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SummitMD

Rushing Angiography for OHCA Patients without ST-Segment Elevation Largely Unbeneficial

Performing coronary angiography immediately for out-of-hospital cardiac arrest (OHCA) patients without ST-segment elevation does not better survival outcomes, findings from the TOMAHAWK trial showed. Steffen Desch, MD (Heart Centre Leipzig, Germany), the principal investigator of TOMAHAWK, presented late-breaking trial findings on the timing of invasive coronary angiography at the European Society of Cardiology (ESC) Congress 2021, stressing that later does not always mean worse. “Like the COACT trial, we found that early angiography was not superior to a delayed and selective approach,” Desch said. “Although COACT restricted enrollment to patients with shockable rhythm, findings from this second and largest randomized trial extends [COACT] findings to those with non-shockable rhythm.” Results were published simultaneously in the New England Journal of Medicine (NEJM)1. COACT2 previously found that a broad, immediate angiography strategy was not superior to a delayed approach. However, the trial only included patients with shockable rhythm, thereby creating uncertainty for a large number of OHCA patients (60%) who do not present ST-segment elevation. “Our findings imply you should take your time and evaluate the clinical course first and - if still indicated - perform coronary angiography in the following days,” Desch said. Coronary angiography is used to scan for myocardial infarction (MI), a significant cause of out-of-hospital cardiac arrest that carries a near 65% mortality rate even after successful resuscitation and hospitalization. Angiographies can help prevent myocardial injury, hemodynamic deterioration, heart failure, rehospitalization, and arrhythmias when the coronary lesion is treatable. However, when the source of OHCA springs from untreatable coronary lesions, invasive angio may do more harm than good by raising risks of procedural complications of renal damage, reperfusion injury, stent thrombosis, bleeding, and cerebral damage. Immediate cardiac cath is not necessary for the majority of patients. Desch, MD Based on the COACT trial, ESC guidelines have already recommended delayed – not immediate – coronary angiography for successfully resuscitated, hemodynamically stable OHCA patients without ST-segment elevation. However, the benefits of an early invasive approach for OHCA with non-shockable rhythm remains poorly defined. The investigator-initiated, randomized, international, multicenter, open-label TOMAHAWK study tested the potential benefits of an immediate coronary angiography for treating or ruling out acute coronary events. Investigators randomly assigned 554 patients from 31 sites in Germany and Denmark who were successfully resuscitated after OHCA to either immediate (n=265) or delayed angiography (n=265). Post-resuscitation ECG showed no patients had evidence of ST-segment elevation, and patients with shockable and non-shockable rhythm were both enrolled (median age 70; female 30%). The primary endpoint was death from any cause at 30-days. Secondary endpoints were a composite of death from any cause or severe neurologic deficit at 30 days. Results showed that mortality rates were 54% in the immediate-angio group and 46% in the delayed-angio group, indicating no significant difference between the two arms and shockable (55.5%) or non-shockable rhythm patients (HR 1.28, 95% CI, 1.00-1.63; P=0.06). The immediate-angio group also had more composite rates of death or severe neurologic deficit than the delayed-angio group (64.3% vs. 55.6%, HR 1.16, 95% CI, 1.00-1.34). Other values, such as peak troponin release, length of intensive care unit (ICU) stay, and MI incidence, proved similar between the two arms. Safety endpoints of moderate or severe bleeding, stroke, and renal replacement therapy showed no significant difference. Notably, the “delays” in proceeding to angio in the TOMAHAWK trial did not bar cardiac revascularization rates. Findings showed that revascularization rates between the immediate-angio and delayed-angio groups were similar and even higher in the delayed angio arm (immediate-angio 37.2% vs. delayed-angio 43.2%). TOMAHAWK findings communicate an important message for OHCA: take the time for careful patient selection instead of rushing to cath. Do-Yoon Kang, MD In a video interview with TCTMD3, Desch speculated that the revascularization rate in the delayed angio arm was possibly higher because physicians were more selective and detailed in assessing the patient. “The higher rate of death and severe neurological deficits in the immediate angio group remains only hypothesis-generating. However, results of the trial suggest that patients without significant coronary lesions as the trigger of cardiac arrest do not benefit from an invasive approach and may even be harmed,” he said. “These results help us avoid unnecessary immediate cardiac catheterizations after OHCA and resolve the issues of ambiguity,, indicating that immediate cardiac cath is not necessary for the majority of patients.” But how late is too late? Findings from the TOMAHAWK trial are likely to change clinical practice - discussants at ESC 2021 and commentators said – helping clinicians buy more time for increased precision and thoroughness in clinical evaluations before rushing to angio. “In my practice, this means I won’t be waking up at 3 a.m. to rush an angio anymore – I would take more time and be more selective,” Desch said to TCTMD, pointing out that the practice of rushed angio for most OHCA patients lacks clinical evidence. However, he stressed that swift angio remains beneficial in certain patients and does not always mean more harm. How much time is too much is also emerging as a critical question. For reference, results showed that the average time to angio in COACT was 5 days and 2 days in TOMAHAWK. On this matter, Desch explained that the optimal time to angio is not straightforward; generally, results from COACT and TOMAHAWK point toward a shift for treatment based on the individual patient. Commenting on study findings to SummitMD, Do-Yoon Kang (Asan Medical Center, Seoul, South Korea) said: “Fewer patients in the delayed angio arm had to undergo an angiography (95.5% vs. 62.2%) and had more radial access (28.0% vs. 40.4%). Patients in the delayed angiography arm also had a higher rate of PCI after being diagnosed with significant coronary disease (37.2% vs. 43.2%). Taken together, the results from TOMAHAWK communicate an important message: take time to carefully select OHCA patients instead of rushing to the cath lab for better outcomes.” https://www.nejm.org/doi/full/10.1056/NEJMoa2101909 https://www.nejm.org/doi/full/10.1056/NEJMoa1816897 https://www.tctmd.com/videos/tomahawk-cardiac-cath-after-ohca.6270337634001

