The prevailing wisdom is that transcatheter aortic valve replacement (TAVR) will waltz into the intermediate-risk category and then skip over to low-risk patients with severe aortic stenosis. That is, if all goes well in two randomized, controlled clinical trials in the U.S. And valves prove durable. And clinical benefits remain. And costs come down. And payers are willing to pay.
Reason for optimism
There has been a lot to make TAVR’s proponents cheer in recent months. Five-year results from the pivotal PARTNER I trial (Placement of AoRTic TraNscathetER Valves Trial) gave inoperable patients treated with Edwards Lifesciences’ balloon-expandable Sapien valve the advantage over those who underwent standard treatment, with a risk of all-cause mortality at five years of 71.8 percent for TAVR vs. 93.6 percent for surgery. Half a decade after implant, the valves showed no signs of deterioration with durable hemodynamics. Pop over to the high-risk patients, and all-cause mortality at five years was similar for TAVR and surgery and TAVR patients had lower stroke rates in an intention-to-treat analysis.
Bookend those results with two-year data from another pivotal randomized clinical trial, this one for Medtronic’s self-expanding Core-Valve device in high-risk patients. This time TAVR emerged as superior, with all-cause mortality rates of 22.2 percent for TAVR vs. 28.6 percent for surgery; stroke rates of 10.9 percent vs. 16.7 percent; superior hemodynamics; and no structural valve failures.
In a subgroup of CoreValve patients with Society of Thoracic Surgeons (STS) risk scores of 7 or less, the survival gap widened by more than 11 percentage points. Yet another trial that captured results on intermediate-risk patients with an average STS score of 5.3—in this case using Edwards’ lower-profile Sapien 3 valve—reported a 30-day all-cause mortality rate of 1.1 percent, an all-stroke rate of 2.6 percent and a disabling-stroke rate of 1 percent. Although single-arm and nonrandomized, the ultra-low rates fueled the buzz at the 2015 American College of Cardiology’s (ACC) scientific sessions in San Diego, where the other TAVR studies also were unveiled.
“We know in high risk we can achieve at least equivalent if not superior survival,” says Michael J. Reardon, MD, a cardiothoracic surgeon at Houston Methodist Hospital in Texas, who as CoreValve’s principal investigator presented the two-year results at ACC.15 on March 15. Reardon also is the co-principal investigator for SURTAVI, Medtronic’s ongoing randomized trial in intermediate-risk patients, and REPRISE III, Boston Scientific’s trial for the Lotus TAVR system in extreme- and high-risk patients.
“It seems fairly reasonable that we will achieve something very similar in this intermediate risk,” he adds. “We know these valves give us hemodynamics that are as good as or better than surgical valves. That will not change according to your risk category. We know that in high risk there are no more strokes now than in heart surgery and there is no reason to think that will change as we go down.”
What will change, if TAVR’s indication expands to include intermediate- and low-risk patients, is the number of potential candidates for a procedure. One meta-analysis estimated the rate of severe aortic stenosis in adults 75 years old and older was 3.4 percent (J Am Coll Cardiol 2013;62:1002–1012). The rate for aortic stenosis—those possible TAVRs-to-be if their disease progresses—was 12.4 percent. The authors calculated that under the current indications, more than 91,000 people in the U.S. qualified for TAVR, with 8,205 more joining the ranks annually.
Speaking at the 2015 Transcatheter Valve Therapies conference in Chicago in early June, Martin B. Leon, MD, director of the Center for Interventional Vascular Therapy at NewYork Presbyterian/Columbia University Medical Center in New York City, emphasized the unmet need in this population. “The majority of U.S. patients with severe AS [aortic stenosis] who are symptomatic are untreated,” he says. “They don’t get either surgery or TAVR. The estimate is that the prevalence of severe AS is about half a million and between surgery and TAVR in 2014, less than 100,000 were treated. There is a tremendous potential for further growth, just in the U.S. alone.”
Supply and demand
The marketing analytics firm GlobalData projected that the compound annual growth rate for TAVR valves will increase 19.7 percent between 2013 and 2020, expanding the market from $881 million to more than $3 billion. The projection is based on sales in the U.S., Germany, France, Italy, Spain, the U.K., Japan, Brazil, China and India, with the U.S. and Germany offering the greatest growth opportunities. Other analyses have the market exceeding $1 billion already and galloping toward fivefold growth by 2025. Many device makers hope to get a piece of that market.
