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AP VALVES & SH 2022

Not just alternative to SAVR: 'TAVR has become standard of treatment for severe, symptomatic AS'

Transcatheter aortic valve replacement (TAVR) is expanding rapidly to younger and lower-risk aortic stenosis (AS) patients, becoming the therapy of choice in select subgroups and trumping even surgical aortic valve replacement (SAVR), an expert said. "At Asan Medical Center (AMC), the rule is that TAVR is the standard treatment when tissue valves are needed for symptomatic severe AS patients over 65 years of age," said Seung-jung Park, MD, PhD (AMC, Seoul, South Korea) at AP VALVES & STRUCTURAL HEART 2022 on Aug 11, which ran for two days at the Grand Walkerhill Seoul in South Korea. As chairman of AMC's Heart Institute, Park highlighted TAVR advances worldwide and at the medical institution over the past decade. Seung-jung Park, MD, PhD presents on improvements of TAVR worldwide and at Asan Medical Center at the AP VALVES & SH 2022 at the Grand Walkerhill Seoul in South Korea on Aug 11. Major randomized controlled trials (RCTs) on TAVR and transcatheter heart valves (THVs) - including the CoreValve, Evolut and Sapien valves - laid the groundwork for device approval in both Europe and the US, ushering in the "era of TAVR" for patients who had no alternative to surgery. TAVR has become comparable with surgery 5 to 8 years since its introduction and SAVR has become the alternative Seung-jung Park, MD, PhD The landmark PARTNER 31 and the Evolut Low Risk2 trials, published simultaneously in the New England Journal of Medicine (NEJM) in May 2019, backed the case for TAVR in lower operative risk groups after results favored TAVR over SAVR for the 30-day and 1-day endpoints of death, disabling stroke or rehospitalization. Meta-analysis3 of the NOTION, SURTAVI, PARTNER 3 and Evolut Low Risk trials, published in the Journal of the American College of Cardiology (JACC) in Sep 2019, also showed 1-year outcomes favoring TAVR over SAVR for all-cause mortality (2.1% vs. 3.5%, RR 0.61; 95% CI, 0.39-0.96, I2=0%) and cardiovascular death (1.6% vs. 2.9%, RR 0.55, 0.33-0.90, p=0.02, I2=0%). TAVR also had lower rates of disabling stroke (0.5 vs 1.7%), atrial fibrillation, life-threatening or disabling bleeding and acute kidney injury but higher rates of permanent pacemaker implantation and moderate or severe paravalvular leak (PVL). On the heels of the major trials, the US Food and Drug Administration (FDA) greenlighted expanded indications for TAVR, for patients at low surgical risk in Aug 20194, causing seismic shifts in both American and European guidelines and boosting the once experimental procedure to a standard of care. The 2020 American College of Cardiology and American Heart Association (ACC/AHA) guidelines gave a Class I recommendation for TAVR for patients over 65 years and the 2021 European Society of Congress and European Association of Cardio-Thoracic Surgeons (ESC/EACTS) guidelines greenlighted TAVR with a Class I indication for patients over 75 years5. "More research is needed for TAVR in bicuspid aortic valve (BAV) disease, aortic and mitral bioprosthetic valve failure, low-flow, low-gradient AS, high-risk aortic regurgitation (AR) and routine use of cerebral protection devices, among others," he said. "Nevertheless, TAVR has become comparable with surgery 5 to 8 years since its introduction, and SAVR has become the alternative." AMC Celebrates 97% Procedural Success Rate During 22 Years of TAVR Following the first operation at AMC in 2010, - undertaken with TAVR pioneer Alain G. Cribier, MD(University of Rouen's Charles Nicolle Hospital, Paris, France),6 - TAVR operations at the South Korean hospital skyrocketed to over 250 cases per year. Last June, AMC's Heart Institute announced becoming the first in Asia to complete 1,000 TAVR cases7 and reported tallying 1,300 cumulative cases this year. Analysis found AMC's Heart Team achieved a procedural success rate of 96.8% (1,101/1,137 patients) with low rates of new permanent pacemakers (6.9%) and moderate or severe paravalvular leaks (4.3%) despite operating on an elderly, high-risk and severe-disease population. The rule at AMC, for tissue valves, is that TAVR has become the standard of treatment in patients with symptomatic severe AS patients over 65 Park Baseline characteristics showed the average patient was 80 years old, 47% were male and the mean Society of Thoracic Surgeons (STS) risk score was 4. Major comorbidities included hypertension (79.1%), diabetes (34.9%), chronic obstructive pulmonary disease (22%), atrial fibrillation (12.4%), stroke (11.7%) and peripheral vascular disease (5.1%). Comparing 30-day and 1-year outcomes between cases from 2021 and all cumulative cases at AMC showed improvements in the endpoints of all-cause mortality (All cases 1.7% vs. 2021 cases 1.9%), and major, disabling strokes (1.0% vs. 0.3%). TAVR also recorded improvements for the 30-day and 1-year endpoints of major vascular complications (5.3% vs. 0.0%), new permanent pacemaker implementation (6.9% vs. 3.0%) and moderate or severe PVR (4.3% vs. 1.1%) - which were aided by implementing a unique "minimalist approach." "Since the first case in 2010, AMC developed a minimalist approach coined the 'MAC' that helps simplify the TAVR procedure," Park said. "Along with impeccable heart team collaboration, we also developed a meticulous pre-TAVR CT measurement algorithm that aids device selection. The MAC approach implies no general anesthesia, no transesophageal echocardiography (TEE), 30-minute procedures, 1-day stays in the CCU, discharge within 3 days and a cardiac rehabilitation program, Park said. Outcomes between balloon-expandable and self-expandable valves were also comparable, although self-expandable valves had a significantly higher rate of new permanent pacemakers (5.3% vs. 15.4%). At AMC, the Edwards Lifesciences’ Sapien 3 valve (73%) accounted for most implants, followed by Sapien XT (Edwards Lifesciences; 10%), Evolut R & PRO (Medtronic; 8%), and CoreValve (Medtronic; 8%). "Although valve durability remains a major issue and more research is needed on patient subgroups, outcomes at AMC have improved over time, thanks to MAC," Park said. "And the rule here, for tissue valves, is that TAVR has become the standard of treatment in patients with symptomatic severe AS patients over 65." CHECK THE SESSION

September 16, 2022 6549
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AP VALVES & SH 2022

Promising new TAVR techniques, valves to realize ideal of '1 procedure, 1 valve' for life

