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AP VALVES & SH 2021 Virtual

Evolut or Sapien? Expert Unravels 'Equation' for Choosing TAVR Device

The complex equation for transcatheter aortic valve replacement (TAVR) device selection becomes more straightforward with the operator's increasing experience with self- or balloon-expandable valves (SEV/BEV), a cardiology expert said this month. Alan C. Yeung, MD (Stanford University School of Medicine, California, USA) identified and explained the main variables that guide the device selection process for TAVR at AP Valves & Structural Heart Virtual (AP VALVES & SH 2021) on August 5. "The issue with selecting a valve is that it is nuance driven, meaning the operator cannot choose the optimal device for a certain patient based on textbook-level knowledge alone. There's no single equation for choosing the correct device; instead, it's a complex process that is the summation of various factors," Yeung said. "Although selecting the optimal valve is a complex process, with enough experience, the equation becomes rather straightforward: the choice depends primarily on the cardiologist's level of experience with a valve, meaning that operators should choose the device they have the most experience with," he added. Valve selection is but one part of the whole TAVR strategy, Yeung stressed. The correct technique should be coupled with the device to maximize outcomes and lower complications. Ultimately, setting one primary goal (i.e., avoiding permanent pacemaker implementation (PPI) or avoiding coronary obstruction) should help narrow the device- and technique-selection. Relative outcome similarities of BEV & SEV devices in SOLVE-TAVI, combined with new trial data, make valve selection nuance-driven. Alan C. Yeung, MD The minimally invasive TAVR procedure has established itself as a safe and effective alternative to surgical aortic valve replacement for patients with aortic stenosis (AS). Recent studies are showing TAVR benefits extend to even low surgical risk patient groups. Despite the expanding indications for TAVR, initial device limitations have resulted in the wide use of only two major newer-generation, U.S. Food and Drug Administration (FDA)-approved devices: the balloon-expandable Sapien system (Sapien 3, Sapien 3 Ultra; Edwards Lifesciences) and the self-expanding CoreValve system (Evolut PRO, Evolut R; Medtronic)1. Although other devices such as the ACURATE neo (Boston Scientific), JenaValve (JenaValve), and Portico valve (Abbott) received European CE Marks, most are still under examination in clinical trials. The FDA also retracted the Lotus Edge system (Boston Scientific) last year. The lack of randomized data that fail to prove benefit of one device over the other has also left clinicians to deal with the ongoing challenge of selecting an optimal valve for patients who often present unique characteristics and varying comorbidities. At AP VALVES & SH 2021, Yeung called to attention the results of the SOLVE-TAVI trial conducted by Holger Thiele, MD (University of Leipzig, Germany) and colleagues and published in the European Heart Journal2 in February of last year. The 2x2 factorial, randomized trial on 447 patients with aortic stenosis evaluated Evolut R (self-expandable valve, SEV) and Sapien 3 (balloon-expandable valve, BEV) in terms of the primary efficacy composite endpoint (all-cause mortality, stroke, moderate/severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30-days), along with anesthesia strategies. Results showed the two systems were similar regarding the primary composite endpoint, indicating equivalency between SEV/BEV (Evolut R 28.4% vs. Sapien 3 26.1%, rate difference -2.39, 90% CI -9.45-4.66, P=0.04). 1-year results regarding composite endpoint and all-cause mortality were also similar. Yeung noted that cardiovascular mortality was higher with Sapien 3 (0.5% vs. 1.8%, HR 3.89, 95% CI 0.44-34.67, P=0.19), but this was most likely due to the stroke rate that was "unusually high" (1.0% vs. 6.9%, HR 7.13, 1.62-31.32, P=0.002). Sapien 3 also had a lower rate of moderate-to-severe paravalvular leakage (PVL), but the difference was not statistically significant (7.0% vs. 4.5%, HR 0.63, 95% CI 0.27-1.45, P=0.35). Evolut R had a higher rate of permanent pacemaker implantation (PPI) than Sapien 3, though this difference was also not significant (24.7% vs. 20.2%, HR 0.79, 95% CI 0.53-1.16, P=0.25). "For 1-year outcomes, there was essentially no difference regarding all-cause mortality and stroke. Sapien had significantly higher stroke risk, but most of it occurred in the initial stages of the procedure; namely, it arose within a month at the hospital and then flattened out in later stages. So, it could also be a fluke possibly attributable to the patient population," Yeung said. Evolut also showed better hemodynamics per echocardiographic findings and proved statistical significance in the mean aortic pressure gradient (Evolut R 6mmHg vs. Sapien 3 10mmHg, P

August 05, 2021 19059

SummitMD

FLOWER-MI: FFR Shows No Benefit over Angio for Complete Revasc in Multi-vessel STEMIs