As of mid-June, Edwards Lifesciences and Medtronic sold the only two FDA-approved TAVR systems in the U.S., and both companies are developing newer generation devices designed to improve outcomes. Edwards Lifesciences, the first to market in the U.S., has added the smaller profile Sapien XT and the even more petite and skirted Sapien 3 to its roster. In June of 2014, the FDA approved the Sapien XT for inoperable and high-risk patients and one year later approved Sapien 3 for high-risk patients. PARTNER II, with Leon as co-principal investigator, is in full swing with the goal of evaluating the safety and effectiveness of Sapien XT and Sapien 3 in inoperable, high-risk and intermediate-risk patients. The Sapien 3 trial focuses solely on intermediate-risk patients.
Medtronic, in the meantime, has debuted the CoreValve Evolut R, a retrievable and repositionable self-expanding valve. It also is a smaller profile device with a skirt, a design that is expected to reduce the risk of paravalvular leak. The Evolut R received FDA approval in late June or extreme- and high-risk patients.
Other companies hope to enter the fray with retrievable, repositionable devices that include a variety of deployment strategies: Boston Scientific, with its preloaded and stent-mounted Lotus valve; Direct Flow Medical, with a double-ring design; and St. Jude Medical, which paused a trial for its self-expanding Portico system to investigate reports of leaflet motion. The FDA gave the trial the go-ahead to resume in June. Even more TAVR devices are under development worldwide.
The design iterations are expected to improve the safety and effectiveness of TAVR, which will be critical in lower-risk patient populations. The newer designs also consider ease of use and in some cases minimize, if not eliminate, the “oops” factor.
“Certainly you want a valve with an excellent hemodynamic profile, which is a given,” says David X. Zhao, MD, director of the Heart and Vascular Center of Excellence and chief of cardiology at Wake Forest Baptist Medical Center in Winston-Salem, N.C. “No valve would fly without that.” Zhao, who is involved in the Lotus REPRISE III and SURTAVI trials, sees the ability to retrieve and reposition a valve as key to optimal implantation. “It will make the procedure safer. If you can put in a device and you don’t like the way it goes, you can put it back in again without a penalty.”
Leon points out that each system is different and requires finesse. “It is a complex interplay between the valve and anatomy and imaging systems and the operator’s ability to precisely implant at the desired location,” he says. “Sizing is critical. Depending on how you size it, you can significantly dial down the [paravalvular regurgitation] rate.”
Achievements and gaps
Many of the clinical concerns with TAVR have diminished, thanks to more experienced operators, changes in imaging protocols, better patient selection and updates in the device designs. Thirty-day stroke and death rates dipped over time in the PARTNER trials, for instance. Few TAVR patients now experience moderate, let alone severe, paravalvular aortic regurgitation with better sizing and sealing. The need for a permanent pacemaker, while not life-threatening, appeared to be an issue with rates of 21.6 percent and 19.8 percent in the extreme-risk and increased-risk CoreValve trials, and it hit 12.5 percent for transfemorally treated patients in the Sapien 3 trial. But lessons learned from earlier experience have helped to reduce that complication, too.
In the case of the Sapien 3, it was adjusting to a different profile compared with the XT. “With what we learned about positioning the valve, the pacemaker rates went from 12 to 4 percent,” says Sapien 3 trial’s co-principal investigator, John Webb, MD. Webb is director of interventional cardiology and the cardiac catheterization laboratories at St. Paul’s Hospital in Vancouver. “The pacemaker rates in the most recent experience are actually very low.”
Sapien 3’s 30-day outcomes have bested surgery on many fronts, with almost 97 percent of patients showing no or mild paravalvular regurgitation, and in those who underwent transfemoral TAVRs, zero disabling strokes, a low death rate with nearly all procedures performed with fully percutaneous access and closure (J Am Coll Cardiol 2014;64:2235–2243). “The remaining thing is durability,” Webb notes.
The importance of durability increases as the patient risk scale goes lower because the higher-risk patients are less likely to outlast their TAVR devices. Proving durability in existing TAVR patients is itself a challenge for the same reason: With an average age in the low- to mid-80s and some recipients already very sick, the chances of surviving long enough to prove 10 to 15 years of durability are slim.
