David L. Brown M.D.

Shahim, B., Malaisrie, S.C., George, I., Thourani, V.H., Biviano, A.B., Russo, M.J., Brown, D.L., Babaliaros, V., Guyton, R.A., Kodali, S.K., Nazif, T.M., McCabe, J.M., Williams, M.R., Généreux, P., Lu, M., Yu, X., Alu, M.C., Webb, J.G., Mack, M.J., Leon, M.B. and Kosmidou, I. (2021). “Atrial Fibrillation and Outcomes After Transcatheter or Surgical Aortic Valve Replacement (from the PARTNER 3 Trial).” Am J Cardiol 148: 116-123.

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The prognostic impact of preexisting atrial fibrillation or flutter (AF) in low-risk patients with severe aortic stenosis treated with transcatheter (TAVR) or surgical aortic valve replacement (SAVR) remains unknown. In this sub-analysis of the PARTNER 3 trial of patients with severe aortic stenosis at low surgical risk randomized 1:1 to TAVR versus SAVR, clinical outcomes were analyzed at 2 years according to AF status. Among 948 patients included in the analysis (452 [47.7%] in the SAVR vs 496 [52.3%] in the TAVR arm), 168 (17.6%) patients had AF [88/452 (19.5%) and 80/496 (16.1%) treated with SAVR and TAVR, respectively]. At 2 years, patients with AF had higher unadjusted rates of the composite outcome of death, stroke or rehospitalization (21.2% vs 12.9%, p = 0.007) and rehospitalization alone (15.3% vs 9.4%, p = 0.03) but not all cause death (3.8% vs 2.6%, p = 0.45) or stroke (4.8% vs 2.6%, p = 0.12). In adjusted analyses, patients with AF had a higher risk for the composite outcome of death, stroke or rehospitalization (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.20-2.71, p = 0.0046) and rehospitalization alone (HR 1.8, 95% CI 0.12-2.9, p = 0.015), but not death or stroke. There was no interaction between treatment modality and AF on the composite outcome (Pinter = 0.83). In conclusion, preexisting AF in patients with severe AS at low surgical risk was associated with increased risk of the composite outcome of death, stroke or rehospitalization at 2 years, irrespective of treatment modality.

Lansky, A.J., Makkar, R., Nazif, T., Messé, S., Forrest, J., Sharma, R., Schofer, J., Linke, A., Brown, D., Dhoble, A., Horwitz, P., Zang, M., DeMarco, F., Rajagopal, V., Dwyer, M.G., Zivadinov, R., Stella, P., Rovin, J., Parise, H., Kodali, S., Baumbach, A. and Moses, J. (2021). “A randomized evaluation of the TriGuard™ HDH cerebral embolic protection device to Reduce the Impact of Cerebral Embolic LEsions after TransCatheter Aortic Valve ImplanTation: the REFLECT I trial.” Eur Heart J May 17;ehab213. [Epub ahead of print].

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AIMS : The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS : This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2-5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2-5 days. Cumulative scores were compared between treatment groups using the Finkelstein-Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: -5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P = 0.0698) and at 5 days (61.7 vs. 76.2%, P = 0.054) compared with controls. CONCLUSION : REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls.

Nazif, T.M., Moses, J., Sharma, R., Dhoble, A., Rovin, J., Brown, D., Horwitz, P., Makkar, R., Stoler, R., Forrest, J., Messé, S., Dickerman, S., Brennan, J., Zivadinov, R., Dwyer, M.G. and Lansky, A.J. (2021). “Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.” JACC Cardiovasc Interv 14(5): 515-527.

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OBJECTIVES: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. BACKGROUND: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. METHODS: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method. RESULTS: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm(3) (-9.7%) and >1,000 mm(3) (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm(3)) and -82.9% (>1,000 mm(3)). CONCLUSIONS: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.

Makkar, R. R., P. Blanke, J. Leipsic, V. Thourani, T. Chakravarty, D. Brown, A. Trento, R. Guyton, V. Babaliaros, M. Williams, H. Jilaihawi, S. Kodali, I. George, M. Lu, J. M. McCabe, J. Friedman, R. Smalling, S. C. Wong, S. Yazdani, D. L. Bhatt, J. Bax, S. Kapadia, H. C. Herrmann, M. Mack and M. B. Leon (2020). “Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic Valves: PARTNER 3 Cardiac Computed Tomography Substudy.” J Am Coll Cardiol 75(24): 3003-3015.