Procedural and technological innovations of novel transcatheter heart valve (THV) systems for transcatheter aortic valve replacements (TAVR) may help open the door to the ideal of one procedure lasting a patient's lifetime, an expert said. TAVR is being used increasingly in younger patients, making lifetime valve durability a top priority, Eberhard Grube, MD (University Hospital Bonn, Germany) said at the Grand Walkerhilll Seoul in South Korea on Aug 11 while presenting at AP VALVES & STRUCTURAL HEART 2022. "Ideally, we want one procedure and one valve lasting a lifetime," Grube said. "Ideal features include durability, simple and predictable deployment, low profile for transfemoral delivery, low complication rates and minimal interference with surrounding structures." Despite THV powerhouses like Edwards Lifesciences (California, US) and Medtronic (Minnesota, US) building on industry-leading THVs and newcomers from China- and Singapore entering the arena, existing valves still entail tradeoffs and compromises on features. "The balancing act between THVs means weighing strong, subjective opinions on features like valve durability, personalized sizing and paravalvular leak (PVL) prevention," Grube said. "Factors like safety, performance, patient-prosthesis mismatch (PPM), retrievability and strategies for future TAVR-in-TAVRs are also important." Grube presents innovation and caveats of transcatheter heart valves for TAVR at the Grand Walkerhill Seoul in South Korea at AP VALVES & SH 2022 on Aug 11. Current THVs are classified as either tissue ("bioprosthetic") or mechanical valves. Bioprosthetic valves are composed partially of animal tissue while mechanical valves are sturdier with material like pyrolytic carbon. THVs also vary in characteristics like valve height, implantation depth, the relative position of the valve or annulus and radial force1. Depending on these characteristics, valves are classified as balloon expandable (BEV) or self-expanding valves (SEV) and supra-annular or intra-annular valves. "The caveat is that significant operator experience is needed to formulate thoughtful impressions on all the different valves but it's difficult to be an 'expert' of more than three TAVR systems," Grube said. "Future TAVR systems should be designed to treat all patients with aortic stenosis (AS), including those at lower operative risk or with bicuspid aortic valve (BAV) anatomy." Innovation in Improved Industry-leading Valves Existing players and newcomers alike are introducing innovation for THVs, either by building new-and-improved versions of leading TAVR systems or developing new ones that showcase novel designs and technologies. "The evolution of heart valves from 1960 to 2020 went from 'non-living' mechanical and bioprosthetic valves to synthetic permanent polymers to 'living' regenerative material and tissue-engineered valves," Grube said. "The CoreValve Evolut R/PRO+ (Medtronic) and Sapien 3 (Edwards Lifesciences) devices are industry standards for SEVs and BEVs, respectively, and new versions continue to demonstrate iterative innovation of leading firms." Sapien X4 by Edwards Lifesciences. Source: Grube slides at AP VALVES & SH 22 The upcoming Sapien X4 THV system, designed as an improvement of Sapien 3 Ultra, uses RESILIA tissue that offers enhanced anti-calcification technology and enables dry storage. It also maintains bovine pericardial leaflets matched for thickness and elasticity. Sapien X4 features a high radial strength, cobalt chromium BEV design; and the novel frame and leaflet design enable adjustable sizing while maintaining valve performance over the diameter range of deployment. The enhanced outer skirt with textured polyethylene terephthalate (PET) also helps minimize PVL and maintain low-profile access. Low frame height and large cells facilitate future coronary access, Grube said. Evolut FX valve by Medtronic. Source: Grube slides at AP VALVES & SH 22 The Evolut FX valve is a next-generation device built upon the Evolut R/PRO+ valves by Medtronic. The "next-in-line" valve features a redesigned nosecone shape, single spine shaft and optimized stability layer with more flexible capsules. It also has three radiopaque inflow markers located adjacent to commissures and positioned at a target implant depth of 3 mm. The ACURATE neo2 valve (Boston Scientific; Massachusetts, US) features enhancements to the previous ACURATE neo valve, improving PVL performance with inner and outer pericardial skirts. "Reducing PVL with the next-generation valve iteration is necessary for the ACURATE neo2 to become a viable option for TAVR patients," Grube said. ACURATE neo2 valve also showcases design updates for improved conformability in irregular, calcified anatomy and a new radiopaque positioning marker. The Navitor valve (Abbott Vascular; Illinois, US) builds upon the Portico valve (Abbott Vascular). Navitor features an inner cuff, PVL-sealing with an outer polyethylene fabric cut, aortic stent cell design to minimize vessel trauma and aid release from the FlexNav delivery system and increased radial force for the 23/25 mm valves sizes. Additional studies on the FlexNav delivery system and Navitor are underway, with the ongoing prospective, multicenter single-arm Navitor study aiming for approval in the EU and US for patients at high- or extreme-surgical risk. Navitor valve by Abbott Vascular. Source: Grube slides at AP VALVES & SH 22 The Jena Trilogy valve is a reboot of the JenaValve by the Irvine, California-based JenaValve Technology The 18-Fr equivalent Coronatix catheter delivery system has a self-expanding nitinol frame with locator technology - aligned with sinuses and a set implant depth for avoiding low implants - that secures and seals valves in native anatomy. JenaValve Trilogy valve by JenaValve Technology. Source: Grube slides at AP VALVES & SH 22 "Results of the first commercial implants with JenaValve Trilogy in 27 patients with AS showed a 100% rate of technical success (VARC-3), 96.3% rate of device success at 30-days (VARC-3), 1 death, no permanent pacemaker implantations and 100% performance as indicated," he said. "These data suggest that treatment of severe AS with the JenaValve Trilogy system is safe and effective, although more work on coronary alignment and bigger studies are needed." JenaValve Trilogy received the CE Mark last year in the EU. The ALIGN-AR trial is underway for approval in the US, Grube said. Promising Newcomers J-valve Ausper valve by JC Medical/Genesis MedTech. Source: Grube slides at AP VALVES & SH 22 Systems from China are introducing novel device designs like dry leaflet technology, PVL prevention and ultra-low profiles. The J-valve Ausper is a spinoff of the J-valve, developed by JC Medical (China), which was acquired by Singapore-based firm Genesis MedTech in February2. The J-valve gained approval from China's National Medical Products Administration (NMPA) in 2017 and for compassionate use in the US by the US Food and Drug Administration (FDA) in 2019. J-valve Ausper is a porcine pericardial tri-leaflet valve with a nitinol short self-expanding frame that allows for transfemoral delivery and the 27-Fr sheathless delivery catheter features independently operated 3D rings, called nitinol claspers, that align with native sinuses, orienting the valve stent and capturing leaflets. VenusA-plus valve valve by Venus Medtech. Source: Grube slides at AP VALVES & SH 22 The VenusA-plus valve (Venus Medtech; Hangzhou, China) is an expansion of the VenusA valve, approved in China in 2017, that features a reinforced shaft and capsule in the delivery system, enabling retrievability and positioning. The VenusA-plus valve gained the NMPA's approval for use in China in 2020 and Thailand in 2021 by the Ministry of Public Health of Thailand. Alternative Materials, Novel Techniques For valve durability, alternative materials are rising as a golden prospect. "It's all about the leaflets and material science innovation, and we are hopeful for new bioprosthetic valve platforms with improved durability profiles," Grube said. "Major valves incorporating alternative material include Sapien X4, Tria and DurAVR." Tria valve by Foldax. Source: Grube slides at AP VALVES & SH 22 The Tria biopolymer aortic valve (Foldax; Utah; US) utilizes new polymer technology engineered to "potentially last a patient's lifetime." Without using animal-sourced tissue, the Tria valve was designed for ease of access and created purely by robotic manufacturing, Grube said. "Studies on the surgical valve demonstrated accurate delivery, excellent hemodynamics at 90-days, no calcification and coronary re-access." DurAVR valve by Anteris Technologies. Source: Grube slides at AP VALVES & SH 22 DurAVR (Anteris Technologies Limited; Australia) is a novel 3D single-piece BEV with a PET skirt to reduce PVL and a single-piece construction designed for commissural alignment. Incorporating new leaflet technology, the DurAVR valve was designed to mimic the natural shape of the aortic valve and restore hemodynamic function to "near-normal levels" for better coaptation and reduced leaflet stress. "The valve's tissue is acellular and detoxified without glutaraldehyde or calcification through a novel tissue engineering process," Grube said. "The anti-calcification tissue engineering process, called ADAPT-TEP, creates acellular tissue for lowering immune response and removes DNA, phospholipids and alpha-gal epitope." Other new techniques like the Leaflex AVRT, lithoplasty, BASILICA and ShortCut Catheter are also promising, he said. "Aortic valve remodeling therapies, like the novel transfemoral transcatheter Leaflex Performer (Pi-Cardia; Israel) employing an aortic valve (AV) scoring mechanism, have improved AV flexibility and reduce stenosis in pre-clinical studies in surgically excised human valves and human feasibility experiences." Shortcut Catheter by Pi-Cardia. Source: Grube slides at AP VALVES & SH 22 "Leaflex can help avoid or defer TAVR in younger patients who likely require multiple treatments including surgery, potentially helping sequence AVR strategies for younger AS patients." The ShortCut Catheter ((Pi-Cardia; Israel) is a "simple" device that splits leaflets and potentially "opens the door to two significant indications for TAVR: splitting leaflets to enable valve-in-valve (ViV) and ‘tricuspidization' of BAVs pre-TAVR." "As new techniques for lifetime AS management and usage of AV remodeling increase, TAVR newcomers are developing novel designs for valves with features like dry leaflet technology and PVL prevention," Grube said. "Tissue engineering concepts are also quickly evolving and may spark a future round of improved valve leaflet designs." CHECK THE SESSION

