Research Spotlight

Vaduganathan, M., B. Claggett, M. Packer, J. J. V. McMurray, J. L. Rouleau, M. R. Zile, K. Swedberg and S. D. Solomon (2018). “Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure.” JACC Heart Fail 6(7): 564-569.

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OBJECTIVES: This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). BACKGROUND: The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. METHODS: The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS: Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro-B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002). CONCLUSIONS: When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials.

Vader, J. M., D. H. Cooper and P. Rao (2018). “Re-Thinking Re-Synching in Left Ventricular Assist Device Recipients.” J Am Heart Assoc 7(12): June 15.

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In this issue of the Journal of the American Heart Association (JAHA), Gopinathannair et al provide meaningful clinical data to inform conjecture surrounding cardiac resynchronization therapy (CRT) and LVAD. This multicenter retrospective study is the largest published experience to date on the utility of CRT in patients with LVAD. A total of 488 continuous flow (CF)‐LVAD patients were studied, 265 with CRT‐D versus 223 with ICD alone. During a mean follow‐up of 620±509 days, no difference in mortality was seen between the CRT‐D group compared with the ICD‐only group (29% versus 25%, logrank P=0.28). In multivariate Cox regression, there was no evidence that CRT influenced survival (hazard ratio for mortality in patients with an ICD as opposed to CRT‐D 1.469 [95% confidence interval 0.859–2.514, P=0.16]). The only variable significantly associated with lower survival was amiodarone use (hazard ratio for mortality 1.77, P=0.01). In other unadjusted analyses, there were no significant differences between CRT‐D and ICD groups in terms of VA rates (43% versus 39%, P=0.3) or ICD shocks (35% versus 29%, P=0.2). All‐cause hospitalization rates were nonsignificantly lower in the CRT‐D group as opposed to the ICD group (0.46 per 100 days versus 0.59 per 100 days, P=0.06), while censoring at 1 year of follow‐up, there was a nonsignificant trend toward higher mortality in the CRT‐D group versus the ICD group (23% versus 15%, P=0.054). In the absence of statistical adjustment for baseline differences in covariates, particularly considering the older age of CRT patients, the meaning of these data is uncertain. Perhaps less ambiguous, the rate of generator changes was significantly higher in the CRT group compared with the ICD‐only group (26% versus 15.5%, P=0.003), though it was not reported whether this higher rate of generator changes contributed to more device infections, or anticoagulation‐related issues such as pocket hematomas or pump thrombosis. Retrospective, uncontrolled, observational data such as these have inherent limitations, but this article raises several important management questions. (Excerpt from text of this commentary, p. 2; no abstract available.)

Turagam, M. K., P. Velagapudi, S. Kar, D. Holmes, V. Y. Reddy, M. M. Refaat, L. Di Biase, A. Al-Ahmed, M. K. Chung, T. Lewalter, J. Edgerton, J. Cox Nu, J. Fisher, A. Natale and D. R. Lakkireddy (2018). “Cardiovascular Therapies Targeting Left Atrial Appendage.” J Am Coll Cardiol Jun 25. [Epub ahead of print].

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Left atrial appendage (LAA) closure has evolved as an effective strategy for stroke prevention in patients with atrial fibrillation who are considered suitable for oral anticoagulation. There is strong evidence based on randomized clinical trials with 1 percutaneous device, as well as a large registry experience with several devices, regarding the safety and efficacy of this strategy. In addition, there is encouraging data regarding the effect of epicardial LAA closure on decreasing arrhythmia burden and improvements in systemic homeostasis by neurohormonal modulation. However, there are several unresolved issues regarding optimal patient selection, device selection, management of periprocedural complications including device-related thrombus, residual leaks, and pericarditis. In this review, we summarize the rationale, evidence, optimal patient selection, and common challenges encountered with mechanical LAA exclusion.

Tjaden, B. L., Jr., H. Sandhu, C. Miller, D. Gable, S. Trimarchi, F. Weaver and A. Azizzadeh (2018). “Outcomes from the Gore Global Registry for Endovascular Aortic Treatment in patients undergoing thoracic endovascular aortic repair for type B dissection.” J Vasc Surg Jun 22. [Epub ahead of print].

