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Low-risk trials Cement a role for TAVR next to or instead of surgery



. Both trials showed that TAVR is not operative in low-risk patients, but PARTNER 3 beats expectations with a clear victory for Sapien 3.

NEW ORLEANS, LA ( UPDATED) – Completely expected new randomized clinical trials testing transcatheter – Aortic valve replacement in low-risk patients for whom surgery is standard provides strong evidence that TAVR has achieved its rightful place in this patient population.

The two studies, PARTNER 3 and Evolut TAVR in the Low-Risk Patient Trial, are scheduled for presentation during a late clinical trial session tomorrow at the American College of Cardiology (ACC) 201

9 Scientific Session. However, the embargo on the data was lifted after Reuters was released early. While the experimental models had slightly different endpoints, the studies at least show that TAVR is similar to surgery in treating low-risk patients with aortic stenosis.

In the Evolut Low-Risk study, which tested the self-growing CoreValve, Evolut R and Evolut PRO (Medtronic) valves in a low-risk patient population, 24-month estimated deaths or disabling strokes were similar in TAVR and surgical arms that meet the definition of statistical noninferiority, but not superiority. The PARTNER 3 trial, however, outperformed non-influence expectations, with investigators reporting that treatment with the balloon-expandable Sapien 3 transcatheter heart (Edwards Lifesciences) was superior to surgery for the prevention of death, stroke and rehabilitation after 1 year, the study's primary endpoint.

Martin Leon, MD (New York Presbyterian / Columbia University Irving Medical Center, New York, NY), one of the leading PARTNER 3 investigators, said they were affected by the positive results. "We didn't think TAVR would be so good," he told TCTMD. "From the standpoint of the hard primary endpoint, the experiment was dramatically positive."

For patients who are enrolled in the trial, it is very difficult to argue that TAVR is not a dominant and superior therapy, Leon said.

"When you put everything together, at least up to 1 year, this is a very exciting therapy, and it should probably give you a lot of different discussion with patients," he said. "Patients and referring physicians should feel empowered to do so – instead of relying on surgical risk grading, good sense, understanding of the anatomy, and the clinical circumstance will allow us to develop a common decision-making process where patients have choices between TAVR and surgery regardless of risk profile. "

Richard Whitlock, MD, PhD (McMaster General Hospital / Population Health Research Institute, Hamilton, Canada), who was not involved in both trials but who is a member of his institution TAVR Heart Layer, said It is difficult to compare clinical studies and praised both studies for good results. However, while the low risk self-expanding TAVR experiment did not rely on surgery, the PARTNER 3 study with the Sapien 3 valve turned off "the socks off."

The results, he said, will change the treatment landscape for severe aortic stenosis.

"All we can say is that this is a new era of valve replacement," Whitlock told TCTMD. "It has always been this turf war, which is unfortunate because I think it prevents patient care between surgeons and interventionists. In many centers, there is less with TAVR because it really is a better team approach to care, but there are centers where heart surgeons and interventionists are already sticking Cardio-surgeons wonder themselves, but if they do not believe that the future of the aortic valve [replacement] is not in a rather dominant position going to TAVR. "

Cardio-surgeons wonder themselves, but if they don't I don't believe the future for the aortic valve [replacement] is not with a fairly dominant position that goes to TAVR. Richard Whitlock

Rishi Puri, MBBS, PhD (Cleveland Clinic, OH), who was not involved in the studies, called both trials "phenomenal," saying that patients are the ones who stand to make the most of the. "This is practice change," he said. "It's going to change the way we treat aortic valve disease forever. It's huge."

Both trials have now been published in the New England Journal of Medicine after an embargo interruption in front of the ACC presentation.

The next limit in TAVR

PARTNER 3 included 1,000 patients with an STS-expected mortality risk of less than 4% (mean STS-PROM score 1.9%) treated at 71 centers. The average age of the patients was 73.4 years, and almost 70% of the patients were male.

The primary compound endpoint of death from any cause, stroke and rehabilitation occurred in 8.5% of patients treated with TAVR and 15.1% of patients treated with surgery ( P < 0.001 for non-individual P = 0.001 for superiority). In an analysis of secondary endpoints, newborn atrial fibrillation was lower among the treated patients, whereas there was no difference in the need for a new permanent pacemaker with the Sapien 3 device. The length of hospital stay was shorter among those treated with TAVR, while the bleeding was significantly greater with surgery.