September 16, 2022 17349
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SummitMD

‘First big step’ for xenotransplantation inches forward elusive future of heart transplantation

The historic series of successful animal-to-human cardiac transplants by American surgeons starting last year indicated a breakthrough in the field of xenotransplantation, experts said, inching forward a potential solution to the shortage of human hearts for transplants As previously reported by SummitMD, the cross-species heart transplant performed in January by the surgical team at the University of Maryland Medical Center (Baltimore, USA) made international headlines after the 57-year-old male patient survived and fared well immediately post-operation. The patient’s extensive medical history – including chronic mild thrombocytopenia, hypertension, nonischemic cardiomyopathy and a prior mitral valve repair – excluded him from benefitting from all other standard treatment, including human heart-to-heart transplants. We’ve taken the first big step for xenotransplants, and we’re going further than ever before, as we have with human-to-human heart transplants. Sang-un Lee, MD, PhD Although the medical team reported incredible improvements – including the patient “sitting alone in a chair and waving to caregivers, free from bed for the first time in 109 days” on day 49 – his death, attributed to xenograft failure of unknown cause, was announced on day 60, marking a two-month survival record. “As with any first-in-the-world transplant surgery,” lead surgeon Bartley P. Griffith, MD (University of Maryland Medical Center, Baltimore, USA) said, “this one led to valuable insights that will hopefully inform transplant surgeons to improve outcomes and potentially provide life-saving benefits to future patients.” Shortly after, surgical teams at NYU Langone Health, led by Nader Moazami, MD (New York, USA), reported the completion of two pig-to-human cardiac transplants for two brain-dead patients last June and July, respectively, finding no evidence of rejection days after the operation. In all three cases, the porcine hearts were genetically modified by United Therapeutics’ owned Revivicor (Blacksburg, Virginia, USA) through a complex process known as somatic cell nuclear transfer. Somatic cell nuclear transfer involves inactivating (“knock out”) animal genes that are incompatible with human ones and injecting (“knock in”) beneficial human genes into animals to regulate processes like coagulation and inflammation. On the recent xenotransplants, experts noted that the innovative gene engineering methods would serve as a major stepping stone for future developments, despite the dismal length of extended survival of the actual transplant and prevailing concerns of zoonosis and immune rejection. “Considering the first human-to-human heart transplant in 1967 lasted 18 days, we cannot call this first attempt at genetically modified porcine-to-human cardiac xenotransplantation a failure or a disappointment,” Sang-un Lee, MD, PhD (Asan Medical Center, Seoul, South Korea) told SummitMD. Just because it took a long time to reach the starting point doesn't mean it will be a long race. Sang-un Lee, MD, PhD “The human heart is a biochemical organ with various functions, but it also acts as a pump,” Lee said. “Currently, the three human-to-human heart transplant strategies that could potentially replace or support failing hearts are mechanical heart pumps, autologous hearts or xenotransplants.” Although progress has been made for the three strategies, each method carries significant drawbacks and limitations that bar use in standard medical practice, Lee said. Mechanical heart transplants – known as left ventricular assist devices (LVADs) – are battery-powered artificial heart pumps that serve as a bridging therapy for heart failure patients who are waitlisted for an actual heart transplant. Autologous heart valves involve securing and engineering healthy stem cells of the recipient’s heart to transplant back into the patient. “Each strategy carries significant limitations,” he said. “Although mechanical heart pumps are used in practice, it cannot fully replace human hearts because it only functions as a pump. Autologous hearts, which covers the biochemical function of a heart, also cannot function alone because it lacks the heart’s pumping ability. Xenotransplantations carry the risk of immune rejection and zoonosis.” “This indicates that autologous hearts should be used with mechanical heart pumps or animals engineered to support the development of the human heart structure,” he said. “It’s difficult to speculate which experimental heart transplant options will reach success first, but we can say we’ve taken the first big step for xenotransplants, allowing us to go further than we’ve gone before. “We experienced the same trial and error with human-to-human heart transplants,” he added. “Just because it took a long time to reach the starting point doesn't mean it will be a long race.” Elizabeth G. Phimister, PhD, the deputy editor of the New England Journal of Medicine (NEJM) also wrote: “The normal function of a pig heart in a human and the avoidance of graft rejection for more than a month is an achievement supported by decades of research in immunity, embryology, genetics, and animal husbandry.” “The basis of genetically modifying an entire animal was established 26 years ago with the ‘cloning’ of a sheep from the nucleus of a mammary cell of a white-faced Finn Dorset sheep. The recent xenotransplant is based on research that has unfolded over decades but it’s only recently that major challenges have been addressed, suggesting future improvements are likely. Elizabeth G. Phimister, PhD “It was by this means that the first pig devoid of alpha-gal was engineered, and this mutant pig has now been bred for more than 11 generations, gaining the Food and Drug Administration (FDA) approval as a New Animal Drug Application just 2 years ago. “Although the recent xenotransplantation is based on research that has unfolded over decades, it is only recently that major challenges, such as maintaining the functionality of the donor’s heart between harvesting and transplantation, have been addressed, suggesting future improvements are likely,” she said. Down to brass tacks: rise and fall of 1st cardiac xenotransplant In a NEJM report published on July 7, Griffith and investigators reported that the transplant recipient had fared well post-surgery, rehabilitating without any cardiovascular support, including venoarterial extracorporeal membrane oxygenation (ECMO). Tests showed that the xenograft functioned normally, with no evidence of immune rejection or porcine endogenous retroviruses (PERV) infection, which raised hopes of extended survival. But vital signs dropped on the evening of day 49: venous oxygen saturation was mixed (33%); left ventricular ejection fraction (LVEF) increased to 70%; both right and left LV walls thickened dramatically; and global longitudinal strain values became increasingly abnormal, leading to recannulation for ECMO. Suspected as an “atypical manifestation of antibody-mediated rejection,” the patient’s deterioration spurred the use of therapeutic plasma-exchange, intravenous immune globulin, complement inhibition with C1 esterase inhibitor and eculizumab, and B-cell depletion with rituximab that “appeared to prevent obvious rejection of the genetically modified xenograft.” Although medical examinations on day 60 showed no infection with PERV or porcine circovirus 3 (PCV3), histological exams revealed scattered myocyte necrosis, interstitial edema and red-cell extravasation without evidence of microvascular thrombosis – findings “not consistent with typical rejection.” The case provides a glimpse of how quickly and profoundly genetic and biologic engineering, along with cell and developmental biology, can be marshalled to attack problems in medicine. Jeffrey L. Platt, MD & Marilia Cascalho, MD, PhD “The pronounced sudden diastolic failure and global pathologic myocardial thickening without systolic dysfunction remain unexplained,” Griffith wrote. “These findings, in combination with focal capillary injury in the virtual absence of complement deposition, are not normally seen in human allotransplantation.” “Endomyocardial biopsies of the xenograft did not show acute cellular or antibody-mediated rejection, and no complement staining was identified until a week after the late dysfunction that led to ECMO support.” Pursuing autopsy revealed the xenograft had swelled nearly double in weight. Investigators also noted that the patient showed low levels of infection with porcine cytomegalovirus (pCMV) – known as suid herpesvirus 2 (SHV-2) – starting on day 20 that increased over time. “Detection of pCMV was unexpected given the husbandry practices, negative surveillance PCR testing of nasal swab specimens from the donor animal before organ transplantation, and the use of antiviral prophylaxis,” they said. “Presence of pCMV in explanted xenografts from nonhuman primate recipients has been correlated with worse outcomes than an absence of pCMV, for unclear reasons.” “Further viral testing is warranted because human herpesvirus 6 (HHV-6), which has been shown to cross-react with pCMV and to be associated with allograft rejection, was also detected in a lung-lavage specimen from this patient,” investigators wrote. Extracting and applying lessons learned In an accompanying editorial, Jeffrey L. Platt, MD and Marilia Cascalho, MD, PhD (University of Michigan Ann Arbor, USA) wrote: “Given past failures, one might justifiably ask whether this recent xenotransplantation provides a glimpse at the future treatment of organ failure, or merely fulfills the longstanding quip that xenotransplantation is and always will be the future of transplantation.” “Regardless, it provides a glimpse of how quickly and profoundly genetic and biologic engineering along with cell and developmental biology can be marshaled to attack problems in medicine,” they said. “A more important question may be whether techniques used to engineer pigs could be applied to generating human tissues and organs for implantation into patients with organ failure,” they asked. “Pluripotent stem cells and other cell types are increasingly explored for the generation of autologous organs through organogenesis or three-dimensional tissue engineering.” A more important question may be whether techniques used to engineer pigs could be applied to generating human tissues and organs for implantation. Platt & Cascalho “Use of autologous organs modified to resist underlying disease would presumably avert the need for — and toxic effects of — lifelong immunosuppression. The advent of such autologous implants would be likely to decrease the demand for allotransplantation.” Autologous organs could also “ironically” increase the demand for reverse xenografts (animals engineered to support the development of human tissues) and xenografts by acting as temporary, bridging therapies for patients waiting on autologous transplants, they said. Going forward, research on methods to apply the utilized genetic modification techniques to humans and reducing the extent of genetic modification in pig genes could help improve long term outcomes, they said: “Several steps could advance clinical application of xenotransplantation for whatever purposes xenografts might fulfill. Reduction in the number and extent of genetic modifications of pigs could benefit the long-term function of xenotransplants, since the untoward insertion of genetic sequences has been associated with myocardial aging. “Still more important will be efforts to decrease the intensity and toxicity of immunosuppression. Since immunity to xenografts may engage narrower pathways of T-cell activation than allografts, perhaps immunosuppression can be focused to reduce longer-term toxic effects for recipients and grafts and possibly autografts.”

