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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 6688

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 20957

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 5294

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 9563

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 10600

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 14450

TCTAP 2022

Was 2021 a bad year for FFR-guided PCI?

Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) can be beneficial for patients with multivessel coronary artery disease (MV-CAD), despite recent negative study results, an expert said. “Was 2021 a bad year for FFR?” asked William F. Fearon, MD(Stanford University School of Medicine, California, USA), the principal investigator of the FAME 3 trial at TCTAP 2022 on Apr 28. “Some investigators have interpreted the FUTURE, FLOWER-MI and FAME-3 studies published last year as negative trials, but that is not necessarily the case.” Last year, the FUTURE, FLOWER-MI and FAME 3 trials found no benefit with FFR-guided PCI compared to angiography-guided PCI for MV-CAD patients, resulting in uncertainty on its role in revascularization. Despite the unfavorable results, Fearon pointed out that the studies included patients with very low rates of negative FFR, indicating that FFR-guided PCI can be beneficial for patients with MV-CAD if the application is appropriate, and results are heeded. “Rules should be followed for any test to be useful, and for FFR, includes deferring PCI when the value is greater than 0.80,” he said. “To optimize benefits, FFR should be applied when the significance of a lesion is uncertain.” Limitations of the FUTURE, FLOWER-MI and FAME 3 studies also bar conclusions from being absolute and prod deeper analysis to understand the role of FFR in revascularization for MV-CAD, he said. FUTURE FUTURE investigators randomized 927 patients to an angiography-guided strategy or FFR-guided strategy with optimal medical therapy (OMT), PCI or coronary artery bypass graft (CABG). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) at 1-year. FUTURE (2021) Design Prospective, randomized, open-label superiority trial in France Patient population MV-CAD (n=927) Randomization (1:1) FFR-guided strategy (PCI+OMT, CABG+OMT, OMT only) vs. angio-guided strategy (PCI+OMT, CABG+OMT, OMT only) Primary endpoint MACCE (death, MI, stroke or unplanned revascularization) at 1-year. Result No difference between FFR arm and control arm: 14.6% vs. 14.4% (HR 0.97, 95% CI, 0.69-1.36; P=0.85) Although the study ended prematurely due to signals of increased mortality in the FFR-guided group, results at 1-year showed no difference in MACCE rates between the two groups. Follow-up results showed no difference in mortality between angiography-guided therapy and FFR-guided therapy, indicating that the early signal of increased mortality with FFR-guidance was a “play of chance,” Fearon said, making it difficult to demonstrate real differences in outcomes. Regarding why FFR-guidance did not outperform angiography guidance, Fearon listed the patient population, FFR-measured lesion characteristics and differing treatment strategies in both groups as major reasons. “FUTURE had a fairly complex patient population with a relatively high SYNTAX score of 19, and more than half had triple-vessel CAD,” he said. “127 lesions were negative (FFR >0.80) but received PCI anyway, which accounted for 27% of the FFR-negative lesions. “Among other limitations, the study was underpowered with only 54% of the planned population enrolled, and 9% of the control group and 17% of the FFR group had OMT only, indicating only 8% of patients in both groups received different treatment.” FLOWER-MI The FLOWER-MI trial studied FFR-guided PCI in 1,163 STEMI patients with MV-CAD who had undergone successful PCI with at least one major vessel with ≥50% diameter stenosis. Patients were randomized to FFR-guided complete revascularization (n=586) or angiography-guided complete revascularization (n=577). The primary composite endpoint included death, myocardial infarction (MI) or unplanned hospitalization with urgent revascularization at 1-year. FLOWER-MI (2021) Design Investigator-initiated, randomized, open-label, multicenter trial with blinded endpoint evaluation in France Patient population STEMI with MV-CAD (n=1,163) Randomization (1:1) FFR-guided complete revascularization vs. angiography-guided complete revascularization Primary endpoint Composite of all-cause death, nonfatal MI or unplanned hospitalization leading to urgent revascularization at 1-year. Result FFR arm vs. angiography arm: 5.5% vs. 4.2% (HR 1.32, 95% CI, 0.78-2.23; P=0.31) Results showed no difference in the 1-year primary composite endpoint but more non-fatal MIs in the FFR-guided group (3.1% vs. 1.7%; HR 1.77, 95% CI, 0.82-3.84) when examining the individual components of the composite endpoint. However, Fearon noted that several trial limitations, including the wide confidence intervals that led FLOWER-MI investigators to warn against “a conclusive interpretation” - need consideration. “It would have been ideal if randomization occurred after operators stated which non-culprit lesions would be treated. Instead, about 100 more lesions were identified in the FFR-guided arm (n=980) than in the angiography arm (n=891), which explains the similar rates of contrast usage and procedure time. “You would expect less contrast and time spent with FFR, but this was not the case since more lesions were interrogated in the FFR arm. “Other limitations include the missing FFR values on 154 lesions in the FFR-guided arm (n=980), and the sizable number of patients with negative FFR (460 lesions with FFR ≤0.80) that received PCI anyways (n=546). This may explain why the FFR and angiography arm had similar numbers of implanted stents in non-culprit lesions (1.1 stents vs. 1.5 stents).” FAME 3 The FAME 3 trial involved 1,500 patients with triple-vessel CAD randomized to FFR-guided PCI or CABG. The composite primary endpoint was MACCE (death, MI, stroke or repeat revascularization) at 1-year. FLOWER-MI Design Multicenter, international, non-inferiority trial Patient population 3-vessel CAD (n=1,500, mean age: 65; male 81%; diabetes 30%; ACS 40%) Randomization (1:1) CABG vs. FFR-guided PCI with DES Primary endpoint MACCE (all-cause death, MI, stroke, or repeat revascularization) at 1-year Result FFR-guided PCI arm vs. CABG: 10.6% vs. 6.9% (HR 1.5, 95% CI, 1.1-2.2). Findings not consistent with non-inferiority of FFR-guided PCI (P=0.35 for non-inferiority). Procedural characteristics showed PCI had a shorter time to procedure (4 min vs. 13 min), duration of procedure (87 min vs. 197 min) and length of hospital stay (3 days vs. 11 days) compared to CABG. Both groups had similar average SYNTAX scores of 26 and number of lesions (n=4). Rates of chronic total occlusion (21% vs. 23%) and bifurcation lesions (69% vs. 66%) were not different. Results showed a higher 1-year MACCE rate in the PCI arm (10.6% vs. 6.9%; HR 1.5, 95% CI, 1.1-2.2, P=0.35 for non-inferiority), resulting in the trial not meeting the preset criteria for non-inferiority. There was no clear difference in the individual components of the primary endpoint. Although there was no statistically significant difference for the composite endpoint of death, MI or stroke, the FFR-guided PCI arm had numerically higher event rates. Patients in the FFR-guided PCI arm had less severe bleeding, kidney injury and atrial fibrillation than CABG. Definite stent thrombosis and symptomatic graft occlusion were rare, and rehospitalization within 30 days occurred less after PCI. Importantly, there was a relationship between outcomes and SYNTAX scores. FFR-guided PCI had numerically lower MACCE rates than CABG for patients with low SYNTAX scores; however, CABG outperformed FFR-guided PCI in patients with intermediate and high SYNTAX scores. Fearon said: “It’s important to remember that only 24% of lesions of the FFR-guided patients in FAME 3 had an FFR>0.80, chronic total occlusion was present in 21% of patients, and mean SYNTAX score was 26. In these patients with mostly positive FFR, as we know from previous studies, CABG had better outcomes than PCI, therefore FFR-guided PCI was less likely to have a benefit. “Both PCI and CABG arms showed favorable results than historical controls, including the SYNTAX trial. CABG did much better than anticipated, and an event rate similar to the SYNTAX trial in FAME 3 would have led to non-inferiority. “These results show that FFR-guided PCI is less likely to benefit patients with complex CAD - where FFR is mostly positive - and in areas where CABG is known to outperform PCI.” CHECK THE SESSION

