An Update On Subclinical Valve Leaflet Thrombosis

Atish Mathur MD MPHStructural Heart Disease

Interventional CardiologyThe Valley Hospital

Disclosures

I, Atish Mathur, DO NOT have a financial interest, arrangement or affiliation with any organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

4 months post-TAVRGradient 23mmHg

Day 1 TTEGradient 10mmHg

67 y/o male physician s/p TAVR with 29mm Sapien3 valve

Worsening shortness of breath 4 months post-TAVRTransvalvular gradients elevated from 10 mmHg to 23 mmHg

Post-anticoagulationGradient 11mmHg

Normalized transvavular gradients with anticoagulation (warfarin, INR 2-3)

Repeat TTE performed after 3 months

Pre-anticoagulationGradient 23mmHg

Resolution of symptoms with anticoagulation

Case 2

85 y/o male s/p TAVR with 23mm Sapien 3 valve

Trivial PVL

Mean gradient 12mmHg

Cardiac CT done 1 month post-TAVRMildly reduced leaflet motion, minimal thrombus with mildly

increased leaflet thickness

Mildly reduced leaflet motion

Mild hypoattenuating opacity Mean gradient 14mmHg

Patient transferred 9 months later for altered mental status

Multiple embolic acute and subacute strokes noted on MRI brainAortic valve gradients elevated on echo

30-day echoMean gradient 14mmHg

Echo nowMean gradient 23mmHg

Patient transferred 9 months later for altered mental status

Extensive thrombus on the aortic valve, with severely reduced leaflet motion

Patient started on anticoagulation with rivaroxaban 10mg daily; repeat imaging pending

Case 3

71 y/o female s/p TAVR with 29mm Sapien 3 valve

Mean gradient 9mmHg

Trivial PVL

Patient admitted 2 weeks later at an outside hospital with stroke

No significant change in gradients3 week echo

Mean gradient 8mmHgDay 1 echo

Mean gradient 9mmHg

CT aortic valve revealed significant thrombus and reduced leaflet motion

Patient admitted a day later to an outside hospital with stroke

Severely reduced leaflet motion Hypoattenuating opacity

Valve Thrombus can occur despite normal gradients and anticoagulation

Case 4

65 y/o male s/p 23mm Sapien 3 valve

Trivial PVL

Mean gradient 13mmHg

Patient complaining of worsening shortness of breath on post-TAVR Day 2

Repeat TTE revealed rise in gradients from 12mmHg to 37mmHgDay 2 echo

Mean gradient 37mmHgDay 1 echo

Mean gradient 13mmHg

CT performed to rule out valve thrombusExtensive thrombus on the aortic valve, with severely

reduced leaflet motionPatient started on anticoagulation with rivaroxaban 10mg daily;

repeat TTE 1 month later revealed decrease in gradients, repeat CT to be done in 3 monthsSeverely reduced leaflet

motion

Hypoattenuating opacities on 2 leaflets

Mean AV gradients decreased from 37mmHg to 23mmHg

Case 5

83 y/o female s/p TAVR with 26mm Evolut valve

Patient enrolled in RESOLVE registryCardiac CT performed at 1 month post-TAVR

Severely reduced leaflet motion Hypoattenuating lesions

Patient already on warfarin, INR 2.5

1 month TTEGradient 5mmHg

Normal valve gradients despite reduced leaflet motion

Day 1 TTEMean gradient 7mmHg

Resolution of thrombus and restoration of normal leaflet motion in 3 months

Case 6

Marti D. et al. JACC: Cardiovascular Interventions 2015

Valve thrombosis 4 years after TAVRNormal gradients; patient started on anticoagulation, repeat CT pending

Chakravarty T. et al. Lancet 2017

Reduced leaflet motion in multiple valve types931 patients post TAVR CT

Sapien Evolut R Lotus Portico Centera Symetis Perimount Magna

Prevalence of reduced leaflet motionTranscatheter vs. surgical bioprosthetic aortic valves: p=0.001

Reduced leaflet motion was present in 106 (11.9%) patients

Transcatheter valves13.4% (101 out of 752)

Surgical valves3.6% (5 out of 138)

Anticoagulation and reduced leaflet motionAnticoagulation vs. no anticoagulation

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Anticoagulation NOACs Warfarin No anticoagulation

8/224 (3.6%) 3/107

(2.8%)

5/117(4.3%)

98/666(14.7%)Anticoagulation vs. no anticoagulation: p<0.0001

NOACs vs. no anticoagulation: p=0.0002Warfarin vs. no anticoagulation: p=0.001NOACs vs. warfarin: p=0.72

Anticoagulation and reduced leaflet motionAnticoagulation vs. antiplatelet therapy

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Anticoagulation NOACs Warfarin DAPT

8/224 (3.6%) 3/107

(2.8%)

5/117(4.3%)

31/208(14.9%)Anticoagulation vs. DAPT: p<0.0001

Anticoagulation vs. monoantiplatelet therapy: p<0.0001

63/405(15.6%)