November 04, 2021 5716

SummitMD

Edoxaban Trial Paints Fragmented Picture for Doacs in AF-TAVR: ENVISAGE-TAVI AF

A patchwork of results from the ENVISAGE-TAVI AF study drew a mixed reaction regarding edoxaban (Lixiana, Daiichi Sankyo) in atrial fibrillation (AF) patients who have undergone transcatheter aortic valve replacement (TAVR). The ENVISAGE-TAVI AF1 trial pitted edoxaban - a direct oral anticoagulant (DOAC) - against vitamin K antagonists (VKAs) and found the DOAC to be comparable to VKA regarding the composite primary outcome of adverse clinical events (17.3 vs. 16.5 per 100 person-years; HR 1.05; 95% CI, 0.85-1.31), P=0.01 for noninferiority). However, edoxaban also had a higher risk of major bleeding according to ISTH definition than VKA (9.7 vs. 7.0 per 100 person-years; HR 1.40, 95% CI, 1.03-1.91, P=0.93 for noninferiority), with gastrointestinal (GI) bleeding as the main culprit. Principal investigator George Dangas, MD (Icahn School of Medicine at Mount Sinai, New York, USA) presented the study findings at the European Society of Cardiology (ESC) Congress 2021 on Aug. 28. The paper was simultaneously published in the New England Journal of Medicine (NEJM). “Overall, this trial showed the noninferiority of edoxaban compared to warfarin or similar analogs concerning the composite efficacy endpoint of adverse clinical events, but we need to pay attention to the higher risk of bleeding with edoxaban,” Dangas said. “Lowering the edoxaban dosage when indicated, and avoiding patients who require antiplatelet therapy is reasonable safety advice based on secondary analyses,” he added, noting that investigators will conduct further analysis on the specific types of bleeding found in the trial. ENVISAGE-TAVI AF: Key Points Multicenter, prospective, randomized, open-label, adjudicator-masked trial sponsored by Daiichi Sankyo Patient enrollment (April 2017-January 2020): 1,426 patients with prevalent/incident AF and indicated for OAC after successful TAVR at 173 centers in 14 countries (mean age 82.1 years; 47.5% women); 99% had AF before TAVR Study protocol: 1:1 randomization to edoxaban 60 mg daily with dose adjustment to 30 mg daily (n=713) or VKA (n=713) Specified antiplatelet therapy (~3 months DAPT after TAVR or continue with single antiplatelet therapy) at physician’s discretion Trial outcomes: Outcomes Edoxaban VKA HR (95% CI) Primary efficacy outcome: NACE (composite of all-cause mortality, MI, ischemic stroke, systemic thromboembolic event, valve thrombosis, major bleeding) 17.3 per 100 person-years 16.5 per 100 person-years 1.05 (0.85-1.31) Primary safety outcome: Major bleeding 9.7 per 100 person-years 7.0 per 100 person-years 1.40 (1.03-1.91) *GI bleeding 5.4 per 100 person-years 2.7 per 100 person-years 2.03 (1.28-3.22) All-cause mortality 10.0 per 100 person-years 11.7 per 100 person-years 0.85 (0.66-1.11) Jean-Phillippe Collet, MD (Pitié-Salpêtrière Hospital, Paris, France) congratulated investigators for the “only positive trial” with NOAC in the population, noting that NOAC safety would depend on concomitant use of antiplatelet therapy and dosing. Ensuing panel discussion centered on balancing the potential benefits and risks of DOACs in the AF-TAVR patient group. Previously, the POPular TAVI cohort A2 trial found that aspirin monotherapy had a lower incidence of all-cause bleeding at 1-year compared to the combination of aspirin and clopidogrel (15.1% vs. 26.6%, RR 0.57, 95% CI, 0.42-0.77, P=0.001). Collet, who ran the ATLANTIS trial that showed apixaban was not superior to standard of care, also pointed out that the “unlikelihood” of all NOACs being the same but took a conservative stance against updating guidelines. Major guidelines from both sides of the Atlantic Ocean have recommended VKAs alone over DOACs in TAVR-AF. The newly updated 2021 ESC Guideline for Valvular Heart Disease (VHD), presented at ESC Congress 2021, reaffirmed the old endorsement of VKAs over DOACs. Up to 33% of patients undergoing TAVR develop AF, a heart condition characterized by an irregular or abnormally fast heart rate. AF poses a higher risk of stroke, requiring treatment with blood-thinners known as oral anticoagulation (OAC). OACs include VKAs such as warfarin or the newer DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban). VKAs had served as the standard of care for many AF patients in the past until an increasing number of studies showed DOACs with a better risk-benefit profile compared to warfarin for preventing thromboembolic events in nonvalvular AF. Nevertheless, the case for DOACs in AF-TAVR has long lacked randomized data. Previous trials comparing DOACs and VKAs were largely observational and showed inconsistent results. Existing randomized controlled trials, such as GALILEO and ATLANTIS, were unfavorable with DOACs failing to reduce thromboembolic complications or present a justifiable bleeding-risk trade-off compared to VKAs. The GALILEO3 trial, published in NEJM in early 2020, was terminated early due to safety concerns with rivaroxaban, even at a low dose of 10 mg. Results showed that 10 mg of the DOAC with aspirin daily had a higher mortality rate than antiplatelets alone (incidence rate 9.8 vs. 7.2 per 100 person-years; HR 1.35; 95% CI, 1.01-1.81, P=0.04). Although OCEAN-TAVI4 results demonstrating mortality benefit with DOACs in select AF-TAVR patients (10.3% vs. 23.3%, HR 0.39; 95% CI, 0.204-0.749; P=0.005) in Nov. 2020 increased hopes, limitations in study design such as its observational nature and small patient population failed to revamp DOAC enthusiasm in the population. The ATLANTIS5 trial, introduced at the 2021 American College of Cardiology (ACC 21)’s Late-Breaking Clinical Trial session, spelled out more bad news as DOAC did not report better outcomes compared to VKA/antiplatelet therapy for 1-year incidence of death, MI, stroke, systemic embolism, and major bleeding (18.4% vs. 20.1%, HR 0.92, 95% CI, 0.73-1.16). Despite mixed results, Dangas remained optimistic about the “valuable” role of edoxaban, considering that ENVISAGE-TAVI AF enrolled only AF patients who were older “by approximately a decade” compared to previous trials. The patient population also had a higher prevalence of heart failure and more bioprosthetic valves. “Our trial only applies to patients with AF, intermediate operative risk, and symptomatic aortic stenosis, and it involved a population of older adults undergoing TAVR,” researchers wrote in the paper. “These results may not apply to younger patients at lower operative risk, patients with asymptomatic aortic stenosis, and those undergoing concomitant PCI.” Van Mieghem NM, Unverdorben M, Hengstenberg C, et al. Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR. N Engl J Med 2021. DOI: 10.1056/NEJMoa2111016 Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med 2020;383(15):1447-1457. DOI: 10.1056/NEJMoa2017815 Dangas GD, Tijssen JGP, Wohrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med 2020;382(2):120-129. DOI: 10.1056/NEJMoa1911425 Kawashima H, Watanabe Y, Hioki H, et al. Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients With Atrial Fibrillation After TAVR. JACC Cardiovasc Interv 2020;13(22):2587-2597. DOI: 10.1016/j.jcin.2020.09.013 Collet JP, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial. Am Heart J 2018;200:44-50. DOI: 10.1016/j.ahj.2018.03.008