PARTNER 3: Primary and Secondary Endpoints

TAVR

(n = 496)

Surgery

(n = 454)

Treatment Effect

] (95% CI)

Death from any cause, stroke and rehabilitation

8.5%

15.1%

0.54 (0.37-0.79)

Death from any reason

1.0% [2.5%] 0.41 (0.14-1.17) Stroke 1.2%

3.1%

0 , 38 (0.15-1.00)

7.3%

11.0%

0.65 (0.42-1.00)

New Permanent Pacemaker

7.3%

5.3%

5.4% [1.65 (0.83-2.33)] New atrial fibrillation

] 0.13 (0.09-0.20)

To TCTMD, Leon said the primary endpoint was adapted to a low-risk patient population because they wanted a lower threshold for significant events. However, the secondary endpoints really speak to the power of the less invasive procedure, he added.

For example, the patient's perspective was only a third of the TAVR patients undergoing general anesthesia, and very few were taken to the intensive care unit after the procedure. TAVR patients were hospitalized for shorter periods after the valve was replaced, and the vast majority were emptied at home or for self-need. "In the first 30 days, they have almost complete recovery to normal functional status," Leon said. Furthermore, the risk of death or disabling stroke at 1 year is only 1% with TAVR (versus 2.9% in surgical arm).

All this, said Leon, "is very powerful from the standpoint of a new treatment for low-risk patients."

With regard to echocardiographic findings, the proportion of patients with moderate or severe paravalvular aortic regurgitation was not significantly different between the TAVR group and the surgical arm, although several patients in the TAVR arm were mild. paravalvular aortic regurgitation of 1 year than the treated surgical (29.4% vs 2.1%). Six patients a total of five in the TAVR arm and a surgically treated patient had evidence suggesting valve thrombosis, including increased valve gradients and imaging showing limited brochure movement.

Evolut low-risk test

Medtronic Evolut TAVR Low-Risk study included 734 patients randomly assigned TAVR and 734 for surgery. As a PARTNER 3, the average age of patients was 74 years, the average STS-PROM score was 1.9% and two-thirds of treated patients were male. Most patients received Evolut R and PRO valves, with only 3.6% treated with CoreValve. From a statistical perspective, the study used a Bayesian design, with the investigators performing a predefined intermediate analysis when 850 patients had reached 12 months of follow-up.

This is practice change. It's going to change the way we treat aortic valve disease forever. Rishi Puri

The primary incidence of death or disabling stroke at 24 months – the primary endpoint of the study – was 5.3% in the TAVR arm and 6.7% in the surgical group, meeting the statistical definition of noninferiority. There was no difference in the risk of death for 24 months, which was 4.5% in both TAVR and the operating arm, but the incidence of disabling stroke at 2 years was 1.1% with TAVR and 3.5% with surgery.

With regard to secondary endpoints, newborn atrial fibrillation was significantly higher in the surgical arm while the incidence of new permanent pacemaker implantation was 17.4% with TAVR arm and 6.1% with surgery, a statistically significant difference. Hemodynamics of the aortic valve were improved in both groups, but mean aortic valve gradients were lower after 12 months in the TAVR arm. Moderate or severe aortic regurgitation was present in 3.5% of TAVR patients after 30 days, but in only 0.5% of surgical patients. In one year, the rate of moderate to severe aortic regurgitation was also higher with the Evolut unit than with surgery.

With regard to limitations, the researchers state that complete 24-month follow-up for the entire cohort has not been achieved, and only 22.3% of patients were treated with the latest generation of Evolut PRO.

Commented on the results of the trials, said Chandan Devireddy, MD (Emory University School of Medicine, Atlanta, GA), the PARTNER 3 data "pop" slightly more than the Evolut data, but there are nuances between two attempts. For example, the pacemaker kit with Evolut is "quite high" and will be a problem for some doctors. Aortic valve area of ​​1 year is, however, 2.3 cm with the Evolut unit, mainly attributed to the unit's supra-ring geometry and 1.7 cm 2 with the Sapien 3. The median aortic vein gradient is also lower with Evolut.

"The battle lines should be drawn along the endpoints doctors think are important," Devireddy told TCTMD. "If you just look at bread and butter, that's how these procedures go, there are some notable differences."

For Devireddy, he was particularly impressed with the very low rate of paravalvular leakage of 1 year with Sapien 3 compared to Evolut. "We know that moderate to severe paravalvular leakage has a morbidity and mortality risk," he said. On the whole, he believes that the fans of either valve "will stay in the path for now" and that only a head-to-head study will determine which valve surpasses the other.

