To the Editor: Makkar et al. (Nov. 19 issue)(1) report possible subclinical leaflet thrombosis in up to 40% of patients involved in a clinical trial of transcatheter aortic-valve replacement (TAVR). In contrast, we found a relatively low incidence (7%) of possible subclinical valve leaflet thrombosis among patients in our series in which 255 patients underwent TAVR with the use of a CoreValve prosthesis. A retrospective review of our series (unpublished data) showed that in 104 patients, cardiac computed tomography (CT) at a median of 7 days after implantation (range, 3 to 87) (in 51 patients), transesophageal echocardiography at a median . . 

Burriesci, Gaetano

Colli, Andrea

Ducci, Andrea

English

Colli, A

Ducci, A

Burriesci, G

UCL Discovery

T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 374;16 nejm.org April 21, 20161590Possible Subclinical Leaflet Thrombosis in Bioprosthetic  Aortic ValvesTo the Editor: Makkar et al. describe the phe-nomenon of reduced leaflet motion in patients who had received bioprosthetic aortic valves. An in vitro study by Ducci et al.1 showed that TAVR produced substantial alteration of the flow pat-tern in the sinuses of Valsalva, creating regions of blood stasis that could lead to thrombus for-mation. This abnormal condition is not observed after conventional surgical aortic-valve replace-ment because the complete resection of the calci-fied leaflets allows preservation of the natural geometry and vortex dynamics of the aortic root. Moreover, with the use of TAVR implants, there is often angular or rotational misalignment with the sinuses and coronary ostia; this could further impair local blood flow.The data reported by Makkar et al. and Ducci et al. suggest that the use of bioprosthetic valves per se is not sufficient to guarantee correct leaf-let dynamics and avoid the need for anticoagula-tion. This finding may be particularly alarming in light of what has been clinically observed with surgical bioprostheses.2-4 The data reported by Ducci and colleagues need to be taken into account when considering the use of TAVR in patients who cannot be treated with anticoagu-lants and in lower-risk patients.Andrea Colli, M.D., Ph.D.University of Padua Padua, Italy colli . andrea . bcn@ gmail . comAndrea Ducci, Ph.D. Gaetano Burriesci, Ph.D.University College London London, United KingdomNo potential conflict of interest relevant to this letter was re-ported.1. Ducci A, Tzamtzis S, Mullen MJ, Burriesci G. Hemodynam-ics in the Valsalva sinuses after transcatheter aortic valve im-plantation (TAVI). J Heart Valve Dis 2013; 22: 688-96.2. Colli A, Verhoye JP, Heijmen R, Antunes M. Low-dose acetyl salicylic acid versus oral anticoagulation after bioprosthetic aor-tic valve replacement: final report of the ACTION Registry. Int J Cardiol 2013; 168: 1229-36.3. Colli A, Mestres CA, Castella M, Gherli T. Comparing warfa-rin to aspirin (WoA) after aortic valve replacement with the St. Jude Medical Epic heart valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis 2007; 16: 667-71.4. Colli A, Marchetto G, Salizzoni S, et al. The TRIBECA study: (TRI)fecta (B)ioprosthesis (E)valuation versus (C)arpentier Mag-na-Ease in (A)ortic position. Eur J Cardiothorac Surg 2016; 49: 478-85.DOI: 10.1056/NEJMc1600179The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY COLLEGE LONDON on May 25, 2016. For personal use only. No other uses without permission.  Copyright © 2016 Massachusetts Medical Society. All rights reserved. 

Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves

COLLI, ANDREA

BURRIESCI, GAETANO

Archivio istituzionale della ricerca - Università di Padova

Original Citation:Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic ValvesPublisher:Published version:DOI:Terms of use:Open Access(Article begins on next page)This article is made available under terms and conditions applicable to Open Access Guidelines, as described athttp://www.unipd.it/download/file/fid/55401 (Italian only)Availability:This version is available at: 11577/3195619 since: 2016-11-23T18:35:56Z10.1056/NEJMc1600179#SA2Università degli Studi di PadovaPadua Research Archive - Institutional RepositoryT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 374;16 nejm.org April 21, 20161590Possible Subclinical Leaflet Thrombosis in Bioprosthetic  Aortic ValvesTo the Editor: Makkar et al. (Nov. 19 issue)1 report possible subclinical leaflet thrombosis in up to 40% of patients involved in a clinical trial of transcatheter aortic-valve replacement (TAVR). In contrast, we found a relatively low incidence (7%) of possible subclinical valve leaflet throm-bosis among patients in our series in which 255 patients underwent TAVR with the use of a CoreValve prosthesis.A retrospective review of our series (unpub-lished data) showed that in 104 patients, cardiac computed tomography (CT) at a median of 7 days after implantation (range, 3 to 87) (in 51 patients), transesophageal echocardiography at a median of 45 days (range, 7 to 421) after implantation (in 76 patients), or both (in 23 patients) was performed. In 101 patients, the findings were deemed to be interpretable. Of these patients, 52% were receiving dual antiplatelet therapy, 19% aspirin or thienopyridine monotherapy, and 29% oral anticoagulation.A definite thrombus was identified in three patients (3%; one patient each on days 31, 44, and 87 after implantation). All three patients were receiving continuous dual antiplatelet ther-apy. An additional four patients (4%) had hypo-attenuated leaflet thickening (two patients on day 7 after implantation and one patient each on days 8 and 47 after implantation). We hypothe-size that besides the antithrombotic strategy, the valve type (bovine vs. porcine) and design (intra-annular vs. supraannular) might also be related to the occurrence of thrombosis, at least in self-expandable nitinol frames.Hielko Miljoen, M.D. Paul Van Herck, M.D., Ph.D. Bernard Paelinck, M.D., Ph.D.Antwerp University Hospital Edegem, Belgium hielko . miljoen@ uza . beNo potential conflict of interest relevant to this letter was re-ported.1. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclini-cal leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015; 373: 2015-24.DOI: 10.1056/NEJMc1600179To the Editor: Makkar et al. describe the phe-nomenon of reduced leaflet motion in patients who had received bioprosthetic aortic valves. An in vitro study by Ducci et al.1 showed that TAVR produced substantial alteration of the flow pat-tern in the sinuses of Valsalva, creating regions of blood stasis that could lead to thrombus for-mation. This abnormal condition is not observed after conventional surgical aortic-valve replace-ment because the complete resection of the calci-fied leaflets allows preservation of the natural geometry and vortex dynamics of the aortic root. Moreover, with the use of TAVR implants, there is often angular or rotational misalignment with the sinuses and coronary ostia; this could further impair local blood flow.The data reported by Makkar et al. and Ducci et al. suggest that the use of bioprosthetic valves per se is not sufficient to guarantee correct leaf-let dynamics and avoid the need for anticoagula-tion. This finding may be particularly alarming in light of what has been clinically observed with surgical bioprostheses.2-4 The data reported by Ducci and colleagues need to be taken into account when considering the use of TAVR in patients who cannot be treated with anticoagu-lants and in lower-risk patients.Andrea Colli, M.D., Ph.D.University of Padua Padua, Italy colli . andrea . bcn@ gmail . comAndrea Ducci, Ph.D. Gaetano Burriesci, Ph.D.University College London London, United KingdomNo potential conflict of interest relevant to this letter was re-ported.1. Ducci A, Tzamtzis S, Mullen MJ, Burriesci G. Hemodynam-ics in the Valsalva sinuses after transcatheter aortic valve im-plantation (TAVI). J Heart Valve Dis 2013; 22: 688-96.2. Colli A, Verhoye JP, Heijmen R, Antunes M. Low-dose acetyl salicylic acid versus oral anticoagulation after bioprosthetic aor-tic valve replacement: final report of the ACTION Registry. Int J Cardiol 2013; 168: 1229-36.3. Colli A, Mestres CA, Castella M, Gherli T. Comparing warfa-rin to aspirin (WoA) after aortic valve replacement with the St. Jude Medical Epic heart valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis 2007; 16: 667-71.4. Colli A, Marchetto G, Salizzoni S, et al. The TRIBECA study: (TRI)fecta (B)ioprosthesis (E)valuation versus (C)arpentier Mag-na-Ease in (A)ortic position. Eur J Cardiothorac Surg 2016; 49: 478-85.DOI: 10.1056/NEJMc1600179The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI PADOVA on November 20, 2016. For personal use only. No other uses without permission.  