“We probably won’t know durability for a decade,” Reardon predicts. “Would we be willing to wait a decade for testing?” Reardon and other researchers point out that surgical valves never had to go through the cauldron of testing that transcatheter valves have. “In some ways, we hold TAVR to this much higher standard than surgical valves.”
One trial that might shed light—eventually—on durability is NOTION (Nordic Aortic Valve Intervention Trial), an all-comers clinical trial that randomized 280 patients to TAVR with CoreValve or surgery. The trial enrolled patients between 2009 and 2013 from two sites in Denmark and one in Sweden who were 70 years old or older and who were candidates for surgical aortic valve replacement and TAVR with no limitations on their predicted risk. As a result, 81.8 percent of the study cohort was considered low risk.
At one year, the rate of the primary outcome (death, MI or stroke) was 13.1 percent for TAVR and 16.3 percent for surgery. At two years, the rates were 15.8 percent and 18.8 percent, respectively. The rate of death from any cause was 8 percent and 9.8 percent, respectively. The trial, which was hampered by slow enrollment, failed to show its goal of superiority. But it nonetheless ignited the TAVR community by appearing to validate the use of TAVR in low-risk patients.
“Only time can tell,” says Lars Sondergaard, MD, DMsc, NOTION’s co-principal investigator and a cardiologist at Rigshospitalet-Copenhagen University Hospital in Denmark. “We need to implant these valves in younger patients to have long-term durability data. … From what I can see from the NOTION data, at least in selective, low-risk patients, you can use TAVR instead of [surgery]. But if you want to introduce it as a routine treatment in younger patients, then you need more long-term data.”
High costs cast a long shadow on TAVR’s future as well. On price alone, surgical aortic valves beat TAVR valves by a long shot. TAVR may only need to establish noninferiority to surgery in PARTNER II and SURTAVI to be embraced clinically, but hospitals and payers may balk at paying for a TAVR device when a surgical valve costs about one sixth that amount. Surgical aortic valve replacement historically contributed handsomely to hospital margins, too.
“Even when demonstrated noninferiority, people will consider the largest margin and that is the way they will go,” Zhao observes. “The argument is, if they are the same with no harm to the patient, why not go after the highest-margin procedure? … I think the price has to come down.”
One economic analysis of intermediate-risk patients in Europe declared surgery the victor over TAVR at one year, mostly due to the cost difference for the valves (Ann Thorac Surg 2012;94:1954–1960). The study period spanned 2006 to 2010, but one of the authors speculated that the results would not be much different today.
“That has not changed very much because the price of the valve is still quite similar,” says A. Pieter Kappetein, MD, PhD, a cardiothoracic surgeon at the Thoraxcenter in the Erasmus Medical Center in Rotterdam, the Netherlands. “Ultimately, the price will go down because there will be competition and then TAVR may match [surgery] in terms of reimbursement.”
Many cardiologists and surgeons expect the FDA to approve other TAVR valves, which should drive down the price tag for all devices. “If you drop TAVR valves from $30,000 to $20,000, most places would be making money,” Reardon predicts.
But it still may not seem like a good deal to payers. Leon stresses that reimbursement remains the biggest obstacle to TAVR’s adoption.
TAVR in inoperable and high-risk patients met an acceptable cost-effectiveness threshold because it improved survival, says David Cohen, MD, MSc, director of cardiovascular research at St. Luke’s Mid America Heart Institute in Kansas City, Mo., and the lead in cost-effectiveness analyses for the PARTNER trials. That advantage is less likely in intermediate-risk patients, though, making the cost-effectiveness equation more challenging.
“If we are not going to improve life expectancy, then we have to have a cost that is tolerable,” he says. Putting the price of the valve aside, TAVR programs can still whittle down costs by reducing complications and improving efficiencies, he showed in a presentation at the Transcatheter Valve Therapies conference. Complications such as bleeding and the need for a pacemaker add to the costs of a procedure. In an analysis of attributable costs, researchers pegged those costs at $11,324, or 24 percent of TAVR costs.
“But the greatest opportunity for cost savings clearly lies in maximizing the efficiency of care in the uncomplicated procedures, that is, using the minimalist approach,” Cohen says.