Monoantiplatelet therapy

Increased gradients in patients with reduced leaflet motion

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Normal leafletmotion

40/714(6%)

Reduced leaflet motion

15/96(16%)

9/632(1%)

13/88(15%)

Mean aortic gradient > 20mmHg

Increase in gradients > 10mmHg

Normal leafletmotion

Reduced leaflet motion

Normal leafletmotion

Reduced leaflet motion

Mean aortic gradient > 20mmHg AND Increase in

gradients > 10mmHg

7/632(1%)

12/88 (14%)

P=0.0002 P<0.0001 P<0.0001

Impact of reduced leaflet motion on clinical outcomes

All clinical events post-TAVR/SAVR included

Normal leaflet motion (N=784) Reduced leaflet motion (N=106)

n/N (%)Rate per 100 person-years

n/N (%)Rate per 100 person-years

Hazard ratio (95% CI)

p-value

All events

Death 34/784 (4·3%) 2·91 4/106 (3·8%) 2·66 0·96 (0·34-2·72) 0·94

Myocardial infarction 4/784 (0·5%) 0·34 1/106 (0·9%) 0·67 1·91 (0·21-17·08) 0·56

Strokes/TIAs 27/784 (3·4%) 2·36 11/106 (10·4%) 7·85 3·27 (1·62-6·59) 0·001

All strokes* 22/784 (2·8%) 1·92 6/106 (5·7%) 4·12 2·13 (0·86-5·25) 0·10

Ischemic strokes 21/784 (2·7%) 1·83 6/106 (5·7%) 4·12 2·23 (0·90-5·53) 0·08

TIAs 7/784 (0·9%) 0·60 6/106 (5·7%) 4·18 7·02 (2·35-20·91) 0·0005

TIA=Transient ischemic attack* All strokes include hemorrhagic and ischemic strokes

No significant difference in strokes; but increased risk of TIAs and strokes/TIAs

• 405 patients with Sapien-XT or Sapien 3 valve undergoing MDCT

• Echocardiograms performed 1-3 months and 12 months post-TAVR

• THV thrombosis noted in 28/405 (7%) of patients

Risk of THV thrombosis was lower in patients on warfarin, compared to those not on warfarin

1.8% vs. 10.7%RR 6.09, 95% CI 1.86-19.84

Impact of subclinical leaflet thrombosis on valve hemodynamics and clinical outcomes

Author N Incidence Valve hemodynamics Clinical outcomes

Pache et al. EHJ 2015

156 10.3% Small, but significant increase in gradients (11.6±3.4 vs. 14.9±5.3 mmHg, P=0.026)

No strokes/TIAs

Hansson et al. ClinCardiology 2016

405 7% Small, but significant increase in gradients (8±3 vs 10±7, p=0.003)

Increased, but not statistically significant, stroke rates (3% vs 12%, p=0.15)

Makkar et al. NEJM 2015

187 13% in registries, 40% in Portico IDE

NA Stroke/TIAs:Portico IDE (0% vs 9%, p=0.14)Registries (0.8% vs 17.6%, p=0.007)

Chakravarty et a. Lancet 2017

931 12% Small, but significant increase in gradients (10.4±6.3 vs 13.8±10, p=0.0004)

Increased rates of TIAs (0.6 vs 4.18 TIAs per 100 person-years, p=0.0005)

• 4D-CT in 75 transcatheter and 30 surgical valves in SAVORY• 84 patients undergoing 2 consecutive 4D-CTs, without change in

pharmacotherapy between the 2 scans, included in the analysis• HALT in 32 patients (38%) and HAM in 17 patients (20%)

HALT and HAM were dynamic,

showing progression in 13

(15.5%) and regression in 9

(10.7%) of patients

• 4D-CT in 75 transcatheter and 30 surgical valves in SAVORY• 84 patients undergoing 2 consecutive 4D-CTs, without change in

pharmacotherapy between the 2 scans, included in the analysis• HALT in 32 patients (38%) and HAM in 17 patients (20%)

The only multivariate predictor of progression was lack of anticoagulation between the 2 scans

• 47 patients undergoing CT after SAVR with sutureless Perceval valve• Timing of CT after SAVR: Median 491 days (range 36-1247 days)

HALT found in 18 (38%) of patientsReduced leaflet motion found in 13 (28%) patients

Dalen M. et al. JAHA 2017

51 patients with leaflet thickening (29 patients treated with anticoagulation and 22 patients treated with DAPT)

Repeat CT obtained in 22 patients on AC and 16 patients on DAPT

Leaflet thickening progressed in 11 of 16

patients

Leaflet thickening regressed in all 22

patients undergoing repeat CT

Ruile P. et al. Clin Res Cardiol 2017

Single center registry of 642 patients undergoing TAVR

Incidence of valve thrombosis

Predictors of valve thrombosis

• 305 CoreValve, 281 Sapien and 56 Lotus

• Oral anticoagulation in 261 patients, DAPT in 377 patients

• 0% valve thrombosis in patients on anticoagulation, 4.5% NO anticoagulation

Jose et al. JACC: Cardiovascular Interventions 2017

Mayo Clinic experience

BPVT referred for surgical intervention

occurssignificantly earlier

than BPV degeneration

Egbe A. et al. JACC 2015

46 cases (12%) of bioprosthetic valve thrombosis out of 397 consecutive explanted bioprosthetic valves

