© Schattauer 2015 Thrombosis and Haemostasis 113.4/2015

1

Antithrombotic treatment in patients undergoing transcatheter aortic valve implantation (TAVI)Vincent J. Nijenhuis1; Naoual Bennaghmouch1; Jan-Peter van Kuijk1; Davide Capodanno2; Jurriën M. ten Berg1

1Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; 2Department of Cardiology, University of Catania, Catania, Italy

SummaryTranscatheter aortic valve implantation (TAVI) is an established treat-ment option for symptomatic patients with severe aortic valvular dis-ease who are not suitable for conventional surgical aortic valve re-placement. Despite improving experience and techniques, ischaemic and bleeding complications after TAVI remain prevalent and impair survival in this generally old and comorbid-rich population. Due to changing aetiology of complications over time, antiplatelet and anti-coagulant therapy after TAVI should be carefully balanced. Empirically, a dual antiplatelet strategy is generally used after TAVI for patients without an indication for oral anticoagulation (OAC; e. g. atrial fibril-lation, mechanical mitral valve prosthesis), including aspirin and a

thienopyridine. For patients on OAC, a combination of OAC and aspirin or thienopyridine is generally used. This review shows that current registries are unfit to directly compare antithrombotic regimens. Small exploring studies suggest that additional clopidogrel after TAVI only affects bleeding and not ischemic complications. However, these studies are lack in quality in terms of Cochrane criteria. Currently, three randomised controlled trials are recruiting to gather more know-ledge about the effects of clopidogrel after TAVI.

KeywordsTranscatheter aortic valve implantation (TAVI), antithrombotic, anti-platelet, anticoagulation, bleeding, stroke, clopidogrel

Correspondence to:Jurriën ten Berg, MD, PhD, FESC, FACCDepartment of CardiologySt. Antonius HospitalKoekoekslaan 13435 CM Nieuwegein, The NetherlandsTel.: +31 30 6099111, Fax: +31 30 6092274E-mail: j.ten.berg@antoniusziekenhuis.nl

Received: October 2, 2014Accepted after minor revision: November 27, 2014Prepublished online: February 5, 2015

http://dx.doi.org/10.1160/TH14-10-0821Thromb Haemost 2015;113: ■■■

Introduction

Transcatheter aortic valve implantation (TAVI) has been shown to be superior to medical therapy in inoperable patients regarding the rate of all-cause mortality for up to five years (1, 2). In high-risk operable patients, TAVI has been previously shown to be non-in-ferior to surgical aortic valve replacement (SAVR) regarding all-cause mortality at one year when using the Edwards Sapien valve (Edwards Lifesciences, Irvine, CA, USA) (ESV) (3). More recently, TAVI proved to be superior to SAVR regarding all-cause mortality at one year when using the Medtronic CoreValve (Medtronic, Minneapolis, MN, USA) (CRS) (4). Despite more optimal results, the risks of vascular, bleeding and thromboembolic complications remain high in this generally frail and comorbid-rich population (5).

After TAVI, a dual antiplatelet strategy (DAPT) is generally used for patients without an indication for oral anticoagulation (OAC; e. g. atrial fibrillation (AF), mechanical mitral valve pros-thesis) including aspirin (low-dose, lifelong) and clopidogrel, 75 mg qD for 1-6 months (6–9). For patients with an indication for OAC, the best treatment regimen after TAVI is unknown but a combination of OAC and aspirin or thienopyridine is generally used (9). However, this recommendation (level of evidence class

C) is purely empirical, and the optimal antiplatelet and -coagu-lation strategy remains to be elucidated (10).

The purpose of this qualitative review is to present the available literature on antithrombotic treatment after TAVI and describe the epidemiology, aetiology and clinical consequences of ischaemic and bleeding complications associated with TAVI. By highlighting the gaps in knowledge, we aim to provide a basis for further re-search.

Methods

A standardised protocol was used for study identification, inclu-sion and data abstraction. Relevant English, French, German and Dutch language studies published from the 18th of February 2004 up to the 9th of September 2014 were identified through PubMed, EMBASE, and Cochrane database searches. The following search terms and strategy were used: (TAVI OR TAVR) OR ((transca-theter OR percutaneous OR transcutaneous OR transarterial OR transvascular OR transfemoral OR transapical OR transaxillary OR transaortic OR transsubclavian OR transcarotid) AND aortic AND (replacement OR implantation)) AND (antithrombotic OR anticoagulation OR antiplatelet OR clopidogrel OR aspirin OR

Review Article

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thienopyridine OR acetylsalicylic acid OR coumadin OR warfa-rin). Inclusion criteria were 1) TAVI procedure related research, AND one of the following: 2) focus on bleeding and/or thrombotic events, or 3) detailed description of antiplatelet/-coagulation regimen. VARC-reporting studies were privileged for more con-sistency in data interpretation. Two investigators (V. J.N, N. B.) in-dependently reviewed the articles using a hierarchical approach, progressing from title to abstract and then to the full article to de-termine whether they met the inclusion criteria. The bibli-ographies of the identified journal articles were further reviewed to identify additional relevant studies. Only registries and rando-mised controlled trials (RCT) describing the antithrombotic regimen after TAVI and outcomes at 30 days were selected with a sample size of at least 100. A schematic overview is provided in ▶ Figure 1.

