually, as the number of studies grew, so too did the indications. The first randomized trial, PARTNER, confirmed the benefit of TAVR in inoperable patients with a 20% reduction in mortality at 1 year, compared with standard medical treatment.
Several years later, other studies, including PARTNER 2, validated TAVR in patients at intermediate risk. At the end of 2019, the technique became a potential first-choice treatment for most patients after it was validated in patients at low risk. Consequently, the US Food and Drug Administration approved TAVR in low-risk patients older than 65 years. The latest European guidance from 2021 set the limit at 75 years, but with the possibility of discussing the option of TAVR with patients from 65 years of age.
The operation has been simplified in line with the initial procedure developed by the team at Rouen University Hospital, prioritizing local anesthesia. With this minimalist approach and the change in the material used, “it very quickly became clear that TAVR was superior to surgery, especially in patients over 75 years of age,” said Eltchaninoff. It remained to be proved, and there still was a great deal of reluctance to validate the procedure, she said, which also allows patients to be discharged from hospital less than 3 days after the operation.
The concept initially imagined by Cribier “was ultimately made a complete reality” and today is used widely around the world, all thanks to the unfailing stubbornness of a small team of interventional cardiologists at Rouen University Hospital.