October 21, 2021 2833

SummitMD

1-Month DAPT in High-Bleeding Risk Noninferior for Ischemic Outcomes, Less Bleeding: MASTER-DAPT

A shorter dual antiplatelet therapy (DAPT) of 1-month may become the "new standard of care" for a subgroup of coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI), MASTER DAPT findings signaled. Results from the trial on high bleeding risk (HBR) patients showed that 1-month DAPT post-PCI was noninferior to a longer DAPT duration of at least 3 months for the primary outcomes of net adverse clinical events (NACE) and major adverse cardiac or cerebral events (MACCE) at 335 days. The slashed DAPT duration also translated to lower incidence of major and clinically relevant nonmajor bleeding. DAPT is a medication regimen that combines a P2Y12 receptor inhibitor (clopidogrel, ticagrelor, or prasugrel) and aspirin to reduce the risk of restenosis and prevent thrombotic complications. Principal investigator Marco Valgimigli, MD (Cardiocentro Ticino Foundation, Lugano, Switzerland) presented the findings at a Hot Line session during the European Society of Cardiology (ESC) Congress 2021 on Aug. 28, with the paper published simultaneously in the New England Journal of Medicine (NEJM)1. "1-month DAPT after PCI in HBR patients maintained the ischemic benefits of therapy while reducing bleeding risk," Valgimigli said. "These results can inform treatment decisions regarding DAPT in PCI-HBR patients, including those with clinical or angiographic high ischemic risk features who do not present postprocedural ischemic events." Major guidelines have broadly endorsed a DAPT duration of at least 12 months after PCI as the standard. However, an evolving PCI landscape and continuing research on subgroups have highlighted that standard DAPT may not be optimal for all PCI patients. Notably, the optimal DAPT duration for HBR patients has remained unclear. The advent of drug-eluting stents (DES) -particularly second-generation DES -and the entry of more potent P2Y12 inhibitors have confounded the problem. In the increasingly complex HBR arena, clinicians have identified a trend of DAPT outcomes that varies on the duration of the regimen; namely, longer DAPT lowers ischemic risk at the expense of higher bleeding risk, while shorter DAPT reduces bleeding risk but elevates ischemic risk. Swinging on this pendulum of elevated ischemic or bleeding risk, physicians have leaned on analyzing individual patient characteristics to strike the right balance between the risks and benefits of DAPT. MASTER DAPT serves as the largest and "first important" randomized trial to report positive results for shorter DAPT in HBR patients, paving the way forward to a new standard of care, according to Gregg W. Stone, MD (Icahn School of Medicine at Mount Sinai, New York, USA). MASTER DAPT: Key Takeaways Investigator-initiated, multicenter, randomized, open-label, noninferiority trial Conducted from February 2017 to December 2019 at 140 sites in 30 countries Patient enrollment/characteristics Enrollment: 4,579 HBR patients with acute/chronic coronary syndrome undergone successful PCI with biodegradable-polymer sirolimus-eluting stent (Ultimaster, Terumo) (mean age: 76 years; 69.3% men) Comorbidities: diabetes 33.6%, chronic kidney disease 18.9%, previous cerebrovascular event 12.4%, peripheral vascular disease 10.6%, concomitant oral anticoagulation 36.4% Study design 1:1 randomization after PCI (median time from index PCI to randomization: 34 days) Randomized to either abbreviated-DAPT (n=2,295) or standard-DAPT (n=2,284) Follow-up data at 335 days for 4,547 patients Primary outcomes (abbreviated- vs. standard-DAPT) NACE: 7.5% vs. 7.7% (HR 0.97; 95% CI; 0.78-1.20) (risk difference -0.23%p, 95% CI, -1.80 to 1.33; p

October 06, 2021 16090

AP VALVES & SH 2021 Virtual

MITRA-FR vs. COAPT: Conflicting Results Harmonize to Deduce Ideal HF-FMR Patient for MitraClip