Fractional flow reserve (FFR)-guided complete revascularization of STEMI patients with multi-vessel disease was not superior to stenting guided by angiography alone, FLOWER-MI findings showed. The first head-to-head study findings in the patient group showed FFR-guided percutaneous coronary intervention (PCI) did not improve 1-year endpoint outcomes of mortality, myocardial infarction (MI), or urgent revascularization compared to angio-guided PCI. Presenting study findings at the annual American College of Cardiology Scientific Sessions (ACC 2021) held last month, principal study investigator Etienne Puymirat, MD (University of Paris; Georges Pompidou Hospital; Paris, France) also explained that FFR-guided complete revascularization was not more cost-effective than angio-guidance alone. “The strategy of using FFR to guide stenting is not superior to the standard angiography technique to treat additional partially blocked arteries,” Puymirat said. “In addition to no [outcome] benefit, we have also shown that - based on the costs in France - the FFR-guided strategy is more expensive.”1 These findings, simultaneously published in the New England Journal of Medicine on May 162, run contrary to the previous FAME trial3 wherein FFR-guided PCI for stable multi-vessel disease patients demonstrated lower 1-year MACE incidence than angio-guided PCI (13.2% vs. 18.3%, P=0.02). Despite the new evidence, experts cautioned against understanding results as definitive, with investigators explaining that “given the wide confidence intervals for the estimate of effect, the findings do not allow for a conclusive interpretation.” FLOWER-MI questions optimal revascularization technique in multi-vessel STEMI Current guidelines recommend routine complete revascularization - also known as PCI for nonculprit lesions - in STEMI patients with multi-vessel disease, albeit without recommending a particular stenting technique. The guideline recommendation for complete revascularization has been backed by studies such as COMPLETE4 trial that demonstrated complete revascularization led to fewer subsequent PCI procedures and less CVD death or MI. Studies such as the DAMANI-3-PRIMULTI5 and COMPARE-ACUTE6 have also shown that FFR-guided complete revascularization of nonculprit arteries is superior to FFR-guided revascularization of culprit lesions only, leading to lower MACE, CV death, and MI incidence as well as fewer subsequent PCI procedures. Therefore, although current evidence implies complete revascularization is better than PCI for culprit lesions only, questions have emerged regarding optimal PCI strategies in the STEMI subgroup, particularly regarding FFR- or angio-guided PCI. To address the evidence gap, FLOWER-MI investigators sought to compare the two strategies for complete revascularization in multi-vessel STEMIs. FFR-PCI ‘not superior’ to angio-PCI but experts caution against results being final The randomized multicenter FLOWER-MI trial conducted in 41 centers across France included 1,171 patients with STEMI and multi-vessel disease (avg. 62 years old; 83% men) who had undergone successful PCI with 50% or more stenosis in at least one additional nonculprit lesion. After the culprit vessel PCI, all patients were immediately randomly assigned to a second non-culprit vessel PCI guided either by FFR (n=586) or by angiography alone (n=577). The second procedure was performed within five days of the first. Patient analysis showed those in the FFR arm had fewer stents placed for nonculprit lesions than in the angiography arm (mean stents: FFR-group 1.01 vs. angio-group 1.50). The primary outcome at 1-year was the composite of death from any cause, nonfatal MI, or unplanned hospitalization leading to urgent revascularization. Follow-up over 12 months showed the primary outcome occurred in 5.5% of the FFR-guided group and 4.2% of the angio-guided group, failing to demonstrate superiority (HR 1.32, 95% CI, 0.78-2.23, P=0.31). The study, therefore, failed to meet its primary endpoint while other composite outcomes also failed to prove the benefit of FFR-guidance over angio-guidance. FFR-guided vs. angio-guided revascularization: Primary outcome: 5.5% vs. 4.2% (HR 1.32, 95% CI, 0.78-2.23, P=0.31) Death: 1.5% vs. 1.7% (HR 0.89, 0.36-2.20) Nonfatal myocardial infarction 3.1% vs. 1.7% (HR 1.77, 0.82-3.84) Unplanned hospitalization requiring urgent revasc: 2.6% vs. 1.9% (HR 1.34, 0.62-2.92) Analysis of the secondary endpoint concerning cost-efficacy indicated FFR-guided PCI cost a median of 500 euros ($600) more than angio-guided PCI (€8,832 vs. €8,322; P

July 21, 2021 13196

SummitMD

'Next-Gen' ADAPTABLE Study Says Low-Dose Aspirin Equal to High-Dose for ASCVD Patients

Recent ADAPTABLE findings showed daily low-dose (81 mg) aspirin is better than a 325 mg dose for preventing secondary coronary events in atherosclerotic cardiovascular disease (ASCVD) patients. Although aspirin has been established as an effective therapy for secondary prevention in ASCVD, the appropriate dose for lowering the risk of death, myocardial infarction, stroke, and bleeding risk has been a subject of a long-standing controversy. Schuyler Jones, MD (Duke University School of Medicine, North Carolina, USA) presented the findings at the annual American College of Cardiology’s Scientific Session (ACC 2021) last month as the lead author with the results published in the New England Journal of Medicine on May 271. “There hasn’t been a clear answer about the most effective and safe dose of aspirin for these patients. Instead, there have been conflicting findings with some research suggesting 81 mg may reduce the risk of bleeding, but the higher dose may provide more effective prevention of heart attacks and stroke,” Jones said2. “But these earlier studies have primarily investigated aspirin (either 81 or 325 mg daily dose) compared to placebo whereas ADAPTABLE was a direct comparison of the two doses.” Jones noted that ADAPTABLE - funded by the Patient-Centered Outcomes Research Institute (PCORI) - was the most extensive study set to find the optimal daily aspirin dose and examine patient outcomes regarding effectiveness and safety. The open-label, parallel, randomized trial heralded as a “next-generation” clinical trial is also the first to be conducted within the National Patient-Centered Clinical Research Network (PCORnet) electronic data infrastructure and the first large-scale electronic health record (EHR)-enabled trial conducted in the U.S. According to the trial design, eligible patients received invitations to participate in the study via mail, email, or phone. Patients further enrolled and randomized themselves into the study through the trial website and completed follow-up every 3 or 6 months. Investigators collected patients’ medical history and clinical events through EHR and insurance documentation. The trial included 15,076 patients with established ASCVD across 40 centers in the U.S. who were randomized to either a daily 81 mg aspirin group (n=7,540) or a daily 325 mg aspirin group (n=7,536). The mean patient age was 68 years, 31% were female, and 38% had diabetes. Analysis of patient characteristics also showed that 96% (13,537) of patients had been taking aspirin before randomization, and among them, 85.3% had been taking a daily 81 mg dose. The primary effectiveness endpoint was defined as a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding that was also assessed in a time-to-event analysis. After a median follow-up of 26.2 months, the primary endpoint occurred in 590 patients (7.28%) of the low-dose group and 569 patients (7.51%) of the high-dose group, indicating no statistically significant difference between the two arms (HR 1.02, 95% CI, 0.91-1.14). The same went for the primary safety endpoint, with hospitalization for major bleeding occurring in 53 patients (0.63%) in the low-dose group and 44 patients (0.6%) in the high-dose group, indicating no significant difference (HR 1.18, 95% CI, 0.79-1.77). However, investigators noted a high incidence of dose-switching from the 325 mg to the 81 mg arm, with 41.6% crossing over to the low-dose group, whereas only 7.1% crossed over from a low-dose to a high-dose arm. Patients on the high dose also adhered to the prescription for a shorter period than those on the low dose, results showed (high-dose: 434 days vs. low-dose: 650 days). Some patients also discontinued aspirin, with 11% in the 325 mg arm stopping treatment and 7% in the 81 mg arm doing the same. “In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose-switching to 81 mg daily with no significant differences in cardiovascular events or major bleeding between patients assigned to either 81 or 325 mg daily,” study authors wrote. While presenting trial findings, Jones recommended the 81 mg over the high dose as the “best choice for patients,” citing improvements in long-term adherence. Despite the positive findings, an accompanying editorial (aptly titled the “need for ADAPTABLE design”)3 identified weaknesses regarding trial design that could have impacted the results. Colin Baigent, MD (University of Oxford, England, UK) wrote that while the “innovative and low-cost methods” to simplify trial execution were noteworthy, the trial fell short in setting up fair comparisons between treatment groups and protecting against biased statistical analyses. These problems, Baigent argued, could have and should have been tested for and weeded out with a pilot study wherein investigators could have reviewed and used unblinded data to tweak the trial design before the main study began. “In the case of ADAPTABLE, one could speculate that a pilot study might have identified the observed preference for the 81 mg dose of daily aspirin,” Baigent wrote. “This may, in turn, have yielded methods to ensure equipoise between aspirin dose preferences, which could have included a run-in period in which patients were sequentially exposed to both aspirin doses, with only those adhering to both regimens being considered for randomization.” Jones, also acknowledging the high cross-over rate, added that he and his colleagues would run additional exploratory analyses to determine the timing, clinical predictors, and reasons for dose switching in the study. “We made every effort to encourage [patients] to stay on their study dose, but people felt very strongly about it,” he said. “In turn, the differential effects of the two doses are less clear since dose switching occurred very frequently, especially in the 325 mg group.” Despite limitations, investigators noted that many patients stayed on the assigned dose for over a year, and the findings are highly generalizable due to the study’s pragmatic set-up: “Patients and clinicians should use the information from the study to talk about the dose of aspirin [patients] prefer.” https://www.nejm.org/doi/full/10.1056/NEJMoa2102137 https://www.acc.org/about-acc/press-releases/2021/05/14/19/57/baby-and-regular-strength-aspirin-work-equally-well-to-protect-heart-health https://www.nejm.org/doi/full/10.1056/NEJMe2106430

