Segelauflagerungen nach TAVI oder SAVR ( HALT, HAM ): - klinische und therapeutische Relevanz? Franz-Josef Neumann

Conflict of Interest Personal: None Institutional: Speaker honoraria, consultancy fees and research grants from Daiichi Sankyo, Astra Zeneca, Sanofi-Aventis, Bayer, Medicines, Bristol, Novartis, Roche, Boston Scientific, Biotronik, Medtronic, Edwards, Ferrer

Leaflet thrombosis after TAVI/SAVR Prevalence of hypo-attenuated leaflet thickening (HALT) depending on concomitant antithrombotic treatment Risk of valve haemodynamic deterioration Risk of heart failure Risk of stroke and other embolic events Therapeutic consequences

Multi-detector CT (MDCT): Hypo-attenuated leaflet thickening (HALT) Baseline After anticoagulation Jander et al., Eur Heart J 2012

4D-MDCT: Hypo-attenuation affecting motion (HAM)

Variable incidence of leaflet thrombosis Timing of 1 st MDCT Incidence Makkar et al., N Engl J Med 2015 (Portico) median 30 days 37% (n=22) Makkar et al., N Engl J Med 2015 (Registries) median 87 days 17% (n=17) Pache et al., Eur Heart J 2015 median 5 days 10% (n=16) Hansson et al., J Am Coll Cardiol 2016 1-3 months 7% (n=28) Ruile et al., Clin Res Cardiol 2016 median 5 days 10% (n=51) Yanagisawa et al., J Am Coll Cardiol Img 2017 1 year 14% (n=10) Vollema et al., Eur Heart J 2017 median 35 days 13% (n=16) Chakravarti et al., Lancet 2017 median 83 days 13% (n=101) Sondergaard et al., Eur Heart J 2017 mean 140 days 25% (n=25) Ruile et al., JACC Cardiovasc Interv 2018 median 5 days 19% (n=120)

Occurence on any valve SAPIEN XT SAPIEN 3 LOTUS CORE VALVE PERCEVEAL

Increased risk of leaflet thrombosis with transcatheter versus surgical valves? Incidence at 1 st MDCT 30% P < 0.001 25% n.s. 26% SAVR TAVI 20% 22% 15% 10% 5% 0% 13% 4% Reduced leaflet motion Chakravarti et al., Lancet 2017 Hypo-attenuated leaflet thickening Sondergaard L et al., Eur Heart J 2017

Reduced risk of HALT with anticoagulation Incidence 15% 10% 5% P < 0.001 10.7% Warfarin No warfarin Adjusted RR 0.18 (95%-CI 0.06 to 0.29) 0% 1.8% Transcatheter Aortic Valve Thrombosis Hansson NC et al., J Am Coll Cardiol 2016

Reduced risk of HALT with anticoagulation Incidence of reduced leaflet motion 20% P < 0.001 n.s. 15% 15.4 % 16.7 % 14.9 % 10% 5% 0% 4.3 % n.s. 2.8 % Chakravarti et al., Lancet 2017

Platelet reactivity AU *min No impact of clopidogrel response ADP-induced platelet reactivity by MEIA p = 0.843 1500 1000 500 0 no (n = 164) Stratz C et al., JACC Cardiovasc Interv, in press HALT yes (n = 36) HTPR (> 468 AU*min) Median (180 AU*min)

Bench studies: Impact of reduced leaflet motion on pressure gradients Mean pressure gradient [mmhg] 45 40 35 30 25 20 15 10 5 0 0 1 2 Leaflets forced closed Valve size 23 mm 25 mm 27 mm 29 mm Makkar RR et al., N Engl J Med 2015

Minor impact of HALT on transvalvular gradients at 1 st MDCT Mean gradient (mmhg) 25 P = 0.10 P = 0.026 P = 0.10 P = 0.056 P < 0.001 20 15 10 5 9.0 10.5 11.6 14.9 8 10 10.4 13.8 0 Makkar (Portico) Pache Hansson No HALT HALT Vollema Chakravarti

Potential increase in gradients with HALT Mean gradient (mmhg) 25 P = 0.056 P = 0.026 20 15 10 12.4 9.4 5 No HALT HALT 0 Vollema EM et al., Eur Heart J 2017 MDCT 6 months

Risk of valve stenosis (> 20 mmhg) with HALT Proportion of patients (%) 20 P = 0.006 P < 0.001 18 15 14 10 No HALT HALT 5 0 0 Hansson 1 Chakravarti Hansson et al., J Am Coll Cardiol 2016; Chakravarti et al., Lancet 2017

Increase in gradients with HALT Valve haemodynamic deterioration 2 patients No patient Serial echocradiography, mean follow-up: 16 months Hein M et al., submitted Antiplatelet therapy n = 44 Anticoaguation n = 18