Analysis of two MitraClip studies with seemingly contradictory results is helping interventional cardiologists chisel a more detailed profile of the optimal candidate for transcatheter edge-to-edge mitral valve repair (TEER) in the realm of heart failure (HF). Results from the COAPT and MITRA-FR studies - both published in 2018 - fueled a heated debate on which patient groups benefit from the transcatheter procedure, mainly since the two randomized controlled trials (RCT) studied the same MitraClip (Abbott Vascular) device and technique on virtually the same HF patient group with secondary mitral regurgitation (MR), but produced antipodal results. Susheel Kodali, MD (New York-Presbyterian Columbia University Irving Medical Center, New York, USA) and panelists at AP Valves & Structural Heart Virtual (AP VALVES & SH 2021) on Aug. 6 discussed in-depth where exactly MitraClip fits on the spectrum of evolving HF therapies. "We have to ask ourselves whether TEER with MitraClip can interrupt or slow progression of a vicious cycle wherein volume overload to the left ventricle (LV) leads to functional mitral regurgitation (FMR), which increases volume overload and dilation for worsening HF, and so forth," Kodali said. "HF has changed over a decade. It was initially just diuretics, then came medications like neuro-hormonals, beta-blockers, ACE inhibitors, etc. Functional status improved with all these therapies, and the improvement - at times - hold for years; however, the question is when functional status decompensates, where does MitraClip fit on the spectrum of guideline-directed medical therapy (GDMT), and LVADs and transplants?" he asked. Through COAPT and MITRA-FR analysis, Kodali drew up a rough answer that pointed to specific patient characteristics that included: Continuing HF symptoms despite maximally-tolerated GDMT Favorable anatomies: lack of calcium, clefts, broad jets, and small mitral valve anatomy (MVA) Disproportionate MR "If we sum up the lessons learned, treatment with MitraClip in patients with worsening heart failure despite GDMT does result in a sustained clinical benefit that translates to benefit in quality of life. Patients who received TEER later, as well as patients with pulmonary hypertension or residual gradient, also benefitted," he said. "But we need future studies to determine whether indications should be broadened to populations such as those with anatomic restrictions or earlier treatment." Also doubling as a speaker and panel discussant at AP VALVES & SH 2021, Saibal Kar, MD (Los Robles Regional Medical Center, California, USA) set clear boundaries for TEER: "MitraClip is reasonable in intermediate-risk patients but not high-risk. This is true at least in the US where trials comparing the clip versus surgery for intermediate-risk show that it is reasonable." "Having said that, I believe there are some anatomies that are better with surgery, such as anterior prolapse," he added. Although he reaffirmed MitraClip for intermediate-risk patients, he also stated that he has problems with low-risk TEER and is "not ready for that." Piecing together the MitraClip puzzle for HF with secondary MR The radically different results between the two studies - COAPT being positive and MITRA-FR being neutral - have spurred much data sifting to pan out the golden TEER candidate in clinical practice. Cardiologists handling HF must sometimes make treatment decisions without all the evidence in place for specific patient groups; this ambiguous grey zone also extends to the non-surgical treatment of HF with secondary MR. The challenge is to go forward rather than stay behind and wait too long with the patient failing multiple rounds of medical therapy. Susheel Kodali, MD MR is a condition where the mitral valve does not correctly coapt - or gather closely together for closure - and causes blood to flow backward into the heart instead of out to the body. Severe MR can block blood flow to the rest of the body, leading to worsening HF symptoms. But MR is "not a single disease entity," Kodali pointed out. It can be classified as either primary MR caused by disease in the mitral leaflets, or secondary MR (also called functional MR) due to coronary disease in the left ventricle (LV) or left atrium (LA), not the mitral valve leaflets. Secondary to surgical repair, TEER with the small metal "clipping" device known as the MitraClip is becoming an increasingly popular transcatheter treatment for secondary MR, in addition to primary MR. MitraClip gained initial U.S. Food and Drug Administration (FDA) approval in 2013 for patients with primary MR and at high risk for mitral valve surgery. The FDA further expanded indications for MitraClip on March 2019 to patients with HF symptoms with moderate-to-severe or severe secondary MR despite maximally-tolerated GDMT1. MitraClip expectations take rollercoaster ride with trial results Before the much compared and contrasted MITRA-FR and COAPT studies, findings from the Abbott Vascular-funded EVEREST II trial published in the New England Journal of Medicine (NEJM) in 2011 showed superior safety and similar outcome improvements with MitraClip compared to surgery in high-risk HF patients, and subsequently increased its hype.2 But in August 2018, Jean-François Obadia, MD (Civils Hospices of Lyon, Lyon, France) and colleagues published the MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation)3 results in NEJM that showed no outcome difference between MitraClip and GDMT versus GDMT alone - dampening the once-high expectations. The prospective RCT - funded by the French Ministry of Health and Research National Program and Abbott Vascular - included 304 HF patients with severe secondary MR (defined as an effective regurgitant orifice area (EROA) ≥ 20 mm2 or regurgitant volume (RV) >30 mL/beat) and LVEF between 15-40% to examine the rate of death or unplanned hospitalization for HF at 1-year. MITRA-FR results showed MitraClip had no benefit over drug therapy alone (OR 1.16, 95% CI 0.73-1.84, p=0.53). Death from any cause (HR 1.11, 95% CI 0.69-1.77) and hospitalization rate (HR 1.13, 95% CI 0.81-1.56) between the two groups also failed to prove significant difference. On the heels of the MITRA-FR publication, however, came findings from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation)4 trial by Gregg W. Stone, MD (Mount Sinai Icahn School of Medicine, New York, USA) and colleagues in the NEJM in September. The COAPT study, once again funded by Abbott, showed that MitraClip slashed risks of HF-related hospitalization and all-cause mortality at 2-years compared to GDMT alone. The multicenter, parallel-controlled, open-label COAPT trial included 614 HF patients from about 80 U.S. and Canadian centers with moderate-to-severe (3+) or severe (4+) secondary MR who remained symptomatic despite maximally tolerated GDMT to either MitraClip with GDMT (n=302) or GDMT alone (n=312). "Dramatic" results at 24 months of follow-up showed the annualized rate of all-hospitalizations for HF was 35.8% per patient-year in the MitraClip group and 67.9% per patient-year in the control group, thereby halving the risk of hospitalization (HR 0.53, 95% CI, 0.40-0.70, p30 mL/beat) while COAPT used the more stringent American guidelines (EROA >30mm2 or RV >45 mL/beat). As a result, MITRA-FR had a mean EROA of 31 ±10 mm2 while COAPT had a mean EROA of 41 ±15 mm2. Mean left ventricular end-diastolic volume (LVEDV) was also larger in MITRA-FR (135 ±35 mL/m2 vs. 101 ±34 mL/m2), indicating patients with larger LVs and less MR. "We have to carefully consider the range and spectrum of LV dysfunction as two patients with the same EROA of 30mm2 may benefit from different therapies," Kodali said. "For instance, two patients with an EROA of 30 mm2 but differing LVEF and LV size/geometry (normal to severely abnormal) will require different treatment ranging from MR correction to LVAD, transplant, or hospice." Patients in MITRA-FR were also more aligned with non-severe MR, while COAPT had more patients with disproportionally severe MR. "The outcomes depended on the procedural result. If you had residual MR (3+ or 4+), the outcomes were not great and looked more like GDMT. But if you had less than 2+ MR, those were the patients that did well," Kodali said. Later treatment with MitraClip also had comparable outcomes as early (initial) treatment. "We can learn something from the crossovers as well. After the 2-year endpoint, 58 patients were allowed to crossover to the MitraClip procedure. Acute results were good with 2+ MR for 96% of patients, even though it had been two years since they were enrolled," he said. "Even later treatment translated into similar clinical benefit, indicating we should focus on earlier treatment." "The challenge is to go forward rather than stay behind and wait too long, with the patient failing multiple rounds of medical therapy," Kodali added. Saibal added to the discussion, "Overall, case selection and attention to detail during the procedure are critical for the procedure's success. Case selection refers to etiology, MR severity, surgical risk, and morphological criteria. Most importantly, you need to know when to stop and which cases to avoid." During his presentation, Saibal emphasized that operators should avoid using MitraClip in patients with mitral valve orifice less than 3.5 cm2; rheumatic MR with commissural fusion; calcified leaflets; severe TR that cannot be treated; recent endocarditis; or MR due to congenital cleft (endocardial cushion defects). Having a good imager is also essential, Saibal said, noting that imagers are just as important as the interventional cardiologists - if not more. CHECK THE SESSION https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100009S028 https://www.nejm.org/doi/full/10.1056/nejmoa1009355 https://www.nejm.org/doi/full/10.1056/NEJMoa1805374 https://www.nejm.org/doi/full/10.1056/NEJMoa1806640 https://clinicaltrials.gov/ct2/show/NCT02444338

