J Thromb Thrombolysis DOI 10.1007/s11239-015-1210-x
Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation. One center experience Manolis Vavuranakis1 • Konstantinos Kalogeras1 • Dimitrios Vrachatis1 Maria Kariori1 • Carmen Moldovan1 • Evelina Mpei1 • Maria Lavda1 • Angelos-Michail Kolokathis1 • Gerasimos Siasos1 • Dimitrios Tousoulis1
•
Springer Science+Business Media New York 2015
Abstract Aim of the present study was to record the antithrombotic approach in AF and non-AF patients undergoing TAVI, and to compare the efficiency of the used regimens combination. Antithrombotic approach of patients undergoing TAVI remains a challenging dispute. It becomes even more complex when need for anticoagulant treatment is required due to concurrent atrial fibrillation. Consecutive patients with severe symptomatic aortic stenosis treated with TAVI, were retrospectively studied. All patients were divided into two groups, matched to age, depending on the existence of atrial fibrillation. The primary end-point was the composite of MACE, while the secondary end-point was the occurrence of major bleeding at follow-up. A total of 80 patients were included in the study. Out of them, 20 patients (80.2 ± 5.4 years) suffered from concurrent atrial fibrillation. This group was matched with 20 patients (80.6 ± 3.7 years) with no need for anticoagulation. AF-group patients were treated with clopidogrel plus acenocoumarol for 3 months. Following that, acetylsalicylic acid plus acenocoumarol were prescribed. Non-AF patients were treated with 3 months clopidogrel plus acetylsalicylic acid followed by single acetylsalicylic acid medication. No statistical significant differences in MACE between AF and non-AF group were identified (p = 0.705, phi coefficient = 0.06) (mean follow-up 23.4 ± 14 months). Similarly, there was no statistical
& Konstantinos Kalogeras [email protected] Manolis Vavuranakis [email protected] 1
1st Department of Cardiology, Hippokration Hospital, University of Athens, 13 Astypaleas, Anoixi, 14569 Attiki, Athens, Greece
significant difference for bleedings among the AF and nonAF patient group (p = 0.658, phi coefficient = 0.14). In patients undergoing TAVI with CoreValve, with concurrent AF, treatment with clopidogrel plus acenocoumarol for 3 months, followed by acetylsalicylic acid plus acenocoumarol, seems safe and effective enough in long-term follow-up. Keywords Antithrombotics TAVI Atrial fibrillation Antiplatelet therapy
Introduction Aortic stenosis (AS) is the most common valvular abnormality necessitating interventional therapy when symptoms arise and stenosis becomes severe [1]. Transcatheter aortic valve implantation (TAVI) has emerged as a promising treatment option for patients who are at high or inoperative surgical risk [2–4]. Despite the first encouraging results from large randomized double-blind trials, regarding the outcome of patients undergoing TAVI, many issues regarding optimal pharmacotherapy are still under debate [2]. Follow-up studies have demonstrated an increased risk for ischemic events including myocardial infarction, stroke and transient ischemic attack within the TAVI population, making indispensable the use of antiplatelet therapy after implantation [5, 6]. A widely used, authority based practice is to prescribe clopidogrel in addition to aspirin for a 3- to 6-month period. At the same time recent studies have questioned the superiority of this practice over single antiplatelet therapy [7]. Considering that bleeding complications continue to affect long-term outcomes in that primarily fragile population, it is of paramount importance to obtain data on optimal
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antiplatelet and anticoagulative strategy in patients undergoing TAVI [8, 9]. Antithrombotic therapeutic approach becomes even more complex when need for anticoagulant treatment is required. Antithrombotic therapy seems to be an efficient treatment for preventing from thromboembolic events if adequate anticoagulation is achieved. A common scenario is a patient with atrial fibrillation undergoing TAVI. A paucity of data is available on the appropriate antithrombotic regimen, as well as on the duration of therapy for these patients, with no specific guidelines established up to now regarding these emerging issues [10–12]. Aim of the present study was to record the antithrombotic therapeutic approach in AF and non-AF patients undergoing TAVI, and to compare the efficiency of the used regimens combination over long term outcome.
Materials and methods
were collected and finally, in order to compare the two different antithrombotic approaches, patients were divided into two groups, matched to age, depending on the existence of atrial fibrillation and subsequent need for anticoagulation therapy: i.
ii.
AF group included patients undergoing TAVI with concurrent atrial fibrillation and need for anticoagulation therapy (CHA2DS2VASc score C 1). Non-AF group included patients undergoing TAVI without concurrent atrial fibrillation and no need for anticoagulation therapy.
Antithrombotic therapy followed in two groups was in advance determined and recorded and regularly reassessed during patients’ follow up visits. All patients undergoing TAVI, were entering the structural heart disease unit database, which includes monthly laboratory follow-up evaluation and recommendation of medical regimen in order to obtain optimal management. Therefore, adequate anticoagulation was ensured.