Extracted data included study design, sample size, baseline characteristics, approach, prosthesis type, and outcome data. Out-

comes examined were mortality, myocardial infarction (MI), stroke, vascular complications and bleeding. The outcomes were defined according to the (updated) Valve Academic Research Consortium (VARC) (11, 12). Due to the small number of studies and differences in study design, we elected not to perform a quantitative review. Instead we presented the outcomes in sum-mary tables (see Suppl. Material available online at www.thrombosis-online.com) for i) all RCTs, ii) all registries mentioning the antithrombotic regimen and follow-up duration, and iii) all studies of antithrombotic regimen in TAVI patients.

ResultsRCTs

Four published RCTs mentioning the antithrombotic regimen after TAVI have been identified (▶ Table 1). The Placement of

Nijenhuis et al. Antithrombotic treatment after TAVI

Figure 1: Systematic search results. Using a blinded, independent re-view assessment, 25 clini-cal trials and/or registries were selected. Of these, fourwere general rando-mised trials, 17 were reg-istries mentioning the antiplatelet regimen after TAVI, two were randomis-ed trials to the antipla-telet regimen after TAVI, and two were retrospec-tive studies to the anti-platelet regimen after TAVI.

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3Nijenhuis et al. Antithrombotic treatment after TAVI

Year

Sample size (N)

Demographics

Age (years)

Female (%)

EuroSCORE (%)

STS Score (%)

AF (%)

Stroke (%)

PAD (%)

Procedure

TF / TA / other (%)

CRS / ESV (%)

Regimen pre/per

Aspirin (mg)

Clopidogrel (loading) (mg)

INR

Maximal ACT (s)

Regimen post

Aspirin (mg / months)*

Clopidogrel (mg / months)

OAC

Outcomes

30-day all-cause mortality (%)

30-day cardiovascular mortality (%)

1-year all-cause mortality (%)

1-year cardiovascular mortality (%)

Myocardial infarction at 30 days (%)

Myocardial infarction at 1 year (%)

Stroke at 30 days (%)

Stroke at 1 year (%)

Major VASC at 30 days (%)

Minor bleeding at 30 days (%)

Major bleeding at 30 days (%)

Major bleeding at 1 year (%)

LTB at 30 days (%)

LTB at 1 year (%)

*All recommend aspirin to be given indefinitely except for CUSPT, which recommended a duration of at least three months (4). ACT activated clotting time; AF atrial fibrillation; CRS Medtronic CoreValve revalving system; ESV Edwards Sapien valve; LTB life threatening bleeding; INR international normalized ratio; NR not reported; PAD peripheral artery disease; TA transapical; TF transfemoral; VASC vascular access site related complication; ~ indefinitely.

PARTNER A (3)

2011

348

84

42

29

11

41

29

43

70 / 30 / 0

0 / 100

75–100

300

NR

≥ 250

75–100 / ~

75 / 6

NR

3.4

3.2

24.2

14.3

0.0

0.4

4.7

6.0

11.0

NR

9.3

14.7

NR

NR

PARTNER B (1)

2010

179

83

54

26

12

33

27

30

100 / 0 / 0

0 / 100

75–100

300

NR

≥ 250

75–100 / ~

75 / 6

NR

5.0

4.5

30.7

19.6

0.0

0.6

6.7

10.0

16.2

NR

16.8

22.3

NR

NR

CUSPT (4)

2014

394

83

47

18

7

41

13

41

82 / 0 / 18

100 / 100

81–325

300

< 1.8

≥ 250

81–325 /3

75 / 3

NR

3.3

3.1

14.2

10.4

0.8

1.9

4.9

8.8

5.9

NR

28.1

29.5

13.6

16.6

CHOICE (13)

2014

238

81

64

22

6

28

20

17

100 / 0 / 0

50 / 50

100

NR

NR

NR

100 / ~

75 / 3

+ clopidogrel for 3 months

7.9

7.2

NR

NR

0.7

NR

7.2

NR

18.1

14.5

30

NR

17.4

NR

Table 1: Current RCTs mentioning the anti-platelet regimen.