August 06, 2021 25934

AP VALVES & SH 2021 Virtual

Data Hints at TAVR Expansion Into Low-risk Bicuspid AS but RCTs on Risky Morphology Still Missing

Heart teams around the world are calling for precise randomized data on transcatheter aortic valve replacement (TAVR) for bicuspid aortic valves (BAV)-aortic stenosis (AS) patients at low surgical risk. Raj R. Makkar, MD (Smidt Heart Institute at Cedars-Sinai, Los Angeles, USA) presented a synopsis of limited but existing TAVR data and sketched the way forward on the understudied and largely RCT-excluded patient group at AP Valves & Structural Heart Virtual (AP VALVES & SH 2021) on August 6. Current data shows TAVR has great potential benefits for low-risk bicuspid AS patients but is being used only "selectively" in the patient group. The lack of concrete evidence for bicuspid AS has ruled out the transcatheter procedure for many patients. "Investigational Device Exemption (IDE) trial data have helped label expansion for TAVR in the past decade, but anatomically heterogeneous bicuspid AS patients with frequent aortopathy - not found in previous IDEs - are becoming more common," Makkar said. Although researchers published favorable study results with both Sapien (Edwards Lifesciences) and Evolut (Medtronic) systems in real-life and registry studies, much-needed RCT data are still missing. It's more than just the eligibility of the first TAVR procedure; it's about how patients will live for the next 8 to 10 years. Raj R. Makkar, MD In the absence of RCT data, heart teams can use existing data and cardiac computer tomography (CT) phenotyping to plan the procedure and minimize risk, especially for patients who are still very much contraindicated for the TAVR procedure, Makkar said. "While bicuspid TAVR is justifiable irrespective of surgical risk, high-risk anatomical features such as extreme calcium, heavy-calcified raphe, and concomitant aortopathy should prompt consideration for surgical AVR in low-risk patients," he said. "We need further randomized trials and prospective registries - especially in patients with lower surgical risk - to guide treatment." TAVR indications expand rapidly as surgery replacement, but BAV data not enough Although TAVR was a novel stenting procedure as little as two decades ago, a series of successful RCTs published over the past 15 years has rapidly expanded its indications to various patient groups. Despite favorable data, these RCTs excluded BAV patients due to safety issues. TAVR is justifiable irrespective of surgical risk, but high-risk anatomical features should prompt consideration for SAVR in low-risk patients. BAV is one of the most common hereditary heart valve diseases wherein the aortic valve has only two cusps instead of three and occurs in about 1-2% of the total population. The condition increases risk of aortic stenosis - a condition when the heart's valve doesn't open properly, leading the reduced or blocked blood flow from the heart to the aorta and body. Treatment for severe BAV may require open-heart surgery (SAVR) to repair or replace the aortic valve. Statistics show nearly 25% of patients over 80 years of age were referred for aortic valve replacement (AVR).12 As opposed to SAVR, the minimally invasive TAVR procedure has become an increasingly popular treatment option for both the elderly and younger populations. "We are going to encounter bicuspid AS with greater frequency as TAVR expands into younger patient groups," Makkar said. "Currently, up to 50% of young patients receiving surgical aortic valve replacement (SAVR) have bicuspid valves." "Surgical outcomes in young bicuspid AS patients are excellent, making it reasonable to expect robust evidence for TAVR to replace SAVR for these patients," he added. The U.S. Food and Drug Administration (FDA) and European health regulators had approved TAVR for low surgical risk patients regardless of aortic valve anatomy in August and November 2019, respectively - thereby expanding TAVR indications beyond intermediate or higher SAVR risk groups.34 However, most international guidelines still take a conservative stance by recommending SAVR - not TAVR - for BAV patients. Cardiologists are now calling for robust data to resolve the treatment ambiguity of the heterogeneous BAV group as they face an increasing number of them in clinical practice. We absolutely need randomized trials and prospective registries to guide treatment for low-risk patients. At AP VALVES & SH 2021, Makkar presented study findings by his research team that examined the difference in mortality and stroke between bicuspid and tricuspid AS patients undergoing TAVR in a registry-based cohort study in 2019 published in the Journal of the American Medical Association (JAMA).5 Researchers ran a propensity-matched analysis on the U.S. Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies (STS/ACC TVT) Registry, including more than 2,700 pairs of bicuspid and tricuspid AS patients (average age: 74; mean STS score: 4.9%). Results showed that TAVR outcomes between bicuspid and tricuspid patients did not differ regarding mortality (30-day mortality: 2.6% vs. 2.5%; HR, 1.04. 95% CI, 0.74-1.47). 30-day stroke rates were higher in bicuspid (2.5% vs. 1.6%; 0.88-0.9%). Implantation of new pacemakers was also "slightly but significantly higher" in bicuspid (9.1% vs. 7.5%, HR 1.23, 1.02-1.49). 1-year mortality rates (10.5% vs 12.0%; HR, 0.90, 0.73-1.10, p=0.31) and 1-year stroke rates (3.4% vs 3.1%; HR, 1.28, 0.91-1.79, p=0.16) were also favorable, indicating no difference between bicuspid and tricuspid. "Procedural outcomes were good in this classic study. The rate of conversion to open surgery for bicuspid AS was 0.9%, which is low but still higher than tricuspid AS," Makkar said. "Annulus rupture (0.3%), aortic dissection (0.3%), and coronary obstruction (0.4%) were all less than 1%." Although researchers ran the analysis with the balloon-expandable Sapien 3 platform, the STS/ACC TVT Registry also compiled similar data on the Evolut R and Evolut PRO valves, he added. 'Excellent' TAVR outcomes after US approval for low-risk groups signal potential Makkar and Sung-han Yoon, MD (Cedars Sinai Medical Center, Los Angeles, USA) also investigated TAVR outcomes in the low-risk patient group after FDA approval for low surgical risk groups in 2019.6 The study7 examined outcomes of nearly 37,000 low-risk bicuspid or tricuspid AS patients who underwent TAVR with Sapien 3 or Sapien 3 Ultra from the STS/ACC TVT Registry from June 2015 to October 2020. Propensity-matching produced 3,168 pairs of bicuspid and tricuspid AS patients. (average age: 68.8; mean STS score: 1.7%) Researchers examined death and stroke incidence as the primary endpoint. Secondary endpoints included procedural complications, echocardiogram outcomes, and functional status outcomes. Findings presented at EURO PCR 2021 and simultaneously published in JAMA showed 30-day outcomes were similar (bicuspid vs. tricuspid AS): Conversion to open heart surgery: 0.4% vs. 0.4%, p=0.85 Annulus rupture: 0.2% vs. 0.1%, p=1.00 Aortic dissection: 0.1% vs. 0%, p=0.5 Coronary obstruction: 0.3% vs. 0.1%, p=0.37 Need for second valve 0.3% vs. 0.1%, p=0.11 All-cause mortality: 0.9% vs. 0.8%, p=0.55 All-stroke: 1.4% vs. 1.2%, p=0.55 In-hospital all-cause mortality: 0.6% vs. 0.4%, p=NS "These are excellent outcomes when compared to tricuspid AS, or even the contemporary surgical series in bicuspid AS," Makkar said. "Conversion to open-heart surgery occurred 1.4% of the time for bicuspid, and this was the same for tricuspid. 30-day mortality was less than 1%, and stroke rates were similar as well." "Even 1-year rates showed no difference," he continued. "If anything, bicuspid AS had lower mortality than tricuspid, and this almost reached statistical significance. This data on nearly 7,000 patients reassures the heart team that bicuspid outcomes are not worse than tricuspid." 1-year mortality and stroke outcomes followed the favorable trend (bicuspid vs. tricuspid AS): 1-year mortality: 8.6% vs. 9.8% (HR 0.90, 0.78-1.04, p=0.157) 1-year stroke: 2.8% vs. 3.1% (HR 0.96, 0.78-1.20, p=0.748) New pacemaker implantation and aortic valve intervention (1.16% vs. 0.4%) rates were higher for bicuspid AS but showed a minimal difference. NYHA and KCCQ scores also improved significantly in both groups, while aortic valve gradient and valve areas were similar. 'Valve morphology plays critical role in TAVR outcomes' In a detailed analysis, Abhjeet Dhoble, MD (University of Texas Health Science Center, Houston, USA), Yoon, and colleagues found that specific BAV morphology such as raphe calcification and leaflet calcification was associated with poorer clinical outcomes8. A quarter of patients presented a combo of calcified raphe and excess leaflet calcium - and that meant more aortic injury. Researchers enrolled 1,034 patients with CT-confirmed bicuspid anatomy from eight countries (Denmark, France, Germany, Israel, Italy, the Netherlands, Switzerland, and the U.S.) and classified them as either type-0 BAV (10.3%); type-1 non-calcified raphe (45.1%); or type-1 calcified raphe 44.6%. Patients underwent TAVR with either Sapien 3 (71.6%) or Evolut R/PRO (18.2%). The mean age was 74.7 years; the mean STS score was 3.7%; transfemoral TAVR accounted for 94.3%. Stroke and mortality results showed: 30-day stroke: 2.4% 30-day mortality: 2% 1-year mortality: 6.7% 2-year mortality: 12.5% Strikingly, multivariate analysis showed 26% of enrolled patients had calcified raphe and excess leaflet calcification and had a significantly higher 2-year all-cause mortality than patients with one or none of these morphological features (25.7% vs. 9.5% vs. 5.9%, log-rank p < 0.001).9 Furthermore, patients with both morphological features had higher rates of aortic root injury (p