August 31, 2022 6206
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AP VALVES & SH 2022

Celebrating 2 decades of TAVI: How 1 inventor, pioneer pushed heart history forward

One clinician bound and determined to "solve a major unmet clinical need" changed medical history with the world's first transcatheter aortic valve intervention (TAVI), providing a life-saving therapeutic option for thousands of patients with aortic stenosis (AS) worldwide. Alain G. Cribier, MD(University of Rouen's Charles Nicolle Hospital, Paris, France) innovator and executor of the groundbreaking intervention, celebrated the 20th anniversary of TAVI at AP VALVES & STRUCTURAL HEART 2022, which kicked off Aug 11 at the Grand Walkerhill Seoul in South Korea. TAVI, which is also called transcatheter aortic valve replacement (TAVR), is a minimally invasive treatment option for patients with severe, symptomatic AS who are not eligible for surgery. Before TAVI, surgical aortic valve replacement (SAVR) was solely the standard of care. TAVR pioneer Alain G. Cribier, MD outlines the history of TAVR and THVs during a remote presentation at the 11th AP VALVES & STRUCTURAL HEART 2022 conference held in Seoul, South Korea on Aug 11. Developing TAVR was always about helping patients. It was a long road, but it was worth the fight, Alain G. Cribier, MD Although critics initially dismissed the "impossible" idea that originated 30 years ago, that didn’t stop Cribier from turning the concept to reality, and he completed the first TAVR operation on Apr 16, 2002, in Rouen, France on a 57-year-old male patient with severe symptoms that had made 3 surgical teams turn him down from surgery. Before TAVI, Cribier also developed and performed the world’s first balloon aortic valvuloplasty (BAV) in 1985 - which utilizes balloon dilation to enlarge aortic valve orifice - and the first mitral commissurotomy (FIM) in 1995, both of which were novel ideas at the time. "It was an attempt to solve a major unmet clinical need," he said. "Studies at the time showed that patients who were not eligible for SAVR - which accounted for 50% of patients in the 1980s - had a 2-year mortality rate of 80%," he said. "Over the past 40 years, the progression of cardiac catheterization techniques for degenerative AS can be divided into two distinct 'seasons: the first BAV in 1985 and the first TAVI in 2002. "These two linked innovations shared a single goal, which was to provide life-saving therapeutic options for patients with asymptomatic AS not eligible for SAVR." The success and development of BAV had the "effect of a bomb" in the medical community, setting off thousands of BAV operations worldwide from 1986 to 1992 and more 1,250 related publications including those from the National Heart, Lung, and Blood Institute (NHLBI) and Mansfield registries. These innovations share a single goal, which is to provide life-saving therapeutic options for patients with asymptomatic AS not eligible for SAVR, Cribier However, BAV carried one major, "unacceptable" limitation of early restenosis that steered Cribier to conceive the concept of TAVI, which he detailed in 1990 as a process of "implanting a valve prosthesis within the diseased calcific native valve, on the beating heart, using regular percutaneous catheter-based techniques and local anesthesia." "The question was whether a balloon expandable stent could be used to keep the valve open and how to design the structure of a transcatheter heart valve (THV) that would allow for high radial force balloon expansion with an external cuff. "Experts from biomedical companies said it was ‘crazy’ and ‘impossible’ since it involved heavily calcified valves and risky surrounding structures like the coronary ostia, mitral valve and His bundle. "They told me there was no chance of crossing a diseased valve with a prosthesis and deploying it and feared it would cause ‘unavoidable life-threatening’ complications," Cribier recalled. "But that wasn’t the end of the story." With no potential sponsors, Cribier launched a New Jersey-based startup called Percutaneous Valve Technologies (PVT) with colleagues Stanton Rowe (CEO of NXT Biomedical, California, USA), Stanley Rabinovich (Principal owner of SBR MedTech Consulting, New Jersey, USA) and Martin B. Leon, MD (Columbia University Irving Medical Center; Cardiovascular Research Foundation (CRF), New York, USA). Despite initial struggles, the startup went on to partner with Israeli biopharmaceutical company Aran R&D (Caesarea, Israel), which quickly helped realize Cribier’s designs for a prototype prosthesis. After running pre-clinical evaluations in animal models, Cribier implemented the prosthesis in the historic first human TAVI procedure in 2002. PVT was later acquired by Edwards Lifesciences for $125 million in 2004, prompting the well-known evolution of the initial Criber-Edwards valve to the Edwards-Sapien valve and finally to the Sapien valve series that are held as the industry standard. They told me there was no chance of crossing a diseased valve with a prosthesis and deploying it, fearing it would cause ‘unavoidable, life-threatening’ complications. Creation of different valves, including the self-expanding CoreValve (Medtronic, USA), "highly contributed to the incredible expansion of TAVI," Cribier said, and development of both the transfemoral and transapical access approach further expanded TAVI to "nearly 100% of candidates." A series of landmark studies, including the PARTNER 3 and Evolut Low Risk trials, have since galvanized the once experimental operation to preferred treatment for many patients with AS, including patients who are younger and at low operative risk, where SAVR was the gold standard. After gaining the CE Mark in Europe in 2007 and the U.S. Food and Drug Administration’s (FDA) approval in 2012, TAVI gained expanded indications in the U.S. in Aug 2019 for low-risk patients over 65 years of age, marking its "apotheosis." "The spectacular worldwide expansion with Sapien3 and Evolut (Medtronic) can be seen through the numbers: more than 15 million patients treated with TAVR in over 80 countries and a four-fold growth rate expected over the next decade." "But it’s not about numbers, and it never was. Developing TAVR was about helping patients I met in my personal experience, and I always tried to move beyond the horizon. "It was a long road, but it was worth the fight." CHECK THE SESSION