Copyright © 2016 Massachusetts Medical Society. All rights reserved. Correspondencen engl j med 374;16 nejm.org April 21, 2016 1591To the Editor: Makkar et al. found that reduced aortic-valve leaflet motion commonly occurred after TAVR or surgical aortic-valve replacement, probably because of leaflet thrombosis. An analy-sis of their CT images showed that most leaflets with reduced motion were facing the noncoro-nary sinus of Valsalva. With identification of the location of the thrombosed leaflet, we can hy-pothesize that a mechanism responsible for this observation was the lack of coronary-bound blood flow in the noncoronary sinus. We have previously found that lack of coronary-bound blood flow in the noncoronary sinus was associ-ated with stasis and reduced wall shear stress in the sinus1; theoretically, this could have increased the risk of thrombosis of the noncoronary leaflet.Two additional factors that may contribute to this observation in TAVR are the misalignment of the prosthetic leaflets and the native sinuses of Valsalva and the abnormal location of the leaflets relative to the aortic annulus. Reduced flow in a coronary sinus because of a partially occluded coronary artery may also place the leaf-let at risk for thrombosis. Studies to corroborate or refute this hypothesis are lacking.Hoda Hatoum, B.S. Juan A. Crestanello, M.D. Lakshmi P. Dasi, Ph.D.Ohio State University Columbus, OH dasi . 1@ osu . eduNo potential conflict of interest relevant to this letter was re-ported.1. Moore BL, Dasi LP. Coronary flow impacts aortic leaflet me-chanics and aortic sinus hemodynamics. Ann Biomed Eng 2015; 43: 2231-41.DOI: 10.1056/NEJMc1600179To the Editor: Makkar et al. present data de-scribing subclinical leaflet thrombosis in biopros-thetic aortic valves. Although this phenomenon may be real, the potential link to neurologic events is unclear, and the trial shows neither a causal nor a temporal link between imaging findings and clinical events.Makkar and colleagues report three total strokes (two with reduced leaflet motion and one with normal leaflet motion), all of which occurred within 24 hours after the index proce-dure. Attributing these events to findings on CT that was performed at a subsequent time point (in two of the patients) is problematic. In addi-tion, “significant” differences in rates of neuro-logic events were driven by three transient is-chemic attacks (TIAs), which are difficult to adjudicate and probably multifactorial in this patient population.As physicians who care for patients who have aortic stenosis, we have concerns that overreac-tion to these findings may lead to the use of aggressive anticoagulation regimens in elderly patients who are at high risk for bleeding. Al-though these findings warrant further study, at present the link to clinical events is weak and therefore major changes to clinical practice are premature.Susheel K. Kodali, M.D.Columbia University Medical Center New York, NY skodali@ columbia . eduVinod H. Thourani, M.D.Emory University Hospital Atlanta, GAAjay J. Kirtane, M.D.Columbia University Medical Center New York, NYDr. Kodali reports receiving consulting fees and research sup-port from Edwards Lifesciences and Medtronic and being a mem-ber of the scientific advisory board of Thubrikar Aortic Valve; and Dr. Thourani, receiving research support from Edwards Life-sciences and Sorin Group, consulting fees from Direct Flow Medical, St. Jude Medical, and Sorin Group, and royalties and fees for intellectual property rights from Apica. No other poten-tial conflict of interest relevant to this letter was reported.DOI: 10.1056/NEJMc1600179The authors reply: We agree with Miljoen et al., Colli et al., and Hatoum et al. that the cause of leaflet thrombosis may be multifactorial, includ-ing but not limited to local flow dynamics in the aortic root after valve replacement, the anti-thrombotic strategy, the valve type and design, and perhaps implantation techniques. The hypoth-esis proposed by Hatoum et al. regarding stasis in the noncoronary sinus due to lack of coronary flow is certainly interesting, but it was not sub-stantiated in our trial, since we observed this finding in multiple leaflets, irrespective of the location of the leaflet in relation to the coronary artery. Trials to elucidate the relative contribu-tion of these factors to the pathogenesis of this phenomenon are lacking.Kodali et al. raise a few issues. Multiple stud-ies have confirmed the presence of subclinical leaflet thrombosis in both transcatheter and explanted surgical aortic valves.1-4 We agree that The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI PADOVA on November 20, 2016. For personal use only. No other uses without permission.  