Study population: inclusion/exclusion criteria End-points/follow-up Consecutive patients with severe symptomatic AS treated with TAVI in our department between June 2008 and September 2012, were retrospectively studied. The inclusion criteria for TAVI were patients with severe AS (valve area \ 1 cm2 or aortic valve (AV) area index \ 0.6 cm2/ m2) who were not eligible for surgical aortic replacement because either of a high logistic EuroSCORE ([20 %), or significant comorbidities and risk factors (e.g. porcelain aorta, liver cirrhosis, radiotherapy, severe connective tissue disease). Exclusion criteria from the study included presence of a metallic or bioprosthetic valve, recent (\6 months) coronary intervention with stent implantation or acute coronary syndrome. Procedure All patients received a CoreValve self-expandable tricuspid porcine bioprosthesis (Medtronic, Minneapolis, Minnesota) through transfemoral or subclavian access. All potential TAVI patients underwent a standard screening procedure and the final decision was made by the heart team (comprising of cardiologists, cardiac surgeons, and anesthesiologists). Full details of the procedure have been previously described [4]. Heart rhythm evaluation and antithrombotic therapy
The primary end-point of the study was the composite of major adverse cardiac events (MACE) including cardiac death, myocardial infarction, any coronary revascularization and stroke at follow-up. All deaths were considered of cardiac origin unless an indisputable noncardiac cause could be recognized. Myocardial infraction was defined as electrocardiographic changes consistent with myocardial infarction or cardiac biomarker elevation (creatine kinaseMB or troponin-I 3 times higher than the upper normal limit). Coronary revascularization included intervention either due to recurrence of ACS, or analogous indication due to angina. Stroke was defined as any acute neurological deficit lasting more than 24 h. The secondary end-point of the study was the occurrence of major bleeding during follow-up, as defined by Bleeding Academic Research Consortium (BARC) definition [13]. As per protocol, all patients undergoing TAVI, are conducted a clinical follow-up or telephone contact at regular time intervals after the procedure by physicians working the database of the structural heart disease unit. Therefore, patients’ follow-up was conducted by telephone communication or caring physician at 24 months after the procedure to identify those who had experienced a primary or secondary end-point. Statistical analysis
As per standard of care of patients undergoing TAVI, heart rhythm was daily assessed after the procedure in the coronary care unit and cardiology ward. ECG recordings
123
Continuous variables are presented as mean ± 1 SD unless stated otherwise. The Shapiro–Wilk test and histograms
Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation…
were utilized to assess the normality of continuous variables distribution. Accordingly, continuous variables’ differences between groups were evaluated by two-tailed, independent Student t test or Mann–Whitney U test when appropriate. Categorical variables’ differences were evaluated with Chi Square test with continuity correction. Propensity score matching was used for AF and non-AF patient group matching. Statistical analysis was performed using SPSS 19 for Windows (SPSS Inc, Shicago, Illinois, USA).
Primary end points: follow up Mean follow-up time for the study population was 23.4 ± 14 months. No statistical significant differences in MACE between AF and non-AF group were identified after following the aforementioned therapeutic strategy (p = 0.705, phi coefficient = 0.06) (Table 2). In detail, among AF-group patients, 4 deaths and 1 stroke (5 MACE) were recorded, while among non-AF group, 3 deaths and 1 stroke (4 MACE). Secondary end points: follow-up (bleedings)
Results Patient characteristics Overall 104 patients, who had undergone TAVI, were considered eligible for the study. According to the exclusion criteria, 24 patients were finally excluded. Therefore, a total of 80 patients (43 males, mean age 80.4 ± 5.4 years) were included in the study. Out of them, 20 patients (8 males, mean age 80.2 ± 5.4 years) suffered from concurrent atrial fibrillation in need for concurrent anticoagulation therapy (AF group). Applying propensity score matching, this group was matched with 20 patients (8 males, mean age 80.6 ± 3.7 years)who underwent TAVI, but with no need for anticoagulant therapy (non-AF group, control group) (Table 1).Baseline clinical and demographic characteristics are presented in Table 1. Antithrombotic therapeutic approach The antithrombotic therapeutic approach followed in our center in the two separate patients groups was the following: AF-group patients were treated with clopidogrel (75 mg/day) plus acenocoumarol (target INR = 2) for 3 months duration. Following that, acetylsalicylic acid (100 mg/day) plus acenocoumarol (same INR target) were prescribed until follow-up contact. Until hospital discharge, they were treated with low-molecular weight (LMWH) heparin twice daily, according to the body weight, renal function and age. Specifically, if creatinine clearance was under 30 ml/min, LMWH was administered once a day, while if patient was over 75 years old, 75 % of the dose was conducted. Non-AF group patients were treated with 3 months clopidogrel (75 mg/day) plus acetylsalicylic acid (100 mg/day), followed by single acetylsalicylic acid medication until follow-up contact. Until hospital discharge, and if considered appropriate by the operator, prophylactic low-molecular heparin dose was given accordingly until patient mobilization.
The secondary end point of bleedings during long-term follow-up, in relation to the antithrombotic therapy, was also explored among the two subgroups. Similarly, it was found that there was no statistical significant difference for bleedings among the AF and non-AF patient group (p = 0.658, phi coefficient = 0.14) (Table 2).