July 05, 2021 3573

SummitMD

In DES-PCI Era, Clopidogrel Gains Traction over Aspirin as Maintenance Monotherapy after DAPT

Korean researchers recently announced head-to-head study results that demonstrated the superiority of clopidogrel over aspirin as an antiplatelet monotherapy after coronary stenting and dual antiplatelet therapy (DAPT). The investigator-initiated HOST-EXAM1 findings were published in The Lancet on May 16 and simultaneously presented by Hyo-soo Kim, MD, PhD (Seoul National University Hospital, Seoul, South Korea) at the annual American College of Cardiology Scientific Sessions (ACC 2021) last month. The study reported a 30% reduction in deaths, heart attacks, strokes, or major bleeding events with clopidogrel monotherapy than aspirin in patients who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DES) without experiencing adverse events during 6 to 18 months of DAPT. Findings also showed clopidogrel monotherapy decreased both the risk of thrombotic and bleeding events compared to aspirin alone. "These data confirm our working hypothesis that long-term maintenance antiplatelet monotherapy with clopidogrel produces better outcomes than aspirin in patients who are free from adverse events at 1-year following coronary stenting," Kim said. The findings break away from current recommendations by both the 2016 American College of Cardiology/American Heart Association (ACC/AHA) and the 2017 European Society of Cardiology/ European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines that recommend aspirin as the standard maintenance monotherapy after DAPT. Although aspirin has been the mainstream treatment for secondary prevention of ischemic events in the patient group, previous studies such as the CAPRIE trial2 (conducted in the "pre-DES" era) on nearly 20,000 patients had already begun to show significant benefits of long-term clopidogrel over aspirin monotherapy. Nearly 20 years later - with clopidogrel no longer a "new" antiplatelet in the market - observational findings3 by Korean researchers led by Tae-kyu Park, MD (Samsung Medical Center, Seoul, South Korea) also hinted at benefits of clopidogrel over aspirin to prevent ischemic events. Although Park and colleagues found positive findings of clopidogrel monotherapy in the era of drug-eluting stents, they called for further randomized trials - noting the lack of studies comparing outcomes of different antiplatelet monotherapies for DES-PCIs. At ACC 2021, Kim likewise noted that "[despite guidelines recommendations,] the optimal single antiplatelet agent for long-term maintenance therapy beyond the DAPT duration has been unclear," adding that physicians in clinical practice are still extending DAPT for as long as 18 months depending on the patient's bleeding risk. The prospective randomized open-label multicenter HOST-EXAM trial conducted across 37 study sites in Korea from March 2014 to May 2018 enrolled and randomized 5,438 patients (avg. age 63 years; 75% men) who had received DES-PCI and went through 6 to 18 months of DAPT therapy without experiencing clinical events. Patients were randomized to receive either clopidogrel monotherapy 75 mg once daily (n=2,710) or aspirin 100 mg once daily (n=2,728), and final analyses were completed in 98.2% (5,338 patients) over 24 months. The primary endpoint was defined as the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome (ACS), and Bleeding Academic Research Consortium (BARC) type bleeding ≥3. Secondary thrombotic endpoints were defined as composite events of cardiac death, non-fatal MI, ischemic stroke, ACS-related readmission, or stent thrombosis. Results showed the primary outcome decreased by 27% in the clopidogrel arm over the aspirin arm (5.7% vs. 7.7%, HR 0.73, 95% CI 0.59-0.90, p=0.0035). Secondary endpoint data also favored clopidogrel over aspirin, with thrombotic events occurring in 3.7% of the clopidogrel arm and 5.5% of the aspirin arm (HR 0.68, 95% CI, 0.52-0.87, p=0.0028). All bleeding events (BARC type≥2) occurred in 2.3% of the clopidogrel group and 3.3% of the aspirin group (HR 0.70, p=0.036). Study investigators concluded that clopidogrel monotherapy "significantly reduced" the risk of primary endpoint incidence, suggesting its superiority for preventing adverse clinical events in the population. "These results confirm that clopidogrel is superior to aspirin for reducing blood-clotting events incidence," Kim said. "What is striking is that clopidogrel also fared better than aspirin at reducing bleeding events." "Such findings that one antiplatelet agent is better than the other for both clotting and bleeding events have been observed in other studies, suggesting that thrombotic and bleeding events are closely associated [especially when considering] patients [discontinue] antiplatelet agents after experiencing bleeding, which ultimately results in thrombotic events," he added. However, Kim warned that these results could only be generalized to patients who have taken long-term DAPT without adverse events: "It may be difficult to extrapolate our results to patients who have received DAPT for a shorter period such as 1 or 3 months, but these results may help physicians select an antiplatelet monotherapy for patients in a chronic stable phase after stenting." Limitations include that the study was not blinded and comprised of a Korean population only, as well as a lower-than-expected number of adverse events reported in both groups. Kim and colleagues said follow-up would be extended to more than 5 years to track long-term outcomes and further understand clopidogrel's safety and efficacy over aspirin. The research team will also run a separate cost-effectiveness study regarding the two medications, noting that clopidogrel costs more than aspirin. The study was funded by the Korea’s Ministry of Health and Welfare and four Korean pharmaceutical firms of Chong Kun Dang, Samjin, Hanmi, and Daewoong. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01063-1/fulltext https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)09457-3/fulltext https://www.ahajournals.org/doi/full/10.1161/CIRCINTERVENTIONS.115.002816