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BACKGROUND: Subclinical leaflet thrombosis, characterized by hypoattenuated leaflet thickening (HALT) and reduced leaflet motion observed on 4-dimensional computed tomography (CT), may represent a form of bioprosthetic valve dysfunction. OBJECTIVES: The U.S. Food and Drug Administration mandated CT studies to understand the natural history of this finding, differences between transcatheter and surgical valves, and its association with valve hemodynamics and clinical outcomes. METHODS: The PARTNER 3 (The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low-Risk Patients With Aortic Stenosis) CT substudy randomized 435 patients with low-surgical-risk aortic stenosis to undergo transcatheter aortic valve replacement (n = 221) or surgery (n = 214). Serial 4-dimensional CTs were performed at 30 days and 1 year and were analyzed independently by a core laboratory. RESULTS: The incidence of HALT increased from 10% at 30 days to 24% at 1 year. Spontaneous resolution of 30-day HALT occurred in 54% of patients at 1 year, whereas new HALT appeared in 21% of patients at 1 year. HALT was more frequent in transcatheter versus surgical valves at 30 days (13% vs. 5%; p = 0.03), but not at 1 year (28% vs. 20%; p = 0.19). The presence of HALT did not significantly affect aortic valve mean gradients at 30 days or 1 year. Patients with HALT at both 30 days and 1 year, compared with those with no HALT at 30 days and 1 year, had significantly increased aortic valve gradients at 1 year (17.8 ± 2.2 mm Hg vs. 12.7. ± 0.3 mm Hg; p = 0.04). CONCLUSIONS: Subclinical leaflet thrombosis was more frequent in transcatheter compared with surgical valves at 30 days, but not at 1 year. The impact of HALT on thromboembolic complications and structural valve degeneration needs further assessment.

Pibarot, P., E. Salaun, A. Dahou, E. Avenatti, E. Guzzetti, M. S. Annabi, O. Toubal, M. Bernier, J. Beaudoin, G. Ong, J. Ternacle, L. Krapf, V. H. Thourani, R. Makkar, S. K. Kodali, M. Russo, S. R. Kapadia, S. C. Malaisrie, D. J. Cohen, J. Leipsic, P. Blanke, M. R. Williams, J. M. McCabe, D. L. Brown, V. Babaliaros, S. Goldman, W. Y. Szeto, P. Genereux, A. Pershad, M. C. Alu, K. Xu, E. Rogers, J. G. Webb, C. R. Smith, M. J. Mack, M. B. Leon and R. T. Hahn (2020). “Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients: The PARTNER 3 Trial.” Circulation Apr 10. [Epub ahead of print].

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Background: The objective of this study is to compare echocardiographic findings in low risk patients with severe aortic stenosis (AS) following surgical (SAVR) or transcatheter aortic valve replacement (TAVR). Methods: The Placement of Aortic Transcatheter Valves 3 (PARTNER 3) trial randomized 1000 patients with severe AS and low surgical risk to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR. Transthoracic echocardiograms obtained at baseline, and at 30 days and 1 year post-procedure were analyzed by a consortium of 2 echocardiography core laboratories. Results: The percentage of moderate/severe aortic regurgitation (AR) was low and not statistically different between TAVR vs. SAVR groups (30 days: 0.8% vs. 0.2%; p=0.38). However, mild AR was more frequent following TAVR vs. SAVR (30 days: 28.8% vs. 4.2 %; p<0.001). At 1 year, mean transvalvular gradient (13.7+/-5.6 vs. 11.6+/-5.0 mmHg; p=0.12) and aortic valve area (1.72+/-0.37 vs. 1.76+/-0.42 cm(2); p=0.12) were similar in TAVR vs. SAVR. The percentage of severe prosthesis-patient mismatch (PPM) at 30 days was low and similar between TAVR and SAVR (4.6 vs. 6.3%, p=0.30). Valvulo-arterial impedance (Zva), which reflects total left ventricular hemodynamic burden, was lower with TAVR vs. SAVR at 1 year (3.7+/-0.8 vs. 3.9+/-0.9 mmHg/mL/m(2) ; p<0.001). Tricuspid annulus plane systolic excursion (TAPSE) decreased and the percentage of moderate/severe tricuspid regurgitation increased from baseline to 1 year in SAVR, whereas remained unchanged in TAVR. Irrespective of treatment arm, high Zva and low TAPSE, but not moderate/severe AR or severe PPM, were associated with increased risk of the composite endpoint of mortality, stroke and re-hospitalization at 1 year. Conclusions: In patients with severe AS and low surgical risk, TAVR with the SAPIEN 3 valve was associated with similar percentage of moderate/severe AR compared with SAVR, but higher percentage of mild AR. Transprosthetic gradients, valve areas, percentage of severe PPM, and LV mass regression were similar in TAVR versus SAVR. SAVR was associated with significant deterioration of RV systolic function and greater tricuspid regurgitation, which persisted at 1 year. High Zva and low TAPSE were associated with worse outcome at 1 year whereas AR or severe PPM were not.