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Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation
Accepted Manuscript
Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation Sisir Siddamsetti MD , Senthil Balasubramanian MD , Srikanth Yandrapalli MD , Aviral Vij MD , Udit Joshi MD , Gilbert Tang MD , Vamsi Kodumuri MD, MPH PII: DOI: Reference:
S0002-9149(18)31415-2 10.1016/j.amjcard.2018.06.048 AJC 23407
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
26 March 2018 20 June 2018 26 June 2018
Please cite this article as: Sisir Siddamsetti MD , Senthil Balasubramanian MD , Srikanth Yandrapalli MD , Aviral Vij MD , Udit Joshi MD , Gilbert Tang MD , Vamsi Kodumuri MD, MPH , Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation , The American Journal of Cardiology (2018), doi: 10.1016/j.amjcard.2018.06.048
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Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation. Sisir Siddamsetti, MD; Senthil Balasubramanian; MD; Srikanth Yandrapalli, MD; Aviral Vij, MD; Udit Joshi, MD; Gilbert Tang, MD and Vamsi Kodumuri, MD, MPH
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Division of Cardiology, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, U.S.A. Affiliations:
Sisir Siddamsetti, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Senthil Balasubramanian, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
Srikanth Yandrapalli, Westchester Medical Center/ New York Medical Center, Valhalla, New York.
Aviral Vij, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Udit Joshi, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Gilbert Tang, Icahn School of Medicine at Mount Sinai Hospital, New York, New York. Vamsi Kodumuri, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Disclosures: The study and the authors did not receive any financial support.
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Conflict of Interest: Nothing to report Corresponding Author:
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Vamsi Kodumuri, Division of Cardiology, John H. Stroger Jr. Hospital of Cook County, 1969, W. Ogden Ave, Room 3620, Chicago, IL, 60612, USA. Phone: (312)-864-3427, Email: [email protected].
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Abstract
The current American College of Cardiology/ American Heart Association (ACC/AHA)
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guidelines (Grade IIb, level of evidence C) recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 6 months followed by lifelong aspirin after transcathter aortic valve implantation (TAVI). However, studies that have compared DAPT to single antiplatelet therapy (SAPT) following TAVI have questioned this recommendation as DAPT has been associated with
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more bleeding events compared to SAPT. We performed a meta-analysis of all the trials that compared DAPT to SAPT in patients undergoing TAVI. Three randomized trials and four nonrandomized studies were included. The primary endpoint was the rate of ischemic stroke.
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Secondary end points were the rates of myocardial infarction (MI), life threatening bleeding (LTB), significant bleeding (LTB and major bleeding) and death. The Mantel-Haenszel random
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effects model was used to calculate the combined odds ratios (OR) and 95% confidence
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intervals (CI) for outcomes at 30 days and up to 6-12 months follow-up. The LTB (OR 2.73, 95% CI 1.31-5.69, P=0.007) and significant bleeding rates (OR 2.76, 95% CI 1.57-4.85, P=0.0004) were
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significantly higher in DAPT arm at 30 days. Significant bleeding (OR 2.24, 95% CI 1.33-3.79,
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P=0.002) was still significantly higher in the DAPT arm but there was only a non-significant trend towards higher LTB (OR 1.93 95% CI 0.61-6.03, P=0.26) at 6-12 month follow up. There was no difference in mortality, ischemic stroke and MI at 30 days or 6-12 month follow up. In conclusion, our meta-analysis shows that DAPT following TAVI does not confer any additional benefit over SAPT in TAVI.
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Introduction Transcatheter aortic valve implantation (TAVI) has become the standard of care for the treatment of severe aortic stenosis in inoperable patients1 and was shown to be non-inferior to
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surgical aortic valve replacement in patients who are at high and intermediate surgical risk2,3. However, the optimal anti-thrombotic regimen after TAVI remains controversial. The initial trials evaluating the efficacy of TAVI 1,2 used dual antiplatelet therapy (DAPT) for 3-6 months
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after TAVI. Prior small observational4,5 and randomized studies6-8 failed to show a significant benefit with DAPT after TAVI compared to single antiplatelet therapy (SAPT). Also, surveys of TAVI operators have shown a wide variation in anti-thrombotic regimen prescriptions after TAVI and especially antiplatelet agents9. Therefore, we performed a meta-analysis of the trials that
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Methods
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thrombotic regimen after TAVI.
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have compared DAPT with aspirin and clopidogrel to SAPT to evaluate the optimal anti-
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We performed a systematic literature review in PubMed, MEDLINE, SCOPUS, and Cochrane for all the related articles until December 2017. Search terms included “TAVR”,
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“TAVI”, “Transcatheter aortic valve replacement”, “anti-thrombotic agents”, “antiplatelet agents”, “dual antiplatelet therapy”, “single antiplatelet”, “aspirin” and “DAPT”. All the results were downloaded to EndNote; a citation manager and duplicate citations were removed. We included all randomized controlled trials (RCT) and observational studies comparing SAPT to DAPT following TAVI. Studies that reported outcomes at 1 month and/or 6 months follow-up
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were included. Studies that reported only in-hospital outcomes were excluded. Studies that used anticoagulants (warfarin or newer oral anticoagulants) in the study groups were excluded. Two authors (S.S and U.J) independently screened each trial from the search criteria, and determined the eligibility for inclusion after full text evaluation. Only published manuscripts
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were included for the analysis. All disagreements between authors regarding eligibility of study inclusion were resolved by discussion. The literature search yielded three RCT’s6-8 and four observational studies4,5,10,11 which were included for the study protocol. The search strategy for
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our analysis is shown in Figure 1. The characteristics of the included trials are described in Table 1 and Table 2. The meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) statement12.