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Aortic Transcatheter Valves (PARTNER) trial A and B compared TAVI to SAVR and optimal medical therapy, respectively (1, 3). These trials used a strategy of low-dose aspirin indefinitely (75–100 mg) and clopidogrel for six months. The Medtronic Cor-eValve U. S. Pivotal Trial (CUSPT) compared TAVI to SAVR, and recommended low to normal dose aspirin indefinitely (81–325 mg) and clopidogrel for three months (4). The Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aor-tic Stenosis: Medtronic CoreValve vs Edwards SAPIEN XT (CHOICE) trial compared a balloon- and self-expandable TAVI, and recommended low-dose aspirin indefinitely (100 mg) and clopidogrel for three months (13). In patients with an indication for OAC, clopidogrel was recommended for three months without aspirin.

Between these trials, baseline characteristics are comparable al-though the mean logistic EuroSCORE, STS score and history of stroke seem higher for the PARTNER trials compared to the later CUSPT and CHOICE trials. Mortality rates range from 3.3 % to 7.9 % at 30 days and 14.2 % to 30.7 % at one year. Thrombo-em-bolic endpoints (i. e. stroke and MI) seem comparable, and vascu-lar complications are lower in the CUSPT compared to the PARTNER trials. However, the rate of major bleeding at 30 days seems higher for the CUSPT and CHOICE trial compared to the PARTNER trials (28.1 % to 30.0 % vs 9.3 % to 16.8 %).

Registries

Seventeen published registries mentioning the antithrombotic regimen after TAVI have been identified which presented results at 30-day follow-up (see Suppl. Material, available online at www.thrombosis-online.com). Of these, six were VARC-reporting studies (▶ Table 2). Between these registries, there is a wide vari-ance in baseline characteristics. The mean logistic EuroSCORE ranges from 14 % to 30 %. A history of stroke ranges from 7 % to 91 %. In the majority of cases, a transfemoral approach is reported. Regarding the antithrombotic regimen, a loading dose of aspirin is not specified in most studies. The loading dose of clopidogrel is either 300 mg or 600 mg. The maximal activated clotting time (ACT) is > 200 s or 250 s to 300 s. Low-dose aspirin is recom-mended indefinitely in most registries, and clopidogrel duration ranges from one month to 3–6 months to 6–12 months. A prosthe-sis-dependent antithrombotic regimen was described in one regis-try, which used clopidogrel for three months after ESV and six months after CRS implantation (14).

In VARC-reporting studies, mortality rates range from 2.4 % to 9.7 % at 30 days. The rates of thromboembolic endpoints seem comparable (MI 0.0 % to 2.0 %, stroke 2.0 % to 6.1 %). The rate of vascular access site related complications (VASC) and bleeding varies widely. Any VASC occurs in 9.7 % to 22.2 %, major bleeding ranges from 1.6 % to 20.9 % and life-threatening bleeding from 1.2 % to 13.9 % at 30 days.

Studies of antithrombotic regimen

Four studies comparing aspirin monotherapy vs DAPT after TAVI have been identified (▶ Table 3). All studies appear to be of li-mited quality in their Methods in terms of Cochrane criteria. Two studies are randomized open-label trials. In the trial by Ussia et al., aspirin was recommended indefinitely (100 mg) in all patients and clopidogrel for three months (75 mg qD) in the clopidogrel-arm (15). No information is available on how patients with an indi-cation for OAC were managed. In the Single Antiplatelet Therapy for TAVI (SAT-TAVI) trial, aspirin was recommended indefinitely (75–160 mg) in all patients and clopidogrel for six months (75 mg qD) in the clopidogrel-arm (16). In de SAT-TAVI, patients on OAC were excluded. Bleeding at 30 days was not different for as-pirin vs DAPT in the trial by Ussia et al. (18 % vs 18 %) and the SAT-TAVI trial (10 % vs 15 %) (15, 16). In the trial by Ussia et al. and the SAT-TAVI, aspirin monotherapy vs DAPT resulted in no differences in 30-day mortality, MI and stroke (15, 16). In the SAT-TAVI trial, the rate of vascular access site related complications (VASC) was lower for aspirin monotherapy vs DAPT (5 % vs 13 %, p< 0.05) (16).

Poliacikova et al. retrospectively compared aspirin monother-apy (N=91) with DAPT (N=58) in their centre (17). Baseline char-acteristics show that AF is more frequent in the DAPT vs aspirin group (28 % vs 11 %, p< 0.001). Clopidogrel was given for six months after TAVI. Bleeding rate at 30 days seemed higher for DAPT vs aspirin (19.0 % vs 8.8 %, P=0.069). Mortality and throm-botic events were not different. The composite of all-cause mortal-ity, acute coronary event, stroke, and major bleeding was higher for DAPT vs aspirin (27.6 % vs 12.1 %).

