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Comparison of Two Antiplatelet Therapy Strategies in Patients Undergoing Transcatheter Aortic Valve Implantation
Comparison of Two Antiplatelet Therapy Strategies in Patients Undergoing Transcatheter Aortic Valve Implantation Eric Durand, MD, PhDa,b,*, Didier Blanchard, MDa,c, Stephan Chassaing, MDc, Martine Gilard, MD, PhDd, Marc Laskar, MDe, Bogdan Borz, MDb, Antoine Lafont, MD, PhDa, Christophe Barbey, MDc, Matthieu Godin, MDb, Christophe Tron, MDb, Rachid Zegdi, MD, PhDa, Didier Chatel, MDc, Olivier Le Page, MDc, Pierre-Yves Litzler, MD, PhDb, Jean-Paul Bessou, MDb, Nicolas Danchin, MDa, Alain Cribier, MDb, and Hélène Eltchaninoff, MDb Dual antiplatelet therapy is commonly used in patients undergoing transcatheter aortic valve implantation (TAVI), but the optimal antiplatelet regimen is uncertain and remains to be determined. The objective of this study was to compare 2 strategies of antiplatelet therapy in patients undergoing TAVI. A strategy using monoantiplatelet therapy (group A, n [ 164) was prospectively compared with a strategy using dual antiplatelet therapy (group B, n [ 128) in 292 consecutive patients undergoing TAVI. The primary end point was a combination of mortality, major stroke, life-threatening bleeding (LTB), myocardial infarction, and major vascular complications at 30 days. All adverse events were adjudicated according to the Valve Academic Research Consortium. The primary end point occurred in 22 patients (13.4%) in the group A and in 30 patients (23.4%) in the group B (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94, p [ 0.026). LTB (3.7% vs 12.5%, p [ 0.005) and major bleedings (2.4% vs 13.3%, p <0.0001) occurred less frequently in the group A, whereas the incidence of stroke (1.2% vs 4.7%, p [ 0.14) and myocardial infarction (1.2% vs 0.8%, p [ 1.0) was not significantly different between the 2 groups. The benefit of a strategy using mono versus dual antiplatelet therapy persisted after multivariate adjustment and propensity score analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p [ 0.033). In conclusion, a strategy using mono versus dual antiplatelet therapy in patients undergoing TAVI reduces LTB and major bleedings without increasing the risk of stroke and myocardial infarction. The results of our study question the justification of dual antiplatelet therapy and require confirmation in a randomized trial. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;-:-e-) Transcatheter aortic valve implantation (TAVI) has been shown to be superior to medical therapy among inoperable patients and noninferior to surgical aortic valve replacement in patients with high surgical risk.1e11 A dual antiplatelet strategy in patients undergoing TAVI is commonly used, including aspirin (75 to 100 mg/day) and clopidogrel (300 mg loading dose on the day before TAVI followed by 75 mg/day for 1 to 6 months).1e12 However, this statement is purely empirical, and the optimal antiplatelet regimen after TAVI remains to be determined. In particular, the risk/ benefit ratio of adding clopidogrel to aspirin is very uncertain in this old and frail population. The aim of our a University Paris-Descartes; AP-HP; European Georges Pompidou Hospital, Departments of Cardiology and Cardiac Surgery, Paris, France; b University Hospital of Rouen, Hospital Charles Nicolle, Departments of Cardiology and Thoracic and Cardiovascular Surgery, INSERM UMR 1096, Rouen, France; cClinique Saint Gatien, Departments of Cardiology and Cardiac Surgery, Tours, France; dUniversité de Bretagne Occidentale, Department of Cardiology, CHU de la Cavale Blanche, EA 4524, Brest, France; and eUniversity Hospital Dupuytren, Department of cardiac Surgery, Limoges, France. Manuscript received July 31, 2013; revised manuscript received and accepted September 27, 2013. See page 6 for disclosure information. *Corresponding author: Tel: (þ33) 232888243; fax: (þ33) 232888327. E-mail address: [email protected] (E. Durand).
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.09.033
prospective multicenter study was to compare the risk/ benefit ratio of 2 strategies using mono versus dual antiplatelet therapy in patients with severe aortic stenosis undergoing TAVI. Methods We prospectively compared 2 strategies of antiplatelet regimen using mono versus dual antiplatelet therapy in 362 consecutive patients enrolled in the FRANCE 2 TAVI registry from January 2010 and December 2011 in 3 French tertiary centers (Clinique Saint Gatien, Tours; European Georges Pompidou Hospital, Paris; and University Hospital of Rouen, Rouen).6 On the basis of criteria specified by the French Ministry of Health, patients included in the registry were symptomatic adults with severe aortic stenosis who were not candidate for surgical aortic valve replacement because of coexisting illnesses. Severe aortic stenosis was defined as an aortic valve area of <0.8 cm2, a mean aortic gradient of 40 mm Hg, or a peak aortic jet velocity of 4.0 m/s. All patients had New York Heart Association class II, III, or IV symptoms. All patients who had undergone implantation on the basis of these criteria were included in the registry without the use of exclusion criteria.6 At each center, a multidisciplinary team determined eligibility for TAVI on www.ajconline.org
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Table 1 Antithrombotic strategies according to baseline antithrombotic regimen Before TAVI
Strategy A Aspirin (75 mg/day)
Naive Aspirin Clopidogrel VKA
þ þ 0 þ (1 month)
Strategy B Clopidogrel
Aspirin (75 mg/day)
Loading Dose (300 mg)*
Maintenance Dose (75 mg/day)
0 0 0 0
0 0 þ 0
þ þ þ (1 month) þ (1 month)
Clopidogrel Loading Dose (300 mg)*
Maintenance Dose (75 mg/day)
þ þ 0 þ
þ (1 month) þ (1 month) þ 0
* Loading dose of clopidogrel was only used for transfemoral procedure. Table 2 Baseline characteristics Variables Age (yrs) Men Height (cm) Weight (kg) Dyslipidemia Hypertension Diabetes mellitus Previous coronary artery disease Previous myocardial infarction Previous coronary bypass Previous stroke Peripheral artery disease Atrial fibrillation Pacemaker “Porcelain” aorta Creatinine level (>200 mmol/L) Chronic obstructive pulmonary disease Chest irradiation New York Heart Association III Logistic EuroSCORE, % Society of Thoracic Surgeons score, % Aortic annulus diameter (mm) Mean aortic gradient (mm Hg) Aortic valve area (cm2) Pulmonary artery systolic pressure (mm Hg) Left ventricular ejection fraction (%) <30% 30%e50% Aspirin Clopidogrel VKA Aspirin or clopidogrel and VKA