Discussion In the present study, we present the antithrombotic strategy followed in our center in TAVI patients with or without concurrent atrial fibrillation and report whether this strategy affects comparatively the long-term outcome among the two populations. We found that use of acenocoumarol plus clopidogrel for 3 months followed by acenocoumarol plus aspirin can be considered a safe and realistic therapeutic approach for AF patients undergoing TAVI. This strategy seems to have similar long-term outcome results with the one followed in non-AF patients, including dual antiplatelet therapy for 3 months followed by aspirin. Despite the more aggressive antithrombotic regimens prescribed in AF patients, comparable MACE rates with nonAF patients were recorded during follow-up. On the other hand, bleeding events did not occur in higher frequency. Conversely to what one would expect, there was no difference in secondary end-point of bleeding events among the two subgroups of the study, despite the anticoagulant therapy in the AF population. That observation can be possibly explained by the fact that all the AF patients had a strict, monthly INR follow-up in our center with high percentage of acenocoumarol on-target treatment. Despite the continuously crescent use of TAVI for severe aortic stenosis treatment, there are still many questions to be answered. Especially in the field of antithrombotic treatment during and after the implantation, the scenery remains cloudy. Unfortunately, no specific guidelines have been established concerning the antiplatelet and anticoagulant medication that should be
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M. Vavuranakis et al. Table 1 Study population: demographic and clinical characteristics; univariate analysis (between AF and NonAF patient groups)
Total population
AF group
Non-AF group
p
Patients, n (males)
40 (16)
20 (8)
20 (8)
1.000
Age, years
80.4 ± 4.5
80.2 ± 5.4
80.6 ± 3.7
0.787 0.152
BMI
25.2 ± 3.6
26.0 ± 3.7
24.4 ± 3.3
Hypertension, n (%)
34 (85)
17 (85)
17 (85)
1.000
CABG, n (%)
6 (15)
3 (15)
3 (15)
1.000
Diabetes mellitus, n (%)
16 (40)
7 (35)
9 (45)
0.747
Smoking, n (%)
7 (17.5)
3 (15)
4 (20)
1.000
CVD, n (%)
2 (5)
1 (5)
1 (5)
1.000
Coronary artery disease, n (%)
19 (47.5)
7 (35)
12 (60)
0.205
NYHA classification
3.0 ± 0.34
3.0 ± 0.22
3.1 ± 0.44
0.657
PASP
44.0 ± 15
48.7 ± 16.6
39.3 ± 11.7
0.047
AVA, cm2
0.61 ± 0.13
0.57 ± 0.15
0.65 ± 0.11
0.076
AVA-i, cm2/m2
0.20 ± 0.04
0.19 ± 0.05
0.21 ± 0.03
0.181
Mean AV gradient, mmHg
46.9 ± 14.8
48.9 ± 17.7
45.0 ± 11.3
0.419
Peak AV gradient, mmHg LVEF, %
79.1 ± 24.3 49.7 ± 10.3
82.5 ± 29.3 49.5 ± 10.9
75.7 ± 18.2 49.8 ± 9.8
0.384 0.928
Logistic EuroSCORE, %
27.9 ± 9.1
27.3 ± 10
28.5 ± 8.3
0.684
CABG coronary artery bypass graft, AV(A-I) aortic valve (area-index), BMI body mass index, CVD cerebrovascular disease, PASP pulmonary artery systolic pressure, LVEF left ventricular ejection fraction, NYHA New York heart association
Table 2 Number of major adverse cardiac events (primary endpoint) and bleedings (secondary endpoint) occurred among patients of two groups (AF and non-AF group) AF group
Non-AF group
p
MACE (% within groups)
5 (25)
4 (20)
0.705
Bleedings (% within groups)
2 (10)
4 (20)
0.658
MACE major adverse cardiac events, AF atrial fibrillation
prescribed. Few data have been published concerning the antiplatelet strategy followed after TAVI, while no data are available about treatment when anticoagulation is also required. Ussia et al. have shown no difference in MACE between dual (aspirin plus clopidogrel) and single (aspirin) antiplatelet therapy in 3 and 6 months post TAVI [7]. Undisputed, anticoagulant therapy with vitamin-K antagonists should be prescribed in AF patients if CHA2DSVASc C 1. However, antiplatelet regimens should be also given in order to prevent platelet aggregation and adhesion within the valve frame, especially during the first months after the procedure, when thromboembolic risk remains high. It seems that enhanced antiplatelet action of clopidogrel, compared to aspirin, offers adequate antiplatelet protection during the first 3 months of implantation until frame endothelization occurs. We believe that single antiplatelet therapy with clopidogrel plus vitamin-K antagonist ensures antithrombotic protection during the first three more thrombogenic months. After that period, a ‘downgrade’ in antiplatelet protection can be
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done replacing clopidogrel with aspirin, aiming simultaneously in lower bleeding risk. The antithrombotic therapeutic approach of TAVI population with concurrent AF can be even more complex when there is a recent acute coronary syndrome or coronary intervention with stent implantation. The need for dual antiplatelet therapy, simultaneously with anticoagulants is imperative, while on the other hand the bleeding risk increases dramatically. Unfortunately, no data are available from clinical trials and patients’ treatment is at the discretion of the operator. However, we believe that based on our results, the antithrombotic strategy we follow, could possibly be effective among that patient group, analogously with large randomized trials that have shown effectiveness of dual (warfarin plus clopidogrel) versus triple therapy (WOEST trial) in AF patients undergoing PCI [14]. Large double-blind randomized trials are required in this unclear field. Finally, the admission in everyday practice of the new oral anticoagulant treatments requires the conduction of studies, exploring the effectiveness of these regimens in TAVI patients with concurrent AF. Study limitations Our study is limited by the fact that it is a registry with a small sample size and retrospective analysis. Using propensity score matching, we tried to match the AF population with an analogous non-AF population, in order
Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation…
to compare similar groups of patients. Inevitably, due to the small population number, the adverse events and bleeding events were also limited. Clinical implications Our study, to our knowledge, is the first to present and explore the antithrombotic strategy followed in TAVI patients with concurrent atrial fibrillation in relation with long-term outcome. As TAVI is going to be increasingly applied as a treatment method in an elderly population, we display a specific and possible safe antithrombotic combination for this patient group.