May 19, 2022 4650

TCTAP 2022

‘CABG helps people live longer’

Coronary artery bypass graft (CABG) surgery extends survival for patients with multivessel disease (MVD) and left main coronary artery disease (LMCAD), an expert said, despite recent guidelines suggesting the contrary. “Evidence demonstrates survival benefits with CABG over optimal medical therapy (OMT) in MVD and even more in LMCAD,” said S. Christopher Malaisrie, MD(Northwestern University Feinberg School of Medicine, Illinois, USA) at TCTAP 2022 on Apr 28. “But [American and European] clinical practice guidelines (CPG) differ in the interpretation of data and appear to undervalue the benefits of CABG,” he said. “As a result, surgical associations have not endorsed their respective continental CPGs that discount ‘old’ data and undervalue new surgical techniques.” Late last year, the American Association for Thoracic Surgery and Society of Thoracic Surgeons (AATS/STS) withdrew their support for the joint 2021 American College of Cardiology, American Heart Association and Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines on coronary artery revascularization, released in the Circulation last December. Surgical associations from Europe, Latin America, India and Japan soon followed suit, independently voicing their concerns in public letters that announced endorsement withdrawals. The main controversy centered on the downgraded recommendations for CABG to improve survival compared to OMT and percutaneous coronary intervention (PCI) for patients with MVD and LMCAD. The recent updates also led to a discrepancy between American and European guidelines, reigniting the fierce debate that followed the public fallout between cardiac surgeons and interventional cardiologists over the joint 2018 European Association for Cardio-Thoracic Surgery (EACTS) and European Society of Cardiology (ESC) guidelines in 2019 due to the controversial EXCEL trial. Survival data for CABG in MVD patients too old? ‘Simply not true’ In the recently updated American guidelines, Malaisrie noted that the writing committee downgraded CABG over OMT to improve survival for MVD patients (Class I  Class IIb, B-R) despite older and modern trials favoring CABG. American, European guidelines on coronary revascularization in SIHD 2021 ACC/AHA/SCAI guideline for coronary artery revascularization Category Recommendation CoR (LoE) Revascularization for survival in SIHD compared with medical therapy In patients with SIHD, normal EF, significant stenosis in 3 major coronary arteries (with or without proximal LAD), and anatomy suitable or CABG, CABG may be reasonable to improve survival IIb (B-R) 2018 ESC/EACTS guidelines on myocardial revascularization Category Recommendation CoR (LoE) Revascularization for stable CAD Proximal LAD stenosis >50% I(A) Source: Malaisrie slides at TCTAP 2022 According to the guideline writing committee, the downgrades aimed to update older recommendations that were based on a handful of registry studies, a meta-analysis and one randomized controlled trial (RCT) “all completed 20 to 40 years ago.” However, Malaisrie said: “The writing group stated that the data [for CABG] was simply too old, but this is not completely true considering modern evidence like MASS II and the meta-analysis by Jeremias both demonstrate survival benefits with CABG over OMT. “Comparing outcomes from historical studies to the modern FAME 3 study also demonstrate advances of CABG to improve 30-day mortality.” The latest FAME 3 study, published this year, had significantly lower rates of 30-day mortality (0.3%) than the 1976 Veterans Administration (VA) study (5.8%), the 1982 ECSS study (3.3%) and the 1983 CASS study (1.4%). FAME 3 further demonstrated an equivalent 30-day mortality rate between CABG and PCI, which helps explain why the AATS/STS’ pulled support from the double downgrade (COR 2b