Overall (n ¼ 292)
Group A (n ¼ 164)
Group B (n ¼ 128)
p
83.6 6.1 140 (47.9) 163.3 8.9 69.9 14.7 152 (52.1) 206 (70.5) 70 (24) 121 (41.4) 36 (12.3) 40 (13.7) 25 (8.6) 38 (13) 82 (28.4) 28 (9.6) 14 (4.8) 23 (7.9) 82 (28.1) 17 (5.8) 230 (78.7) 20.1 12.0 7.2 5.3 21.8 1.9 49.3 17.3 0.62 0.15 44.3 13.4 57.1 14.1 2 (0.7) 72 (24.7) 138 (47.3) 21 (7.2) 88 (30.1) 33 (11.3)
82.7 6.3 90 (54.9) 163.2 8.9 69.8 14.8 97 (59.1) 116 (70.7) 40 (24.4) 82 (50) 22 (13.4) 30 (18.3) 13 (7.9) 28 (17.1) 37 (23) 18 (11) 6 (3.7) 12 (7.3) 56 (34.1) 10 (6.1) 131 (79.9) 20.0 12.4 7.4 6.1 22.5 2.1 50.1 15.2 0.61 0.16 44.1 12.8 54.4 13.6 2 (1.2) 51 (31.1) 92 (56.1) 13 (7.9) 46 (28) 26 (15.9)
84.6 5.8 50 (39.1) 163.4 9.0 70.1 14.7 55 (43) 90 (70.3) 30 (23.4) 39 (30.5) 14 (10.9) 10 (7.8) 12 (9.4) 10 (7.8) 45 (35.2) 10 (7.8) 8 (6.3) 11 (8.6) 26 (20.3) 7 (5.5) 99 (77.4) 20.2 11.6 6.9 4.0 21.3 1.6 48.3 19.5 0.63 0.14 44.6 14.1 60.5 14.0 0 21 (16.4) 46 (35.9) 8 (6.3) 42 (32.8) 7 (5.5)
0.001 0.007 0.868 0.856 0.006 0.938 0.850 0.001 0.523 0.010 0.661 0.020 0.023 0.362 0.274 0.688 0.009 0.820 0.730 0.482 0.299 <0.0001 0.314 0.074 0.999 <0.0001 0.506 0.004 0.001 0.582 0.379 0.005
Data presented as mean SD or n (%). Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy. Hypertension was defined as a systolic blood pressure of 140 mm Hg, a diastolic blood pressure of 90 mm Hg, or taking antihypertensive medication. Dyslipidemia was defined as taking cholesterol-lowering drugs. Previous coronary artery disease was defined as at least a coronary stenosis >50%, previous myocardial infarction, or previous revascularization by percutaneous coronary intervention or coronary bypass. Diabetes mellitus was defined as a fasting plasma glucose level of 7.0 mmol/L (126 mg/dl), glycated hemoglobin (HbA1C) 6.5%, or taking antidiabetic medication. Peripheral artery disease was defined as claudication, carotid occlusion or stenosis >50%, amputation for arterial disease, or previous or planned intervention on the abdominal aorta, limb arteries, or carotids. Logistic EuroSCORE and Society of Thoracic Surgeons scores: for further details, see the report by Durand et al.16
the basis of systematic clinical evaluation, angiographic assessment, computed tomography, and echocardiography. Criteria for the use of nontransfemoral approaches were
based on the diameter, degree of tortuosity, and atheroma of the aortoiliofemoral arterial tree, as assessed by computed tomography. SAPIEN devices (Edwards Lifesciences,
Valvular Heart Disease/Antiplatelet Therapy and TAVI Table 3 Procedural characteristics
Table 4 End points in the overall cohort
Overall, Group A, Group B, n ¼ 292 (%) n ¼ 164 (%) n ¼ 128 (%) Access Transfemoral Transapical Subclavian Surgical cutdown* General anesthesia* Type of valve CoreValve Edwards Size of valve (Edwards) 23 mm 26 mm 29 mm Size of valve (CoreValve) 26 mm 29 mm 31 mm Success
p
End Point
Overall, n ¼ 292 (%)
Group A, n ¼ 164 (%)
Group B, n ¼ 128 (%)
Primary end point 30-Day death Stroke Major Minor Transient ischemic attack Myocardial infarction Vascular complications Major Minor Vascular surgery Stent graft Bleeding complications Life threatening Major Minor Transfusions Acute kidney injury Pacemaker
52 25 8 3 3 2
(17.8) (8.6) (2.7) (1) (1) (0.7)
22 (13.4) 13 (7.9) 2 (1.2) 0 1 (0.6) 1 (0.6)
30 12 6 3 2 1
(23.4) (9.4) (4.7) (2.3) (1.6) (0.8)
0.026 0.661 0.144 0.083 0.583 1.0
3 38 22 16 8 10 54 22 21 11 44 19 25
(1) (13) (7.5) (5.5) (2.7) (3.4) (18.5) (7.5) (7.2) (3.8) (15.1) (6.5) (8.6)
2 13 9 4 5 2 14 6 4 4 12 7 21
1 25 13 12 3 8 40 16 17 7 32 12 4
(0.8) (19.5) (10.2) (9.4) (2.3) (6.3) (31.2) (12.5) (13.3) (5.5) (25) (9.4) (3.1)
1.0 0.003 0.134 0.017 1.0 0.024 <0.0001 0.005 <0.0001 0.221 <0.0001 0.079 0.003
0.079 236 54 2 67 98
(80.8) (18.5) (0.7) (28.2) (33.6)
54 (18.5) 238 (81.5)
138 24 2 64 98
(84.1) (14.6) (1.2) (45.7) (59.8)
98 (76.6) 30 (23.4) 0 3 (3.1) 0
54 (32.9) 110 (67.1)
0 128 (100)
<0.0001 <0.0001 <0.0001
0.007 120 (50.4) 112 (47.1) 6 (2.5)
16 35 3 281
3
(29.6) (64.8) (5.6) (96.2)
60 (54.5) 44 (40) 6 (5.5)
16 35 3 159
(29.6) (64.8) (5.6) (97)
60 (46.9) 68 (53.1) 0
0 0 0 122 (95.3)
0.466
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy. * Transfemoral and subclavian procedures only.
Irvine, California) were implanted by either the transfemoral or the transapical route in 3 centers, whereas transfemoral or subclavian route was used for CoreValve devices (Medtronic, Minneapolis, Minnesota) in only 2 centers, as previously described.1e11 All patients provided written informed consent before undergoing the procedure. Of 362 patients included in the 3 centers, 70 were pretreated by the combination of aspirin and clopidogrel before TAVI and were thus excluded from this study. In the remaining 292 patients, 2 antiplatelet strategies, as summarized in Table 1, were compared. A strategy using monoantiplatelet therapy (aspirin or clopidogrel antiplatelet therapy alone, group A) was prospectively and consecutively adopted in 2 centers for all the TAVI procedures since January 2010 (Clinique Saint Gatien, Tours and European Georges Pompidou Hospital, Paris). In naive antiplatelet therapy patients, aspirin alone (75 mg) was introduced the day before TAVI and followed lifelong. In patients previously treated by aspirin, aspirin alone was continued during and after TAVI. In patients previously treated by clopidogrel, clopidogrel was continued during TAVI without either additional loading dose the day before TAVI or association with aspirin. The second strategy using common dual antiplatelet therapy (group B) was systematically adopted in the University Hospital of Rouen. A 300-mg loading dose of clopidogrel was systematically administered on the day before TAVI in all the transfemoral procedures followed by a 1-month maintenance dose of 75 mg/day plus aspirin 75 mg/day lifelong. In transapical cases, no loading dose of clopidogrel was administered before TAVI, and 1-month maintenance dose of 75 mg/day was introduced the day after TAVI in association with 75 mg/day of aspirin lifelong.13 Patients previously treated by clopidogrel were not reloaded for transfemoral procedures.
(1.2) (7.9) (5.5) (2.4) (3) (1.2) (8.5) (3.7) (2.4) (2.4) (7.3) (4.3) (12.9)
p
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy.