Durand et al. prospectively compared two strategies with (N=128) and without (N=164) clopidogrel after TAVI in patients enrolled in the FRANCE 2 registry in three centres (18). In the as-pirin group, aspirin was started the day prior to TAVI (75 mg with-out loading) or continued. In patients on OAC, additional aspirin was given for one month. In the DAPT group, aspirin was given indefinitely (75 mg qD), and clopidogrel was started (300 mg) the day prior to TAVI and continued for one month (75 mg qD). Pa-tients on OAC received additional aspirin for one month and a loading dose of clopidogrel (300 mg) without continuation.

Compared to the DAPT group, baseline characteristics were very different (e. g. age, gender, coronary artery disease, chronic obstructive pulmonary disease) as were procedural factors (e. g. anaesthesia, surgical cut down, prosthesis type). Mortality rates and thrombo-embolic events were not different between both groups. Compared to the aspirin group, major and minor VASC were more frequent in the DAPT group (10 % vs 6 % and 9 % vs 2 %, respectively). Major and life-threatening bleeding were also more frequent in the DAPT vs aspirin group (13 % vs 2 % and 13 % vs 4 %, respectively). Also the number of patients receiving blood transfusions was higher in the DAPT vs aspirin group (25 % vs 7 %).

Nijenhuis et al. Antithrombotic treatment after TAVI

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Discussion

This review found that direct comparison of the antithrombotic regimen in current retrospective registries is not possible, because i) a large number of studies does not report the antithrombotic regimen, ii) baseline characteristics between studies vary greatly li-miting the generalisability, and iii) a large number of studies does not report outcomes in accordance with VARC. Trials on the opti-

mal antithrombotic therapy after TAVI thus far have only been ex-planatory, and are of limited study quality in terms of Cochrane criteria.

Current clinical practice on antithrombotic therapy after TAVI is purely empirical. It is mainly based on the experience with the Siegburg first-in-man study of CRS (19). Transient thrombocy-topenia occurred in all patients but was severe and prolonged in patients who received no loading dose of clopidogrel vs those who

Nijenhuis et al. Antithrombotic treatment after TAVI

First author

Year

Sample size (N)

Demographics

Age (years)

Female (%)

STS Score (%)

EuroSCORE (%)

AF (%)

Stroke (%)

PAD (%)

Procedure

TF / TA / other (%)

CRS / ESV / other (%)

Regimen pre

Aspirin (loading) (mg)

Clopidogrel (loading) (mg)

Maximal ACT (s)

Regimen post

Aspirin (mg / months)

Clopidogrel (mg / months)

Outcomes at 30 days

All-cause mortality (%)

Myocardial infarction (%)

Stroke (%)

Major VASC (%)

VASC (%)

Minor bleeding (%)

Major bleeding (%)

LTB (%)

ACT activated clotting time; AF atrial fibrillation; ESV Edwards Sapien Valve; CRS Medtronic CoreValve Revalving System; IV intravenous; LTB life threatening bleed-ing; NR not reported; PAD peripheral artery disease; TA transapical; TF transfemoral; VASC vascular Access Site related Complication; ~ indefinitely. * Most transapical cases did not receive clopidogrel because of concerns of bleeding. † antiplatelet therapy (aspirin and clopidogrel) without anticoagulant therapy was maintained in 7 patients (36 %) in whom the risk of bleeding was considered greater than the risk of thromboembolism. ‡ Preferably, no dual antiplatelet was given and aspirin or ticlopidine (250–500mg) monotherapy was used starting 3 days before TAVI.

Nuis (48)†

2012

214

80

50

6

14

30

91

21

97 / 0 / 3

100 / 0 / 0

80

600

250–300

80 / 6

75 / 6

8.4

NR

6.1

NR

NR

NR

NR

NR

Borz (57)

2012

250

83

54

NR

23

NR

NR

22

76 / 24 / 0

0 / 100 / 0

250 IV

300

NR

NR / ~

NR / 1

7.6

2.0

2.4

6.4

18

4.8

9.2

13.2

Tchetche (52)

2012

943

81

46

NR

21

NR

16

25

84 / 9 / 6

NR

NR

300

200–300

NR

75 / 1–6

7.2

1.6

2.6

10.7

22.2

10.8

20.9

13.9

Gilard (53)

2012

3195

83

49

14

22

27

10

21

76 / 18 / 6

32 / 68 / 0

≤ 160

300

NR

≤ 160 / ~

75 / 1

9.7

1.2

4.1

4.7

9.7

7.4

4.5

1.2

Griese (79)

2013

162

82

70

NR

17

33

8

NR

100 / 0 / 0

19 / 81 / 0

100

NR

> 250

100 / NR

75 / NR

5.6

NR

NR

4.3

9.9

14.2

3.7

9.9

Abramowitz (49)

2014

249

83

47

NR

26

NR

8

12

NR

NR

NR

NR

NR

100 / NR

75 / 6

2.4

0.0

2.0

3.2

10.0

NR

1.6

NR

Table 2: Registries mentioning the antiplatelet regimen after TAVI.