Three authors (S.S, S.B and U.J) independently performed data extraction from each trial
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that included the following: number of patients in each treatment arm, duration of DAPT,
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length of follow-up and number of events for each outcome (ischemic stroke, MI, life threatening and major bleeding and death). The primary end point studied was rate of ischemic
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strokes. The secondary end points were the rates of MI, life threatening bleeding (LTB),
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significant bleeding (LTB and major bleeding) and death. The outcomes were analyzed at 30 days and at 6 to 12 months. All outcomes were based on the accepted consensus definitions
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described by Valve Academic Research Consortium (VARC)13. Data was analyzed on an intention to treat basis. Measures of heterogeneity, including
Cochran’s Q-statistic and I2 index tests, were computed. An I2 index of 25% was considered to indicate significant heterogeneity. The Mantel-Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). P value of less than or equal to 0.05
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was considered to be significant. The meta-analysis was performed using Review Manager (RevMan) Version 5.3. Study quality was assessed by using Cochrane risk of bias tool for RCTs (Figure 2) and Newcastle-Ottawa scale for nonrandomized studies (Table 4).
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Results
Three randomized trials 6-8 and four non-randomized studies4,5,10,11 involving 1389 patients were included, of which 772 patients received DAPT and 617 received SAPT. The
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baseline characteristics were similar between the two treatment arms. The mean age of the population studied was 82 years and included 55.6% females. Two studies5,6 used Medtronic CoreValve (MCV) only and three studies7,8,10 used Edward’s SAPIEN XT valve (ESV) while Durand
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et al4 used both MCV and ESV (Table 1). Aspirin was used as the SAPT strategy in all the patients in majority of the trials. However, 8% of patients in Durand et al4 study and some patients in
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the study by Mangieri et al11 (number of patients not specified) received clopidogrel as SAPT
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strategy while the remaining patients received aspirin. 2 studies reported outcomes at 30 days only and 2 studies reported outcomes at 12 months only, while 3 studies reported outcomes at
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30 days and 6-12months. Outcomes at 30 days and 6-12 months are shown in Figure 3 and
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Figure 4 respectively.
At 30 days follow up, LTB (OR 2.73, 95% CI 1.31-5.69, P=0.007) and significant bleeding
(OR 2.76, 95% CI 1.57-4.85, P=0.0004) rates were significantly higher in the DAPT arm compared to SAPT. There was no significant difference in the rate of Ischemic stroke (OR 0.81, 95% CI 0.16-3.95, P=0.79), MI (OR 1.37, 95% CI 0.32-5.85, P=0.43) and mortality (OR 1.31, 95% CI 0.74-2.33, P=0.35).
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At 6-12 months follow up, significant bleeding rates (OR 2.24, 95% CI 1.33-3.79, P=0.002) were significantly higher in the DAPT arm and there was a non-significant trend towards higher LTB (OR 1.93 95% CI 0.61-6.03, P=0.26) in the DAPT arm. There was no significant difference in the rate of ischemic stroke (OR 0.81, 95% CI 0.16-3.95, P=0.79), MI (OR
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2.82, 95% CI 0.85-9.33, P=0.09) and mortality (OR 1.05, 95% CI 0.64-1.72, P=0.84).
Discussion
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In this meta-analysis, we analyzed the outcomes at 30 days and up to 6-12 months from all the RCTs and observational studies that compared DAPT to SAPT after TAVI. The results of our study show that DAPT after TAVI significantly increases LTB and significant bleeding when compared to SAPT without any benefit in ischemic and thromboembolic endpoints.
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The rate of stroke following TAVI in various trials has been reported to be between
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1.2%-6%14-16. Stroke following TAVI Is classified as acute (<24 hours), subacute (1-30 days) and late (>30 days), depending on the timing of the stroke after the procedure. The lack of benefit
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of DAPT for stroke prevention is likely related to the pathophysiology of stroke following TAVI.
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In a study that evaluated the predictors of stroke after TAVI, acute (<24 hours) stroke was associated with procedural events like wire manipulation, balloon post-dilation of the valve
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prosthesis and valve dislodgement/embolization. This finding was corroborated by two other studies that evaluated the cerebral embolic burden during the TAVI procedure with transcranial Doppler examination17,18. They found that high-Intensity transient signals (HITS), which are surrogate markers for micro embolization were highest during wire manipulation of the calcific aortic arch and during valve deployment. Thus, acute stroke maybe related to the mechanical
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interaction between the valve prosthesis and the calcific native aortic valve for which DAPT may not be helpful. Subacute (1-30 days) and late strokes (>30 days) were associated with newonset atrial arrhythmias and chronic atrial arrhythmias respectively and DAPT has not been shown to be beneficial in preventing strokes related to atrial arrhythmias19. The above reasons
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may explain the lack of benefit of DAPT in preventing ischemic strokes post TAVI. Use of
cerebral embolic protection devices and certain procedural changes such as avoiding balloon pre-dilation and rapid pacing and decreasing contact with the aortic arch have shown to
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decrease stroke after TAVI20,21. However, these strategies need to be further evaluated in larger studies.