Minimal and frugal
The minimalist approach replaces some protocols in a traditional TAVR procedure with alternatives that can save time and money. Programs may use a cath lab rather than a hybrid operating room, conscious sedation rather than general anesthesia, transthoracic rather than transesophageal echocardiography and bypass the intensive care unit in uncomplicated, transfemoral cases. These changes may help to reduce resource use and shorten length of stay. Webb’s team has shown success with its minimalist approach and is conducting a study to assess same-day discharge for patients relatively low-risk for TAVR treated with the Sapien XT using what they call the multidisciplinary, multimodality but minimalist (3M) approach.
At one year, they reported a survival rate of 92 percent. Complication rates were low, with bleeding, major vascular complications and pacemaker rates of 1.4, 2.7 and 2.7 percent, respectively, and a median length of stay of one day. “The argument would be that if you have a procedure where the hospital stay is dramatically less and the procedural costs are dramatically less, [then] the benefits may outweigh the increased cost of the valve,” Webb says.
Cohen is collaborating on 3M cost-effectiveness analyses. In the meantime, some TAVR programs have been tracking savings and outcomes. Emory University Hospitals in Atlanta, for instance, saved $10,000 per procedure using a minimalist approach without compromising care (J Am Coll Cardiol Intv 2014;7:898-904).
Webb recommends a cautious approach to ensure that TAVR in intermediate and then low-risk patients moves forward without missteps. “Not every TAVI center has equivalent results just as not every surgical center has equivalent results,” he says, using the alternate term for TAVR. “There needs to be oversight and some centralization of this procedure to achieve the good results we have seen in the trials.”
Patients naturally prefer a less invasive approach such as TAVR over surgery, and the benefits of a quicker recovery and a quicker return to their daily lives will appeal to them, and possibly payers, too. As the risk scale gets lower, though, the expectation of an excellent outcome rises. As some members of TAVR teams put it, when a doctor says “low risk,” a patient hears “no risk.”
Zhao points out that surgical aortic valve replacement for intermediate- and low-risk patients, while more invasive, is still very effective.
PARTNER II and SURTAVI will provide definitive data on safety and effectiveness, and with time durability will be addressed. With competition, costs should drop and make TAVR more affordable for payers and more profitable for hospitals, especially if they employ other cost-saving strategies.
“When everything is said and done,” Zhao predicts, “transcatheter aortic valve probably will be the main approach of aortic valve replacement in probably 80 to 90 percent of patients in five to 10 years.”
Doing TAVRs with Less Radiation
Operators and staff who perform PCI procedures in the cath lab have become increasingly concerned about the occupational hazard of radiation exposure. One hospital in Northern Ireland is proactively taking lessons learned to improve safety in another setting: its transcatheter aortic valve replacement (TAVR or TAVI) program.
“TAVI will ramp up in the next three to five years,” observes Ganesh Manoharan, MD, a cardiologist at the Royal Victoria Hospital in Belfast and a member of its TAVR heart team. “This will become an important issue.”
PCI operators and staff have reported orthopedic problems from wearing heavy gear to protect them from radiation. Other consequences of long-term exposure to radiation during procedures include cataracts and the possibility of cancers. TAVR, like PCI, requires fluoroscopic guidance, posing similar radiation concerns.
Manoharan’s group enrolled 72 TAVR patients over 11 months at the hospital, with half undergoing TAVR using standard image acquisition settings—15 pulse-progressive fluoroscopy and 15 frames per seconds—and half with modified settings—3.75-7.5 pulse-progressive fluoroscopy and 3.75-7.5 frames per second (Catheter Cardiovasc Interv 2015;85:1256-1261).
Both groups had 31 transfemoral and five subclavian procedures. The median cumulated dose area product with the standard setting was 102.4 Gy*cm2 vs. 74.6 Gy*cm2 with the lower setting. They reported no significant differences in screening time, procedure time, contrast volume or procedural outcomes.
The physicians have looked for other ways to diminish exposure to the heart team, including shielding and assigning two heart teams in rotations. “There is more we can do,” Manoharan insists, adding that industry needs to get involved as well to mitigate future health problems.
Procedural Characteristics for Patients Who Had Transfemoral TAVRStandard settings (TF)Modified settings (TF)Number of patients3131Radiation dose (DAP - Gy*cm2) (median)102.474.6Screening time (minutes)23.919Procedure time (minutes) (median)118.5113Contrast volume (ml)210169