In patients previously treated by vitamin K antagonist (VKA), VKA was stopped 3 to 5 days before TAVI to obtain an international normalized ratio of <1.5 and was reintroduced 1 or 2 days after TAVI in both groups. In group B, patients received a 300 mg loading dose of clopidogrel the day before TAVI without additional maintenance dose after TAVI and 75 mg/day of aspirin during 1 month in association with VKA. Finally, procedural parenteral anticoagulation consisted of a 70-IU/kg bolus of unfractionated heparin in both groups. The procedural characteristics for the 2 prostheses have been described previously.3e11 Transarterial access was obtained percutaneously or after surgical cutdown. The femoral access was closed percutaneously (Prostar XL; Abbott Vascular, Chicago, Illinois) or surgically. The choice between general and local anesthesia for transfemoral implantation was left up to the individual teams. The primary end point was a combination of mortality, major stroke, life-threatening bleeding (LTB), myocardial infarction, and major vascular complications at 30 days. Secondary 30-day end points were transfusion, any vascular complication, any stroke, any bleeding, acute kidney injury, and success rate. All adverse events were adjudicated according to the Valve Academic Research Consortium. Data were recorded on a standardized electronic case report form and sent to a central database (Axonal) over the Internet. Data from 3 of the 34 centers participating in the FRANCE 2 TAVI registry were obtained for this study. Database quality control was performed by checking data against source documents for 10% of patients in randomly selected centers, as previously described.6 Statistical analysis was performed using SPSS software (version 17.0; SPSS Inc., Chicago, Illinois). Discrete variables are expressed as percentages, and quantitative variables are expressed as mean SD. Comparisons were made
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Table 5 End points in the propensity scoreematched cohort End Point Primary end point 30-Day death Stroke Major Minor Transient ischemic attack Myocardial infarction Vascular complications Major Minor Vascular surgery Stent graft Bleeding complications Life threatening Major Minor Transfusions Acute kidney injury Pacemaker
Table 6 Univariate analysis for predictive factors of the combined end point
Overall, Group A, Group B, n ¼ 182 (%) n ¼ 91 (%) n ¼ 91 (%)
p
27 15 4 1 2 1
(14.8) (8.2) (2.2) (0.5) (1.1) (0.5)
13 (13.4) 8 (8.8) 2 (2.2) 0 1 (1.1) 1 (1.1)
22 7 2 1 1
(24.2) (7.7) (2.2) (1.1) (1.1) 0
0.137 1.000 1.0 1.0 1.0 1.0
3 25 16 9 7 8 37 16 13 8 30 11 17
(1.0) (13.7) (8.8) (4.9) (3.8) (4.4) (20.3) (8.8) (7.1) (4.4) (15.1) (6) (9.3)
2 8 5 3 4 1 9 3 2 4 7 2 14
1 17 11 6 3 7 28 13 11 4 23 9 3
(0.8) (18.7) (12.1) (6.6) (3.3) (7.7) (30.8) (14.3) (12.1) (4.4) (25.3) (9.9) (3.3)
1.0 0.064 0.210 0.508 1.00 0.070 0.002 0.021 0.022 1.0 0.005 0.065 0.013
(1.2) (8.8) (5.5) (3.3) (4.4) (1.1) (9.9) (3.3) (2.2) (4.4) (7.7) (2.2) (15.6)
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy.
with chi-square or Fisher’s exact test for discrete variables and by unpaired Student t and Wilcoxon signed-rank tests for continuous variables, when appropriate. A backward logistic regression multivariate analysis was used to assess independent correlates of the primary combined end point. The model was built on the basis of the univariate association between the variable and the primary combined end point with a p ¼ 0.05 and an elimination p ¼ 0.10. All the variables listed in Tables 2 to 4 and the strategies of antiplatelet therapy were tested. In addition, a propensity score for getting mono rather than dual antiplatelet therapy strategy was calculated using multiple logistic regressions. The propensity score was used as a covariate, together with the strategy used, in a further backward logistic regression multivariate analysis of the primary end point. The propensity score was also used to match 2 cohorts of patients, one receiving mono and the other dual antiplatelet therapy. Comparison between propensity scoreematched cohorts used paired Student t tests for continuous variables and McNemar tests for discrete variables. For all analyses, a p value <0.05 was considered significant. Results Baseline characteristics are listed in Table 2. Patients implanted in the group A were younger, with a greater proportion of men, had more frequently previous coronary artery disease, previous cardiac surgery, peripheral artery disease, and chronic obstructive pulmonary disease than in those implanted in the group B. Left ventricular ejection fraction was also significantly lower in the group A. In contrast, patients implanted in the group B had a greater incidence of atrial fibrillation. The proportion of patients treated by aspirin was significantly greater in the group A, probably related to the greater incidence of coronary and peripheral artery diseases. Furthermore, the proportion of
Variable
Age Men Hypertension Diabetes History of coronary artery disease History of peripheral artery disease History of stroke Atrial fibrillation Logistic EuroSCORE Society of Thoracic Surgeons score Left ventricular ejection fraction 50% Creatinine level >200 mmol/L VKA before TAVI Aspirin before TAVI Clopidogrel before TAVI Aspirin or clopidogrel and vitamin K antagonist before TAVI Transapical access Percutaneous arterial access* Sheath >18Fr CoreValve† Strategy Az
Univariate Analysis HR
95% CI
p
1.02 0.82 1.35 0.75 0.97 0.81 1.14 1.19 1.00 0.99 1.52 0.58 0.86 1.29 2.26 0.97
0.97e1.07 0.45e1.49 0.71e2.54 0.38e1.46 0.53e1.77 0.35e1.89 0.38e3.49 0.60e2.36 0.98e1.03 0.93e1.05 0.72e3.20 0.22e1.55 0.45e1.63 0.70e2.36 0.51e9.99 0.38e2.48
0.39 0.51 0.36 0.39 0.91 0.63 0.81 0.63 0.85 0.64 0.27 0.28 0.64 0.41 0.28 0.94
1.42 2.03 1.38 0.94 0.51
0.69e2.94 0.85e4.86 0.44e2.20 0.44e2.01 0.28e0.94
0.34 0.11 0.24 0.94 0.03
CI ¼ confidence interval; HR ¼ hazard ratio. * For calculation of the HR, percutaneous arterial access was compared with a surgical cutdown. † For calculation of the HR, CoreValve was compared with an Edwards prosthesis. z For calculation of the HR, strategy A (monoantiplatelet therapy) was compared with the strategy B (dual antiplatelet therapy).