MI after TAVI in various trials and registries have ranged from 1-6%22. In our analysis, there was no significant difference in the rate of MI between the two treatment arms after
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TAVI. Again, the lack of benefit with DAPT in preventing MI may be related to the
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pathophysiology of MI following TAVI. The rate of symptomatic coronary occlusion in a study following TAVI was found to be only 0.6%23. It means that there might be other potential
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factors causing MI after TAVI like direct myocardial injury during the procedure, hemodynamic
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shifts causing hypotension and bleeding from DAPT. Even in cases when MI is due to coronary obstruction, the most common mechanism of coronary obstruction is due to blocking of the
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coronary ostium by the displaced native aortic valve cusp rather than due to thrombosis23. Patients undergoing TAVI are elderly with a mean age more than 80 years and may have
multiple co-morbidities predisposing them to higher bleeding risk. In our analysis, both life threatening bleeding (LTB) and significant bleeding (LTB and major bleeding) was found to be significantly higher in patients receiving DAPT compared to SAPT. This finding is especially
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important as multiple analysis have shown LTB and major bleeding to be a predictor of increased mortality24,25. Accurate vascular access with the help of imaging modalities such as multi-detector computed tomography (MDCT) to carefully assess vascular anatomy routinely has been associated with fewer bleeding complications26. Use closure devices and newer TAVI
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devices that require smaller sheaths are other potential options to further decrease bleeding risk in the future. The current 2017 ACC/AHA guidelines update also give a IIb (LOE B)
recommendation for using warfarin for 3 months after TAVI. Imaging studies that have shown
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lower rate of prosthetic valve thrombosis and higher rate of resolution of valve thrombosis after initiation of warfarin in patients who developed valve thrombosis post TAVI27,28. Given these findings anticoagulation with warfarin may be more reasonable compared to DAPT following TAVI in appropriate patients.
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Our study had several limitations. There was significant heterogeneity between the
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trials and to account for this heterogeneity random effects model was used to calculate the outcomes. As there was paucity in randomized data we combined both randomized and non-
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randomized studies and that might have introduced selection bias. Clopidogrel was used as
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SAPT strategy in a few patients in 2 trials and this might have confounded outcome results. The study population was relatively small and 12-month data was not available for all the studies.
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In conclusion, the results of our meta-analysis suggest that DAPT does not confer any benefit in preventing stroke, MI or mortality when compared to SAPT but it increases major and life-threatening bleeding rates. Our analysis does not support current ACC/AHA guidelines of using DAPT for 6 months after TAVI. Further larger scale RCTs are required to evaluate the adequate anti-thrombotic regimen after TAVI.
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Legends Figure 1 PRISMA Flow diagram of study selection
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None
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Figure 2 Cochrane risk of bias tool for randomized controlled trials
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Figure 3 Meta- analysis at 30 days follow up DAPT, dual antiplatelet therapy; LTB, life-threatening bleeding; MI, myocardial infarction; SAPT, single antiplatelet therapy;
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Figure 4 Meta- analysis at 6 months to 12 months follow up DAPT, dual antiplatelet therapy; LTB, life-threatening bleeding; MI, myocardial infarction; SAPT, single antiplatelet therapy;
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Study
Endpoint Type of Follow study & year up (months)
Antiplatelet
Stabile
RCT, 2011
1 and 6
30-day mortality
aspirin vs aspirin/clopidogrel or NA aspirin/ticlopidine
Ussia
RCT, 2011
1 and 6
death, MI, stroke, conversion to surgery and LTB
aspirin vs aspirin/clopidogrel
Poliacikova
Retrospective, 1 and 6 2013
mortality, ACS, stroke or major bleeding
Durand
Prospective, 2014
mortality, major stroke, LTB and MI
Mangieri
Retrospective, 12 2017
Ichibori
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Table 1. Study characteristics of trials comparing dual antiplatelet therapy to single antiplatelet therapy following Transcatheter aortic valve implantation
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ES: 100%
120 (100%)
CV: 100%
74 (94%)
aspirin vs aspirin/clopidogrel
NA
CV: 100%
167 (98%)
aspirin (clopidogrel if already on it) vs aspirin/clopidogrel
TF: 81%, rest: TA and TS
ES: 82% CV: 18%
281 (96%)
aspirin or clopidogrel vs aspirin/clopidogrel
TF: 100%
ES: 50% NA Rest: others
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mortality, major bleeding, CVA and redo-AVR
Valve type, Procedure success, % N (%)
TF: 97% TS: 3%
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1
Approach TAVR, %
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Retrospective, 12 2017
Rodes-Cabau
RCT, 2017
1 and 3
death, MI, stroke, and major bleeding or LTB