August 06, 2021 21469

AP VALVES & SH 2021 Virtual

4 Upcoming and Novel LAAO Devices and Best Multimodal Imaging for Challenging Cases

New and upcoming devices and advanced techniques in the arena of left atrial appendage occlusion (LAAO) are garnering attention for the treatment of nonvalvular atrial fibrillation. Philippe Garot, MD (Institut Cardiovasculaire Paris-Sud (ICPS), Massy, France) ran through the current landscape and future of LAAO devices and techniques for AF patients at AP Valves & SH 2021 Virtual on August 6. "The question is about how to improve results in challenging LAAO procedures due to complex anatomy or device-related issues that can cause problems with co-axiality and device conformity, among others," Garot said. "Positioning and sizing of the device are crucial for a good procedure, especially considering procedural complications like peri-device leakage (PDL), device-related thrombosis (DRT), incomplete occlusion, stroke, and others may occur in more challenging cases and worsen outcomes." Results from the EWOLUTION registry1 and the PROTECT-AF2 trial with the forerunning Watchman device (Boston Scientific) demonstrated around a 10% risk of implant failure during LAAO. However, Garot pointed out that the figures are now down to 1-2%. Initial studies with Watchman reported risk of device-related serious adverse events (SAEs) occurred in 8.7% of patients. This number is now less than 3% in the modern era - indicating serious risks are few but present in challenging LAAOs. "We want to fight failure to implant and serious periprocedural adverse events. Advanced techniques and occluders are promising," Garot said. Commonly used occluding devices include the Amplatzer Amulet (Abbott), LAmbre (Lifetech Scientific), and the Watchman series. Noteworthy upcoming devices include the SeaLA LAA Occluder, Conformal LAA Seal, Appligator, and Endomatic Sepiola Closure. 4 upcoming new LAAO devices raise expectations for better outcomes Four upcoming devices in early trials have gotten hype for their sealing capabilities and ability to conform to "all" anatomies. Some are even called "no-implant" LAA occluders. Overall, Garot looked forward to reducing procedural complication rates arising from mismatched device-LAA sizing/positioning by tailoring the device to anatomical size with novel devices and techniques. - SeaLA LAA Occluder (Hangzhou Valued Medtech Co., Ltd.) The umbrella-shaped nitinol SeaLA LAA Occluder comes in a two-part plate and waist structure in 11 different sizes.34 It features a low-profile delivery sheath and an additional (double dual) seal disk that helps guide LAAO procedures. Nine "small but strong hooks" are also fully retrievable and repositionable. The combined China Food and Drug Administration (CFDA) registry demonstrated success rates of 97% (163/168 patients) with 1-year peri-device leak rates greater than >3 mm occurring in 0 out of 152 patients. Device-related thrombosis occurred in 4 out of 152 patients (0.02%), and stroke occurred in 2 patients (0.01%). - Conformal LAA Seal (CLAAS, Conformal Medical) CLAAS has a foam-based architecture designed to address the broad spectrum of LAA anatomies. The device comes in 2 sizes - the regular 27 mm device and the larger 35 mm device. The device eliminates the need for general anesthesia and transesophageal echocardiography (TEE). CLAAS features a flexible tether that eliminates the cable attachment site, an expanded polytetrafluoroethylene (ePTFE) cover for fewer thrombogenic events, and a compliant endoskeleton that conforms to anatomy. "We can implant CLAAS in an off-axis positioning, which is different from regular devices used today," Garot said. "We also don't have cable; instead, there are thin needles and sutures to fix the device, mitigating the risk of putting in the device when positioning." Early feasibility studies such as the Prague single-center study (n=15) and a U.S. multicenter study (n=22) showed promising results. The procedural success rate in the Prague-single center study was successful in 15 out of 15 patients with no complications. LAA size ranged from 11-28 mm. The U.S. multicenter study showed an 82% success rate (18/22 patients), 2 leaks, and 1 device-related thrombosis. Analysis showed the procedure failed in 4 LAAs that were "too large" while the average LAA size ranged from 9-31 mm. The upcoming prospective multicenter randomized controlled CONFORM pivotal trial is recruiting 1,400 patients. CONFORM will pit the CLAAS device against Watchman, with the primary endpoint defined as 1-year clinical events and device seal outcomes and the secondary endpoint including 18-month stroke and systemic embolism. - Appligator (Append Medical) The Appligator is a new concept; namely, it allows for LAA closure without implant. "The device comes across as simpler than device closure since it doesn't require LAA measurements. It also possibly realizes the potential of one size fits all (anatomies)," Garot said. "It's simpler than a transpericardial LAA closure and allows for complete sealing (invagination suction) of the appendage that can be completely reversed to the left atrium, then fixed," he continued. "One case result (shown via control CT) demonstrated good outcomes but some reported appendage invagination inside the left atrium. However, this was not associated with complications in the pre-clinical phase." - Endomatic Sepiola LAA Closure Another future device is the Sepiola. The device is said to be non-thrombogenic and fits all anatomies with suturing-like hermetic sealing capabilities. The device comes out the catheter tip of the sheath and out to the wall, then grabs the appendage wall while retracting continuously for complete appendage occlusion without exposing parts of the device to blood. "Device closure without leaving the device exposed to the blood is, of course, important due to the absence of device embolization and device-related thrombosis," Garot said. "Although all these devices mentioned are only in pre-clinical trials, they create excitement as we can look forward to new devices for our patients." 'Multimodal imaging capacities and strong technique crucial' Although novel devices are coming, time to approval may take years, Garot noted, indicating the increased importance of multimodal imaging and beneficial techniques. Multimodal imaging is crucial for a good analysis of the appendage and planification, especially for positioning/sizing, and anticipate difficulties in challenging LAAO, Garot said. Noted imaging products and software include: XR/CT or TEE/XR Fusion 3mensio (Pie Medical Imaging) FEops HEARTguide (FEops) Valve Assist (GE) 3D printing. "Procedures with dedicated planification are critical," Garot noted. "We routinely use 3mensio for all patients, but we also use different imaging modalities fusion with X-ray and CT overlay during the procedure." "The Feops computer-based simulation also helps in both complex and routine cases with positioning and sizing," he added. "We don't use 3D printing yet, but it may be reasonable to use - especially for teaching." CHECK THE SESSION https://www.sciencedirect.com/science/article/pii/S1547527117307154 https://www.ahajournals.org/doi/10.1161/circulationaha.112.114389 https://citoday.com/articles/2018-may-june/the-spectrum-of-devices-for-percutaneous-left-atrial-appendage-occlusion https://cdn.doctorsonly.co.il/2019/10/ehra-eapci-expert-consensus-statement-on-catheter-based-left-atrial-appe...%D7%9E%D7%A1%D7%9E%D7%9A-%D7%94%D7%A0%D7%97%D7%95%D7%AA-%D7%A9%D7%A2%D7%A8%D7%99-%D7%A6%D7%93%D7%A7.pdf