patients treated by the association of an antiplatelet therapy (aspirin or clopidogrel) and VKA was also significantly greater in the group A. Other variables listed in Table 2 were not significantly different between the 2 groups. Procedural characteristics are summarized in Table 3. The implantation approach was transfemoral preferentially in both groups with a greater proportion of patients who underwent TAVI through a transapical approach in the group B. Transarterial access was performed percutaneously in most patients in the group B, whereas it was used in only 54.3% in the group A. A CoreValve device was used in about 1/3 of cases in the group A, whereas all the procedures were performed with an Edwards prosthesis in the group B. Success rate was high and similar in both groups. In the group A, 2 patients presenting with myocardial infarction early after TAVI were treated by percutaneous coronary intervention and were therefore switched to dual antiplatelet therapy. In the group B, 1 patient presenting with hemorrhagic stroke early after TAVI stopped clopidogrel. In other cases, the treatment was not modified after TAVI. End points in the overall cohort are summarized in Table 4. The primary end point occurred less frequently in the group A than in the group B (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94, p ¼ 0.03). Thirty-day mortality rate was low and similar between the 2 groups. Bleeding complications were more frequent in the group B. The incidence of LTB and major bleedings was dramatically
Valvular Heart Disease/Antiplatelet Therapy and TAVI
increased in the group B compared with the group A. In contrast, the occurrence of minor bleeding was similar between the 2 groups. Similarly, the transfusion rate was 3.4 more frequent in the group B compared with the group A. Overall, vascular complications were also significantly more frequent in the group B, although the frequency of major vascular complications was not significantly different between the 2 groups. The use of stent graft for iliofemoral artery rupture of failure of percutaneous closure device was also significantly greater in the group B. Importantly, the use of a monoantiplatelet therapy was not associated with an increased risk of stroke and myocardial infarction. Propensity score matching was performed to build 2 matched cohorts of 91 patients with similar baseline characteristics (Supplemental material). End points in the propensity scoreematched cohort are summarized in Table 5. The frequency of the primary 30-day combined end point in the propensity scoreematched cohort (14.3% vs 24.2%) was similar to that of the overall cohort (13.4% vs 23.4%), although the difference was not statistically significant (p ¼ 0.137). Other end point analyses are summarized in Table 5. Interestingly, the results were closely similar to those obtained in the overall cohort with a significant decrease in LTB and major bleedings in patients treated by a monoantiplatelet therapy without increasing risk of stroke and myocardial infarction. The results of the univariate analysis are summarized in Table 6. The only factor that had a significant association with the primary end point was a strategy using monoantiplatelet therapy. Interestingly, other potential confounding factors were not significant. Better outcome associated with a strategy using monoantiplatelet therapy was further confirmed when the propensity score was introduced into the model for multivariate analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p ¼ 0.033). Discussion TAVI has emerged as an alternative to surgical aortic valve replacement in patients considered at very high or prohibitive surgical risk. Nowadays, the procedure is associated with a very high success rate, but major periprocedural ischemic complications such as myocardial infarction and stroke occur in about 2% (0% to 17%) and 3% (2% to 7%), respectively.1e11 Dual antiplatelet therapy including aspirin (long-term) and clopidogrel (300-mg loading dose and 75-mg/day maintaining dose for 1 to 6 months) is commonly used to reduce such ischemic complications.12 However, this strategy is empirical, and available studies have not yet shown the superiority of dual antiplatelet therapy over aspirin alone in preventing ischemic events in patients undergoing TAVI. Patients undergoing TAVI nowadays are usually octogenarians with frequent co-morbidities such as hypertension, abnormal renal function, or previous cerebrovascular disease, increasing the risk of bleeding. Furthermore, the TAVI procedures itself is associated with a risk of major vascular complications and LTB or major bleedings. It is well known that clopidogrel on top of aspirin is associated with a higher rate of major bleeding, especially in elderly patients. It is therefore of major clinical relevance to determine the risk/benefit ratio of dual antiplatelet therapy in
5
patients undergoing TAVI procedures to recommend the most appropriate treatment in this high-risk population. The present study compared 2 strategies of antiplatelet therapy in 292 consecutive patients undergoing TAVI. The results of our study strongly suggest that a strategy using monoantiplatelet therapy is significantly associated with a significant reduction of LTB and major bleedings and transfusions compared with a strategy using dual antiplatelet therapy. Importantly, the monoantiplatelet strategy did not increase the risk of myocardial infarction or stroke. Only 2 small randomized studies have recently compared a strategy of aspirin alone versus a 3-month combination of aspirin and clopidogrel in patients undergoing TAVI.14,15 In the first trial, 79 patients undergoing TAVI using the thirdgeneration 18Fr CoreValve were randomized to receive aspirin 100 mg/day lifelong or clopidogrel 300-mg loading dose on the day before TAVI followed by 3 months of clopidogrel 75 mg/day in addition to aspirin 100 mg/day.14 The primary composite 30-day end point (death, myocardial infarction, major stroke, urgent or emergency conversion to surgery, or LTB) was not significantly different between the 2 groups (13% vs 15%, p ¼ 0.71). Compared with our study, they did not observe a significant reduction of LTB and major bleedings between the 2 strategies.14 The Single Antiplatelet Therapy for TAVI trial, presented in 2011 at the Transcatheter Cardiovascular Therapeutics meeting, randomized 120 patients to antiplatelet therapy with aspirin alone (n ¼ 60) versus aspirin plus clopidogrel (n ¼ 60).15 The rate of overall bleeding was higher in the aspirin plus clopidogrel group than with aspirin alone, although the difference was not significant (15% vs 10%, p ¼ 0.2). There was also a trend toward reduction in the number of required red blood cell transfusions in patients treated with aspirin alone. In contrast, there was no case of myocardial infarction during the follow-up, and the incidence of stroke was similar between the 2 groups. Interestingly, there was a significant reduction in overall vascular complications with aspirin alone (5% vs 13%, p ¼ 0.03), although the study was claimed to be underpowered to further assess the significance of these findings. The results of these 2 small randomized studies therefore suggest that a strategy of adding clopidogrel to aspirin for 3 to 6 months after TAVI is not superior to aspirin alone and question the utility of dual antiplatelet therapy in patients undergoing TAVI. In our prospective study, which included the largest number of patients in this topic (n ¼ 292) and whose data were obtained from the national prospective FRANCE 2 registry, we report a significant reduction in LTB and major bleedings without increasing the risk of ischemic events (stroke or myocardial infarction) using a strategy of monoantiplatelet therapy in both the overall and propensity-matched cohorts. Importantly, our findings were confirmed after multivariate adjustment and propensity score analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p ¼ 0.033). The results of our study are limited by its design because the 2 antiplatelet therapy strategies were not randomized. The monoantiplatelet therapy strategy was adopted prospectively and consecutively in the 2 centers of the group A and was compared with a traditional strategy using dual antiplatelet therapy adopted prospectively and consecutively in the third center. We therefore cannot exclude that this
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allocation bias could influence the results of our study. The observation of an increased risk in patients with dual compared with those with monoantiplatelet therapy must be therefore interpreted with a fair amount of caution. However, to limit the influence of unknown confounding factors that could have also impacted the prognosis, we have performed several analysis strategies: (1) by adjusting the analysis for a very wide range of possible confounding factors including demographics, cardiovascular risk factors, medical history, antithrombotic medications before TAVI, and procedural characteristics that could limit the risk of bias in our conclusions, (2) by calculating a propensity score for the use of a strategy of monoantiplatelet therapy and using a matching procedure, based on the propensity score, to further limit the potential imbalances between patients receiving a strategy of mono versus dual antiplatelet therapy, and (3) by adding the propensity score as a covariate in the multivariate models. Hence, although we cannot formally exclude the impact of other unmeasured confounding factors, we believe that the favorable observed effects of the strategy using a monoantiplatelet therapy in patients undergoing TAVI are robust and reliable. In contrast, the follow-up of this study was limited to 30 days. A longer follow-up period might also provide more information, although clopidogrel was stopped at 1 month in the dual antiplatelet therapy group. Acknowledgment: The authors thank the scientific committee of the FRANCE 2 study organization and Axonal for providing the database of the patients included in 3 of 34 centers of the national FRANCE 2 TAVI registry.
5.
6.
7.
8.
9.
10.
Disclosures Drs. Cribier, Litzler, and Eltchaninoff are proctors for Edwards Lifesciences, and Dr. Cribier is a consultant for Edwards Lifesciences.
11.