aspirin vs aspirin/clopidogrel or TA:53%, rest: ES: 100% aspirin/ticlopidine TF, TS and Tao
138 (96%)
death, MI, ischemic stroke or TIA, or major bleeding or LTB
aspirin vs aspirin/clopidogrel
195 (88%)
TF: 69%, rest: TF and TA
ES: 100%
ACS, acute coronary syndrome; AVR, aortic valve replacement; CV, CoreValve; CVA, cerebrovascular accident; DF, Direct Flow; ES, Edward’s Sapien; LTB, life-threatening bleeding; MI, myocardial infarction; MACE, major adverse cardiac events; MC, multicenter; NACE, net adverse cardiac events; RCT, randomized controlled trial; TA, transapical; Tao, transaortic;
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TAVR, transcatheter aortic valve replacement; TC, transcarotid; TF, transfemoral; TS, transsubclavian; TIA, transient ischemic attack;
Table 2. Baseline characteristics of patients included in the trials Ichibori
Durand
Ussia
Stabile
Overall
Overall
Overall
Overall
Overall
Overall
Overall
N
171
439
144
292
79
120
222
Age (years)
82±6
83±8
83±6
84±6
81±4
81±5
79±9
Women
80 (53%)
276 (63%)
BMI (kg/m2)
27±5
25± 4
HTN
NA
351 (80%)
DM
37 (22%)
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Mangieri
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Patient Poliacikova characteristics
RodesCabau
152 (52%)
43 (54%) 80 (67%)
93 (41%)
NA
NA
NA
NA
NA
206 (70%)
66 (84%) 114 (95%)
173 (78%)
108 (25%)
46 (32%)
70 (24%)
21 (27%) 32 (27%)
77 (34%)
160 (36%)
NA
23 (8%)
11 (14%) NA
140 (63%)
51 (12%)
NA
82 (28%)
10 (13%) NA
NA
NA
NA
NA
38 (13%)
7 (9%)
NA
50 (22%)
Porcelain aorta
NA
NA
NA
14 (5%)
2 (3%)
NA
29 (13%)
Prior CVE
NA
61 (14%)
35 (24%)
25 (9%)
10 (13%) NA
46 (27%)
AC
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AF PAD
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Renal disease 11 (6%)
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92 (64%)
NA
NA
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Prior MI
NA
76 (17%)
NA
36 (12%)
11 (14%) NA
46 (21%)
Prior PCI
41 (24%)
110 (25%)
36 (25%)
NA
21 (27%) NA
NA
Prior CABG
43 (25%)
90 (21%)
20 (14%)
40 (14%)
6 (8%)
81 (36%)
Mean aortic gradient (mmHg)
NA
NA
53±18
49±17
53 ±17
62±15
43 ± 16
Logistic Euro score (%)
NA
21.1±14.6
24.8±16.9
20.1±12.0
21±13
24.2± 10.2
NA
STS score (%)
NA
7.6±71
11.4±10.2
7.2±5.3
7.3±4
10.05±5.9
6.3±4.5
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NA
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AF, atrial fibrillation; AVA- aortic valve area; BMI, body mass index; CABG coronary artery bypass graft; CVE, cerebrovascular event; HTN, hypertension; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STS, society of thoracic surgery.
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Table 3. Summary table for Meta-Analysis Outcomes comparing Dual Antiplatelet Therapy vs Single Antiplatelet Therapy following Transcatheter Aortic Valve Replacement Studies
Odds Ratio (Confidence P Value Interval)
Ischemic stroke 30 days
3
0.81 (0.16-3.95)
0.79
MI 30 days
5
1.37 (0.32-5.85)
0.67
LTB 30 days
4
2.73 (1.31-5.69)
0.007
Significant bleeding 30 days
5
2.76 (1.57-4.85)
0.0004
Mortality 30 days
5
1.31 (0.74-2.33)
0.35
Ischemic stroke 6 months
3
0.81 (0.16-3.95)
0.79
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Outcomes
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4
2.82 (0.85-9.33)
0.09
LTB 6 months
3
1.93 (0.61-6.03)
0.26
Significant bleeding 12 months 5
2.24 (1.33-3.79)
0.002
Mortality 12 months
1.05 (0.64-1.72)
0.84
6
LTB, life threatening bleeding; MI, myocardial infarction.
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MI 12 months
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Table 4. Assessment of Quality of Nonrandomized Studies using the Newcastle-Ottawa Scale Study Selection Comparability Outcome Poliacikova 2013 ★★★★ ☆☆ ★★☆ Durand 2014 ★★★★ ★★ ★★★ Ichibori 2017 ★★★★ ★★ ★★☆ Mangieri 2017 ★★★★ ★☆ ★★★
Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation Sisir Siddamsetti MD , Senthil Balasubramanian MD , Srikanth Yandrapalli MD , Aviral Vij MD , Udit Joshi MD , Gilbert Tang MD , Vamsi Kodumuri MD, MPH PII: DOI: Reference:
S0002-9149(18)31415-2 10.1016/j.amjcard.2018.06.048 AJC 23407
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
26 March 2018 20 June 2018 26 June 2018
Please cite this article as: Sisir Siddamsetti MD , Senthil Balasubramanian MD , Srikanth Yandrapalli MD , Aviral Vij MD , Udit Joshi MD , Gilbert Tang MD , Vamsi Kodumuri MD, MPH , Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation , The American Journal of Cardiology (2018), doi: 10.1016/j.amjcard.2018.06.048
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Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation. Sisir Siddamsetti, MD; Senthil Balasubramanian; MD; Srikanth Yandrapalli, MD; Aviral Vij, MD; Udit Joshi, MD; Gilbert Tang, MD and Vamsi Kodumuri, MD, MPH
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Division of Cardiology, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, U.S.A. Affiliations:
Sisir Siddamsetti, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Senthil Balasubramanian, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
Srikanth Yandrapalli, Westchester Medical Center/ New York Medical Center, Valhalla, New York.
Aviral Vij, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Udit Joshi, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Gilbert Tang, Icahn School of Medicine at Mount Sinai Hospital, New York, New York. Vamsi Kodumuri, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois.
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Disclosures: The study and the authors did not receive any financial support.
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Conflict of Interest: Nothing to report Corresponding Author:
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Vamsi Kodumuri, Division of Cardiology, John H. Stroger Jr. Hospital of Cook County, 1969, W. Ogden Ave, Room 3620, Chicago, IL, 60612, USA. Phone: (312)-864-3427, Email: [email protected].