August 18, 2022 10626
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SummitMD

Time to halt routine, post-TAVR oral anticoagulant therapy, CT scans: insights from the ADAPT-TAVR t...

For patients who have undergone transcatheter aortic valve replacement (TAVR), recent studies are negating the assumed significance of subclinical leaflet thrombosis (SLT) and subsequently knocking out the need for routine oral anticoagulant (OAC) therapy and computed tomography (CT) imaging. Findings from ADAPT-TAVR reported that asymptomatic SLT – also known as hypo-attenuating leaflet thickening (HALT) – was not significantly associated with adverse clinical outcomes, including cerebral thromboembolism and neurological dysfunction, in patients after TAVR. For antithrombotic therapy, there was a trend - that reached borderline statistical significance - for reduced SLT rates with edoxaban (Lixiana; Daiichi Sankyo), a direct oral anticoagulant (DOAC), compared to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel (Plavix; Bristol-Myers Squibb-Sanofi). Lead investigator Duk-Woo Park, MD, PhD(Asan Medical Center, Seoul, South Korea) presented the findings of the multicenter, open-label randomized trial on 220 patients across five centers in South Korea, Taiwan and Hong Kong at the American College of Cardiology 2022 conference (ACC 2022) on Apr 4. Results were published simultaneously in the Circulation. "The most important clinical message of the trial is that SLT – an imaging phenomenon – did not affect clinical outcomes such as thromboembolic events and mortality of TAVR patients,” Park said at ACC 2022. “Therefore, the presence of SLT should not dictate the type of antithrombotic therapy after TAVR for preventing SLT.” “Findings also do not support routine screening surveillance with CT scans to detect SLT,” he said. “Lack of evidence also warns against imaging-guided antithrombotic strategies when there is no hemodynamic or clinical significance.” Park noted that study limitations of open-label design, limited study population and short six-month follow-up required caution and curbed the findings as “hypothesis-generating” that would benefit from validation from future large-scale randomized clinical trials. ADAPT-TAVR Funded by Daiichi Sankyo Korea Co., Ltd. and CardioVascular Research Foundation (Seoul, Korea) Objective: Examine whether DOAC therapy with edoxaban reduces the risk of leaflet thrombosis and related cerebral thromboembolic after TAVR compared to DAPT (clopidogrel and aspirin). Confirm a causal relationship between SLT and cerebral thromboembolism or neurological/neurocognitive dysfunction. Design: Investigator-initiated, multicenter, open-label randomized trial 220 patients (mean age: 80; 41.9% male; mean STS score: 3.3; BAV in 90%) Patients randomized to receive edoxaban 60 or 30 mg once daily (n=110) or DAPT with aspirin and clopidogrel (n=110). *61.3% received edoxaban 30 mg according to dose-reduction criteria 4D cardiac CT conducted at 6 months; serial brain MRI for neurological/neurocognitive assessments performed at baseline and 6 months Outcomes Endpoint Edoxaban DAPT RR (95% CI)P value Primary Leaflet thrombosis on 4D CT at 6-months 9.8% 18.4% 0.53 (0.26-1.09) Secondary New cerebral lesions on brain MRI 25.0% 20.2% P=0.40 Neurological / Neurocognitive dysfunction National Institutes of Health Stroke Scale (NIHSS) 5.0% 3.7% P=0.74 Modified Rankin Scale 2.0% 0.9% P=0.69 Montreal Cognitive Assessment 30.0% 22.2% P=0.20 Safety Bleeding 11.7% 12.7% 0.93 (0.44-1.96) Conclusions: Overall incidence of leaflet thrombosis on CT scans was less frequent (8.5% difference; RR 0.53) with edoxaban than DAPT, although not statistically significant. No significant difference between groups for new cerebral thromboembolism (via brain MRI) or new neurological/neurocognitive dysfunction. No association between SLT and temporal changes of new cerebral thromboembolic lesions and neurological endpoints. Latest findings clear up confusion on SLT significance Along with ADAPT-TAVR, studies are continuing to update information on the clinical significance of SLT, which had raised alarms in early reports. SLT was not associated with high rates of cerebral thromboembolism and strong oral anticoagulation was not required for the average patient without an OAC indication. Duk-Woo Park, MD, PhD. TAVR, a minimally invasive stenting procedure for patients with symptomatic, severe aortic stenosis (AS) who are at higher surgical risk, carries the risk of transcatheter heart valve (THV) thrombosis. THV thrombosis – classified as either clinical valve thrombosis or SLT – is a rare but potentially serious TAVR complication that could obstruct blood flow and result in adverse clinical outcomes, including stroke. Although clinical valve thrombosis requires intervention for the symptoms of heart failure (HF), the clinical significance of SLT is still unclear because of insufficient evidence on its association with adverse clinical outcomes that include thromboembolic events, stroke, or mortality. The effectiveness and necessity of antithrombotic therapy to prevent SLT and neurological outcomes, particularly in patients without an OAC indication, is also controversial. Recently, results from a long-term, prospective, observational registry by Maneul Hein, MD (University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany) and colleagues, published in JACC: Cardiovascular Interventions in June, echoed ADAPT-TAVR findings, reporting no significant association between HALT and adverse clinical outcomes. The observational study found that HALT was not associated with death or cerebrovascular events during a median follow-up of 3.25 years (Kaplan-Meier 3-year estimates for survival: 70.1% vs 74.0%, P=0.597), although it was associated with symptomatic hemodynamic valve deterioration (9.4% vs. 1.5%; p