vs. COR 1) that did not “reflect their interpretation of the best treatment” for ischemic heart disease. And although the guideline committee acknowledged the development of modern surgical techniques, Malaisrie continued, it was overshadowed by the emphasis on OMT advancements, including the increased use and recognition of antiplatelet, statins, beta-blocker, and ARB/ACE inhibitors. “Although we agree on the significant advances of medical therapy, developments in surgical techniques for CABG were undervalued,” he said. Strong evidence for CABG in LMCAD hampered by weaker US LoE For LMCAD, Malaisrie pointed out the subtle – but seemingly arbitrary – lower level of evidence (LoE) for CABG in American guidelines (US: Class I; B-R vs. EU: Class I; A), despite the “overwhelmingly positive” evidence for surgery over OMT and no new studies suggesting otherwise. American, European guidelines on coronary revascularization for LMCAD 2021 ACC/AHA/SCAI guideline for coronary artery revascularization Category Recommendation CoR (LoE) Revasc for survival in SIHD compared with medical therapy In patients with SIHD and significant LM stenosis, CABG is recommended to improve survival I(B-R) 2018 ESC/EACTS guidelines on myocardial revascularization Category Recommendation CoR (LoE) Revasc for stable CAD LM disease with stenosis >50% I(A) Source: Malaisrie slides at TCTAP 2022 “Classical evidence, including the VA and CASS trials, has been overwhelmingly positive for CABG compared to OMT,” he said. “And all contemporary trials comparing revascularization with medical therapy have excluded patients with significant stenosis of the left main artery.” “But American and European guidelines differ in the evidence level even though the writing committee acknowledges that CABG data comes from older randomized trials and no new data refutes the older RCTs supporting CABG,” he added. Weak CABG recommendations in MVD, LMCAD at odds with evidence on PCI vs. CABG On the topic of CABG versus PCI in patients with MVD or LMCAD, Malaisrie noted that the updated guidelines have a weaker recommendation for CABG compared to European guidance (US: Class IIa; B-R vs. EU: Class I; A) despite results from several international landmark trials. Particularly, results from the 10-year SYNTAX, ASCERT, FREEDOM and BEST studies demonstrated survival benefits with CABG over PCI for MVD patients, he said. As an “important” trial, the 5-year results of the BEST trial by Seung-Jung Park, MD and investigators comparing PCI with everolimus-eluting stents versus CABG showed a higher occurrence of the primary endpoint (composite of death, myocardial infarction (MI) or target-vessel revascularization) with PCI at 2-years. Results also found no significant difference for the composite safety endpoint (death, MI or stroke). The anticipated 10-year follow-up is underway, Malaisrie said. American, European guidelines on CABG vs. PCI for MVD, LMCAD (2021 ACC/AHA/SCAI) Patients with complex disease CoR (LoE) Category 2a (B-R) In patients who require revascularization for multivessel CAD with complex or diffuse CAD (e.g., SYNTAX score >33), it is reasonable to choose CABG over PCI to confer a survival advantage (2018 ESC/EACTS) Three-vessel CAD without diabetes mellitus Category CABG PCI Three-vessel disease with low SYNTAX score (0-22) I(A) I(A) Three-vessel disease with intermediate or high SYNTAX score (>22) I(A) III(A) Source: Malaisrie’s slides at TCTAP 2022 For LMCAD, both US and EU guidelines gave a Class I recommendation for CABG over PCI. However, the EACTS pulled endorsement for the 2018 EACTS/EACTS guidelines after the publication of the 5-year EXCEL trial. “Recommendations for LMCAD are similar with both giving a Class I recommendation for CABG, but the EACTS withdrew its support from the 2018 EACTS/ESC guideline recommendations on left main disease (SYNTAX score