Conclusions In patient undergoing TAVI with CoreValve, with concurrent AF, treatment with clopidogrel plus acenocoumarol for 3 months, followed by acetylsalicylic acid plus acenocoumarol since then, seems safe and effective enough in long-term follow-up. Further research for new and even safer antithrombotic regimen combinations is required.
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM, Thomas JD (2014) 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63(22):2438–2488. doi:10.1016/j.jacc.2014. 02.537 2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S (2010) Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 363(17):1597–1607. doi:10.1056/NEJMoa1008232 3. Vahanian A, Alfieri O, Al-Attar N, Antunes M, Bax J, Cormier B, Cribier A, De Jaegere P, Fournial G, Kappetein AP, Kovac J, Ludgate S, Maisano F, Moat N, Mohr F, Nataf P, Pierard L, Pomar JL, Schofer J, Tornos P, Tuzcu M, van Hout B, Von Segesser LK, Walther T (2008) Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European association of cardio-thoracic surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). EuroIntervention 4(2):193–199
4. Vavuranakis M, Voudris V, Vrachatis DA, Thomopoulou S, Toutouzas K, Karavolias G, Tolios I, Sbarouni E, Lazaros G, Chrysohoou C, Khoury M, Brili S, Balanika M, Moldovan C, Stefanadis C (2010) Transcatheter aortic valve implantation, patient selection process and procedure: two centres’ experience of the intervention without general anaesthesia. Hell J Cardiol 51(6):492–500 5. Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F, Weber M, Johansson U, Wendt D, Jakob HG, Forsting M, Sack S, Erbel R, Eggebrecht H (2010) Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation 121(7):870–878. doi:10.1161/CIRCULATIONAHA.109. 855866 6. Ghanem A, Muller A, Nahle CP, Kocurek J, Werner N, Hammerstingl C, Schild HH, Schwab JO, Mellert F, Fimmers R, Nickenig G, Thomas D (2010) Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging. J Am Coll Cardiol 55(14):1427–1432. doi:10.1016/j.jacc.2009. 12.026 7. Ussia GP, Scarabelli M, Mule M, Barbanti M, Sarkar K, Cammalleri V, Imme S, Aruta P, Pistritto AM, Gulino S, Deste W, Capodanno D, Tamburino C (2011) Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 108(12):1772–1776. doi:10. 1016/j.amjcard.2011.07.049 8. Moretti C, D’Amico M, D’Ascenzo F, Colaci C, Salizzoni S, Tamburino C, Presbitero P, Marra S, Sheiban I, Gaita F (2014) Impact on prognosis of periprocedural bleeding after TAVI: midterm follow-up of a multicenter prospective study. J Interv Cardiol 27(3):293–299. doi:10.1111/joic.12115 9. Stepinska J, Czerwinska K, Witkowski A, Dabrowski M, Chmielak Z, Kusmierski K, Hryniewiecki T, Demkow M (2013) Risk factors for bleeding complications in patients undergoing transcatheter aortic valve implantation (TAVI). Cardiol J 20(2):125–133. doi:10.5603/CJ.2013.0024 10. Poliacikova P, Cockburn J, de Belder A, Trivedi U, HildickSmith D (2013) Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation—comparison of regimes. J Invasive Cardiol 25(10):544–548 11. Collet JP, Montalescot G (2013) Antithrombotic and antiplatelet therapy in TAVI patients: a fallow field? EuroIntervention 9:S43– S47. doi:10.4244/EIJV9SSA9 12. Lynch DR Jr, Dantzler D, Robbins M, Zhao D (2013) Considerations in antithrombotic therapy among patients undergoing transcatheter aortic valve implantation. J Thromb Thrombolysis 35(4):476–482. doi:10.1007/s11239-013-0886-z 13. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW (2011) Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 57(3):253–269. doi:10.1016/j.jacc.2010.12.005 14. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van ‘t Hof AW, ten Berg JM (2013) Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 381(9872):1107–1115. doi:10.1016/S0140-6736(12)62177-1
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Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation. One center experience Manolis Vavuranakis1 • Konstantinos Kalogeras1 • Dimitrios Vrachatis1 Maria Kariori1 • Carmen Moldovan1 • Evelina Mpei1 • Maria Lavda1 • Angelos-Michail Kolokathis1 • Gerasimos Siasos1 • Dimitrios Tousoulis1
•
Springer Science+Business Media New York 2015