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Abstract
The current American College of Cardiology/ American Heart Association (ACC/AHA)
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guidelines (Grade IIb, level of evidence C) recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 6 months followed by lifelong aspirin after transcathter aortic valve implantation (TAVI). However, studies that have compared DAPT to single antiplatelet therapy (SAPT) following TAVI have questioned this recommendation as DAPT has been associated with
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more bleeding events compared to SAPT. We performed a meta-analysis of all the trials that compared DAPT to SAPT in patients undergoing TAVI. Three randomized trials and four nonrandomized studies were included. The primary endpoint was the rate of ischemic stroke.
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Secondary end points were the rates of myocardial infarction (MI), life threatening bleeding (LTB), significant bleeding (LTB and major bleeding) and death. The Mantel-Haenszel random
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effects model was used to calculate the combined odds ratios (OR) and 95% confidence
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intervals (CI) for outcomes at 30 days and up to 6-12 months follow-up. The LTB (OR 2.73, 95% CI 1.31-5.69, P=0.007) and significant bleeding rates (OR 2.76, 95% CI 1.57-4.85, P=0.0004) were
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significantly higher in DAPT arm at 30 days. Significant bleeding (OR 2.24, 95% CI 1.33-3.79,
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P=0.002) was still significantly higher in the DAPT arm but there was only a non-significant trend towards higher LTB (OR 1.93 95% CI 0.61-6.03, P=0.26) at 6-12 month follow up. There was no difference in mortality, ischemic stroke and MI at 30 days or 6-12 month follow up. In conclusion, our meta-analysis shows that DAPT following TAVI does not confer any additional benefit over SAPT in TAVI.
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Introduction Transcatheter aortic valve implantation (TAVI) has become the standard of care for the treatment of severe aortic stenosis in inoperable patients1 and was shown to be non-inferior to
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surgical aortic valve replacement in patients who are at high and intermediate surgical risk2,3. However, the optimal anti-thrombotic regimen after TAVI remains controversial. The initial trials evaluating the efficacy of TAVI 1,2 used dual antiplatelet therapy (DAPT) for 3-6 months
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after TAVI. Prior small observational4,5 and randomized studies6-8 failed to show a significant benefit with DAPT after TAVI compared to single antiplatelet therapy (SAPT). Also, surveys of TAVI operators have shown a wide variation in anti-thrombotic regimen prescriptions after TAVI and especially antiplatelet agents9. Therefore, we performed a meta-analysis of the trials that
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Methods
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thrombotic regimen after TAVI.
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have compared DAPT with aspirin and clopidogrel to SAPT to evaluate the optimal anti-
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We performed a systematic literature review in PubMed, MEDLINE, SCOPUS, and Cochrane for all the related articles until December 2017. Search terms included “TAVR”,
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“TAVI”, “Transcatheter aortic valve replacement”, “anti-thrombotic agents”, “antiplatelet agents”, “dual antiplatelet therapy”, “single antiplatelet”, “aspirin” and “DAPT”. All the results were downloaded to EndNote; a citation manager and duplicate citations were removed. We included all randomized controlled trials (RCT) and observational studies comparing SAPT to DAPT following TAVI. Studies that reported outcomes at 1 month and/or 6 months follow-up
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were included. Studies that reported only in-hospital outcomes were excluded. Studies that used anticoagulants (warfarin or newer oral anticoagulants) in the study groups were excluded. Two authors (S.S and U.J) independently screened each trial from the search criteria, and determined the eligibility for inclusion after full text evaluation. Only published manuscripts
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were included for the analysis. All disagreements between authors regarding eligibility of study inclusion were resolved by discussion. The literature search yielded three RCT’s6-8 and four observational studies4,5,10,11 which were included for the study protocol. The search strategy for
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our analysis is shown in Figure 1. The characteristics of the included trials are described in Table 1 and Table 2. The meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) statement12.
Three authors (S.S, S.B and U.J) independently performed data extraction from each trial
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that included the following: number of patients in each treatment arm, duration of DAPT,
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length of follow-up and number of events for each outcome (ischemic stroke, MI, life threatening and major bleeding and death). The primary end point studied was rate of ischemic
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strokes. The secondary end points were the rates of MI, life threatening bleeding (LTB),
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significant bleeding (LTB and major bleeding) and death. The outcomes were analyzed at 30 days and at 6 to 12 months. All outcomes were based on the accepted consensus definitions
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described by Valve Academic Research Consortium (VARC)13. Data was analyzed on an intention to treat basis. Measures of heterogeneity, including
Cochran’s Q-statistic and I2 index tests, were computed. An I2 index of 25% was considered to indicate significant heterogeneity. The Mantel-Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). P value of less than or equal to 0.05
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was considered to be significant. The meta-analysis was performed using Review Manager (RevMan) Version 5.3. Study quality was assessed by using Cochrane risk of bias tool for RCTs (Figure 2) and Newcastle-Ottawa scale for nonrandomized studies (Table 4).