May 13, 2022 7263

TCTAP 2022

Is CABG the best approach for multivessel, left main CAD?

A leading cardiac surgeon stressed that percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) are complementary, not antagonistic, interventions for patients with coronary artery disease (CAD). As a writing committee member of the recently updated American guidelines, Mario F.L. Gaudino, MD(Weill Cornell Medical College, Cornell University, New York, USA) presented his perspective on optimal revascularization for CAD patients at TCTAP 2022. “We are essentially comparing two different interventions,” he said at the virtual conference on Apr 27 while comparing revascularization strategies for multivessel disease (MVD) and left main disease (LMD). The subject incited heavy antagonism between interventional cardiologists and cardiac surgeons who have stood at odds regarding the benefits of CABG and PCI in patients with stable ischemic heart disease (SIHD). The recent 2021 American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines on coronary artery revascularization stoked the conflict with the controversial downgraded CABG recommendation in MVD (Class I → Class IIb) and Class IIa recommendation for PCI in LMD as a reasonable alternative to CABG. Despite the ongoing feud, Gaudino emphasized that studies show both PCI and CABG are acceptable and complementary strategies in MVD and LMD, and subgroups benefit differently from each approach. Results from the 5-year and 10-year follow-up of the SYNTAX trial showed similar mortality rates between CABG and PCI, but CABG had better long-term clinical outcomes and lower rates of myocardial infarction (MI) and repeat revascularization, particularly in complex disease. An individual pooled analysis also showed patients with diabetes benefitted more from CABG. For risk stratification with the SYNTAX score, a meta-analysis by Gaudino and investigators found no significant association between the score and the comparative effectiveness of PCI and CABG: “While we believe the complexity of coronary lesion matters – and more for PCI than CABG – the SYNTAX score should not be used to guide clinical decision-making, per se.” As for CABG drawbacks, findings from SYNTAX and other quality-of-life (QoL) studies showed that CABG was associated with more periprocedural complications and discomfort during recovery. These findings applied to patients with LMD. The NOBLE study found no difference in survival or stroke between PCI and CABG for patients with LMCAD but significant reductions with CABG for MI and major adverse cardiovascular events (MACE), including repeat revascularization. QoL analysis of the EXCEL trial showed that patients faced a higher upfront risk with CABG but obtained a longer period of benefit, indicating that patients “fit enough for the risk” could benefit more from surgery. “But it’s not just about survival; it’s also about QoL,” Gaudino said. “The two revascularization strategies are highly effective in relieving angina-related QoL, but CABG has a high upfront cost regarding physical limitations after surgery.” The recent meta-analysis by Sabatine and investigators published in the Lancet last November also showed no difference between PCI and CABG for survival, indicating that PCI had comparable outcomes to surgery for the first two years while being less invasive. Drawbacks of PCI included higher rates of MI and repeat revascularization compared to CABG, although MI outcomes varied according to the definition used, Gaudino said. “Surgery has consistently shown similar mortality and reduced risk of MI and repeat revascularization for patients with MVD and LMD, amenable by either CABG or PCI. A difference favoring surgery is evident for patients with diabetes and complex disease. “Although surgery shows better long-term clinical outcomes, it is associated with higher periprocedural risk and longer recovery rates. PCI demonstrated comparable results to surgery for the first two years as a less invasive strategy. “Exempting the relative risk (RR), the absolute difference between the two is small, which becomes evident in the long-term follow-up. Ultimately, PCI and CABG are two different interventions performed for different patients with different aims.” CHECK THE SESSION

May 13, 2022 5515

TCTAP 2022

‘Modern trials on SIHD revascularization show no mortality benefit with CABG over medical therapy’