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6 Nijenhuis et al. Antithrombotic treatment after TAVI

Year

Group

Number of patients

Demographics

Age (years)

Female (%)

EuroSCORE (%)

AF (%)

Stroke (%)

PAD (%)

Ejection Fraction (%)

Procedure

TF (%)

TA (%)

Other (%)

CRS (%)

ESV (%)

Regimen pre

ASA (mg)

Clopidogrel (loading dose in mg)

INR

Maximal ACT (s)

Regimen post

ASA (mg)*

Clopidogrel (mg / months)

OAC

Outcomes

30-day all-cause mortality (%)

6 month all-cause mortality (%)

Myocardial infarction at 30 days (%)

Stroke at 30 days (%)

Major VASC at 30 days (%)

Minor bleeding at 30 days (%)

Major bleeding at 30 days (%)

Life-threatening bleeding at 30 days (%)

All bleeding at 30 days (%)

AF atrial fibrillation; DAPT dual antiplatelet therapy; ESV Edwards Sapien Valve; CRS Medtronic CoreValve Revalving System; IV intravenous; INR not reported; NP not performed; PAD peripheral artery disease; TA transapical; TF transfemoral; VASC vascular Access Site related Complication. *All recommend aspirin to be given indefinitely.

Ussia (15)

2011

Aspirin

39

81

59

21

15

10

10

54

100

0

0

100

0

100

-

NR

200–250

100

-

NR

10.0

13.0

0.0

5.0

NR

10.0

30

5.0

18.0

DAPT

40

80

50

23

10

5

8

51

95

0

5

100

0

100

300

NR

200–250

100

75 / 3

NR

10.0

10.0

0.0

3.0

NR

8.0

5.0

5.0

18.0

SAT-TAVI (16)

2014

Aspirin

60

81

60

25

0

NR

NR

51

NR

NR

NR

0

100

75–160

NR

NP

> 250

75–160

-

NP

3.3

5.0

0.0

3.3

0.0

1.7

3.3

5.0

10.0

DAPT

60

80

67

23

0

NR

NR

52

NR

NR

NR

0

100

75–160

NR

NP

> 250

75–160

75 / 6

NP

1.7

5.0

0.0

1.7

5.0

5.0

3.3

6.6

15.0

Poliacikova (17)

2013

Aspirin

91

82

54

NR

11

NR

NR

NR

NR

NR

NR

100

0

300

-

NR

NR

75

-

NR

3.3

NR

NR

2.2

3.3

NR

NR

NR

8.8

DAPT

58

82

55

NR

28

NR

NR

NR

NR

NR

NR

100

0

300

300

NR

NR

75

75 / 6

NR

6.9

NR

NR

3.4

5.2

NR

NR

NR

19.0

Durand (18)

2014

Aspirin

164

83

45

20

23

8

17

NR

84

15

1

33

67

75

300

< 1.5

NR

75

-

1 month aspirin

7.9

NR

1.2

1.2

5.5

2.4

2.4

3.7

8.5

DAPT

128

85

60

20

35

9

8

NR

77

23

0

0

100

75

300

< 1.5

NR

75

75 / 1

1 month aspirin + single dose clopi-dogrel (300 mg)

9.4

NR

0.8

4.7

10.2

5.5

13.3

12.5

31.3

Table 3: Current studies to the role of DAPT vs aspirin after TAVI.

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7

did. However, another more recent study showed that persistent thrombocytopenia is similar in patients with and without clopido-grel (20). Also, studies appeared suggesting the majority of pa-tients are low-responders to clopidogrel and that these patients show a higher decrease in platelet number vs normal-responders (21, 22). Since a platelet drop is associated with worse outcomes after TAVI (i. e. stroke, bleeding, mortality) (23), the role of clopi-dogrel after TAVI remains dubious.