Supplementary Data Supplementary data related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.amjcard. 2013.09.033. 1. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, Derumeaux G, Anselme F, Laborde F, Leon MB. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106: 3006e3008. 2. Cribier A, Eltchaninoff H, Tron C, Bauer F, Agatiello C, Nercolini D, Tapiero S, Litzler PY, Bessou JP, Babaliaros V. Treatment of calcific aortic stenosis with the percutaneous heart valve mid-term follow-up from the initial feasibility studies: the French experience. J Am Coll Cardiol 2006;47:1214e1223. 3. Thomas M, Schymik G, Walther T, Himbert D, Lefèvre T, Treede H, Eggebrecht H, Rubino P, Michev I, Lange R, Anderson WN, Wendler O. Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) registry. A European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 2010;122: 62e69. 4. Rodés-Cabau J, Webb JG, Cheung A, Ye J, Dumont E, Feindel CM, Osten M, Natarajan MK, Velianou JL, Martucci G, DeVarennes B, Chisholm R, Peterson MD, Lichtenstein SV, Nietlispach F, Doyle D, DeLarochellière R, Teoh K, Chu V, Dancea A, Lachapelle K, Cheema
12.
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A, Latter D, Horlick E. Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience. J Am Coll Cardiol 2010;55:1080e1090. Lefèvre T, Kappetein AP, Wolner E, Nataf P, Thomas M, Schächinger V, De Bruyne B, Eltchaninoff H, Thielmann M, Himbert D, Romano M, Serruys P, Wimmer-Greinecker G; PARTNER EU Investigator Group. One-year follow-up of the multi-center European PARTNER transcatheter heart valve study. Eur Heart J 2011;32:148e157. Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, Leprince P, Leguerrier A, Lievre M, Prat A, Teiger E, Lefevre T, Himbert D, Tchetche D, Carrié D, Albat B, Cribier A, Rioufol G, Sudre A, Blanchard D, Collet F, Dos Santos P, Meneveau N, Tirouvanziam A, Caussin C, Guyon P, Boschat J, Le Breton H, Collart F, Houel R, Delpine S, Souteyrand G, Favereau X, Ohlmann P, Doisy V, Grollier G, Gommeaux A, Claudel JP, Bourlon F, Bertrand B, Van Belle E, Laskar M; FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705e1715. Tamburino C, Capodanno D, Ramondo A, Petronio AS, Ettori F, Santoro G, Klugmann S, Bedogni F, Maisano F, Marzocchi A, Poli A, Antoniucci D, Napodano M, De Carlo M, Fiorina C, Ussia GP. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299e308. Zahn R, Gerckens U, Grube E, Linke A, Sievert H, Eggebrecht H, Hambrecht R, Sack S, Hauptmann KE, Richardt G, Figulla HR, Senges J; German Transcatheter Aortic Valve Interventions-Registry Investigators. Transcatheter aortic valve implantation: first results from a multi-centre real-world registry. Eur Heart J 2011;32:198e204. Durand E, Borz B, Godin M, Tron C, Litzler PY, Bessou JP, Bejar K, Fraccaro C, Sanchez-Giron C, Dacher JN, Bauer F, Cribier A, Eltchaninoff H. Transfemoral aortic valve replacement with the Edwards SAPIEN and Edwards SAPIEN XT prosthesis using exclusively local anesthesia and fluoroscopic guidance: feasibility and thirty-day outcomes. JACC Cardiovasc Interv 2012;5:461e467. 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; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597e1607. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ; PARTNER Trial Investigators. Transcatheter versus aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187e2198. Rodés-Cabau J, Dauerman HL, Cohen MG, Mehran R, Small EM, Smyth SS, Costa MA, Mega JL, O’Donoghue ML, Ohman EM, Becker RC. Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events. J Am Coll Cardiol 10 Apr 2013. http://dx.doi.org/10.1016/j.jacc.2013.03.029; pii: S0735e1097(13)01401-0. Borz B, Durand E, Godin M, Tron C, Canville A, Litzler PY, Bessou JP, Cribier A, Eltchaninoff H. Incidence, predictors and impact of bleeding after transcatheter aortic valve implantation using the balloonexpandable Edwards prosthesis. Heart 2013;99:860e865. Ussia GP, Scarabelli M, Mule M, Barbanti M, Sarkar K, Cammalleri V, Immè S, Aruta P, Pistritto AM, Gulino S, Deste W, Capodanno D, Tamburino C. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2011;108:1772e1776. Stabile E, Sorropago G, Pucciarelli A, Cota L, Ambrosini V, Salemme L, Agrusta M, Rubino P. SAT-TAVI (single antiplatelet therapy for TAVI): a randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation [abstract]. J Am Coll Cardiol 2011;58:B218. Durand E, Borz B, Godin M, Litzler PY, Bessou JP, Dacher JN, Bauer F, Cribier A, Eltchaninoff H. Performance analysis of EuroSCORE II compared to the original logistic EuroSCORE and STS scores for predicting 30-day mortality after transcatheter aortic valve replacement. Am J Cardiol 2013;111:891e897.
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.09.033
prospective multicenter study was to compare the risk/ benefit ratio of 2 strategies using mono versus dual antiplatelet therapy in patients with severe aortic stenosis undergoing TAVI. Methods We prospectively compared 2 strategies of antiplatelet regimen using mono versus dual antiplatelet therapy in 362 consecutive patients enrolled in the FRANCE 2 TAVI registry from January 2010 and December 2011 in 3 French tertiary centers (Clinique Saint Gatien, Tours; European Georges Pompidou Hospital, Paris; and University Hospital of Rouen, Rouen).6 On the basis of criteria specified by the French Ministry of Health, patients included in the registry were symptomatic adults with severe aortic stenosis who were not candidate for surgical aortic valve replacement because of coexisting illnesses. Severe aortic stenosis was defined as an aortic valve area of <0.8 cm2, a mean aortic gradient of 40 mm Hg, or a peak aortic jet velocity of 4.0 m/s. All patients had New York Heart Association class II, III, or IV symptoms. All patients who had undergone implantation on the basis of these criteria were included in the registry without the use of exclusion criteria.6 At each center, a multidisciplinary team determined eligibility for TAVI on www.ajconline.org
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Table 1 Antithrombotic strategies according to baseline antithrombotic regimen Before TAVI
Strategy A Aspirin (75 mg/day)
Naive Aspirin Clopidogrel VKA
þ þ 0 þ (1 month)
Strategy B Clopidogrel
Aspirin (75 mg/day)
Loading Dose (300 mg)*
Maintenance Dose (75 mg/day)
0 0 0 0
0 0 þ 0
þ þ þ (1 month) þ (1 month)
Clopidogrel Loading Dose (300 mg)*
Maintenance Dose (75 mg/day)
þ þ 0 þ
þ (1 month) þ (1 month) þ 0
