Cardiol Ther (2018) 7:71–77 https://doi.org/10.1007/s40119-018-0111-4 ORIGINAL RESEARCH Impact of Antithrombotic Regimen on Mortality, Ischemic, and Bleeding Outcomes after Transcatheter Aortic Valve Replacement . . . Anubodh Varshney Ryan A. Watson Andrew Noll . . . KyungAh Im Jeffrey Rossi Pinak Shah Robert P. Giugliano Received: March 30, 2018 / Published online: May 19, 2018 The Author(s) 2018 2014. Antithrombotic regimens were classiﬁed ABSTRACT as single or dual antiplatelet therapy (AP), single antiplatelet plus anticoagulant (SAC), or triple Introduction: Optimal antithrombotic therapy therapy (TT). The primary endpoint was a after transcatheter aortic valve replacement composite of death, myocardial infarction (MI), (TAVR) remains unclear. We evaluated the stroke, and major bleeding. Adjusted hazard association between antithrombotic regimens ratios (HRs) were obtained with best subset and outcomes in TAVR patients. variable selection methods using bootstrap Methods: We retrospectively analyzed consec- resampling. utive patients who underwent TAVR at a single Results: Of 246 patients who underwent TAVR, academic center from April 2009 to March 241 were eligible for analysis with 133, 88, and Enhanced digital features To view enhanced digital 20 patients in the AP, SAC, and TT groups, features for this article, go to https://doi.org/10.6084/ respectively. During a median 2.1-year follow- m9.ﬁgshare.6205685. up, 53.5% had at least one endpoint—the most common was death (68%), followed by major A. Varshney bleeding (23%), stroke (6%), and MI (3%). At Brigham and Women’s Hospital Department of Medicine and Harvard Medical School, Boston, MA, 2 years, the composite outcome occurred in USA 70% of TT, 42% of SAC, and 31% of AP patients. Compared to AP, adjusted HRs for the com- R. A. Watson Department of Medicine, Division of Cardiology, posite outcome were 2.88 [95% Conﬁdence Thomas Jefferson University Hospital, Philadelphia, intervals (CI) (1.61–5.16); p = 0.0004] and 1.66 USA (95% CI [1.13-2.42]; p = 0.009) in the TT and A. Noll J. Rossi SAC groups, respectively. Mortality rates at Department of Cardiovascular Medicine, Cleveland 2 years were 61% in the TT, 32% in the SAC, Clinic, Cleveland, OH, USA and 26% in the AP groups (p = 0.005). Conclusions: The risk of the composite out- K. Im R. P. Giugliano (&) Thrombolysis in Myocardial Infarction (TIMI) Study come of death, MI, stroke, or major bleeding at Group, Brigham and Women’s Hospital, Harvard 2-year follow-up was signiﬁcantly higher in Medical School, Boston, MA, USA TAVR patients treated with TT or SAC versus AP, e-mail: firstname.lastname@example.org even after multivariate adjustment. P. Shah R. P. Giugliano Brigham and Women’s Hospital Heart and Vascular Keywords: Antithrombosis; Aortic stenosis; Center and Harvard Medical School, Boston, MA, USA Transcatheter aortic valve replacement 72 Cardiol Ther (2018) 7:71–77 procedural characteristics were collected. INTRODUCTION Patients were then prospectively followed for ascertainment of study outcomes. The Institu- Transcatheter aortic valve replacement (TAVR) tional Review Board of Partners Healthcare in has become an established treatment for Boston, Massachusetts, approved the study, and patients with symptomatic, severe aortic signed informed consent was obtained from stenosis with intermediate, high, or prohibitive each patient. All procedures performed in surgical risk [1–5]. Despite advances in patient studies involving human participants were in selection, operator experience, and valve deliv- accordance with the 1964 Helsinki Declaration ery systems, ischemic and bleeding complica- and its later amendments or comparable ethical tions remain important concerns after TAVR, as standards. they are associated with increased morbidity and mortality [6–8]. However, limited data are available comparing long-term outcomes with Antithrombotic Regimen varying antithrombotic regimens after TAVR. Current guidelines recommend dual anti- The antithrombotic regimen was noted pre- platelet therapy with aspirin (indeﬁnitely) and TAVR, at the time of discharge from TAVR clopidogrel (for 1–6 months) after TAVR in admission, at 30 days, at 1 year, and through patients with no indication for therapeutic oral April 2016 using electronic health records and anticoagulation (OAC). In patients with an telephone follow-up. Antithrombotic regimens indication for