Abstract Aim of the present study was to record the antithrombotic approach in AF and non-AF patients undergoing TAVI, and to compare the efficiency of the used regimens combination. Antithrombotic approach of patients undergoing TAVI remains a challenging dispute. It becomes even more complex when need for anticoagulant treatment is required due to concurrent atrial fibrillation. Consecutive patients with severe symptomatic aortic stenosis treated with TAVI, were retrospectively studied. All patients were divided into two groups, matched to age, depending on the existence of atrial fibrillation. The primary end-point was the composite of MACE, while the secondary end-point was the occurrence of major bleeding at follow-up. A total of 80 patients were included in the study. Out of them, 20 patients (80.2 ± 5.4 years) suffered from concurrent atrial fibrillation. This group was matched with 20 patients (80.6 ± 3.7 years) with no need for anticoagulation. AF-group patients were treated with clopidogrel plus acenocoumarol for 3 months. Following that, acetylsalicylic acid plus acenocoumarol were prescribed. Non-AF patients were treated with 3 months clopidogrel plus acetylsalicylic acid followed by single acetylsalicylic acid medication. No statistical significant differences in MACE between AF and non-AF group were identified (p = 0.705, phi coefficient = 0.06) (mean follow-up 23.4 ± 14 months). Similarly, there was no statistical
& Konstantinos Kalogeras [email protected] Manolis Vavuranakis [email protected] 1
1st Department of Cardiology, Hippokration Hospital, University of Athens, 13 Astypaleas, Anoixi, 14569 Attiki, Athens, Greece
significant difference for bleedings among the AF and nonAF patient group (p = 0.658, phi coefficient = 0.14). In patients undergoing TAVI with CoreValve, with concurrent AF, treatment with clopidogrel plus acenocoumarol for 3 months, followed by acetylsalicylic acid plus acenocoumarol, seems safe and effective enough in long-term follow-up. Keywords Antithrombotics TAVI Atrial fibrillation Antiplatelet therapy
Introduction Aortic stenosis (AS) is the most common valvular abnormality necessitating interventional therapy when symptoms arise and stenosis becomes severe [1]. Transcatheter aortic valve implantation (TAVI) has emerged as a promising treatment option for patients who are at high or inoperative surgical risk [2–4]. Despite the first encouraging results from large randomized double-blind trials, regarding the outcome of patients undergoing TAVI, many issues regarding optimal pharmacotherapy are still under debate [2]. Follow-up studies have demonstrated an increased risk for ischemic events including myocardial infarction, stroke and transient ischemic attack within the TAVI population, making indispensable the use of antiplatelet therapy after implantation [5, 6]. A widely used, authority based practice is to prescribe clopidogrel in addition to aspirin for a 3- to 6-month period. At the same time recent studies have questioned the superiority of this practice over single antiplatelet therapy [7]. Considering that bleeding complications continue to affect long-term outcomes in that primarily fragile population, it is of paramount importance to obtain data on optimal
123
M. Vavuranakis et al.
antiplatelet and anticoagulative strategy in patients undergoing TAVI [8, 9]. Antithrombotic therapeutic approach becomes even more complex when need for anticoagulant treatment is required. Antithrombotic therapy seems to be an efficient treatment for preventing from thromboembolic events if adequate anticoagulation is achieved. A common scenario is a patient with atrial fibrillation undergoing TAVI. A paucity of data is available on the appropriate antithrombotic regimen, as well as on the duration of therapy for these patients, with no specific guidelines established up to now regarding these emerging issues [10–12]. Aim of the present study was to record the antithrombotic therapeutic approach in AF and non-AF patients undergoing TAVI, and to compare the efficiency of the used regimens combination over long term outcome.
Materials and methods
were collected and finally, in order to compare the two different antithrombotic approaches, patients were divided into two groups, matched to age, depending on the existence of atrial fibrillation and subsequent need for anticoagulation therapy: i.
ii.
AF group included patients undergoing TAVI with concurrent atrial fibrillation and need for anticoagulation therapy (CHA2DS2VASc score C 1). Non-AF group included patients undergoing TAVI without concurrent atrial fibrillation and no need for anticoagulation therapy.
Antithrombotic therapy followed in two groups was in advance determined and recorded and regularly reassessed during patients’ follow up visits. All patients undergoing TAVI, were entering the structural heart disease unit database, which includes monthly laboratory follow-up evaluation and recommendation of medical regimen in order to obtain optimal management. Therefore, adequate anticoagulation was ensured.