Contemporary trials on stable ischemic heart disease (SIHD) are refuting notions that coronary artery bypass graft (CABG) extends survival more than optimal medical therapy (OMT), an expert said recently. And such data were reflected in the updated, albeit controversial, 2021 American College of Cardiology, American Heart Association and Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines on coronary artery revascularization published in Circulation last December. At TCTAP 2022 on Apr 27, Sripal Bangalore, MD(New York University School of Medicine, New York, USA) addressed the confusion surrounding the controversial recommendations, having served on the writing committee of the 109-page document drafted to replace the 2012 ACC/AHA guidelines for SIHD. “The recommendations on triple-vessel disease generated the controversy, and the notion was that the guideline committee simply downgraded CABG recommendations,” he said. “But the committee considered various factors like recent studies that showed no survival benefit with revascularization compared to OMT.” “In the 1980s, there was a clear benefit with CABG in triple-vessel disease at 6-months when comparing surgery to no surgery,” he said. “But fast forward to the BARI 2D trial in 2009 that looked at CABG versus medical therapy in the same population, and results show no difference between CABG and medical therapy. “This is purely looking at the mortality endpoint of CABG only, not percutaneous coronary intervention (PCI), and studies show less benefit than the ‘80s.” Controversial 2021 US CABG recommendations trigger surgical backlash Major American surgical groups, including the American Association for Thoracic Surgery (AATS) and the Society of Thoracic Surgeons (STS), and several international surgical associations withdrew endorsement for the updated guidelines last December. The main objections pertained to the knockdown of CABG from a Class I to a Class IIb and the equalizing of PCI to CABG (both Class IIb) for patients with multivessel disease (MVD) and normal ejection fraction (EF). Also protested was the Class IIa recommendation for PCI as a reasonable alternative to CABG to improve survival for patients with left main disease (LMD). Among other disagreements, using the ISCHEMIA trial as the only evidence to back the changes fueled the controversy. 2021 ACC/AHA/SCAI myocardial revascularization guidelines COR LOE Recommendation Left main disease I B-R In patients with SIHD and significant LM stenosis, CABG is recommended to improve survival IIa B-NR In selected patients with SIHD and significant LM stenosis where PCI can provide equivalent revasc to CABG, PCI is reasonable to improve survival Multivessel disease IIb B-R In patients with SIHD, normal EF, significant stenosis in 3 major coronary arteries (w/ or w/o proximal LAD) and anatomy suitable for CABG, CABG may be reasonable to improve survival IIb B-R In patients with SIHD, normal EF, significant stenosis in 3 major coronary arteries (w/ or w/o proximal LAD) and anatomy suitable for PCI, the usefulness of PCI to improve survival is uncertain. ‘Updates reflect mortality benefits of CABG found in modern trials’ Bangalore cleared up the “confusion” at the virtual conference, noting that the committee sifted out older data and backed contemporary ones for purely the mortality endpoint. “Most of the confusion comes from the mortality and composite endpoints,” he said. “For the Class IIb recommendation for CABG in MVD, the guideline focuses only on the benefit of survival, not the primary composite endpoint.” While older studies showed a clear survival benefit with CABG compared to no CABG, advances in modern medical therapy closed the gap between CABG and OMT to a non-existent difference. Meta-analysis of older studies showed that although CABG had survival benefits to 5-years, the curves began to converge at 10-years and result in a smaller absolute difference. Meanwhile, contemporary trials in the “modern era of OMT” like COURAGE (2007), BARI 2D (2009) and FAME 2 (2012) consistently showed no significant difference between revascularization and OMT for the mortality endpoint for SIHD patients. Recent trials like ISCHEMIA and ISCHEMIA-CKD also showed no survival benefit with revascularization than medical therapy alone. We’re not saying don’t revascularize for triple-vessel disease; other reasons for revasc can include preventing other CVD events, improving QoL and considering patient preference. Bangalore, MD A modern meta-analysis published in 2020 on 14 randomized controlled trials (RCTs) and 14,877 patients by Bangalore’s research team (average follow-up: 4.5 years) also showed routine revascularization was not associated with improved survival but lowered the risk of nonprocedural myocardial infarction (MI) and unstable angina. Results also showed revascularization led to greater freedom from angina but at the expense of higher rates of procedural MI. “Although RCTs in the pre-OMT era showed a clear benefit with CABG for improving survival compared to no surgery, these studies were conducted with no medical therapy,” Bangalore said. “Now, recent SIHD studies on revascularization show no improvement in cardiac death with revascularization compared to OMT.” “Although a recent meta-analysis by Navarese showed a near 20% mortality reduction with coronary revascularization and medical therapy (RR 0.79, 95% CI, 0.67–0.93, P

May 12, 2022 12351