TAVI valve dysfunction in unselected cohorts Latib A et al., Circ Cardiovasc Interv. 2015 0.61 % valve thrombosis within 2 years; N = 4,266 Responsive to anticoagulation Del Trigo M et al., J Am Coll Cardiol 2016 4.5 % valve haemodynamic deterioration within 4 years; N = 1,521 Absence of anticoagulation as independent predictor, P = 0.026 Jose J et al., J Am Coll Cardiol Intv 2017 2.8 % valve thrombosis within 1.9 years on average; N = 642 Odds ratio for anticoagulation 0.01 (95%-CI 0.00 to 0.32), P = 0.008

Potential increase in gradients with HALT Change in mean pressure gradient P = 0.01 Change in leaflet restriction score

Thrombus extend score Risk of recurrence of early HALT after discontinuation of anticoagulation Anticoagulation DAPT day 5 3 months 6 months Ruile et al., Clin Res Cardiol 2016

Transcatheter heart valve thrombosis reversible after switch to anticoagulation in most patients Latib A et al., Circ Cardiovasc Interv. 2015

Symptoms of heart failure with valve thrombosis Proportion of patients with valve thrombosis and symptoms of heart failure (%) 75 65 % 50 39 % 25 Detection of valve thrombosis by clinical follow-up by systematic 4D-MSCT 0 Latib et al. Circ Cardiovasc Interv. 2015 Jose et al. JACC Cardiovasc Intv 2017 2.5 % Ruile et al. JACC Cardiovasc Intv 2018

Leaflet thrombosis after TAVI Prevalence of hypo-attenuated leaflet thickening (HALT) depending on concomitant antithrombotic treatment Risk of valve haemodynamic deterioration Risk of heart failure Risk of stroke and other embolic events Therapeutic consequences

Risk of major events with leaflet thrombosis Proportion of patients (%) 15 10 P = 0.94 P = 0.56 P = 0.001 P = 0.10 P < 0.001 10 5 4 4 0 Death Chakravarti et al., Lancet 2017 1 1 Myocardial infarction 3 Stroke/TIA 6 3 Stroke No HALT 1 TIA HALT 6

Increased risk of stroke/tia with leaflet thrombosis? Proportion of patients (%) 15 P = 0.16 P = 0.15 n.s. n.s. P = 0.001 10 9 12 10 5 0 1 Makkar (Portico) 3 Hansson 3 0 0 0 Vollema Yanagisawa 3 Chakravarti No HALT HALT

No detectable impact of HALT on death or stroke Ruile P et al., JACC Cardiovasc Interv 2018

Study-level meta-analysis: No significant increase in risk of stroke with leaflet thrombosis Study RR (95%-CI) Makkar et al. (2015) Hansson et al. (2016) Chakravarty et al. (2017) Ruile et al. (2018) Yanagisawa et al. (2017) Overall (I 2 = 16.6%, p = 0.31) 1.59 (0.88 4.53) Rashid HN et al., Eurointervention 2018; Ruile P et al., JACC Cardiovasc Interv 2018

Study-level meta-analysis: Increase in risk of stroke/tia with leaflet thrombosis Study RR (95%-CI) Makkar et al. (2015) Hansson et al. (2016) Chakravarty et al. (2017) Yanagisawa et al. (2017) Ruile et al. (2018) Overall (I 2 = 17.7%, p = 0.30) 2.41 (1.13 5.14) Rashid HN et al., Eurointervention 2010; Ruile P et al., JACC Cardiovasc Interv 2018

Proportion of patients (%) Risk of anticoagulation + aspirin after TAVI - Preliminary results of GALILEO - 15 10 5 8.8 11.4 0 Death or thrombo-embolic event 3.3 Death 6.8 2.4 4.2 Bleeding event Clopidogrel 75 mg Rivaroxaban 10 mg + Aspirin for 90 days

Segelthrombose nach TAVI/SAVR Eine Segelthrombose kann bei jeder biologischen Aortenklappenprothese auftreten. Nach TAVI liegt die Häufigkeit bei 10 bis 20 %. Fehlende Antikoagulation ist der stärkste prädisponierende Faktor. Die asymptomatische Segelthrombose ist mit einem Risiko für nachfolgende Verschlechterung der Klappenfunktion verbunden. Diese ist unter Antikoagulation reversibel. Herzinsuffizienz wegen Segelthrombose mit kompromitierter Klappenfunktion ist selten. Die Assoziation der Segelthrombose mit thromb-embolischen Ereignissen ist unklar. Die therapeutischen Konsequenzen der Segelthrombose sind unklar.