Study population: inclusion/exclusion criteria End-points/follow-up Consecutive patients with severe symptomatic AS treated with TAVI in our department between June 2008 and September 2012, were retrospectively studied. The inclusion criteria for TAVI were patients with severe AS (valve area \ 1 cm2 or aortic valve (AV) area index \ 0.6 cm2/ m2) who were not eligible for surgical aortic replacement because either of a high logistic EuroSCORE ([20 %), or significant comorbidities and risk factors (e.g. porcelain aorta, liver cirrhosis, radiotherapy, severe connective tissue disease). Exclusion criteria from the study included presence of a metallic or bioprosthetic valve, recent (\6 months) coronary intervention with stent implantation or acute coronary syndrome. Procedure All patients received a CoreValve self-expandable tricuspid porcine bioprosthesis (Medtronic, Minneapolis, Minnesota) through transfemoral or subclavian access. All potential TAVI patients underwent a standard screening procedure and the final decision was made by the heart team (comprising of cardiologists, cardiac surgeons, and anesthesiologists). Full details of the procedure have been previously described [4]. Heart rhythm evaluation and antithrombotic therapy
The primary end-point of the study was the composite of major adverse cardiac events (MACE) including cardiac death, myocardial infarction, any coronary revascularization and stroke at follow-up. All deaths were considered of cardiac origin unless an indisputable noncardiac cause could be recognized. Myocardial infraction was defined as electrocardiographic changes consistent with myocardial infarction or cardiac biomarker elevation (creatine kinaseMB or troponin-I 3 times higher than the upper normal limit). Coronary revascularization included intervention either due to recurrence of ACS, or analogous indication due to angina. Stroke was defined as any acute neurological deficit lasting more than 24 h. The secondary end-point of the study was the occurrence of major bleeding during follow-up, as defined by Bleeding Academic Research Consortium (BARC) definition [13]. As per protocol, all patients undergoing TAVI, are conducted a clinical follow-up or telephone contact at regular time intervals after the procedure by physicians working the database of the structural heart disease unit. Therefore, patients’ follow-up was conducted by telephone communication or caring physician at 24 months after the procedure to identify those who had experienced a primary or secondary end-point. Statistical analysis
As per standard of care of patients undergoing TAVI, heart rhythm was daily assessed after the procedure in the coronary care unit and cardiology ward. ECG recordings
123
Continuous variables are presented as mean ± 1 SD unless stated otherwise. The Shapiro–Wilk test and histograms
Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation…
were utilized to assess the normality of continuous variables distribution. Accordingly, continuous variables’ differences between groups were evaluated by two-tailed, independent Student t test or Mann–Whitney U test when appropriate. Categorical variables’ differences were evaluated with Chi Square test with continuity correction. Propensity score matching was used for AF and non-AF patient group matching. Statistical analysis was performed using SPSS 19 for Windows (SPSS Inc, Shicago, Illinois, USA).
Primary end points: follow up Mean follow-up time for the study population was 23.4 ± 14 months. No statistical significant differences in MACE between AF and non-AF group were identified after following the aforementioned therapeutic strategy (p = 0.705, phi coefficient = 0.06) (Table 2). In detail, among AF-group patients, 4 deaths and 1 stroke (5 MACE) were recorded, while among non-AF group, 3 deaths and 1 stroke (4 MACE). Secondary end points: follow-up (bleedings)
Results Patient characteristics Overall 104 patients, who had undergone TAVI, were considered eligible for the study. According to the exclusion criteria, 24 patients were finally excluded. Therefore, a total of 80 patients (43 males, mean age 80.4 ± 5.4 years) were included in the study. Out of them, 20 patients (8 males, mean age 80.2 ± 5.4 years) suffered from concurrent atrial fibrillation in need for concurrent anticoagulation therapy (AF group). Applying propensity score matching, this group was matched with 20 patients (8 males, mean age 80.6 ± 3.7 years)who underwent TAVI, but with no need for anticoagulant therapy (non-AF group, control group) (Table 1).Baseline clinical and demographic characteristics are presented in Table 1. Antithrombotic therapeutic approach The antithrombotic therapeutic approach followed in our center in the two separate patients groups was the following: AF-group patients were treated with clopidogrel (75 mg/day) plus acenocoumarol (target INR = 2) for 3 months duration. Following that, acetylsalicylic acid (100 mg/day) plus acenocoumarol (same INR target) were prescribed until follow-up contact. Until hospital discharge, they were treated with low-molecular weight (LMWH) heparin twice daily, according to the body weight, renal function and age. Specifically, if creatinine clearance was under 30 ml/min, LMWH was administered once a day, while if patient was over 75 years old, 75 % of the dose was conducted. Non-AF group patients were treated with 3 months clopidogrel (75 mg/day) plus acetylsalicylic acid (100 mg/day), followed by single acetylsalicylic acid medication until follow-up contact. Until hospital discharge, and if considered appropriate by the operator, prophylactic low-molecular heparin dose was given accordingly until patient mobilization.
The secondary end point of bleedings during long-term follow-up, in relation to the antithrombotic therapy, was also explored among the two subgroups. Similarly, it was found that there was no statistical significant difference for bleedings among the AF and non-AF patient group (p = 0.658, phi coefficient = 0.14) (Table 2).