July 29, 2022 6438
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TCTAP 2022

‘Maximize OMT to reduce mortality for SIHD patients’

Innovations of optimal medical therapy (OMT) have left resounding, positive effects on survival in patients with stable coronary artery disease (CAD), an expert said, underscoring the need to maximize OMT, including managing risk factors. Sripal Bangalore, MD(New York University School of Medicine, New York, USA) addressed the evolution and role of OMT, or guideline-directed medical therapy (GDMT), in patients with stable CAD and multivessel disease (MVD) on Apr 29 at TCTAP 2022. “Atherosclerosis is a systemic condition, meaning systemic GDMT is fundamental for optimal management, even after revascularization,” Bangalore said. “OMT should involve managing lifestyle and behavioral risk factors, achieving physiological goals, and adhering to pharmacotherapy.” Stable CAD, also known as stable ischemic heart disease (SIHD), is a heart condition that requires medical therapy and, at times, invasive revascularization with coronary bypass artery graft (CABG) surgery or percutaneous coronary intervention (PCI). “All SIHD patients should receive a set of lifestyle interventions and OMT, which are critically important for managing stable CAD,” Bangalore said. “Medical therapy should be the backbone of all treatment, including first-line for patients treated with PCI or CABG.” Evidence supports GDMT for lifestyle interventions like diet, weight loss, exercise and smoking cessation. Medications include antiplatelet therapy with aspirin (75-162 mg daily), lipid-lowering statin therapy, beta-blockers and hypertension drugs like angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). ‘Modern OMT diminishes survival benefits of CABG, PCI’ Improvements in OMT also displace some of the known survival benefits of revascularization in stable CAD, Bangalore said on the controversial topic. As previously reported by SummitMD, comparing studies on revascularization versus OMT from the 1970s to the present day showed diminished survival benefits of PCI and CABG in the “OMT era.” “Randomized controlled trials (RCTs) in the OMT era consistently show no difference in mortality between revascularization and OMT for the individual endpoints,” Bangalore said. “One of the biggest problems today is that people paint broad strokes of CABG and revascularization as superior to OMT based on the composite endpoint without looking at individual endpoints. “But data on the mortality endpoint sends a consistent message. The COURAGE trial in 2007 and the BARI 2D trial in 2009 showed no difference in death, and even the FAME 2 trial from 2012, largely viewed as a positive trial for PCI, showed no difference in mortality.” The recent ISCHEMIA and ISCHEMIA-CKD trials found no difference in survival between revascularization and OMT, despite the “lingering confusion” on the curves separating for the endpoint of death: “Again, the two curves are superimposed with no curves crossing for 5-years.” When pooling the data into a meta-analysis, Bangalore and investigators found no difference between revascularization and OMT for the endpoint of mortality (RR 0.99, 95% CI, 0.90-1.09). Modern trials also demonstrate similar mortality rates between CABG and OMT in patients with triple-vessel disease, an area of much “confusion,” he said. BARI 2D, for instance, showed similar mortality rates between CABG and OMT in patients with triple-vessel disease (revascularization 86.4 vs. OMT 83.6, p=0.33). Analysis of ISCHEMIA that stratified patients by 1-, 2- or 3-vessel disease showed no difference between OMT and revascularization for the 5-year mortality endpoint. “When asking if OMT modulates the survival benefit of revascularization in stable CAD, the answer seems to be yes, there is a diminishing, not non-existent, survival benefit when medical therapy is optimized.” OMT goals still not reached But more needs to be done to maximize medical therapy and manage risk factors, two major aspects that could improve prognosis and increase survival benefits for patients with SIHD, Bangalore said. Posthoc study of SYNTAX showed that OMT reduced mortality by 36% at 5-years, greater than the 26% reduction of CABG or PCI in the same time frame (HR 0.64; 95% CI, 0.48-0.85, p=0.002). “Interestingly, only 29.1% of patients at baseline were taking OMT before revascularization compared to the 41.3% at discharge after PCI or CABG,” Bangalore said. “At 5-years, only 1/3 of patients in both groups were taking OMT (PCI 39.6% vs. CABG 35.7%), indicating more needs to be done to maximize medical therapy for patients undergoing PCI and CABG.” Cardiovascular risk analysis of the BARI 2D trial also emphasized the importance of maximized OMT. Results showed that managing six risk factors (RF) of smoking, high-density lipoprotein cholesterol (

May 26, 2022 15218
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TCTAP 2022

Post-PCI FFR, pressure pullback gradient to predict prognosis after revascularization

An expert outlined key takeaways on using fractional flow reserve (FFR) and pressure pullback gradient (PPG) after percutaneous coronary intervention (PCI) to predict post-revascularization clinical outcomes. “Post-PCI FFR is nothing new, and was used to assess coronary artery stenosis and post-PCI physiology since the late 1970s” Carlos Collet, MD, PhD(OLV Hospital, Aalst, Belgium) said at TCTAP 2022 on Apr 29. “The question is whether post-PCI FFR can be a marker of prognosis or is just a bystander in the relationship between coronary artery disease (CAD) pattern and major adverse cardiovascular events (MACE).” FFR is an imaging tool used to assess lesion significance and characterize disease before stent implantation to optimize PCI. PPG is a novel metric that helps identifies CAD phenotypes on a scale of 0 (diffuse disease) to 1 (focal disease) based on FFR pullbacks and tailor revascularization strategies. Link between low post-PCI FFR and MACE: causality or association? Several studies have identified a relationship between post-PCI FFR and factors like clinical outcomes, clinical characteristics, and CAD patterns. An individual patient-level meta-analysis on 2,400 patients by Collet and investigators, currently under review, found that lower post-PCI FFR increased the risk of target-vessel failure (TVF, OR per 0.10 FFR units: 0.56, 95% CI, 0.45-0.69, p

May 26, 2022 4986
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TCTAP 2022

Moving from ‘broad guidelines’ to patient-specific care: 1st line CCTA for stable CAD