OAC, guidelines generally rec- were classiﬁed as single or dual antiplatelet ommend against the use of triple therapy therapy only (AP), single antiplatelet plus anti- [9–12]. However, these recommendations have coagulant therapy (SAC), or triple therapy (TT) been made empirically and vary amongst pro- with DAPT plus OAC. Patients were grouped fessional societies, leading to heterogeneity in according to the antithrombotic regimen at the clinical practice . time of latest follow-up for the purposes of the We sought to examine the association statistical analysis. between different antithrombotic regimens and the risk of mortality, ischemic, and bleeding Outcomes outcomes in a non-selected clinical population undergoing TAVR. Speciﬁcally, we compared The primary endpoint was the composite of outcomes among TAVR patients prescribed death, myocardial infarction (MI), stroke, or single or dual antiplatelet therapy (AP), a single major bleeding (requiring hospitalization, life- antiplatelet agent plus OAC (SAC), or triple threatening, or fatal). Outcomes were assessed therapy (TT) with dual antiplatelet therapy according to Valve Academic Research Consor- (DAPT) and OAC. tium-2 deﬁnitions  at discharge, 30 days, 1 year, and through April 2016 using electronic medical record data and telephone follow-up METHODS with a standardized questionnaire. Study Population Statistical Analysis We retrospectively analyzed consecutive patients who underwent TAVR at Brigham and To determine associations between antithrom- Women’s Hospital in Boston, Massachusetts, botic therapy group and the primary composite from April 2009 through March 2014. Baseline outcome, a Cox proportional hazards model medical history, routine laboratory testing, was used. A multivariable model was developed electrocardiography, echocardiography, with best subset variable selection methods CHA2DS2-VASc score, ATRIA score, New York using bootstrap resampling in order to account Heart Association functional classiﬁcation, pre- for model variation due to small sample size procedure antithrombotic regimen, and TAVR . The ﬁnal model included adjustment for Cardiol Ther (2018) 7:71–77 73 chronic lung disease, prior percutaneous coro- (Fig. 1). Mortality rates at 2 years were 61%, nary intervention (PCI), male sex, age, and low- 32%, and 26% (p = 0.005) in the TT, SAC, and gradient aortic stenosis (deﬁned as left ventric- AP groups, respectively, while major bleeding ular ejection fraction \ 50%, aortic valve rates were 29%, 18%, and 9.1%, respectively area \ 1.0 cm , and mean aortic valve gradi- (p = 0.02). Rates of stroke and MI were low and ent \ 40 mmHg). Results are reported as adjus- similar among groups. ted hazard ratios (HR) and 95% conﬁdence A total of 132 patients in the cohort had an intervals (CI). Proportional hazards assumption indication for OAC (88.6% had atrial ﬁbrillation for the ﬁnal model was assessed by score tests or ﬂutter), including 40 in the AP group, 76 in using scaled Schoenfeld residuals. Crude the SAC group, and 16 in the TT group. Among cumulative event rates were calculated by the patients with an indication for OAC, the com- complement of Kaplan–Meier survival esti- posite outcome occurred in 69% of TT, 38% of mates, and log-rank test p values are also SAC, and 38% of AP patients (p = 0.06) at 2-year reported. All reported p values are two-sided, follow-up. and signiﬁcance level was set at alpha 0.05. Analyses were performed using SAS version 9.4 DISCUSSION (SAS Institute Inc., Cary, NC, USA). This study evaluated the association between RESULTS post-TAVR antithrombotic regimen and the composite outcome of death, MI, stroke, or Table 1 outlines the baseline characteristics of major bleeding in a single-center cohort of 241 each study group. A total of 246 patients consecutive patients with at least 2-year follow- underwent TAVR from April 2009 to March up. Patients treated with TT or SAC versus AP 2014. Of these, ﬁve patients were excluded for had a higher incidence of the composite out- the following reasons: prescribed no come, even after multivariate adjustment. This antithrombotic therapy (n = 2) and incomplete ﬁnding was driven by an increase in both mor- post-discharge follow-up (n = 3), leaving 241 tality and major bleeding in the TT and SAC patients for ﬁnal analysis. The baseline charac- groups. teristics among the AP (n = 133), SAC (n = 88), TAVR patients