Durability and long-term results

The PARTNER 3 investigators admit that their results do not address the issue of long-term structural valve deterioration, and both trials plan to follow patients for at least a decade. In addition, both experiments have serial CT angiography substitutes, which appear to detect abnormalities in the valve blade function. The results of both of these sub-studies are expected for the TCT 2019 meeting.

To TCTMD, Whitlock said that there is a need for long-term data given that the study's follow-up was relatively short. One of the major problems, he said, is that TAVR is already offered in many centers to low-risk patients, and Whitlock worries units may begin to enter younger and younger patients who were not studied.

"At Our Center, we're pretty conservative," he said. "When I look at these results, our mission will be:" Fantastic, lower risk for patients in 1 year, but we really don't know what the long-term results the 5-year positive results are going to be. "We hate to throw lots of these valves into 60-year-olds, and then suddenly at 5 years of age, these valves do not realize that patients need other intervention."

In clinical practice, Whitlock said his group will stay close to the patients being studied in both trials, which would be a low risk patient of about 75 years and older. He stressed that it is still crucial for the PARTNER 3 and Evolut Low-Risk Trial investigators to continue following these patients for the next 5 to 10 years to track any sustainability problems that could potentially occur with transcatheter heart valves.

To TCTMD, Leon noted that about 10% of patients in PARTNER 3 were 65 years and younger, and that he would place a transcatheter heart valve in these younger patients. While durability is a problem, he said he is confident in the procedure, noting that there is significant accumulated data-out for at least 5 years, showing that these valves are staying up. Moreover, most surgical valves have not been subjected to the same level of control facing transcatheter heart valves. "Yes, we must follow people for at least 10 years, and that is certainly a limitation, but we must understand that limitation with perspective," Leon said.

The test comparisons are difficult

The two trials vary so much that it makes it difficult to compare, says Puri. Both studies showed the same thing – lowering the risk threshold for TAVR in the setting of severe aortic stenosis – but reversed it in different ways. They used different endpoints, statistical patterns and transcatheter valves.

And while Evolut valves were not superior to surgery, Puri pointed out good results in the TAVR arm. For example, the death or disabling stroke was only 0.8% in 30 days compared to 2.6% in surgery, a "clear winner for TAVR," Puri said. Death from any cause at 30 days was also lower with TAVR-0.5% versus 1.3% compared to surgery. Like the others, Puri pointed to the higher rate of pacemaker implantation with Evolut as one of the downsides.

To TCTMD, Sanjay Kaul, MD (Cedars Sinai Medical Center, Los Angeles, CA), it is said that cross-trial comparisons are invidious, but it is still "we love to do it" . opinion, the Evolut Low-risk TAVR study is a more rigorous study than PARTNER 3, and its primary endpoint is more clinically meaningful. In addition, the follow-up is longer, it included several patients, and the noninferiority margin was stricter, he noted.

Furthermore, rehabilitation is the most widespread "and undoubtedly the least important" aspect of the primary endpoint of PARTNER 3, and it interferes with the outcome against TAVR given that hospital admissions are more likely in surgical patients.

" In my opinion, PARTNER 3 is an attempt designed to deliver a victory for TAVR, not an attempt to really reinforce the patient," wrote Kaul in an email. "Almost 80% of all AVR measures are done in the low-risk category. So there seems to be a leading driver to" capture the market. I am disappointed that the FDA allowed such a trial design. What about the favorable TAVR data in the short term ( even when it comes to hard endpoints of death or disabling strokes) How does the FDA respond in such a scenario if they already approved the indication based on 1 year data? Recall approved indication for low risk patients? It is very difficult to put the genius back in the bottle. "

Regarding whether the TAVR should be the standard strategy across the risk spectrum, Kaul said he will see long-term follow-up data before making any recommendations for this low-risk population.

While almost all the experts look for long-term follow-up, most doctors see these two attempts as good news for TAVR in the low-risk setting. To TCTMD, Puri said that most doctors have all treated patients at the lower end of the risk spectrum, mainly because they simply do not want surgery. Now he said, we can tell these patients that "in good hands we can achieve results that are as good as very good surgical results."

Devireddy makes a similar comment, saying that the paradigm of treating severe, calcific aortic stenosis changed fundamentally today. "Patients do better with TAVR, in my opinion," he said.


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