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OBJECTIVE: The Global Registry for Endovascular Aortic Treatment (GREAT) is a prospective multicenter registry collecting real-world data on the performance of W. L. Gore (Flagstaff, Ariz) aortic endografts. The purpose of the present study was to analyze the implementation and outcomes of thoracic endovascular aortic repair (TEVAR) in GREAT patients with type B aortic dissection (TBAD). METHODS: From 2010 to 2016, >5000 patients were enrolled in the GREAT from 113 centers in 14 countries across 4 continents. The study population comprised those treated for TBAD. The primary outcomes of interest were mortality and freedom from aortic events (AEs). RESULTS: A total of 264 patients (80% male; mean age, 62 years) underwent TEVAR for the treatment of 170 (64%) acute and 94 (36%) chronic cases of TBAD. Chronic TBAD patients required significantly longer endograft coverage than did acute TBAD patients (P = .05). Early postoperative complications occurred in 9% of patients, with no difference in chronic vs acute dissection (P = .11). The 30-day aortic mortality and all-cause mortality were 1.5% and 2.3%, respectively, with no differences based on chronicity. During a mean follow-up of 26 months, the total aortic mortality was 2.7% and the total all-cause mortality was 12.5%. The all-cause mortality was significantly greater for chronic vs acute TBAD (19.2% vs 8.8%, respectively; P = .02). On multivariate analysis, patients with acute uncomplicated dissections had significantly improved overall survival compared with all other categories of dissections (93% vs 83% at 2 years; P < .05). A proximal landing zone diameter >40 mm was associated with an increased risk of retrograde type A dissection (18% vs 2%; P = .02). Patients undergoing left subclavian artery (LSA) coverage experienced a twofold greater rate of AEs compared with noncoverage patients (P < .01). Patients who underwent LSA revascularization experienced a 1.5-fold greater rate of AEs compared with patients covered without revascularization (P = .04). CONCLUSIONS: TEVAR for TBAD using the conformable GORE TAG thoracic endoprosthesis device can be performed with a low incidence of aortic mortality and complications. Acute uncomplicated TBAD patients had a significantly lower mortality rate than that of other patients. Larger proximal landing zones were associated with more frequent retrograde type A dissection. LSA involvement (coverage and/or revascularization) was associated with an increased risk of AEs during follow-up.

Tang, G. H. L., S. Zaid, I. George, O. K. Khalique, Y. Abramowitz, Y. Maeno, R. R. Makkar, H. Jilaihawi, N. Kamioka, V. H. Thourani, V. Babaliaros, J. G. Webb, N. M. Htun, A. Attinger-Toller, H. Ahmad, R. Kaple, K. Sharma, J. A. Kozina, T. Kaneko, P. Shah, S. A. Hirji, N. D. Desai, S. Anwaruddin, D. Jagasia, H. C. Herrmann, S. S. Basra, M. A. Szerlip, M. J. Mack, M. Mathur, C. W. Tan, C. W. Don, R. Sharma, S. Gafoor, M. Zhang, S. R. Kapadia, S. L. Mick, A. Krishnaswamy, N. Amoroso, A. Salemi, S. C. Wong, A. S. Kini, J. Rodes-Cabau, M. B. Leon and S. K. Kodali (2018). “Impact of Aortic Root Anatomy and Geometry on Paravalvular Leak in Transcatheter Aortic Valve Replacement With Extremely Large Annuli Using the Edwards SAPIEN 3 Valve.” JACC Cardiovasc Interv Jun 26. [Epub ahead of print].

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OBJECTIVES: The aim of this study was to determine factors affecting paravalvular leak (PVL) in transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 (S3) valve in extremely large annuli. BACKGROUND: The largest recommended annular area for the 29-mm S3 is 683 mm(2). However, experience with S3 TAVR in annuli >683 mm(2) has not been widely reported. METHODS: From December 2013 to July 2017, 74 patients across 16 centers with mean area 721 +/- 38 mm(2) (range: 684 to 852 mm(2)) underwent S3 TAVR. The transfemoral approach was used in 95%, and 39% were under conscious sedation. Patient, anatomic, and procedural characteristics were retrospectively analyzed. Valve Academic Research Consortium-2 outcomes were reported. RESULTS: Procedural success was 100%, with 2 deaths, 1 stroke, and 2 major vascular complications at 30 days. Post-dilatation occurred in 32%, with final balloon overfilling (1 to 5 ml extra) in 70% of patients. Implantation depth averaged 22.3 +/- 12.4% at the noncoronary cusp and 20.7 +/- 9.9% at the left coronary cusp. New left bundle branch block occurred in 17%, and 6.3% required new permanent pacemakers. Thirty-day echocardiography showed mild PVL in 22.3%, 6.9% moderate, and none severe. There was no annular rupture or coronary obstruction. Mild or greater PVL was associated with larger maximum annular and left ventricular outflow tract (LVOT) diameters, larger LVOT area and perimeter, LVOT area greater than annular area, and higher annular eccentricity. CONCLUSIONS: TAVR with the 29-mm S3 valve beyond the recommended range by overexpansion is safe, with acceptable PVL and pacemaker rates. Larger LVOTs and more eccentric annuli were associated with more PVL. Longer term follow-up will be needed to determine durability of S3 TAVR in this population.