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Results
Three randomized trials 6-8 and four non-randomized studies4,5,10,11 involving 1389 patients were included, of which 772 patients received DAPT and 617 received SAPT. The
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baseline characteristics were similar between the two treatment arms. The mean age of the population studied was 82 years and included 55.6% females. Two studies5,6 used Medtronic CoreValve (MCV) only and three studies7,8,10 used Edward’s SAPIEN XT valve (ESV) while Durand
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et al4 used both MCV and ESV (Table 1). Aspirin was used as the SAPT strategy in all the patients in majority of the trials. However, 8% of patients in Durand et al4 study and some patients in
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the study by Mangieri et al11 (number of patients not specified) received clopidogrel as SAPT
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strategy while the remaining patients received aspirin. 2 studies reported outcomes at 30 days only and 2 studies reported outcomes at 12 months only, while 3 studies reported outcomes at
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30 days and 6-12months. Outcomes at 30 days and 6-12 months are shown in Figure 3 and
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Figure 4 respectively.
At 30 days follow up, LTB (OR 2.73, 95% CI 1.31-5.69, P=0.007) and significant bleeding
(OR 2.76, 95% CI 1.57-4.85, P=0.0004) rates were significantly higher in the DAPT arm compared to SAPT. There was no significant difference in the rate of Ischemic stroke (OR 0.81, 95% CI 0.16-3.95, P=0.79), MI (OR 1.37, 95% CI 0.32-5.85, P=0.43) and mortality (OR 1.31, 95% CI 0.74-2.33, P=0.35).
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At 6-12 months follow up, significant bleeding rates (OR 2.24, 95% CI 1.33-3.79, P=0.002) were significantly higher in the DAPT arm and there was a non-significant trend towards higher LTB (OR 1.93 95% CI 0.61-6.03, P=0.26) in the DAPT arm. There was no significant difference in the rate of ischemic stroke (OR 0.81, 95% CI 0.16-3.95, P=0.79), MI (OR
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2.82, 95% CI 0.85-9.33, P=0.09) and mortality (OR 1.05, 95% CI 0.64-1.72, P=0.84).
Discussion
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In this meta-analysis, we analyzed the outcomes at 30 days and up to 6-12 months from all the RCTs and observational studies that compared DAPT to SAPT after TAVI. The results of our study show that DAPT after TAVI significantly increases LTB and significant bleeding when compared to SAPT without any benefit in ischemic and thromboembolic endpoints.
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The rate of stroke following TAVI in various trials has been reported to be between
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1.2%-6%14-16. Stroke following TAVI Is classified as acute (<24 hours), subacute (1-30 days) and late (>30 days), depending on the timing of the stroke after the procedure. The lack of benefit
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of DAPT for stroke prevention is likely related to the pathophysiology of stroke following TAVI.
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In a study that evaluated the predictors of stroke after TAVI, acute (<24 hours) stroke was associated with procedural events like wire manipulation, balloon post-dilation of the valve
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prosthesis and valve dislodgement/embolization. This finding was corroborated by two other studies that evaluated the cerebral embolic burden during the TAVI procedure with transcranial Doppler examination17,18. They found that high-Intensity transient signals (HITS), which are surrogate markers for micro embolization were highest during wire manipulation of the calcific aortic arch and during valve deployment. Thus, acute stroke maybe related to the mechanical
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interaction between the valve prosthesis and the calcific native aortic valve for which DAPT may not be helpful. Subacute (1-30 days) and late strokes (>30 days) were associated with newonset atrial arrhythmias and chronic atrial arrhythmias respectively and DAPT has not been shown to be beneficial in preventing strokes related to atrial arrhythmias19. The above reasons
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may explain the lack of benefit of DAPT in preventing ischemic strokes post TAVI. Use of
cerebral embolic protection devices and certain procedural changes such as avoiding balloon pre-dilation and rapid pacing and decreasing contact with the aortic arch have shown to
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decrease stroke after TAVI20,21. However, these strategies need to be further evaluated in larger studies.
MI after TAVI in various trials and registries have ranged from 1-6%22. In our analysis, there was no significant difference in the rate of MI between the two treatment arms after
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TAVI. Again, the lack of benefit with DAPT in preventing MI may be related to the
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pathophysiology of MI following TAVI. The rate of symptomatic coronary occlusion in a study following TAVI was found to be only 0.6%23. It means that there might be other potential
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factors causing MI after TAVI like direct myocardial injury during the procedure, hemodynamic
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shifts causing hypotension and bleeding from DAPT. Even in cases when MI is due to coronary obstruction, the most common mechanism of coronary obstruction is due to blocking of the
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coronary ostium by the displaced native aortic valve cusp rather than due to thrombosis23. Patients undergoing TAVI are elderly with a mean age more than 80 years and may have
multiple co-morbidities predisposing them to higher bleeding risk. In our analysis, both life threatening bleeding (LTB) and significant bleeding (LTB and major bleeding) was found to be significantly higher in patients receiving DAPT compared to SAPT. This finding is especially
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important as multiple analysis have shown LTB and major bleeding to be a predictor of increased mortality24,25. Accurate vascular access with the help of imaging modalities such as multi-detector computed tomography (MDCT) to carefully assess vascular anatomy routinely has been associated with fewer bleeding complications26. Use closure devices and newer TAVI
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devices that require smaller sheaths are other potential options to further decrease bleeding risk in the future. The current 2017 ACC/AHA guidelines update also give a IIb (LOE B)
recommendation for using warfarin for 3 months after TAVI. Imaging studies that have shown
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lower rate of prosthetic valve thrombosis and higher rate of resolution of valve thrombosis after initiation of warfarin in patients who developed valve thrombosis post TAVI27,28. Given these findings anticoagulation with warfarin may be more reasonable compared to DAPT following TAVI in appropriate patients.