• Valve thrombosis (n=46)• Matched cases of valve degeneration (n=92)

• 75 patients undergoing TAVR with self-expanding THV• 4D-CT performed post-TAVR

No difference in THV size, overall THV expansion, eccentricity or implantation depth between patients

with/without HALT

• 75 patients undergoing TAVR with self-expanding THV

• 4D-CT performed post-TAVR

Regional THV underexpansion at the

inflow level associated with HALT

Meta-analysis of 6 studies including 198 cases of leaflet thrombosis in 1704 patients (11.6% prevalence)

Increased rates of cerebrovascular events with leaflet thrombosisOdds ratio 3.38 (95% CI 1.78-6.41)

Rashid HN. et al. EuroIntervention 2018

Meta-analysis of 6 studies including 198 cases of leaflet thrombosis in 1704 patients (11.6% prevalence)

No impact of leaflet thrombosis on mortality

Rashid HN. et al. EuroIntervention 2018

Why is CT important?

• Echo gradients can be “normal”

• Not all patients with high gradients have thrombus. CT helps identify that subset and tailor treatment

• Morphologic details are spectacular and may provide mechanistic insights

Clinical implications

• These data support the ongoing clinical trials of routine anticoagulation and CT imaging substudies as TAVR moves into lower risk patients

• In the appropriate clinical setting such as TIAs, stroke, new onset heart failure; or even small increase in gradients post-procedure should lead to vigilance and CT imaging.

• The reduced leaflet motion observed on CT secondary to leaflet thrombosis and increase in gradients may provide insights into one of the preventable mechanisms of structural valve deterioration

The choice of therapy (SAVR or TAVR) and device is best guided by clinical outcomes data in clinical trials rather than a single imaging finding such as

subclinical leaflet thrombosis

Deeb M. et al. JACC 2016Mack M. et al. Lancet 2015

Despite excellent clinical outcomes of newer generation valves, these findings can help further optimize adjunctive pharmacotherapy which may result in further improvements.

Leon M. et al. NEJM 2017Reardon M. et al. NEJM 2017

Not looking for subclinical leaflet thrombosis with CT imaging will not solve the problem of subclinical leaflet

thrombosis

To solve these issues we must look at them in 4D!

CT scanning does not cause bleeding..

Primary end-point is death, MI, stroke, non-CNS systemic emboli, symptomatic valve thrombosis, deep vein thrombosis or pulmonary embolism,major bleedings

over 720 days of treatment exposure.

1520 patients after successful TAVI procedure

Rivaroxaban 10 mg ODand Aspirin 75-100mg OD

Clopidogrel 75 mg ODAspirin 75-100 mg OD

GALILEO (Global multicenter, open-label, randomized, event-driven, active-controlled study comparing a

rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement (TAVR) to Optimize clinical outcomes will compare rivaroxaban-based)

R 1:1

Aspirin 75-100 mg ODRivaroxaban 10 mg OD

Drop of aspirin Drop of clopi

Primary end-point is a composite of death, MI, stroke, systemic emboli, intracardiac or bioprosthesis thrombus, episode of deep vein thrombosis or

pulmonary embolism,major bleedings over one year follow-up.

1509 patients after successful TAVI procedure

VKA Apixaban 5mg bid* DAPT/SAPT

R 1:1

*2.5mg bid if creatinine clearance 15-29mL/min or if two of the following criteria: age≥80 years, weight≤60kg or creatinine≥1,5mg/dL (133µMol).

Stratum 1Indication for OAT

Stratum 2No indication for OAT

R 1:1

ATLANTIS (Anti-Thrombotic Strategy to Lower All cardiovascular and Neurologic Ischemic and Hemorrhagic Events after Trans-Aortic Valve Implantation for Aortic Stenosis)

2017 ACC/AHA guidelines for TAVR

Bonow R. et al. Circulation 2017

Conclusions• In a heterogeneous cohort of aortic bioprosthetic valves, the reduced leaflet

motion occurred 12 % of the time on 4D CT.

• Patients undergoing SAVR, compared with TAVR, had lower incidence of reduced leaflet motion (3.6% vs. 12%; p<0.04). However, patients undergoing SAVR were different than TAVR reflecting contemporary practice with lower age and fewer comorbidities.

• Anticoagulation with both warfarin and NOACs and not DAPT which is the standard of care were effective in prevention and treatment of reduced leaflet motion.

• Majority of cases of subclinical leaflet thrombosis diagnosed by 4D CT are hemodynamically silent and hence missed by TTE

• While the death, MI and stroke rates were not significantly different between the 2 groups, subclinical leaflet thrombosis was associated with increased rates of TIAs and strokes/TIAs.

Thank You !

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