Recent American guidelines on chest pain may help clinicians choose the right noninvasive cardiac test, or skip it entirely, for patients at intermediate risk for coronary artery disease (CAD) based on chest pain symptoms and the presence of risk factors, an expert said. “For the first time, we have a guideline on chest pain that helps provide direction,” said Manesh R. Patel, MD(Duke Heart Center, Durham, North Carolina) at TCTAP 2022 on Apr 28. “Over a decade ago, we found that risk stratification with noninvasive testing needed significant improvement.” “Now, the guideline and its pretest probabilities bring us closer to precisely identifying an appropriate cardiovascular test to diagnose and risk-stratify for CAD in patients at intermediate-risk,” he said. Published in the Journal of the American College of Cardiology (JACC) last October and co-written with five medical societies, the 2021 American Heart Association (AHA) and American College of Cardiology (ACC) guidance provides recommendations on the historically ambiguous area of evaluating and diagnosing chest pain. Although the guideline warns against routine testing in low-risk patients, first-line coronary computed tomographic angiography (CCTA) and stress testing – including stress echocardiography, positron emission tomography (PET), single-photon emission computed tomography (SPECT) or cardiac magnetic resonance (MR) – were green-lighted for intermediate- and high-risk patients. CCTA was particularly strongly recommended in patients with chest pain at intermediate risk for CAD to identify atherosclerotic plaque or obstructive CAD (Class I; LoE: A). In cases of stenosis or inconclusive CCTA, the guidelines recommend fractional flow reserve-computed tomography (FFRct) to diagnose vessel-specific ischemia or aid clinical decisions (Class IIa; LoE: B). Stress testing earned a Class I recommendation (LoE: B) to diagnose myocardial ischemia and estimate the risk of major adverse cardiovascular events (MACE) in intermediate-risk patients with emergency chest pain and suspected acute coronary syndrome (ACS). Stress testing without imaging got a Class IIa (LoE: B) endorsement to exclude ischemia. Early imaging to ‘move paradigm’ on chest pain, ischemia cascade Imaging with earlier disease can push forward classic teaching on chest pain and improve the poor diagnostic yield of coronary angiography found a decade prior, Patel said. In 2009, Patel and investigators discovered that only a minority of patients (37.6%) without known disease who underwent elective cardiac catheterization had obstructive CAD, indicating problems with the real-world use of noninvasive tests that should have theoretically improved risk stratification and reduced invasive catheterizations in patients without obstructive CAD. “The system was broken since excess heart catheterizations were not identified and pre-angiography information had little value.” Patel said. “And the system was based on stress testing with almost no CT or FFRCT, so opportunities existed.” “Accurate anatomic and function evaluation is ideal, but the reality of noninvasive cardiac testing – whether stress echo, stress treadmill or stress SPECT – was no lesion-specific information and high rates of false positives and false negatives. “Now, earlier CCTA offers visualization of CAD that helps inform treatment decisions and creates an earlier pathway. Good pictures make it hard to argue the presence of atherosclerosis and whether there is no disease or a complex burden.” Although four prospective, multicenter studies - ACCURACY, EUROPE, MEDIC and CorE64 – demonstrated the sensitivity and specificity of stress testing and CCTA, results varied depending on the enrolled population. Meanwhile the negative predictive values of CCTA were remarkably high in all studies. Overcoming these limitations, the 2015 PROMISE trial, co-authored by Patel and investigators, randomized 10,003 symptomatic patients to either first-line CCTA or functional testing (exercise electrocardiography, nuclear stress testing or stress echo). Baseline characteristics included hypertension in 65%, diabetes in 21% and dyslipidemia in 67% (mean age: 60; women 52%). Investigators found no statistically significant difference in the composite primary endpoint of death, MI, hospitalization for unstable angina or major procedural complication at 25-months (CCTA 3.3% vs. functional testing 3.0%, aHR 1.04; 95% CI, 0.83-1.29, P=0.75), indicating CCTA did not improve clinical outcomes over functional testing in symptomatic patients with suspected CAD. CCTA had fewer secondary endpoint events of catheterizations showing no obstructive CAD than functional testing (3.4% vs. 4.3%, P=0.022). Interestingly, more patients underwent revascularization, including coronary artery bypass graft (CABG), in the CCTA arm than in the functional arm (6.2% vs. 3.2%, P=0.022). “Revascularization rates with CABG were almost two-fold (72 vs. 38),” Patel said. “But there was no significant difference in death or non-fatal MI at 3-years between the groups, although graphs showed early separation and late catch-up.” However, the SCOT-HEART trial published in the New England Journal of Medicine (NEJM) in 2018 fatal MI at 5-years without significantly raising rates of coronary angiography or revascularization compared to standard of care alone. Accordingly, CCTA became more popular for patients with stable chest pain. Evolving data for CCTA, FFRCT to enhance precision for chest pain tests Focus is now on increasing precision, Patel said: “In addition to imaging in CAD, hopes of combining anatomy and function are on the rise. Multiple companies have performed FFRct with computational fluid dynamics to predict downstream pressure drop.” Early data from a 2012 study, for instance, showed CCTA plus noninvasive FFRct improved diagnostic accuracy compared to CT alone in stable patients with suspected or known CAD and intermediate stenosis, which led to studies like DISCOVER-FLOW, DeFACTO and NXT that provided HeartFlow FFRct data. The PLATFORM study also showed that CCTA and FFRct were associated with a significantly lower rate of invasive angiography showing no obstructive CAD, effectively reducing the number of patients without obstructive disease from being sent to the cath lab. Conducted by Patel and investigators, the ADVANCE Registry found FFRct compared to CT alone changed management in 2/3 of 5,083 enrolled patients, and 1-year results showed patients with abnormal CT-FFRs had worse outcomes than those with normal measurements, regardless of stenosis severity. “Data for CCTA, FFR-CT, and all tests actually, are evolving significantly,” he said. “More science is coming, including the development of a risk-prediction score based on the PROMISE trial. “The ongoing PRECISE trial, which finished enrolling 2,100 patients, is also underway to study a precision-based testing algorithm that excludes testing in low-risk patients but offers first-line CCTA in intermediate- and high-risk groups.” CHECK THE SESSION

May 26, 2022 9169
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TCTAP 2022