Currently, the American guidelines recommends low-dose acetylsalicylic acid (81 mg qD) indefinitely and clopidogrel (75 mg qD) for 3–6 months after TAVI (6, 7). The Canadian statement on TAVI recommends the use of low-dose acetylsalicylic acid indefi-nitely and clopidogrel for 1–3 months (8). The European guide-lines confirm that a combination of low-dose aspirin and a thiëno-pyridine is generally used, despite the lack of evidence (9). Regard-ing antithrombotic therapy in patients on OAC undergoing TAVI (e. g. AF or mechanical mitral prosthesis), the American guidelines recommends low-dose aspirin on top of OAC but avoidance of any other antiplatelet therapy whenever possible (7). Also the Cana-dian statement discourages the use of triple antithrombotic ther-apy (8). The recent European consensus document on this subject states that these patients are recommended to be treated similar to patients receiving a stent without TAVI (10). Recommendations are summarised in ▶ Table 5.

In the included studies, Atrial Fibrillation (AF) was found in 27 % to 41 %. The high burden of AF is important, since chronic AF is associated with a higher late mortality in patients under-going TAVI (24). Cessation of OAC in patients with AF is inde-pendently associated with stroke and mortality (25). Also, in pa-tients with a CHA2DS2-VASC score ≥ 2 undergoing coronary stent implantation, OAC is independently associated with less risk of mortality, stroke, or systemic embolism (26). OAC and con-comitant antiplatelet therapy has been shown to increase the risk for major bleeding in patients with AF (27–29). Sørensen et al. showed that in patients with AF and an acute MI, the bleeding risk was approximately three times higher for OAC + clopidogrel vs OAC alone whereas mortality rates did not differ (30). The experi-ence with patients undergoing bioprosthetic SAVR suggests that OAC monotherapy may be sufficient to prevent thrombotic events (10).

Like in surgical aortic bioprosthetic valves, endothelialisation and incorporation of the CRS takes approximately three months (31, 32). Valve thrombosis occurs only sporadically: only 13 poten-tial cases are described in current literature of which 12 regards ESV and 1 CRS (33–41). Of these, 10 cases occurred after the criti-cal period of three months (4 months to 2 years). Also, transient increased pressure gradients without signs of prosthetic thrombo-sis have been described after three months, possibly dependent on antiplatelet therapy (42). However, histopathology was not per-

Nijenhuis et al. Antithrombotic treatment after TAVI

Figure 2: Risk of is-chaemic and bleeding complications before and after TAVI. Risk of bleeding, stroke and myo-cardial infarction (MI) be-fore and after TAVI. Illus-tration by Vincent Blinde, vmblinde@gmail.com.

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formed in many cases deterring to distinguish plain thrombosis from structural prosthetic deterioration. This raises the question if valve thrombosis is an anticoagulant or an antiplatelet issue, and the role of antiplatelet therapy to prevent valve thrombosis should be further investigated.

The stroke rate at 30 days ranges from 0.0 % to 9.0 % (1, 3, 4, 13, 14, 17, 18, 24, 43–70). Of all strokes within 30 days, over 50 % is

acute and occurs within 24 h after TAVI (▶ Figure 2 and ▶ Table 4) (71). Acute stroke is most frequent of ischaemic origin and strongly related to procedural factors (71). First, manoeuvres dur-ing catheter and delivery system manipulation, passing atheroma-tous aortic lesions and crossing the severely calcified aortic valve, might result in cerebral emboli. A dual filter–based embolic pro-tection device (Montage Dual Filter System, Claret Medical, Inc),

Nijenhuis et al. Antithrombotic treatment after TAVI

Acute

Cardiac troponin elevations

Coronary complications• Spontaneous• Complicated synchronous PCI• Aortic debris embolism• Coronary ostium blockage

– Aortic leaflet fragment– Valve malposition– Patient-prosthesis mismatch

Secondary to ischaemic imbalance• Rapid ventricular pacing• Hypotension• Vascular and bleeding complications• Cardiogenic shock Injury not related to myocardial ischaemia• Left ventricular puncture for the transapical

approach• Pacing• Defibrillator shocks

Stroke

IschaemicEmbolic• Anatomical

– Valve calcification– Aortic arch atheroma

• Mechanical– Balloon pre- or postdilation– Valve positioning– Valve implantation– Valve dislodgment/embolisation

Non-embolic secondary to ischaemic imbalance in the presence of local atherosclerosis (lacunar)• Rapid ventricular pacing• Hypotension• Vascular and bleeding complications• Cardiogenic shockHaemorrhagic

Subacute

Coronary complications• Spontaneous• Aortic debris embolism• Coronary ostium blockage

– Aortic leaflet fragment– Valve malposition– Patient-prosthesis mismatch

Secondary to ischaemic imbalance• Hypotension• Vascular and bleeding complications • Hypovolaemic shock• Severe anaemia Injury not related to myocardial ischaemia• Left ventricular puncture for the transapical approach• Cardiac contusion secondary to prosthesis manipulation• Cardiac contusion secondary to the prosthetic radial force• Pacing• Defibrillator shocks• MyocarditisMultifactorial• Heart failure• Sepsis• SIRS• Renal failure• Severe acute neurological diseases