June 21, 2021 9832

SummitMD

Asan Medical Center First in Asia to Complete 1,000 TAVI Cases

Asan Medical Center (AMC) announced completing 1,000 transcatheter aortic valve implantation (TAVI) procedures last month, reaching a new milestone both domestically and in Asia. The AMC Heart Institute's Heart Team - led by interventional cardiologists Seung-jung Park, Duk-woo Park, Do-yoon Kang, and Dae-hee Kim as well as cardiac surgeons Suk-jung Choo, Joon-Bum Kim, and Ho-jin Kim - performed the TAVI procedure on a 90-year old female patient with severe aortic stenosis on May 6th. CAPTION: (From right) AMC Heart Institute Professors Duk-woo Park, Seung-jung Park, Ju Hyeon Kim performs the 1000th TAVI procedure on an aortic stenosis patient on May 6. AMC has now become the first hospital - both in Korea and in Asia - to complete 1,000 TAVI cases, the hospital said. The team achieved a 99 percent success rate in the past five years with an overall success rate of 96 percent, despite the characteristics of a high-risk and severe-disease elderly patient group. Analysis showed that the average patient was 80-years old and most had comorbidities such as hypertension (80 percent), diabetes (33 percent), stroke (12 percent), and chronic obstructive pulmonary disease or COPD (22 percent). The heart team also recorded an “exceptionally” low rate of complications, including a one percent occurrence of both severe stroke and 30-day mortality. “The Heart Team has maintained low complication and mortality rates for 1,000 patients, thanks to its organic and strong teamwork,” AMC Heart Institute Chairman Seung-jung Park said. “We recognize and thank all members who have contributed to reaching this milestone.” The 1,000th cumulative case is also this year’s 100th procedure, the hospital said. “Asan Medical Center has completed 100 TAVI procedures within four months and we expect to perform more than 300 by the end of this year, marking a similar or even higher procedural and success rate than medical centers abroad, such as the U.S.,” Professor Duk-woo Park said. Based on these recent efficacy and safety results, domestic experts have noted the possibility of expanded reimbursements that could ultimately raise the TAVI utilization rate. Although local health authorities currently reimburse up to 20 percent, the expansion of TAVI indications to a larger demographic coupled with better success rates may expand reimbursement, they said. AMC Heart Institute began performing TAVIs in Korea in 2010 with a team led by TAVI pioneer Alain Cribier, MD (Hospital Charles Nicolle, France) and Seung-jung Park, and has since expanded to become a multi- and inter-disciplinary team comprised of interventional cardiologists, cardiac surgeons, anesthesiologists, and radiologists. TAVIs at AMC Heart Institute are carried out in a hybrid operating room equipped with cutting-edge imaging devices and tailored procedural and surgical equipment. Regarded as one of the most difficult cardio-cerebrovascular intervention strategies in the field of cardiology, TAVI is a minimally invasive heart procedure that replaces a deteriorating aortic valve in patients with aortic stenosis. The severity and risk of aortic stenosis - characterized by the narrowing of the heart’s aortic valve - increase with age and ultimately impairs the heart’s ability to pump blood to the body. Severe cases are known for a 50 percent mortality rate within two years of diagnosis. Although aortic stenosis has been primarily treated with open-heart surgery, recent advances in stenting techniques and devices have made it possible for even elderly patients with severe aortic valve disease to receive TAVI without general anesthesia.