Discussion In the present study, we present the antithrombotic strategy followed in our center in TAVI patients with or without concurrent atrial fibrillation and report whether this strategy affects comparatively the long-term outcome among the two populations. We found that use of acenocoumarol plus clopidogrel for 3 months followed by acenocoumarol plus aspirin can be considered a safe and realistic therapeutic approach for AF patients undergoing TAVI. This strategy seems to have similar long-term outcome results with the one followed in non-AF patients, including dual antiplatelet therapy for 3 months followed by aspirin. Despite the more aggressive antithrombotic regimens prescribed in AF patients, comparable MACE rates with nonAF patients were recorded during follow-up. On the other hand, bleeding events did not occur in higher frequency. Conversely to what one would expect, there was no difference in secondary end-point of bleeding events among the two subgroups of the study, despite the anticoagulant therapy in the AF population. That observation can be possibly explained by the fact that all the AF patients had a strict, monthly INR follow-up in our center with high percentage of acenocoumarol on-target treatment. Despite the continuously crescent use of TAVI for severe aortic stenosis treatment, there are still many questions to be answered. Especially in the field of antithrombotic treatment during and after the implantation, the scenery remains cloudy. Unfortunately, no specific guidelines have been established concerning the antiplatelet and anticoagulant medication that should be
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M. Vavuranakis et al. Table 1 Study population: demographic and clinical characteristics; univariate analysis (between AF and NonAF patient groups)
Total population
AF group
Non-AF group
p
Patients, n (males)
40 (16)
20 (8)
20 (8)
1.000
Age, years
80.4 ± 4.5
80.2 ± 5.4
80.6 ± 3.7
0.787 0.152
BMI
25.2 ± 3.6
26.0 ± 3.7
24.4 ± 3.3
Hypertension, n (%)
34 (85)
17 (85)
17 (85)
1.000
CABG, n (%)
6 (15)
3 (15)
3 (15)
1.000
Diabetes mellitus, n (%)
16 (40)
7 (35)
9 (45)
0.747
Smoking, n (%)
7 (17.5)
3 (15)
4 (20)
1.000
CVD, n (%)
2 (5)
1 (5)
1 (5)
1.000
Coronary artery disease, n (%)
19 (47.5)
7 (35)
12 (60)
0.205
NYHA classification
3.0 ± 0.34
3.0 ± 0.22
3.1 ± 0.44
0.657
PASP
44.0 ± 15
48.7 ± 16.6
39.3 ± 11.7
0.047
AVA, cm2
0.61 ± 0.13
0.57 ± 0.15
0.65 ± 0.11
0.076
AVA-i, cm2/m2
0.20 ± 0.04
0.19 ± 0.05
0.21 ± 0.03
0.181
Mean AV gradient, mmHg
46.9 ± 14.8
48.9 ± 17.7
45.0 ± 11.3
0.419
Peak AV gradient, mmHg LVEF, %
79.1 ± 24.3 49.7 ± 10.3
82.5 ± 29.3 49.5 ± 10.9
75.7 ± 18.2 49.8 ± 9.8
0.384 0.928
Logistic EuroSCORE, %
27.9 ± 9.1
27.3 ± 10
28.5 ± 8.3
0.684
CABG coronary artery bypass graft, AV(A-I) aortic valve (area-index), BMI body mass index, CVD cerebrovascular disease, PASP pulmonary artery systolic pressure, LVEF left ventricular ejection fraction, NYHA New York heart association
Table 2 Number of major adverse cardiac events (primary endpoint) and bleedings (secondary endpoint) occurred among patients of two groups (AF and non-AF group) AF group
Non-AF group
p
MACE (% within groups)
5 (25)
4 (20)
0.705
Bleedings (% within groups)
2 (10)
4 (20)
0.658
MACE major adverse cardiac events, AF atrial fibrillation
prescribed. Few data have been published concerning the antiplatelet strategy followed after TAVI, while no data are available about treatment when anticoagulation is also required. Ussia et al. have shown no difference in MACE between dual (aspirin plus clopidogrel) and single (aspirin) antiplatelet therapy in 3 and 6 months post TAVI [7]. Undisputed, anticoagulant therapy with vitamin-K antagonists should be prescribed in AF patients if CHA2DSVASc C 1. However, antiplatelet regimens should be also given in order to prevent platelet aggregation and adhesion within the valve frame, especially during the first months after the procedure, when thromboembolic risk remains high. It seems that enhanced antiplatelet action of clopidogrel, compared to aspirin, offers adequate antiplatelet protection during the first 3 months of implantation until frame endothelization occurs. We believe that single antiplatelet therapy with clopidogrel plus vitamin-K antagonist ensures antithrombotic protection during the first three more thrombogenic months. After that period, a ‘downgrade’ in antiplatelet protection can be
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done replacing clopidogrel with aspirin, aiming simultaneously in lower bleeding risk. The antithrombotic therapeutic approach of TAVI population with concurrent AF can be even more complex when there is a recent acute coronary syndrome or coronary intervention with stent implantation. The need for dual antiplatelet therapy, simultaneously with anticoagulants is imperative, while on the other hand the bleeding risk increases dramatically. Unfortunately, no data are available from clinical trials and patients’ treatment is at the discretion of the operator. However, we believe that based on our results, the antithrombotic strategy we follow, could possibly be effective among that patient group, analogously with large randomized trials that have shown effectiveness of dual (warfarin plus clopidogrel) versus triple therapy (WOEST trial) in AF patients undergoing PCI [14]. Large double-blind randomized trials are required in this unclear field. Finally, the admission in everyday practice of the new oral anticoagulant treatments requires the conduction of studies, exploring the effectiveness of these regimens in TAVI patients with concurrent AF. Study limitations Our study is limited by the fact that it is a registry with a small sample size and retrospective analysis. Using propensity score matching, we tried to match the AF population with an analogous non-AF population, in order
Antithrombotic therapy in patients undergoing TAVI with concurrent atrial fibrillation…
to compare similar groups of patients. Inevitably, due to the small population number, the adverse events and bleeding events were also limited. Clinical implications Our study, to our knowledge, is the first to present and explore the antithrombotic strategy followed in TAVI patients with concurrent atrial fibrillation in relation with long-term outcome. As TAVI is going to be increasingly applied as a treatment method in an elderly population, we display a specific and possible safe antithrombotic combination for this patient group.