August 06, 2021 14659

AP VALVES & SH 2021 Virtual

Upfront Protection Needed for 'Rare But Real' Risk of TAVR-related Coronary Artery Occlusion

Interventional teams need to pan out and choreograph the identification, prevention, and procedural techniques for coronary artery occlusion (CAO) that can occur duringtranscatheter aortic valve replacement (TAVR), an expert said recently. Employing strategies before and during the procedure, such as a pre-procedural CT or primary bail-out procedural techniques like "chimney" (snorkel) stenting and BASILICA, can mitigate the risk of TAVR-related CAO. Lars Sondergaard, MD (Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark) emphasized these points during an online 'Live Case & Lecture 2: TAVR - Coronary Access' lecture at the 10th AP Valves & Structural Heart Virtual (AP VALVES & SH 2021) conference on Aug. 5. "The lesson here is this," Sondergaard said. "If you are concerned about coronary artery occlusion during the procedure, then protect it upfront." CAO is a rare but highly fatal complication that may occur during TAVR through either a direct obstruction of coronary flow (i.e., displaced native leaflet tissue of the valve flows towards coronary ostium) or an indirect reduction of coronary flow (i.e., displaced leaflet tissue contacts the sinotubular junction and seals off coronary sinuses). Such occlusions of the coronary artery rarely occur, accounting for less than 1% of TAVR cases, but they carry a high risk of mortality of about 40-50%1. "Coronary artery occlusion during TAVR is a rare but often fatal complication; it is important to identify patients at risk, and we can do this by assessing certain characteristics," said Sondergaard. "Most often, the complication occurs in patients undergoing valve-in-valve (ViV) procedures due to failing or degenerative surgical bioprosthetic valves. So screening with pre-procedural CT for certain high-risk anatomical features can lower risk." For procedural techniques, he said: "Chimney stenting is relatively simple and safe but has re-accessing and stent failure concerns, while the BASILICA that is taking off in Europe and the U.S. is also an option, but it's more technically challenging and carries a risk of failure." 'ViV procedures, certain coronary features raise TAVR-related CAO risk' TAVR-related CAO is a bigger problem in native aortic valves with distinct coronary height coronary sinus, and/or aortic root size, Sondergaard said, as well as for patients undergoing ViV procedures for degenerated bioprosthetic aortic valves. For patients with native aortic valves, characteristics that heighten CAO risk include low coronary take-off, shallow sinus of the Valsalva, low sinotubular junction, and long, calcified cusps; these elements call for pre-procedural coronary protection. Opposing these characteristics are the "low-risk" elements such as high coronary take-off, wide Valsalva sinus, high sinotubular junction, and short, non-calcified cusps.2 For TAVR in degenerated surgical bioprostheses, Sondergaard also flagged low coronary take-off, shallow sinus of Valsalva, or low sinotubular junction as higher-risk. Surgical bioprostheses with externally mounted leaflets or short valve-to-coronary (VTC) distance (< 4 mm) require extra caution, he added. Insights from the VIVID registry3 that examined the CAO risk according to the type of surgical bioprosthesis showed that the risk was significantly higher in patients stented with externally mounted leaflets than those stented with internally mounted leaflets (6.4% vs. 0.7%, p

August 05, 2021 7818

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 18990

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 13023

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

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