June 15, 2021 6200

TCTAP 2021 Virtual

Future Journey of Transcatheter Mitral Valve Interventions

The incidence of mitral regurgitation (MR) in Western countries and in individuals above 75 years of age is almost 1.7 percent and 10 percent, respectively, and surgery is currently the gold standard for treatment of severe MR, despite the adoption of minimally invasive techniques. The presence of severe comorbidities, however, precludes surgical treatment in up to 50 percent of patients with severe MR [Testa et al, The Journal of Thoracic and Cardiovascular Surgery 2019;2:319-327.]. Transcatheter mitral valve repair by means of leaflet plication may be an alternative therapeutic option, as proven by the encouraging results of the edge-to-edge technique with the MitraClip system (Abbott Vascular Inc, Menlo Park, Calif) in the COAPT trial [Stone G et al NEJM 2018]. The recent introduction of the PASCAL technology (Edwards) has increased treatment options for patients with suitable anatomy. However, there are still many situations where the plication can be unsuccessful or even contraindicated for high risk of leaflet tearing: An alternative treatment is based on the “direct annuloplasty” of the mitral annulus, and several devices have been introduced, although none of them are applicable to a wide range of patients and are instead typically oriented to patients with left ventricular dysfunction and/or left ventricular remodelling. Another alternative to leaflet plication is the “chordal repair”, which could be effective in highly selective patients. Several transcatheter mitral valve replacement (TMVR) devices have also been developed, each with specific pros and cons, and some under investigation: Future direction hints towards a transeptal approach to deliver a mitral valve device that could be recaptured and repositioned if the result is unsatisfactory. It is important to consider the inherent risk of LVOT obstruction in all these technologies. However, currently only about 300 patients have been treated by means of transcatheter mitral valve replacement, and there is a strong need for more evidence. In conclusion, for good surgical candidates, surgery will remain as the gold standard, regardless of the aetiology of the MR. For poor surgical candidates, leaflet plication is currently the first line therapeutic approach. However, direct annuloplasty and transcatheter mitral valve replacement are currently under evaluation, and future direction is clearly heading towards an individualized approach that weighs the pros and cons of all the available options. In the context of individualized choices for patients at high surgical risk and within the framework of a larger tool box, transcatheter mitral valve replacement seems to be the most effective, reproducible, and repeatable therapy. CHECK THE SESSION

April 24, 2021 8573

TCTAP 2021 Virtual

Antithrombotics after TAVR: seeking an optimal strategy in an unsolved game

Duk-Woo Park, MD, PhD (Asan Medical Center, Korea), addressed issues related to optimal antithrombotic regimen in patients treated with transcatheter aortic valve replacement (TAVR) during a lecture presented at TCTAP 2021 Virtual that kicked off April 21. Park highlighted the most relevant recent trial results and underscored the benefits of oral anticoagulation (OAC) monotherapy and single antiplatelet therapy (SAPT) in patients with and without pre-TAVR indication for OAC, respectively. He pointed out that despite the data concerning the association between antithrombotic regimen and subclinical trans-catheter heart valve thrombosis, a clear link between this phenomenon and hard adverse clinical events has yet to be demonstrated. Thromboembolic and bleeding complications still remain common adverse events after TAVR. For a considerable time, the proposed recommendations concerning management of antithrombotic therapy in patients undergoing TAVR were based on expert opinion, with treatment strategies empirically on par with the ones adopted in percutaneous coronary intervention (PCI). In 2011, a research team led by Gian Ussia, MD (Ferrarotto Hospital, University of Catania, Italy)1did not find superiority of adding clopidogrel to aspirin for three months after TAVR in a small randomized sample size. In 2017, the ARTE randomized controlled trial (RCT) on 222 patients showed SAPT (versus dual antiplatelet therapy, DAPT) tended to reduce the occurrence of early major adverse events following TAVR2. Only in recent years have new RCTs reassessed the issue, shedding light on existing uncertainties. In fact, the GALILEO randomized controlled trial published in 2019 proved for the first time that - in patients without an established indication for OAC after TAVR - a treatment strategy including rivaroxaban (10mg daily) was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy3. Based on the evidence, the 2020 ACC/AHA Guideline on the management of patients with valvular heart disease suggested SAPT and three- to six-month DAPT for TAVR recipients as “reasonable” strategies in the absence of other indications for OAC, albeit without a strong level of evidence(respectively, COR:2a/LOE B and COR:2b/LOE:B)4. Recently, important new findings have emerged from the POPular TAVI trial last March and October. The RCT was designed to assess outcomes in two different cohorts: cohort B and A. In cohort B, patients before TAVR were randomized 1:1 ratio to either not receive clopidogrel or to receive clopidogrel for three months in addition to OAC for appropriate indications. In cohort A, TAVR patients without an indication for long-term OAC were randomized in a 1:1 ratio to receive aspirin alone versus aspirin plus clopidogrel for three months. One-year primary outcomes were defined as all bleeding and non-procedure-related bleeding. The two one-year secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (MI) and a composite of death from cardiovascular causes, ischemic stroke, or MI. In cohort B, OAC alone was associated with a lower incidence of serious bleeding events than dual antithrombotic therapy (DAT) (primary endpoints’ RR 0.63 and 0.64; 95% CI 0.43-0.90 and 0.44-0.92; P values 0.01 and 0.02, respectively); yet, OAC alone was respectively superior and non-inferior concerning the two assessed secondary endpoints5. In cohort A, the one-year incidence of bleeding (primary endpoints’ RR 0.57 and 0.61; 95% CI 0.42-0.77 and 0.44-0.83; P values 0.001 and 0.005, respectively) and the composite of bleeding or thromboembolic events (RR 0.74; 95% CI for superiority, 0.57-0.95; P=0.04) were significantly less frequent with SAPT than with DAPT administered for three months6. The recently published European Society of Cardiology (ESC) consensus document for TAVR patients not treated with PCI in the previous three months7 endorsed the evidence from these trials. The consensus document underscores that the choice of the optimal antithrombotic regimen is complex in TAVR patients undergoing recent PCI ( First Author/Trial Year Compared Strategies Populations Primary Endpoints Timeline Main Result Ussia et al1 2011 3-months DAPT vs. ASA 79 patients without underlying indication for OAC or recent stent implantation Composite of death, MI, major stroke, LTB, or urgent conversion to surgery 6 months Primary end point: No significant difference for SAPT vs DAPT (15% vs. 18% respectively; p=0.85) Rodés-Cabau et al/ARTE2 2017 3-months DAPT vs. ASA 222 patients without underlying indication for OAC or recent stent implantation Composite of death, MI, stroke or TIA, or LTMB 3 months Primary end point: 15.3% vs. 7.2% for DAPT and SAPT respectively (OR, 2.31; 95% CI, 0.95-5.62; P=0.065) Dangas et al/GALILEO3 2019 Rivaroxaban 10 mg + 3-months ASA vs. ASA+ 3-mo Clopidogrel 1644 patients without an established indication for OAC Death, any stroke, MI, symptomatic valve thrombosis, DVT/PE, non-central nervous system systemic embolism, life- threatening, disabling or major VARC-2 bleeding 17 months Primary end point: 9.8% vs. 7.2% for DAT vs. DAPT (OR, 1.35; 95% confidence CI, 1.01-1.81; P=0.04) Brouwer J et al/POPULAR TAVI - Cohort A6 2020 3-months DAPT vs ASA 665 patients without an established indication for OAC 1)All bleeding (including minor, major, and life-threatening or disabling bleeding) and 2)Non-procedure-related bleeding 12 months Primary end points: 1) 15.1% vs. 26.6% for SAPT and DAPT respectively (OR, 0.57; 95% CI, 0.42-0.77; P=0.001) and 2) 15.1% vs. 24.9% for SAPT and DAPT respectively (OR, 0.61; 95% CI, 0.44-0.83; P=0.005) Nijenhuis VJ et al/ POPULAR TAVI - Cohort B5 2020 OAC + 3-months clopidrogrel vs OAC alone 326 patients receiving OAC for appropriate indications 1)all bleeding (including minor, major, and life-threatening or disabling bleeding) and 2)non-procedure-related bleeding 12 months Primary end points: 1) 21.7% vs. 34.6% for OAC alone and DAT respectively (OR, 0.63; 95% CI, 0.43-0.90; P=0.01) and 2) 21.7% vs. 34% for OAC alone and DAT respectively (OR, 0.64; 95% CI, 0.44-0.92; P=0.02) Collet JP et al/ ATLANTIS8 Ongoing Apixaban vs. standard of care Estimated 1509 patients Efficacy: Death, MI, stroke, systemic emboli, bioprosthesis thrombus, DVT/PE; safety: life-threatening, disabling or major VARC-2 bleeding 12 months - Van Mieghem NM et al/ENVISAGE-TAVI AF9 Ongoing Edoxaban ± antiplatelet therapy vs VKA ± antiplatelet therapy Estimated 1400 patients with atrial fibrillation Efficacy: death, MI, stroke, systemic embolism, valve thrombosis, ISTH major VARC-2 bleeding; Safety: ISTH major bleeding 24 months - Park H et al/ ADAPT-TAVR10 Ongoing 6-months Edoxaban vs. 6-months ASA+clopidogrel Estimated 220 patients without indication for long-term OAC Leaflet thrombosis of 4 dimension-computed tomography scan 6 months - ASA: acetylsalicylic acid; CI: confidence interval; DAPT: dual antiplatelet therapy; DAT: dual antithrombotic therapy; DVT: deep vein thrombosis; ISTH: International Society of Thrombosis and Haemostasis; LTB: life-threatening bleeding; LTMB: life-threatening and major bleeding; MI: myocardial infarction; OAC: oral anticoagulation; OR: odds ratio; PE: pulmonary embolism; SAPT: single antiplatelet therapy; TIA: transient ischemic attack; VARC-2: Valve Academic Research criteria; VKA: vitamin K antagonist. CHECK THE SESSION