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Our study had several limitations. There was significant heterogeneity between the
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trials and to account for this heterogeneity random effects model was used to calculate the outcomes. As there was paucity in randomized data we combined both randomized and non-
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randomized studies and that might have introduced selection bias. Clopidogrel was used as
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SAPT strategy in a few patients in 2 trials and this might have confounded outcome results. The study population was relatively small and 12-month data was not available for all the studies.
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In conclusion, the results of our meta-analysis suggest that DAPT does not confer any benefit in preventing stroke, MI or mortality when compared to SAPT but it increases major and life-threatening bleeding rates. Our analysis does not support current ACC/AHA guidelines of using DAPT for 6 months after TAVI. Further larger scale RCTs are required to evaluate the adequate anti-thrombotic regimen after TAVI.
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18. Szeto WY, Augoustides JG, Desai ND, Moeller P, McGarvey ML, Walsh E, Bannan A,
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Herrmann HC, Bavaria JE. Cerebral embolic exposure during transfemoral and transapical transcatheter aortic valve replacement. J Card Surg 2011;26:348-354.
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19. Investigators AWGotA, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-1912.
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20. Seeger J, Gonska B, Otto M, Rottbauer W, Wohrle J. Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement Significantly Reduces Death and Stroke Compared With Unprotected Procedures. JACC Cardiovasc Interv 2017;10:2297-2303. 21. Kleiman NS, Maini BJ, Reardon MJ, Conte J, Katz S, Rajagopal V, Kauten J, Hartman A, McKay
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R, Hagberg R, Huang J, Popma J, CoreValve I. Neurological Events Following Transcatheter Aortic Valve Replacement and Their Predictors: A Report From the CoreValve Trials. Circ Cardiovasc Interv 2016;9.
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22. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, Smith C, Serruys PW, Kappetein AP, Leon MB. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. Journal of the American College of Cardiology 2012;59:2317-2326.
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23. Ribeiro HB, Webb JG, Makkar RR, Cohen MG, Kapadia SR, Kodali S, Tamburino C, Barbanti
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M, Chakravarty T, Jilaihawi H, Paradis JM, de Brito FS, Jr., Canovas SJ, Cheema AN, de Jaegere PP, del Valle R, Chiam PT, Moreno R, Pradas G, Ruel M, Salgado-Fernandez J, Sarmento-Leite R,
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Toeg HD, Velianou JL, Zajarias A, Babaliaros V, Cura F, Dager AE, Manoharan G, Lerakis S,
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Pichard AD, Radhakrishnan S, Perin MA, Dumont E, Larose E, Pasian SG, Nombela-Franco L, Urena M, Tuzcu EM, Leon MB, Amat-Santos IJ, Leipsic J, Rodes-Cabau J. Predictive factors,
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management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. Journal of the American College of Cardiology 2013;62:1552-1562.
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24. Halliday BP, Dworakowski R, Brickham B, Wendler O, MacCarthy P. Usefulness of periprocedural bleeding to predict outcome after transcatheter aortic valve implantation. Am J Cardiol 2012;109:724-728. 25. Borz B, Durand E, Godin M, Tron C, Canville A, Litzler PY, Bessou JP, Cribier A, Eltchaninoff H.
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Incidence, predictors and impact of bleeding after transcatheter aortic valve implantation using the balloon-expandable Edwards prosthesis. Heart 2013;99:860-865.
26. Toggweiler S, Gurvitch R, Leipsic J, Wood DA, Willson AB, Binder RK, Cheung A, Ye J, Webb
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JG. Percutaneous aortic valve replacement: vascular outcomes with a fully percutaneous procedure. Journal of the American College of Cardiology 2012;59:113-118.
27. Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, De Backer O, Asch FM, Ruiz CE, Olsen NT, Trento A, Friedman J, Berman D, Cheng W, Kashif M, Jelnin V, Kliger CA, Guo H,
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Pichard AD, Weissman NJ, Kapadia S, Manasse E, Bhatt DL, Leon MB, Sondergaard L. Possible
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Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. The New England journal of medicine 2015;373:2015-2024.
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28. Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM, Jensen KT, Blanke
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P, Leetmaa T, Tang M, Krusell LR, Klaaborg KE, Christiansen EH, Terp K, Terkelsen CJ, Poulsen SH, Webb J, Botker HE, Norgaard BL. Transcatheter Aortic Valve Thrombosis: Incidence,
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Predisposing Factors, and Clinical Implications. J Am Coll Cardiol 2016;68:2059-2069.