IschaemicEmbolic• Novel atrial fibrillation• Valve thrombosis dislodgementNon-embolic secondary to ischaemic imbalance• Severe paravalvular leakage• Heart failure• Sepsis• SIRS• Vascular and bleeding complications• Severe anaemiaHaemorrhagic• Trauma• Hypertension• Anticoagulant/antiplatelet therapy

Late

Coronary complications• Spontaneous Secondary to ischaemic imbalance• Hypotension• Bleeding• Severe anaemia Injury not related to myocardial ischaemia• Pacing• Defibrillator shocks• MyocarditisMultifactorial• Heart failure• Sepsis• Renal failure

IschaemicEmbolic• EndocarditisNon-embolic• Chronic atrial fibrillation• Peripheral vascular disease• Prior cerebrovascular disease• Secondary to ischaemic imbalance

– Hypotension– Peripheral bleeding– Severe anaemia

Haemorrhagic• Trauma• Hypertension• Amyloidosis• Coagulopathy• Anticoagulant/antiplatelet therapy• Arteriovenous malformation• Vasculitis• Neoplasm

Table 4: Likely causes of cardiac troponin elevations and stroke after TAVI.

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showed to reduce the number and volume of cerebral lesions as determined by DW-MRI subtraction at two and seven days after TAVI (72). In another study, embolic material was captured in 75 % during TAVI with the same device (73). Second, thrombus formation might be promoted through activation of the coagu-lation pathway by the use of exogenous materials. Third, nonem-bolic stroke can occur during periods of ischaemic imbalance in the presence of local atherosclerosis. For example, hypoperfusion after rapid right ventricular pacing during valve prosthesis deploy-ment might be related to ischaemic brain injury (74).

Regarding subacute and late strokes, more conventional risk factors play a role such as chronic and novel AF, peripheral vascu-lar disease, and prior cerebrovascular events (▶ Figure 2 and ▶ Table 4) (71). After 30 days, the proportion of haemorrhagic stroke inclines (75). At the critical time period of three months, no new cerebral lesions have been identified in a study using mag-netic resonance imaging (76). It is thus likely that the hypothetical ongoing thrombogenicity in the first three months after TAVI does not play a major role in the occurrence of stroke. Registries and trials exploring the antithrombotic regimen have not found an as-sociation between the antithrombotic regimen and the rate of stroke.

Since its changing aetiology over time (ischaemic embolic and nonembolic, haemorrhagic), temporary additional antithrombotic therapy may be advocated for as both effective (prevention of valve thrombosis) as noneffective (haemorrhagic stroke, ischaemic cer-ebral imbalance [watershed infarction]) in the prevention of stroke. Regarding acute stroke due to thrombus formation, the his-topathologic study by van Mieghem et al. suggests that heparin dosage may be of more importance than antiplatelet therapy (73). Therefore, the rate of stroke in accordance to the antithrombotic regimen remains to be further elucidated in sufficiently powered RCTs.

The rate of MI at 30 days after TAVI ranges from 0.0 % to 5.1 % (1, 3, 4, 13, 17, 18, 24, 43–45, 47, 49, 51–55, 57, 59–62, 64, 65, 68, 70). During TAVI in the acute period, there is some increase in the rate of MI although very limited compared to the increase in stroke rate (▶ Figure 2). Acute MI can occur as a consequence of coronary complications, although this is rarely the cause (0.66 %) (▶ Table 4) (77). Every procedure is associated with some degree

of myocardial tissue compression and periods of tissue hypoperfu-sion. Direct cardiac injury is caused by the transapical approach, which involves puncture of the left ventricular apex. These pro-cedural factors are most likely not influenced by antithrombotic therapy.

Thus far, registries and trials exploring the antithrombotic regimen have not found an association between the antithrom-botic regimen and the rate of MI. However, aspirin is suggested to be associated with an increased risk of MI after noncardiac sur-gery, possibly due to a higher rate of bleeding inducing a supply and demand imbalance (78). Thus, the antithrombotic regimen is expected not to affect the rate of acute MI whereas it might even provoke so in the subacute phase. However, this remains hypo-thetical and should be further elucidated.