* Loading dose of clopidogrel was only used for transfemoral procedure. Table 2 Baseline characteristics Variables Age (yrs) Men Height (cm) Weight (kg) Dyslipidemia Hypertension Diabetes mellitus Previous coronary artery disease Previous myocardial infarction Previous coronary bypass Previous stroke Peripheral artery disease Atrial fibrillation Pacemaker “Porcelain” aorta Creatinine level (>200 mmol/L) Chronic obstructive pulmonary disease Chest irradiation New York Heart Association III Logistic EuroSCORE, % Society of Thoracic Surgeons score, % Aortic annulus diameter (mm) Mean aortic gradient (mm Hg) Aortic valve area (cm2) Pulmonary artery systolic pressure (mm Hg) Left ventricular ejection fraction (%) <30% 30%e50% Aspirin Clopidogrel VKA Aspirin or clopidogrel and VKA
Overall (n ¼ 292)
Group A (n ¼ 164)
Group B (n ¼ 128)
p
83.6 6.1 140 (47.9) 163.3 8.9 69.9 14.7 152 (52.1) 206 (70.5) 70 (24) 121 (41.4) 36 (12.3) 40 (13.7) 25 (8.6) 38 (13) 82 (28.4) 28 (9.6) 14 (4.8) 23 (7.9) 82 (28.1) 17 (5.8) 230 (78.7) 20.1 12.0 7.2 5.3 21.8 1.9 49.3 17.3 0.62 0.15 44.3 13.4 57.1 14.1 2 (0.7) 72 (24.7) 138 (47.3) 21 (7.2) 88 (30.1) 33 (11.3)
82.7 6.3 90 (54.9) 163.2 8.9 69.8 14.8 97 (59.1) 116 (70.7) 40 (24.4) 82 (50) 22 (13.4) 30 (18.3) 13 (7.9) 28 (17.1) 37 (23) 18 (11) 6 (3.7) 12 (7.3) 56 (34.1) 10 (6.1) 131 (79.9) 20.0 12.4 7.4 6.1 22.5 2.1 50.1 15.2 0.61 0.16 44.1 12.8 54.4 13.6 2 (1.2) 51 (31.1) 92 (56.1) 13 (7.9) 46 (28) 26 (15.9)
84.6 5.8 50 (39.1) 163.4 9.0 70.1 14.7 55 (43) 90 (70.3) 30 (23.4) 39 (30.5) 14 (10.9) 10 (7.8) 12 (9.4) 10 (7.8) 45 (35.2) 10 (7.8) 8 (6.3) 11 (8.6) 26 (20.3) 7 (5.5) 99 (77.4) 20.2 11.6 6.9 4.0 21.3 1.6 48.3 19.5 0.63 0.14 44.6 14.1 60.5 14.0 0 21 (16.4) 46 (35.9) 8 (6.3) 42 (32.8) 7 (5.5)
0.001 0.007 0.868 0.856 0.006 0.938 0.850 0.001 0.523 0.010 0.661 0.020 0.023 0.362 0.274 0.688 0.009 0.820 0.730 0.482 0.299 <0.0001 0.314 0.074 0.999 <0.0001 0.506 0.004 0.001 0.582 0.379 0.005
Data presented as mean SD or n (%). Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy. Hypertension was defined as a systolic blood pressure of 140 mm Hg, a diastolic blood pressure of 90 mm Hg, or taking antihypertensive medication. Dyslipidemia was defined as taking cholesterol-lowering drugs. Previous coronary artery disease was defined as at least a coronary stenosis >50%, previous myocardial infarction, or previous revascularization by percutaneous coronary intervention or coronary bypass. Diabetes mellitus was defined as a fasting plasma glucose level of 7.0 mmol/L (126 mg/dl), glycated hemoglobin (HbA1C) 6.5%, or taking antidiabetic medication. Peripheral artery disease was defined as claudication, carotid occlusion or stenosis >50%, amputation for arterial disease, or previous or planned intervention on the abdominal aorta, limb arteries, or carotids. Logistic EuroSCORE and Society of Thoracic Surgeons scores: for further details, see the report by Durand et al.16
the basis of systematic clinical evaluation, angiographic assessment, computed tomography, and echocardiography. Criteria for the use of nontransfemoral approaches were
based on the diameter, degree of tortuosity, and atheroma of the aortoiliofemoral arterial tree, as assessed by computed tomography. SAPIEN devices (Edwards Lifesciences,
Valvular Heart Disease/Antiplatelet Therapy and TAVI Table 3 Procedural characteristics
Table 4 End points in the overall cohort
Overall, Group A, Group B, n ¼ 292 (%) n ¼ 164 (%) n ¼ 128 (%) Access Transfemoral Transapical Subclavian Surgical cutdown* General anesthesia* Type of valve CoreValve Edwards Size of valve (Edwards) 23 mm 26 mm 29 mm Size of valve (CoreValve) 26 mm 29 mm 31 mm Success
p
End Point
Overall, n ¼ 292 (%)
Group A, n ¼ 164 (%)
Group B, n ¼ 128 (%)
Primary end point 30-Day death Stroke Major Minor Transient ischemic attack Myocardial infarction Vascular complications Major Minor Vascular surgery Stent graft Bleeding complications Life threatening Major Minor Transfusions Acute kidney injury Pacemaker
52 25 8 3 3 2
(17.8) (8.6) (2.7) (1) (1) (0.7)
22 (13.4) 13 (7.9) 2 (1.2) 0 1 (0.6) 1 (0.6)
30 12 6 3 2 1
(23.4) (9.4) (4.7) (2.3) (1.6) (0.8)
0.026 0.661 0.144 0.083 0.583 1.0
3 38 22 16 8 10 54 22 21 11 44 19 25
(1) (13) (7.5) (5.5) (2.7) (3.4) (18.5) (7.5) (7.2) (3.8) (15.1) (6.5) (8.6)
2 13 9 4 5 2 14 6 4 4 12 7 21
1 25 13 12 3 8 40 16 17 7 32 12 4
(0.8) (19.5) (10.2) (9.4) (2.3) (6.3) (31.2) (12.5) (13.3) (5.5) (25) (9.4) (3.1)
1.0 0.003 0.134 0.017 1.0 0.024 <0.0001 0.005 <0.0001 0.221 <0.0001 0.079 0.003
0.079 236 54 2 67 98
(80.8) (18.5) (0.7) (28.2) (33.6)
54 (18.5) 238 (81.5)
138 24 2 64 98
(84.1) (14.6) (1.2) (45.7) (59.8)
98 (76.6) 30 (23.4) 0 3 (3.1) 0
54 (32.9) 110 (67.1)
0 128 (100)
<0.0001 <0.0001 <0.0001
0.007 120 (50.4) 112 (47.1) 6 (2.5)
16 35 3 281
3
(29.6) (64.8) (5.6) (96.2)
60 (54.5) 44 (40) 6 (5.5)
16 35 3 159
(29.6) (64.8) (5.6) (97)
60 (46.9) 68 (53.1) 0
0 0 0 122 (95.3)
0.466
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy. * Transfemoral and subclavian procedures only.
Irvine, California) were implanted by either the transfemoral or the transapical route in 3 centers, whereas transfemoral or subclavian route was used for CoreValve devices (Medtronic, Minneapolis, Minnesota) in only 2 centers, as previously described.1e11 All patients provided written informed consent before undergoing the procedure. Of 362 patients included in the 3 centers, 70 were pretreated by the combination of aspirin and clopidogrel before TAVI and were thus excluded from this study. In the remaining 292 patients, 2 antiplatelet strategies, as summarized in Table 1, were compared. A strategy using monoantiplatelet therapy (aspirin or clopidogrel antiplatelet therapy alone, group A) was prospectively and consecutively adopted in 2 centers for all the TAVI procedures since January 2010 (Clinique Saint Gatien, Tours and European Georges Pompidou Hospital, Paris). In naive antiplatelet therapy patients, aspirin alone (75 mg) was introduced the day before TAVI and followed lifelong. In patients previously treated by aspirin, aspirin alone was continued during and after TAVI. In patients previously treated by clopidogrel, clopidogrel was continued during TAVI without either additional loading dose the day before TAVI or association with aspirin. The second strategy using common dual antiplatelet therapy (group B) was systematically adopted in the University Hospital of Rouen. A 300-mg loading dose of clopidogrel was systematically administered on the day before TAVI in all the transfemoral procedures followed by a 1-month maintenance dose of 75 mg/day plus aspirin 75 mg/day lifelong. In transapical cases, no loading dose of clopidogrel was administered before TAVI, and 1-month maintenance dose of 75 mg/day was introduced the day after TAVI in association with 75 mg/day of aspirin lifelong.13 Patients previously treated by clopidogrel were not reloaded for transfemoral procedures.
(1.2) (7.9) (5.5) (2.4) (3) (1.2) (8.5) (3.7) (2.4) (2.4) (7.3) (4.3) (12.9)
p
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy.