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Legends Figure 1 PRISMA Flow diagram of study selection
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Figure 2 Cochrane risk of bias tool for randomized controlled trials
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Figure 3 Meta- analysis at 30 days follow up DAPT, dual antiplatelet therapy; LTB, life-threatening bleeding; MI, myocardial infarction; SAPT, single antiplatelet therapy;
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Figure 4 Meta- analysis at 6 months to 12 months follow up DAPT, dual antiplatelet therapy; LTB, life-threatening bleeding; MI, myocardial infarction; SAPT, single antiplatelet therapy;
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Study
Endpoint Type of Follow study & year up (months)
Antiplatelet
Stabile
RCT, 2011
1 and 6
30-day mortality
aspirin vs aspirin/clopidogrel or NA aspirin/ticlopidine
Ussia
RCT, 2011
1 and 6
death, MI, stroke, conversion to surgery and LTB
aspirin vs aspirin/clopidogrel
Poliacikova
Retrospective, 1 and 6 2013
mortality, ACS, stroke or major bleeding
Durand
Prospective, 2014
mortality, major stroke, LTB and MI
Mangieri
Retrospective, 12 2017
Ichibori
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Table 1. Study characteristics of trials comparing dual antiplatelet therapy to single antiplatelet therapy following Transcatheter aortic valve implantation
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ES: 100%
120 (100%)
CV: 100%
74 (94%)
aspirin vs aspirin/clopidogrel
NA
CV: 100%
167 (98%)
aspirin (clopidogrel if already on it) vs aspirin/clopidogrel
TF: 81%, rest: TA and TS
ES: 82% CV: 18%
281 (96%)
aspirin or clopidogrel vs aspirin/clopidogrel
TF: 100%
ES: 50% NA Rest: others
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mortality, major bleeding, CVA and redo-AVR
Valve type, Procedure success, % N (%)
TF: 97% TS: 3%
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Approach TAVR, %
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Rodes-Cabau
RCT, 2017
1 and 3
death, MI, stroke, and major bleeding or LTB
aspirin vs aspirin/clopidogrel or TA:53%, rest: ES: 100% aspirin/ticlopidine TF, TS and Tao
138 (96%)
death, MI, ischemic stroke or TIA, or major bleeding or LTB
aspirin vs aspirin/clopidogrel
195 (88%)
TF: 69%, rest: TF and TA
ES: 100%
ACS, acute coronary syndrome; AVR, aortic valve replacement; CV, CoreValve; CVA, cerebrovascular accident; DF, Direct Flow; ES, Edward’s Sapien; LTB, life-threatening bleeding; MI, myocardial infarction; MACE, major adverse cardiac events; MC, multicenter; NACE, net adverse cardiac events; RCT, randomized controlled trial; TA, transapical; Tao, transaortic;
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TAVR, transcatheter aortic valve replacement; TC, transcarotid; TF, transfemoral; TS, transsubclavian; TIA, transient ischemic attack;
Table 2. Baseline characteristics of patients included in the trials Ichibori
Durand
Ussia
Stabile
Overall
Overall
Overall
Overall
Overall
Overall
Overall
N
171
439
144
292
79
120
222
Age (years)
82±6
83±8
83±6
84±6
81±4
81±5
79±9
Women
80 (53%)
276 (63%)
BMI (kg/m2)
27±5
25± 4
HTN
NA
351 (80%)
DM
37 (22%)
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Patient Poliacikova characteristics
RodesCabau
152 (52%)
43 (54%) 80 (67%)
93 (41%)
NA
NA
NA
NA
NA
206 (70%)
66 (84%) 114 (95%)
173 (78%)
108 (25%)
46 (32%)
70 (24%)
21 (27%) 32 (27%)
77 (34%)
160 (36%)
NA
23 (8%)
11 (14%) NA
140 (63%)
51 (12%)
NA
82 (28%)
10 (13%) NA
NA
NA
NA
NA
38 (13%)
7 (9%)
NA
50 (22%)
Porcelain aorta
NA
NA
NA
14 (5%)
2 (3%)
NA
29 (13%)
Prior CVE
NA
61 (14%)
35 (24%)
25 (9%)
10 (13%) NA
46 (27%)
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Renal disease 11 (6%)
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NA
NA
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Prior MI
NA
76 (17%)
NA
36 (12%)
11 (14%) NA
46 (21%)
Prior PCI
41 (24%)
110 (25%)
36 (25%)
NA
21 (27%) NA
NA
Prior CABG
43 (25%)
90 (21%)
20 (14%)
40 (14%)
6 (8%)
81 (36%)
Mean aortic gradient (mmHg)
NA
NA
53±18
49±17
53 ±17
62±15
43 ± 16
Logistic Euro score (%)
NA
21.1±14.6
24.8±16.9
20.1±12.0
21±13
24.2± 10.2
NA
STS score (%)
NA
7.6±71
11.4±10.2
7.2±5.3
7.3±4
10.05±5.9
6.3±4.5
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AF, atrial fibrillation; AVA- aortic valve area; BMI, body mass index; CABG coronary artery bypass graft; CVE, cerebrovascular event; HTN, hypertension; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STS, society of thoracic surgery.
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Table 3. Summary table for Meta-Analysis Outcomes comparing Dual Antiplatelet Therapy vs Single Antiplatelet Therapy following Transcatheter Aortic Valve Replacement Studies
Odds Ratio (Confidence P Value Interval)
Ischemic stroke 30 days
3
0.81 (0.16-3.95)
0.79
MI 30 days
5
1.37 (0.32-5.85)
0.67
LTB 30 days
4
2.73 (1.31-5.69)
0.007
Significant bleeding 30 days
5
2.76 (1.57-4.85)
0.0004
Mortality 30 days
5
1.31 (0.74-2.33)
0.35
Ischemic stroke 6 months
3
0.81 (0.16-3.95)
0.79
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4
2.82 (0.85-9.33)
0.09
LTB 6 months
3
1.93 (0.61-6.03)
0.26
Significant bleeding 12 months 5
2.24 (1.33-3.79)
0.002
Mortality 12 months
1.05 (0.64-1.72)
0.84
6
LTB, life threatening bleeding; MI, myocardial infarction.
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MI 12 months
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Table 4. Assessment of Quality of Nonrandomized Studies using the Newcastle-Ottawa Scale Study Selection Comparability Outcome Poliacikova 2013 ★★★★ ☆☆ ★★☆ Durand 2014 ★★★★ ★★ ★★★ Ichibori 2017 ★★★★ ★★ ★★☆ Mangieri 2017 ★★★★ ★☆ ★★★