April 24, 2021 8978

TCTAP 2021 Virtual

Antithrombotic Therapy in East Asian with ACS/PCI: Updated Evidences for East-Asian Paradox

The East Asian Paradox - a term coined by Young-Hoon Jeong, MD (Changwon Gyeongsang National University Hospital, Korea) in 2012 - is growing in importance with the development of potent antiplatelet agents. These potent antiplatelet agents are used frequently in acute coronary syndromes (ACS) patients after percutaneous coronary intervention (PCI) with direct oral anticoagulants (DOAC), which are essential for the management in patients with atrial fibrillation. At TCTAP 2021 Virtual, Glenn N. Levine (Baylor College of Medicine, Texas, USA) presented insights on antithrombotic therapy in East Asians with ACS and undergoing PCI. Levine was a member of an international group that systematically looked at the concept of the East Asian paradox in patients with ACS or undergoing PCI. East Asians have a higher prevalence of CYP2C19 loss of function alleles (East Asians 60% vs. whites 30%) leading to high on-treatment platelet reactivity (HTPR). Furthermore, East Asians demonstrate 30 to 47 percent higher degree of platelet inhibition with prasugrel and up to 40 percent higher degree of platelet inhibition with ticagrelor compared to whites at any given dose. The prasugrel 5mg dose seemed to confer the same degree of platelet inhibition as the standard 10mg dose in East Asians. The East Asian “paradox” refers to (1) similar or lower incident of stent thrombosis compared to Caucasian patients despite HTPR on clopidogrel and (2) the fact that East Asians are at greater risk of bleeding. East Asians have an increased risk of intracranial hemorrhage (ICH) on warfarin compared to Caucasians, despite a similar INR, and some studies also report an increased risk of bleeding on the same doses of DAPT. Levine explained that the East Asian paradox is probably multifactorial, including hemostatic and thrombotic differences pertaining to hemostatic factors, endothelial function activation, and pharmacokinetic/pharmacodynamics aspects. Pharmacokinetic/pharmacodynamics considerations include smaller body size and lower BMI, differences in drug metabolism, and relatively lower renal clearance of drugs in East Asians. Levine discussed the therapeutic window of antiplatelet therapy, which is bound by low on-treatment platelet reactivity (LPR) below which bleeding predominates, and high on-treatment platelet reactivity (HPR), above which thrombotic events prevail. This window is different for East Asians, indicating a shift to the right. Namely, East Asians are “therapeutic” at higher LPR and HPR because of the increased risk of bleeding and lower risk of thrombotic events, respectively. Over the last decade, data has emerged to suggest that this East Asian paradox extends to DOACs also, with East Asians and Caucasians differing significantly in their response to antithrombotic agents. The annual risk of ICH with DOAC therapy appears to be much higher in East Asians at the same DOAC dose. Furthermore, in the HOST-REDUCE-POLYTECH-ACS trial, de-escalation of prasugrel from 10mg to 5mg in 3,000 South Korean patients with ACS undergoing PCI resulted in significantly lower bleeding with no increase in ischemic endpoints. These concepts were recently iterated in a position statement document published last year, which emphasized the different therapeutic windows for inhibition of platelet P2Y12 receptors and DOACs “Since data, trial results, dosing, and recommendations from U.S. and European population studies influence guideline recommendations, they should not necessarily be directly extrapolated to East Asian populations, Levine said. “Ultimately, tailored or personalized therapy in East Asians, particularly dosing continues to be advisable.” CHECK THE SESSION