The reported rate of bleeding after TAVI is highly variable. Major bleeding at 30 days ranges from 1.6 % to 31.4 % (1, 3, 4, 13, 18, 44, 49, 52–54, 56, 57, 61–63, 65, 68, 70, 79, 80). Life-threatening bleeding at 30 days ranges from 1.2 % to 24.3 % (4, 13, 18, 52–54, 56, 61, 65, 68, 70, 79, 80). Four studies have been performed in which the role of DAPT was analysed (▶ Table 3). In two rando-mised studies, the rate of bleeding, thrombotic endpoints and mortality were not different for aspirin vs DAPT (15, 81). Two retrospective studies showed that although mortality and throm-botic events were not different, bleeding occurred significantly less in patients receiving aspirin vs DAPT (17, 18). Moreover, the number of patients receiving blood transfusions seemed higher in the DAPT vs aspirin group, though the studies were underpower-ed regarding this outcome (18).

Thus, additional clopidogrel seems to increase the risk of bleed-ing. This is of primary importance, since major and life-threaten-ing bleeding are an important predictor of both acute and late mortality after TAVI (57, 68, 80, 82, 83). Moreover, both major and minor bleeding result in a reduced quality of life (84). This finding is not to be underestimated, since mortality in this fragile popu-lation remains high and improvement of quality of life should per-haps be equally important as improvement in survival.

Currently, two small trials investigating the antithrombotic regimen after TAVI are recruiting as well as one large RCT. The Aspirin Vs Aspirin + ClopidogRel Following Transcatheter Aortic Valve Implantation (ARTE) pilot trial (NCT01559298) compares

Nijenhuis et al. Antithrombotic treatment after TAVI

Aspirin

Additional anti-platelet therapy

OAC

ESC/EACTS guidelines (9)

Low-dose, indefinitely

Thienopyridine early after TAVI

a combination of OAC and aspirin or thienopyridine is generally used, but should be weighed against increased risk of bleeding

AHA/ACC guidelines (6)

Low-dose (75–100 mg qD), indefinitely (Class IIb;level of evidence: C)

Clopidogrel 75 mg qD for 6 months

ACCF/AATS/SCAI/STS expert consensus (85)

Low-dose (81 mg qD), indefi-nitely

Clopidogrel 75 mg qD for 3–6 months

no clopidogrel

CCS position statement (8)

Low-dose, indefinitely

thienopyridine for 1–3months

avoid triple therapy unless definite indication exists

Table 5: Current recommendations for antithrombotic therapy after TAVI.

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the efficacy of aspirin monotherapy (80 mg qD of at least six months) vs aspirin (80 mg qD for at least six months) + clopido-grel (75 mg qD for three months) in preventing death, MI, is-chaemic stroke/transient ischaemic attack (TIA) or life threaten-ing/major bleeding (primary endpoint) at one year in 200 patients without the need for OAC . The Dual Antiplatelet Therapy Vs Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI (AUREA) trial (NCT01642134) compares the efficacy of duoplavin (aspirin 80 mg/d + clopidogrel 75 mg/d for three months) vs OAC in preventing cerebral thromboembolism as-sessed with MRI (primary endpoint) at three months in 124 pa-tients without the need for OAC. Both of these studies have an open design, and no blinded endpoint assessment. Also, these trials recruit in countries which use only ESV valves and no other types of valve prostheses (e. g. CRS until recently, Jenavalve, Di-rectFlow, Engager, Symetis Accurate). The antithrombotic therapy after TAVI in patients with an indication for OAC has not been studied.

However, major gaps in knowledge remain (▶ Table 6). One study that tries to overcome abovementioned issues, is the antiPla-telet therapy fOr Patients undergoing TAVI (POPular-TAVI) trial (NCT02247128). The POPular-TAVI trial is a multicentre open-label RCT with all-comers design testing the safety, net-clinical benefit and efficacy of omission of clopidogrel compared to a strat-egy using aspirin (≤ 100 mg qD for at least one year, recommended lifelong) + clopidogrel (75 mg qD for three months) (cohort A) or OAC + clopidogrel (cohort B) in 1,000 patients during one year follow-up. The hypothesis is that the omission of clopidogrel in the first three months after TAVI is safer and not less beneficial than the addition of clopidogrel to aspirin or OAC.

Conclusion

Despite improving experience and techniques, ischaemic and bleeding complications after TAVI remain prevalent and impair survival. Due to changing aetiology of complications over time, antithrombotic therapy after TAVI should be carefully balanced. Current registries prove unfit to directly compare antithrombotic regimens. Small exploring studies suggest that additional clopido-grel after TAVI only affects bleeding and not ischaemic compli-cations. Currently, three randomised controlled trials are recruit-

ing to gather more knowledge about the effects of clopidogrel after TAVI.

Conflicts of interestNone declared.

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Nijenhuis et al. Antithrombotic treatment after TAVI

Antiplatelet therapy versus OAC

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Optimal combination in patients with an (new) indication for OAC

NOAC after TAVI

Table 6: Major gaps in evidence in anti-thrombotic therapy after TAVI.

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