Similarities, differences between EBC MAIN and DKCRUSH-V

Optimal treatment of left main (LM) bifurcation lesions during percutaneous coronary intervention (PCI) may depend on anatomy, evidenced by analysis of the EBC MAIN and DKCRUSH-V trials on provisional- and two-stenting. Optimal treatment of LM bifurcations remains controversial. Although provisional stenting is the conventional method of treatment, recent studies from Chinese investigators demonstrated that two-stenting with the Double Kissing (DK) Crush technique outperformed provisional stenting. The 2018 European Society of Cardiology and European Association for Cardio-Thoracic Surgery (ESC/EACTS) guideline on myocardial revascularization has since recommended DK Crush over provisional T-stenting for true LM bifurcation lesions (Class IIb, B). The 2011 American College of Cardiology Foundation, American Heart Association and Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guideline also recommends two-stenting for complex bifurcations (Class IIa, B) but recommends provisional stenting as the initial approach for bifurcation lesions when the side branch (SB) is not large and for mild to moderate focal ostial disease (Class I, A). Although differences in data and perspectives fueled a divide, analyses of trials on the respective stenting techniques have created a more holistic perspective on the optimal treatment for LM bifurcations that incorporate coronary anatomy. “Both investigators and cardiologists agree that provisional stenting is better for simple distal LM lesions defined by DEFINITION criteria,” Shaoliang Chen, MD, PhD(Nanjing Medical University, Jiangsu, China) said at TCTAP 2022 on Apr 27. “But I suggest the two-stent technique, particularly DK Crush, for complex LM lesions when SB lesion length is greater or equal to 10 mm, SB diameter stenosis is greater or equal to 70%, and two other high-risk factors are present” he said. Comparison of the two trials showed that both were designed to test for superiority and had a similar sample size (EBC MAIN: 467 vs. DKCRUSH-V: 482). But the studies diverged in the use of two-stent techniques. In EBC MAIN, culotte was used most frequently in the two-stent arm (53%), followed by the T and protrusion (TAP) (33%) and DK Crush (5%). On the other hand, DKCRUSH-V used only the DK Crush technique (100%). The 1-year primary endpoint event criteria also differed with EBC Main defining composite outcomes as all-cause death, myocardial infarction (MI) and target-lesion revascularization (TLR), and DKCRUSH-V inclduing cardiac death, target-vessel MI (TVMI) and TLR. EBC MAIN also assumed a “very high” 1-year primary endpoint rate of 25% in the two-stent arm compared to the 7% assumed rate of DKCRUSH-V. Other differences included SYNTAX scores (EBC MAIN: A dissection, TIMI 75~90% compromise). Intravascular ultrasound (IVUS) use was about 40% in both studies. Chen noted that absolute TLR rates (EBC MAIN: 6.1% vs. DKCRUSH-V: 7.9%) were “a bit high” in DKCRUSH-V but emphasized that 32% of lesions in DKCRUSH-V were complex bifurcations, indicating the 1-year TLR rates were similar between trials. CHECK THE SESSION

May 26, 2022 10212
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TCTAP 2022

No ‘one-size-fits-all’ approach to treat CAD with PCI before or after TAVR, heart expert says

Managing coronary artery disease (CAD) in patients undergoing transcatheter aortic valve replacement (TAVR) means treading the delicate benefit-risk balance of coronary intervention, an expert said recently. “CAD and TAVR often coincide, but the need for coronary revascularization before or after remains unsettled, indicating the decision may depend on patient characteristics like age and comorbidities,” Nicolas M. Van Mieghem, MD, PhD(Erasmus University Medical Center, Rotterdam, Netherlands) said at TCTAP 2022 on Apr 28. “It’s always a balancing act when treating significant stenosis before or after TAVR,” he said. “Although word is still out on the best strategy, multiple trials like TAVI-PCI and POTUS are ongoing for controversial pre- and post-TAVR PCI issues.” TAVR is a minimally invasive procedure that replaces a diseased aortic valve with a prosthetic, or man-made, valve for patients with aortic stenosis (AS), characterized by narrowing valves. Since the U.S. Food and Drug Administration (FDA) approval in 2011, TAVR has become standard of care for patients with severe AS who are ineligible for surgical aortic valve replacement (SAVR). The procedure also gained expanded indications for younger, lower-risk populations. To treat or not to treat: co-existing CAD with AS The prevalence of CAD in patients with severe AS is reportedly high, with studies showing at least half of AS patients with co-existing CAD. However, the issue of CAD diagnosis and treatment in AS patients undergoing TAVR has evolved into one of major controversy, owing to inconsistent study findings on the treatment of CAD and subsequent TAVR outcomes. The exclusion of patients with non-revascularized CAD in major TAVR trials like the PARTNER I and U.S. CoreValve High Risk Study also confounded the development of standard treatment for TAVR candidates with CAD in guidelines. Issues of coronary access after TAVR have also become an increasing problem, indicating the need for a feasible and reproducible post-TAVR CAD treatment strategy. Particularly, the expansion of TAVR into lower-risk patients with longer life expectancy foreshadows more repeat coronary angiographies and revascularization with percutaneous coronary intervention (PCI) after the procedure. “The question is when to treat significant stenosis – before or after TAVR,” Mieghem said. “There are benefits and risks for both, so it’s not a one-size-fits-all approach since some patients need valve implants first while others require priority CAD treatment.” ‘Impact of complete revasc, pre-TAVR PCI not significant’ Mieghem noted that the lack of a standard CAD management strategy calls for assessing patient and valve characteristics to determine the benefits and risks of PCI before TAVR. A single-center cohort study on 250 patients who received either complete or incomplete revascularization found no difference in overall survival between the two groups, and patients with complete revascularization gained only “modest” reductions in the SYNTAX score compared to those with incomplete revascularization. The results were replicated in the small randomized ACTIVATION trial that compared pre-TAVR PCI versus no pre-TAVR PCI in 235 elderly patients at intermediate-risk at 17 centers in the U.K. (mean age 83, STS score 4.4). Findings showed no significant improvement with pre-TAVR PCI over no coronary intervention at 1-year for the primary composite endpoint (PCI arm 41.5% vs. no-PCI arm 44.0%; difference -2.5%; 1-sided upper 95% CI limit: 8.5%; 1-sided noninferiority test P = 0.067). PCI also had higher rates of mortality (13.4% vs. 12.1%) and all-cause bleeding (p=0.021). “If we compare the outcomes of complete revascularization versus incomplete revascularization –and we’re talking about more than 250 patients – there was basically no difference between the two,” Mieghem said. “RCT data also shows no clinical impact with PCI, which had increased bleeding risk due to the more intense antithrombotic regime.” Post-TAVR coronary access For coronary access after TAVR, Mieghem stressed the importance of valve specifications and the relationship between transcatheter heart valves (THV), coronary physiology and aortic root anatomy, among the numerous known determinants. Post-TAVI determinants of coronary access Patient-related: TAV-related (procedure): Abnormal, difficult or height take-off of coronary VIV TAV-in-TAV Length and calcification volume of the native valve Commissural alignment Height or width of the aortic bulb TAV type Sinus of Valsalva dimensions Implantation height Sinotubular junction dimensions TAV/Sinus of Valsalva relation “The spatial relationship between the valve frame, sinuses and coronary ostia is important, as is the push-away of the native/bioprosthetic leaflets compared to sinuses and coronary ostia,” he said. “You need to be aware of the specifics of the valve being implanted and confirm details like the fabric of the skirt ceiling, height of the fabric and framework.” A previous study on the risk of impaired coronary access and obstruction after redo TAVR showed that 96% of CoreValve patients had coronary access issues versus only 4% of patients with a balloon expandable valve (BEV). The findings triggered an editorial that identified coronary height, transcatheter frame height, THV leaflet height, commissural alignment and THV to coronary distance as the most important factors for coronary access. “Expect no issues with a valve remaining below the coronary ostia,” Mieghem said. “But when interacting with the ostia, the commissural alignment and the distance between the valve and wall become important.” The RE-ACCESS study further found that the use of Evolut R/PRO transcatheter aortic heart valves (TAV) (OR 29.6; 95% CI, 2.6-335.0; p

May 23, 2022 14092
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