Copyright © 2016 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 374;16 nejm.org April 21, 20161592the cause of neurologic events (strokes or TIAs) in patients undergoing TAVR, especially in the im-mediate postprocedural period, is multifactorial. Hence, as we noted in our article, any associa-tion of subclinical leaflet thrombosis with neu-rologic events is “preliminary and inconclusive.” Nonetheless, the significantly increased rate of TIAs, all of which occurred late and after CT studies, requires further investigation.Routine anticoagulation in patients after TAVR cannot be recommended at present, given the high risk of bleeding in the current TAVR popu-lation and the uncertain clinical significance of this finding. However, these findings provide a sound rationale for some of the planned trials of various antithrombotic regimens after TAVR and call into question current guidelines regarding dual antiplatelet therapy. The response of the Food and Drug Administration — to incorporate CT imaging substudies in the upcoming trials of TAVR that involve low-risk patients — is appro-priate. Given the findings of our trial, identifica-tion of elevated aortic-valve gradients, heart fail-ure, or thromboembolic events in patients with bioprosthetic aortic valves should prompt physi-cians to consider CT to rule out valve thrombosis.Colli and colleagues suggest caution in the use of TAVR in low-risk patients or those who cannot receive anticoagulants without adverse effects. The pivotal trials that established the net clinical benefit of TAVR involved high-risk pa-tients who were not the most appropriate candi-dates for anticoagulation. Although our imaging findings are thought provoking, the expansion of TAVR should be guided primarily by large randomized trials or registries that are focused on clinical outcomes and that measure net clini-cal benefit. Our trial may stimulate further re-search on antithrombotic strategies after TAVR.Raj R. Makkar, M.D.Cedars–Sinai Heart Institute Los Angeles, CA makkarr@ cshs . orgGregory Fontana, M.D.Cedars–Sinai Medical Center Los Angeles, CALars Søndergaard, M.D.Rigshospitalet Copenhagen, DenmarkSince publication of their article, the authors report no fur-ther potential conflict of interest.1. Leetmaa T, Hansson NC, Leipsic J, et al. Early aortic trans-catheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv 2015; 8(4): e001596.2. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015; 8(4): e001779.3. Egbe AC, Pislaru SV, Pellikka PA, et al. Bioprosthetic valve thrombosis versus structural failure: clinical and echocardio-graphic predictors. J Am Coll Cardiol 2015; 66: 2285-94.4. Pache G, Schoechlin S, Blanke P, et al. Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2015 October 7 (Epub ahead of print).DOI: 10.1056/NEJMc1600179Ibrutinib for Chronic Lymphocytic LeukemiaTo the Editor: It is not surprising that Burger et al. (Dec. 17 issue)1 report positive results in the Study of Ibrutinib as Initial Therapy for Pa-tients with Chronic Lymphocytic Leukemia (RESONATE-2), a randomized trial of ibrutinib versus chlorambucil in older patients with chron-ic lymphocytic leukemia (CLL). Chlorambucil has served as a comparator in trials of bendamus-tine, alemtuzumab, ofatumumab, and obinutu-zumab, and longer durations of progression-free survival have been reported with each agent.2-5 In addition, these trials have shown longer dura-tions of overall survival with the use of ibrutinib and obinutuzumab.1,2We reviewed our experience in the Connect CLL Disease Registry (ClinicalTrials.gov number, NCT01081015). This prospective observational study, which was conducted from March 2010 through January 2014, involved 1494 patients with CLL in the United States. We observed that only 40 of 889 patients with CLL (4.5%) received chlorambucil monotherapy as first-line therapy, and event-free survival with this agent was infe-rior to that with all other commonly used first-line regimens, even after adjustment for the pa-tient’s age, performance status, and Charlson comorbidity index score (hazard ratio for disease progression, relapse, or death, 2.7; 95% confi-dence interval, 1.3 to 3.7; P = 0.008). Because of the superiority of alternative first-line regimens and the infrequent use of chlorambucil mono-therapy, we do not think that chlorambucil monotherapy should serve as a comparator regi-men in future studies of CLL.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI PADOVA on November 20, 2016. For personal use only. No other uses without permission.  Copyright © 2016 Massachusetts Medical Society. All rights reserved. 

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Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves

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