April 23, 2021 6178

TCTAP 2021 Virtual

A New Radiation Protocol to Reduce Radiation for Complex PCI

Radiation injury in interventional cardiology is largely overlooked since most interventional procedures in the lab do not exceed the threshold radiation dose that causes harm. But for interventionists who perform complex PCI procedures - especially on CTO patients wherein the procedure duration is prolonged - management of radiation dose is crucial for preventing serious radiation injury both to the patient and the operating staff. During the Hot Topic session on CTO held at TCTAP 2021 Virtual, the second session was dedicated to “The Quest for Safety” in CTO-PCI. Gerald Werner, MD, PhD (Klinikum Darmstadt, Germany) spoke about the topic of radiation safety, adding to the previous two talks on management of anti-thrombotic and coronary perforation in CTO. “Radiation injury is one of the few avoidable complications of complex PCI in general, and especially in CTO-PCI,” Werner said. “But radiation safety doesn’t get enough attention because radiation injury is rarely reported in studies, and they occur days or even weeks after the initial procedure.” Radiation skin injury is dose-dependent and occurs when certain threshold dose (Gy) is exceeded. With different amounts of exposure, the types of skin injury could range from transient erythema (2 Gy), permanent epilation (7 Gy), dry desquamation (14 Gy) or dermal necrosis (18 Gy). Werner paralleled the radiation dose rate to the speed of a car. Akin to a driver who needs to keep an eye on the speedometer of the car to be safe, complex PCI operators need to know the dose rate (Gy/s) during the procedure, which is shown instantaneously on the angiography machines. Studies published over the years have shown that patient radiation exposure (Air Kerma, Gy) decreased from 10 Gy to about 2 Gy. Despite the progress, Werner pointed out more room for improvement. Radiation exposure is also related to the complexity of the PCI procedure. In 2017, Werner and his team found that the Air Kerma was 2.1 Gy, 2.7 Gy and 3.5 Gy for J-CTO score of 0-1, 2-3, and 4-5, respectively, but also noted individual variability in radiation procedures due to individual practice. In a recently published paper, Werner’s team compared the median fluoroscopy time of different operators and Air Kerma at two different years (2012 and 2017). Results showed that although there was overall improvement in reducing the median Air Kerma between the two periods, there was a large variation of median Air Kerma between operators even though median fluoroscopy time was similar. “Improvement in managing radiation exposure can be achieved through continuous discussion and education on radiation safety during live cases and CTO courses,” Werner said. Several ways to reduce radiation exposure for a given procedure were suggested, including lowering the fluoroscopy rate from 15 fps to 7.5 fps as the easiest method. The lowering of the fluoroscopy rate, while reducing the fluoroscopy exposure, leaves the total radiation time at a high level due to a larger contribution to the total dose by cine runs. Secondly, further reduction of cine runs to 7.5 fps will cut down total dose significantly in suitable patients, Werner said. Thirdly, reducing the number of cine runs as much as possible and using fluoroscopy storage to record important procedure steps rather than cine recording was also stressed. Finally, changing the angulation of working views could also reduce the dose rate. For example, when working on RCA, changing from LAO 450 to LAO 300 will cut down the dose rate by nearly 30 percent. “The rule of “as low as reasonably achievable” - or ALARA - should be applied from the beginning to the end of the procedure, Werner said. Werner’s approach to radiation management for complex PCI was to use cine runs of 15 fps only for the initial bilateral imaging to visualize the collaterals and only in potential using retrograde approach. The cine run will be halved at 7.5 fps and the lowest fluoroscopy protocol is used for the rest of the procedure. Werner used fluoroscopy storage and low radiation angulation for visualizing and storing balloons or stents movement in the vessel. Modern angiography machines come with low radiation exposure features, but not every lab can afford to change or upgrade their machines frequently. With newly published data, Werner noted a large disparity in dose rate index amongst individuals who use the same machines from different manufacturers. One particular machine that stands out is Philips Clarity which limits the outliers amongst the operators. By using the same machines and new radiation protocol, Werner reported in his paper that the Air Kerma had been slashed by nearly 75 percent over 10 years, initially by reducing the fluoroscopy frame rate and later by reducing the number of required cine runs. Before the new radiation protocol, 10.4 percent of their patients exceeded Air Kerma of 5 Gy, which is the threshold for causing radiation damage. The 5 Gy threshold was never exceeded after the new radiation protocol was introduced, even with patients with BMI >30, or when procedure fluoroscopy time was more than 120 minutes. Similarly, maximum skin entry dose (mGy) rarely exceeded the threshold of 2 Gy after the new radiation protocol. Werner noted that, “The latest and biggest steps we achieved was reducing cine angiography by three times. This brought us to an average Air Kerma in our CTO procedures to the lowest-reported 700 mGy.” One significant advantage of reducing radiation dose exposure to patients is a decrease in occupational exposure for the operators and cath lab staffs. Although acknowledging concerns that scatter dose at C-arm may increase during low-dose protocol, Werner pointed out that these low-dose scatter are negligible when using modern shielding technique. For occupation protection for operators, Werner mentioned Biotronik‘s suspended radiation protection system, Zero-Gravity, - wherein operators are protected from both radiation and back injury due to the weight of the lead apron. He was also enthusiastic about the new Rampart IC M1128 shielding system, a full-bodied radiation protection where operators can work without the individual lead apron. Werner concluded that in his practice, radiation is no longer the reason for abandoning a procedure. “It is true that most interventionist still do not understand how to optimize the radiation exposure dose for both patients and themselves,” he said. “This is mainly because most do not realize their machines are better than they believe, and by tweaking the angiography machines’ settings, the total radiation exposure dose could be significantly reduced without upgrading to a new machine.” “The ultimate wish for CTO operators is to have an effective lead shielding system that can reduce radiation to patients and themselves and also can get rid of the personal lead apron to work in just scrubs to reduce back injury,” Werner added. CHECK THE SESSION