In patients previously treated by vitamin K antagonist (VKA), VKA was stopped 3 to 5 days before TAVI to obtain an international normalized ratio of <1.5 and was reintroduced 1 or 2 days after TAVI in both groups. In group B, patients received a 300 mg loading dose of clopidogrel the day before TAVI without additional maintenance dose after TAVI and 75 mg/day of aspirin during 1 month in association with VKA. Finally, procedural parenteral anticoagulation consisted of a 70-IU/kg bolus of unfractionated heparin in both groups. The procedural characteristics for the 2 prostheses have been described previously.3e11 Transarterial access was obtained percutaneously or after surgical cutdown. The femoral access was closed percutaneously (Prostar XL; Abbott Vascular, Chicago, Illinois) or surgically. The choice between general and local anesthesia for transfemoral implantation was left up to the individual teams. The primary end point was a combination of mortality, major stroke, life-threatening bleeding (LTB), myocardial infarction, and major vascular complications at 30 days. Secondary 30-day end points were transfusion, any vascular complication, any stroke, any bleeding, acute kidney injury, and success rate. All adverse events were adjudicated according to the Valve Academic Research Consortium. Data were recorded on a standardized electronic case report form and sent to a central database (Axonal) over the Internet. Data from 3 of the 34 centers participating in the FRANCE 2 TAVI registry were obtained for this study. Database quality control was performed by checking data against source documents for 10% of patients in randomly selected centers, as previously described.6 Statistical analysis was performed using SPSS software (version 17.0; SPSS Inc., Chicago, Illinois). Discrete variables are expressed as percentages, and quantitative variables are expressed as mean SD. Comparisons were made
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Table 5 End points in the propensity scoreematched cohort End Point Primary end point 30-Day death Stroke Major Minor Transient ischemic attack Myocardial infarction Vascular complications Major Minor Vascular surgery Stent graft Bleeding complications Life threatening Major Minor Transfusions Acute kidney injury Pacemaker
Table 6 Univariate analysis for predictive factors of the combined end point
Overall, Group A, Group B, n ¼ 182 (%) n ¼ 91 (%) n ¼ 91 (%)
p
27 15 4 1 2 1
(14.8) (8.2) (2.2) (0.5) (1.1) (0.5)
13 (13.4) 8 (8.8) 2 (2.2) 0 1 (1.1) 1 (1.1)
22 7 2 1 1
(24.2) (7.7) (2.2) (1.1) (1.1) 0
0.137 1.000 1.0 1.0 1.0 1.0
3 25 16 9 7 8 37 16 13 8 30 11 17
(1.0) (13.7) (8.8) (4.9) (3.8) (4.4) (20.3) (8.8) (7.1) (4.4) (15.1) (6) (9.3)
2 8 5 3 4 1 9 3 2 4 7 2 14
1 17 11 6 3 7 28 13 11 4 23 9 3
(0.8) (18.7) (12.1) (6.6) (3.3) (7.7) (30.8) (14.3) (12.1) (4.4) (25.3) (9.9) (3.3)
1.0 0.064 0.210 0.508 1.00 0.070 0.002 0.021 0.022 1.0 0.005 0.065 0.013
(1.2) (8.8) (5.5) (3.3) (4.4) (1.1) (9.9) (3.3) (2.2) (4.4) (7.7) (2.2) (15.6)
Group A: monoantiplatelet therapy; Group B: dual antiplatelet therapy.
with chi-square or Fisher’s exact test for discrete variables and by unpaired Student t and Wilcoxon signed-rank tests for continuous variables, when appropriate. A backward logistic regression multivariate analysis was used to assess independent correlates of the primary combined end point. The model was built on the basis of the univariate association between the variable and the primary combined end point with a p ¼ 0.05 and an elimination p ¼ 0.10. All the variables listed in Tables 2 to 4 and the strategies of antiplatelet therapy were tested. In addition, a propensity score for getting mono rather than dual antiplatelet therapy strategy was calculated using multiple logistic regressions. The propensity score was used as a covariate, together with the strategy used, in a further backward logistic regression multivariate analysis of the primary end point. The propensity score was also used to match 2 cohorts of patients, one receiving mono and the other dual antiplatelet therapy. Comparison between propensity scoreematched cohorts used paired Student t tests for continuous variables and McNemar tests for discrete variables. For all analyses, a p value <0.05 was considered significant. Results Baseline characteristics are listed in Table 2. Patients implanted in the group A were younger, with a greater proportion of men, had more frequently previous coronary artery disease, previous cardiac surgery, peripheral artery disease, and chronic obstructive pulmonary disease than in those implanted in the group B. Left ventricular ejection fraction was also significantly lower in the group A. In contrast, patients implanted in the group B had a greater incidence of atrial fibrillation. The proportion of patients treated by aspirin was significantly greater in the group A, probably related to the greater incidence of coronary and peripheral artery diseases. Furthermore, the proportion of
Variable
Age Men Hypertension Diabetes History of coronary artery disease History of peripheral artery disease History of stroke Atrial fibrillation Logistic EuroSCORE Society of Thoracic Surgeons score Left ventricular ejection fraction 50% Creatinine level >200 mmol/L VKA before TAVI Aspirin before TAVI Clopidogrel before TAVI Aspirin or clopidogrel and vitamin K antagonist before TAVI Transapical access Percutaneous arterial access* Sheath >18Fr CoreValve† Strategy Az
Univariate Analysis HR
95% CI
p
1.02 0.82 1.35 0.75 0.97 0.81 1.14 1.19 1.00 0.99 1.52 0.58 0.86 1.29 2.26 0.97
0.97e1.07 0.45e1.49 0.71e2.54 0.38e1.46 0.53e1.77 0.35e1.89 0.38e3.49 0.60e2.36 0.98e1.03 0.93e1.05 0.72e3.20 0.22e1.55 0.45e1.63 0.70e2.36 0.51e9.99 0.38e2.48
0.39 0.51 0.36 0.39 0.91 0.63 0.81 0.63 0.85 0.64 0.27 0.28 0.64 0.41 0.28 0.94
1.42 2.03 1.38 0.94 0.51
0.69e2.94 0.85e4.86 0.44e2.20 0.44e2.01 0.28e0.94
0.34 0.11 0.24 0.94 0.03
CI ¼ confidence interval; HR ¼ hazard ratio. * For calculation of the HR, percutaneous arterial access was compared with a surgical cutdown. † For calculation of the HR, CoreValve was compared with an Edwards prosthesis. z For calculation of the HR, strategy A (monoantiplatelet therapy) was compared with the strategy B (dual antiplatelet therapy).