Conclusions In patient undergoing TAVI with CoreValve, with concurrent AF, treatment with clopidogrel plus acenocoumarol for 3 months, followed by acetylsalicylic acid plus acenocoumarol since then, seems safe and effective enough in long-term follow-up. Further research for new and even safer antithrombotic regimen combinations is required.
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM, Thomas JD (2014) 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63(22):2438–2488. doi:10.1016/j.jacc.2014. 02.537 2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S (2010) Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 363(17):1597–1607. doi:10.1056/NEJMoa1008232 3. Vahanian A, Alfieri O, Al-Attar N, Antunes M, Bax J, Cormier B, Cribier A, De Jaegere P, Fournial G, Kappetein AP, Kovac J, Ludgate S, Maisano F, Moat N, Mohr F, Nataf P, Pierard L, Pomar JL, Schofer J, Tornos P, Tuzcu M, van Hout B, Von Segesser LK, Walther T (2008) Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European association of cardio-thoracic surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). EuroIntervention 4(2):193–199
4. Vavuranakis M, Voudris V, Vrachatis DA, Thomopoulou S, Toutouzas K, Karavolias G, Tolios I, Sbarouni E, Lazaros G, Chrysohoou C, Khoury M, Brili S, Balanika M, Moldovan C, Stefanadis C (2010) Transcatheter aortic valve implantation, patient selection process and procedure: two centres’ experience of the intervention without general anaesthesia. Hell J Cardiol 51(6):492–500 5. Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F, Weber M, Johansson U, Wendt D, Jakob HG, Forsting M, Sack S, Erbel R, Eggebrecht H (2010) Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation 121(7):870–878. doi:10.1161/CIRCULATIONAHA.109. 855866 6. Ghanem A, Muller A, Nahle CP, Kocurek J, Werner N, Hammerstingl C, Schild HH, Schwab JO, Mellert F, Fimmers R, Nickenig G, Thomas D (2010) Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging. J Am Coll Cardiol 55(14):1427–1432. doi:10.1016/j.jacc.2009. 12.026 7. Ussia GP, Scarabelli M, Mule M, Barbanti M, Sarkar K, Cammalleri V, Imme S, Aruta P, Pistritto AM, Gulino S, Deste W, Capodanno D, Tamburino C (2011) Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 108(12):1772–1776. doi:10. 1016/j.amjcard.2011.07.049 8. Moretti C, D’Amico M, D’Ascenzo F, Colaci C, Salizzoni S, Tamburino C, Presbitero P, Marra S, Sheiban I, Gaita F (2014) Impact on prognosis of periprocedural bleeding after TAVI: midterm follow-up of a multicenter prospective study. J Interv Cardiol 27(3):293–299. doi:10.1111/joic.12115 9. Stepinska J, Czerwinska K, Witkowski A, Dabrowski M, Chmielak Z, Kusmierski K, Hryniewiecki T, Demkow M (2013) Risk factors for bleeding complications in patients undergoing transcatheter aortic valve implantation (TAVI). Cardiol J 20(2):125–133. doi:10.5603/CJ.2013.0024 10. Poliacikova P, Cockburn J, de Belder A, Trivedi U, HildickSmith D (2013) Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation—comparison of regimes. J Invasive Cardiol 25(10):544–548 11. Collet JP, Montalescot G (2013) Antithrombotic and antiplatelet therapy in TAVI patients: a fallow field? EuroIntervention 9:S43– S47. doi:10.4244/EIJV9SSA9 12. Lynch DR Jr, Dantzler D, Robbins M, Zhao D (2013) Considerations in antithrombotic therapy among patients undergoing transcatheter aortic valve implantation. J Thromb Thrombolysis 35(4):476–482. doi:10.1007/s11239-013-0886-z 13. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW (2011) Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 57(3):253–269. doi:10.1016/j.jacc.2010.12.005 14. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van ‘t Hof AW, ten Berg JM (2013) Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 381(9872):1107–1115. doi:10.1016/S0140-6736(12)62177-1
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