April 23, 2021 8722

TCTAP 2021 Virtual

Antithrombotic Therapy after CTO-PCI: A Long Way to Go

Michael S. Lee MD, (UCLA School of Medicine, California, USA) presented on the issue of choice and duration of antithrombotic therapy after CTO-PCI during a Hot Topic session at TCTAP 2021 Virtual. During the session, chronic total occlusion CTO experts from around the world discussed antithrombotic therapy strategies to achieve best long-term patency after CTO-PCI. Lee pointed out that although detailed discussions on the technical aspects are plenty, clinical recommendations from various CTO-PCI consensus papers are few for intraprocedural and longer-term antithrombotic therapy. Unfractionated heparin (UFH) was the most standard anticoagulation during PCI including CTO intervention whereas bivalirudin was the alternative. In the NAPLES 3 study, which included high bleeding-risk patients undergoing elective PCI through the femoral approach, there was no difference in term of major bleeding between the UFH and bivalirudin group. And in the NAPLES 4 study, there was no difference regarding 30-day major adverse cardiovascular event (MACE) between UFH and bivalirudin. However, Lee pointed out that most studies did not specifically address the optimal choice of intraprocedural anticoagulation in CTO-PCI. Chinese investigators explored the use of bivalirudin during CTO-PCI for high bleeding risk patients. In the trial, the first seven of nine patients with standard application of bivalirudin exhibited acute thrombogenesis in the procedure. Heparin was then added in decreasing amounts in the next eight patients wherein no thrombosis occurred; however, two patients had bleeding complications. The subsequent 72 patients were randomly compared with standard bivalirudin usage plus additional bivalirudin bolus vs UFH bolus. Results showed no statistical difference in terms of periprocedural myocardial infarction and bleeding in this small cohort of patients and the authors concluded that monotherapy with bivalirudin in CTO-PCI should be used with caution, considering potential risk of thrombogenesis during a prolonged CTO procedure. There were also two small-scale clinical studies from Chinese investigators that compared bivalirudin and UFH in high bleeding risk patients undergoing CTO-PCI (2,3). Again, there was no statistical significance of MACE in short- and intermediate-terms between both groups. “The result of these studies may not be generalizable to all patients and the choice of anticoagulation needs to be individualized in CTO interventions, but heparin definitely has advantage because you can reverse its effect by protamin,” Lee said. Lee also touched upon the controversy regarding encountering major perforation during CTO intervention and considering coronary thrombosis risk after protamine reversal. The choice and duration of antiplatelet therapy after CTO-PCI was then discussed, although Lee noted data on this aspect is “very limited.” In the Samsung Medical Center CTO registry, 512 patients after 12-month event-free period of their index CTO-PCI were classified into either 12-month dual antiplatelet therapy (DAPT) or prolonged DAPT (4). There was no difference in terms of MACE and bleeding endpoints in the entire and the propensity-matched population. The author concluded that there is no indication to prolong DAPT beyond 12-months in this group of patients. Complex and High-Risk PCI (CHIP patients) are becoming more common and includes PCI in various complex anatomy such as CTO. There has always been bleeding and ischemic paradox in treating this group of high-risk patients. “Ischemic risk is higher during initial period after CHIP-PCI and patients may require more potent antiplatelet strategy whereas bleeding risk will be higher in later period and less potent antiplatelet strategy will be required,” Lee said. “This will be the rationale of de-escalation of DAPT in CHIP population if we want to achieve the best clinical outcome.” The upcoming TAILORED-CHIP trial (TAILored versus COnventional AntithRombotic StratEgy IntenDed for Complex High-Risk PCI), is expected to provide more insight on the optimal DAPT in CHIP population such as CTO-PCI and will involve 2,000 patients undergoing CHIP-PCI including CTO subset. Standard 12-month DAPT of aspirin and clopidogrel will be adopted in the conventional arm. In the tailored arm, low-dose (60mg) ticagrelor plus aspirin will be used during the early six-month period (Early Escalation) whereas clopidogrel alone will be used during the late six-month period (Late De-escalation). The primary endpoint will be a composite outcome of death, myocardial infarction, stroke, stent thrombosis, urgent revascularization and clinically relevant bleeding (BARC 2, 3 or 5) at 12 months. This trial hopefully will provide more insight on the optimal DAPT regimen in CHIP population including CTO-PCI, Lee said. Reference Chenguang Li 1, Yi Shen 2, Rende Xu 1, Yuxiang Dai 1, Shufu Chang 1, Hao Lu 1, Lei Ge 1, Jianying Ma 1, Juying Qian 1, Junbo Ge 1. . Exploration of Bivalirudin Use during Percutaneous Coronary Intervention for High Bleeding Risk Patients with Chronic Total Occlusion. Int Heart J. 2018 Mar 30;59(2):293-299 Yong Wang 1, Hong-Wei Zhao 1, Cheng-Fu Wang 1, Chun-Yu Fan 1, Xiao-Jiao Zhang 1, Yu Zhu 1, De-Feng Luo 1, Guo-Ning Yu 2, Ai-Jie Hou 1, Bo Luan 1. Efficacy and safety of bivalirudin during percutaneous coronary intervention in high-bleeding-risk elderly patients with chronic total occlusion: A prospective randomized controlled trial. Catheter Cardiovasc Interv. 2019 Feb 15;93(S1):825-831. Chenguang Li 1, Rende Xu 1, Yi Shen 2, Yuxiang Dai 1, Feng Zhang 1, Jianying Ma 1, Lei Ge 1, Juying Qian 1, Junbo Ge 1. Bivalirudin in percutaneous coronary intervention for chronic total occlusion: A single-center pilot study. atheter Cardiovasc Inter. 2018 Mar 1;91(4):679-685. Seung Hwa Lee 1, Jeong Hoon Yang 1, Seung-Hyuk Choi 1, Taek Kyu Park 1, Woo Jin Jang 2, Young Bin Song 1, Joo-Yong Hahn 1, Jin-Ho Choi 1, Hyeon-Cheol Gwon 1. Duration of dual antiplatelet therapy in patients treated with percutaneous coronary intervention for coronary chronic total occlusion. PLoS One. 2017 May 5;12(5):e0176737. CHECK THE SESSION

April 23, 2021 51030