patients treated by the association of an antiplatelet therapy (aspirin or clopidogrel) and VKA was also significantly greater in the group A. Other variables listed in Table 2 were not significantly different between the 2 groups. Procedural characteristics are summarized in Table 3. The implantation approach was transfemoral preferentially in both groups with a greater proportion of patients who underwent TAVI through a transapical approach in the group B. Transarterial access was performed percutaneously in most patients in the group B, whereas it was used in only 54.3% in the group A. A CoreValve device was used in about 1/3 of cases in the group A, whereas all the procedures were performed with an Edwards prosthesis in the group B. Success rate was high and similar in both groups. In the group A, 2 patients presenting with myocardial infarction early after TAVI were treated by percutaneous coronary intervention and were therefore switched to dual antiplatelet therapy. In the group B, 1 patient presenting with hemorrhagic stroke early after TAVI stopped clopidogrel. In other cases, the treatment was not modified after TAVI. End points in the overall cohort are summarized in Table 4. The primary end point occurred less frequently in the group A than in the group B (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94, p ¼ 0.03). Thirty-day mortality rate was low and similar between the 2 groups. Bleeding complications were more frequent in the group B. The incidence of LTB and major bleedings was dramatically
Valvular Heart Disease/Antiplatelet Therapy and TAVI
increased in the group B compared with the group A. In contrast, the occurrence of minor bleeding was similar between the 2 groups. Similarly, the transfusion rate was 3.4 more frequent in the group B compared with the group A. Overall, vascular complications were also significantly more frequent in the group B, although the frequency of major vascular complications was not significantly different between the 2 groups. The use of stent graft for iliofemoral artery rupture of failure of percutaneous closure device was also significantly greater in the group B. Importantly, the use of a monoantiplatelet therapy was not associated with an increased risk of stroke and myocardial infarction. Propensity score matching was performed to build 2 matched cohorts of 91 patients with similar baseline characteristics (Supplemental material). End points in the propensity scoreematched cohort are summarized in Table 5. The frequency of the primary 30-day combined end point in the propensity scoreematched cohort (14.3% vs 24.2%) was similar to that of the overall cohort (13.4% vs 23.4%), although the difference was not statistically significant (p ¼ 0.137). Other end point analyses are summarized in Table 5. Interestingly, the results were closely similar to those obtained in the overall cohort with a significant decrease in LTB and major bleedings in patients treated by a monoantiplatelet therapy without increasing risk of stroke and myocardial infarction. The results of the univariate analysis are summarized in Table 6. The only factor that had a significant association with the primary end point was a strategy using monoantiplatelet therapy. Interestingly, other potential confounding factors were not significant. Better outcome associated with a strategy using monoantiplatelet therapy was further confirmed when the propensity score was introduced into the model for multivariate analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p ¼ 0.033). Discussion TAVI has emerged as an alternative to surgical aortic valve replacement in patients considered at very high or prohibitive surgical risk. Nowadays, the procedure is associated with a very high success rate, but major periprocedural ischemic complications such as myocardial infarction and stroke occur in about 2% (0% to 17%) and 3% (2% to 7%), respectively.1e11 Dual antiplatelet therapy including aspirin (long-term) and clopidogrel (300-mg loading dose and 75-mg/day maintaining dose for 1 to 6 months) is commonly used to reduce such ischemic complications.12 However, this strategy is empirical, and available studies have not yet shown the superiority of dual antiplatelet therapy over aspirin alone in preventing ischemic events in patients undergoing TAVI. Patients undergoing TAVI nowadays are usually octogenarians with frequent co-morbidities such as hypertension, abnormal renal function, or previous cerebrovascular disease, increasing the risk of bleeding. Furthermore, the TAVI procedures itself is associated with a risk of major vascular complications and LTB or major bleedings. It is well known that clopidogrel on top of aspirin is associated with a higher rate of major bleeding, especially in elderly patients. It is therefore of major clinical relevance to determine the risk/benefit ratio of dual antiplatelet therapy in
5
patients undergoing TAVI procedures to recommend the most appropriate treatment in this high-risk population. The present study compared 2 strategies of antiplatelet therapy in 292 consecutive patients undergoing TAVI. The results of our study strongly suggest that a strategy using monoantiplatelet therapy is significantly associated with a significant reduction of LTB and major bleedings and transfusions compared with a strategy using dual antiplatelet therapy. Importantly, the monoantiplatelet strategy did not increase the risk of myocardial infarction or stroke. Only 2 small randomized studies have recently compared a strategy of aspirin alone versus a 3-month combination of aspirin and clopidogrel in patients undergoing TAVI.14,15 In the first trial, 79 patients undergoing TAVI using the thirdgeneration 18Fr CoreValve were randomized to receive aspirin 100 mg/day lifelong or clopidogrel 300-mg loading dose on the day before TAVI followed by 3 months of clopidogrel 75 mg/day in addition to aspirin 100 mg/day.14 The primary composite 30-day end point (death, myocardial infarction, major stroke, urgent or emergency conversion to surgery, or LTB) was not significantly different between the 2 groups (13% vs 15%, p ¼ 0.71). Compared with our study, they did not observe a significant reduction of LTB and major bleedings between the 2 strategies.14 The Single Antiplatelet Therapy for TAVI trial, presented in 2011 at the Transcatheter Cardiovascular Therapeutics meeting, randomized 120 patients to antiplatelet therapy with aspirin alone (n ¼ 60) versus aspirin plus clopidogrel (n ¼ 60).15 The rate of overall bleeding was higher in the aspirin plus clopidogrel group than with aspirin alone, although the difference was not significant (15% vs 10%, p ¼ 0.2). There was also a trend toward reduction in the number of required red blood cell transfusions in patients treated with aspirin alone. In contrast, there was no case of myocardial infarction during the follow-up, and the incidence of stroke was similar between the 2 groups. Interestingly, there was a significant reduction in overall vascular complications with aspirin alone (5% vs 13%, p ¼ 0.03), although the study was claimed to be underpowered to further assess the significance of these findings. The results of these 2 small randomized studies therefore suggest that a strategy of adding clopidogrel to aspirin for 3 to 6 months after TAVI is not superior to aspirin alone and question the utility of dual antiplatelet therapy in patients undergoing TAVI. In our prospective study, which included the largest number of patients in this topic (n ¼ 292) and whose data were obtained from the national prospective FRANCE 2 registry, we report a significant reduction in LTB and major bleedings without increasing the risk of ischemic events (stroke or myocardial infarction) using a strategy of monoantiplatelet therapy in both the overall and propensity-matched cohorts. Importantly, our findings were confirmed after multivariate adjustment and propensity score analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p ¼ 0.033). The results of our study are limited by its design because the 2 antiplatelet therapy strategies were not randomized. The monoantiplatelet therapy strategy was adopted prospectively and consecutively in the 2 centers of the group A and was compared with a traditional strategy using dual antiplatelet therapy adopted prospectively and consecutively in the third center. We therefore cannot exclude that this
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The American Journal of Cardiology (www.ajconline.org)
allocation bias could influence the results of our study. The observation of an increased risk in patients with dual compared with those with monoantiplatelet therapy must be therefore interpreted with a fair amount of caution. However, to limit the influence of unknown confounding factors that could have also impacted the prognosis, we have performed several analysis strategies: (1) by adjusting the analysis for a very wide range of possible confounding factors including demographics, cardiovascular risk factors, medical history, antithrombotic medications before TAVI, and procedural characteristics that could limit the risk of bias in our conclusions, (2) by calculating a propensity score for the use of a strategy of monoantiplatelet therapy and using a matching procedure, based on the propensity score, to further limit the potential imbalances between patients receiving a strategy of mono versus dual antiplatelet therapy, and (3) by adding the propensity score as a covariate in the multivariate models. Hence, although we cannot formally exclude the impact of other unmeasured confounding factors, we believe that the favorable observed effects of the strategy using a monoantiplatelet therapy in patients undergoing TAVI are robust and reliable. In contrast, the follow-up of this study was limited to 30 days. A longer follow-up period might also provide more information, although clopidogrel was stopped at 1 month in the dual antiplatelet therapy group. Acknowledgment: The authors thank the scientific committee of the FRANCE 2 study organization and Axonal for providing the database of the patients included in 3 of 34 centers of the national FRANCE 2 TAVI registry.
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Disclosures Drs. Cribier, Litzler, and Eltchaninoff are proctors for Edwards Lifesciences, and Dr. Cribier is a consultant for Edwards Lifesciences.
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