are at high risk for both and TT (n = 20) groups were similar, with the ischemic and bleeding events by virtue of co- exception of rates of atrial ﬁbrillation or ﬂutter morbidities and the procedure itself. Both types (p \ 0.01), indication for OAC (p \ 0.01), aortic of complications are associated with increased valve mean gradient (p = 0.044), and aortic morbidity and mortality. Moreover, TAVR valve peak velocity (p = 0.047) (Table 1). Over- patients frequently undergo pre-emptive coro- all, 67.2% of cases were done with a trans- nary artery stenting, which necessitates DAPT, femoral approach, while 16.2% and 15.8% of and approximately half have atrial ﬁbrillation cases were performed via a transapical and requiring OAC. Given this complex interplay, transaortic approach, respectively. identifying an antithrombotic regimen that Of the 241 patients followed for a median of achieves an optimal balance between ischemic 2.1 years (interquartile range, 0.7–2.9 years), protection and bleeding risk mitigation is 53.5% (n = 129) had at least one endpoint. The paramount in this patient population. Never- components of the composite outcome in the theless, guideline recommendations for cohort were distributed as death (68%), major antithrombotic therapy after TAVR remain bleeding (23%), stroke (6%), and MI (3%) at empiric, and are extrapolated from the PCI 2-year follow-up. The risk of the composite experience and early TAVR clinical trial proto- outcome was highest with TT (70%; HR 2.88, cols . 95% CI 1.61–5.16, p = 0.0004) and intermediate Our analysis indicates that treatment with with SAC (42%; HR 1.66, 95% CI 1.13–2.42, TT or SAC is associated with adverse clinical p = 0.009), compared to AP (31%) at 2 years outcomes compared to treatment with AP alone 74 Cardiol Ther (2018) 7:71–77 Table 1 Patient characteristics by study group AP (n = 133) SAC (n = 88) TT (n = 20) Overall (n = 241) p value Age (years) 80.9 ± 10.0 81.0 ± 7.9 80.9 ± 6.3 80.9 ± 9.0 0.68 Male sex, n (%) 63 (47.4) 53 (60.2) 12 (60) 128 (53.1) 0.14 BMI (kg/m ) 26.6 ± 7.4 28.2 ± 5.9 28.1 ± 5.3 27.3 ± 6.8 0.053 Atrial ﬁbrillation or ﬂutter, n (%) 31 (23.3) 72 (81.8) 14 (70) 117 (48.5) \0.001 Prior DVT/PE, n (%) 9 (6.8) 11 (12.5) 2 (10) 22 (9.1) 0.35 CHA2DS2-VASc score 5.2 ± 1.3 5.5 ± 1.2 5.7 ± 1.1 5.4 ± 1.3 0.10 ATRIA score 2.7 ± 1.0 2.7 ± 0.8 3.1 ± 0.8 2.7 ± 0.9 0.20 Indication for OAC, n (%) 40 (30.1) 76 (86.4) 16 (80) 132 (54.8) \0.001 Prior GI bleeding, n (%) 23 (17.3) 9 (10.2) 4 (20) 36 (14.9) 0.28 Dyslipidemia, n (%) 105 (78.9) 72 (81.8) 20 (100) 197 (81.7) 0.076 Hypertension, n (%) 117 (88) 81 (92) 20 (100) 218 (90.5) 0.19 Diabetes mellitus, n (%) 52 (39.1) 37 (42) 7 (35) 96 (39.8) 0.82 Prior PCI, n (%) 37 (27.8) 25 (28.4) 9 (45) 71 (29.5) 0.28 Peripheral arterial disease, n (%) 30 (22.6) 19 (21.6) 6 (30) 55 (22.8) 0.72 Cerebrovascular disease, n (%) 14 (10.5) 16 (18.2) 4 (20) 34 (14.1) 0.20 Chronic lung disease, n (%) 49 (36.8) 41 (46.6) 8 (40) 98 (40.7) 0.35 On hemodialysis, n (%) 5 (3.8) 2 (2.3) 1 (5) 8 (3.3) 0.76 NYHA class, n (%) 0.86 I 0 (0) 1 (1.2) 0 (0) 1 (0.4) II 7 (5.7) 5 (5.9) 2 (10.5) 14 (6.2) III 82 (66.7) 55 (64.7) 11 (57.9) 148 (65.2) IV 34 (27.6) 24 (28.2) 6 (31.6) 64 (28.2) LVEF (%) 52.9 ± 15.0 54.4 ± 14.2 55.3 ± 16.8 53.7 ± 14.8 0.60 Aortic valve area (cm ) 0.6 ± 0.2 0.7 ± 0.2 0.7 ± 0.1 0.7 ± 0.2 0.65 Aortic valve mean gradient (mmHg) 47.0 ± 13.8 41.7 ± 12.3 43.1 ± 15.6 44.8 ± 13.6 0.045 Aortic valve peak velocity (m/s) 4.4 ± 0.6 4.2 ± 0.6 4.3 ± 0.8 4.3 ± 0.6 0.047 Low gradient AS , n (%) 24 (18) 11 (12.5) 2 (10) 37 (15.4) 0.42 Moderate or severe MR, n (%) 47 (38.5) 33 (38.4) 7 (36.8) 87 (38.3) 0.99 Valve sheath access site n (%) 0.41 Transfemoral 93 (69.9) 56 (63.6) 13 (65) 162 (67.2) Transapical 15 (11.3) 20 (22.7) 4 (20) 39 (16.2) Transaortic 24 (18) 11 (12.5) 3 (15) 38 (15.8) Cardiol Ther (2018) 7:71–77 75 Table 1 continued AP (n = 133) SAC (n = 88) TT (n = 20) Overall (n = 241) p value Other 1 (0.8) 1 (1.1) 0 (0) 2 (0.8) Continuous variables are presented as mean ± standard deviation AP antiplatelet therapy, SAC single antiplatelet plus oral anticoagulant therapy, TT triple therapy, BMI body mass index, DVT deep venous thrombosis, PE pulmonary embolism, ATRIA anticoagulation and risk factors in atrial ﬁbrillation, OAC oral anticoagulation, GI gastrointestinal, PCI percutaneous coronary intervention, NYHA New York Heart Association, LVEF left ventricular ejection fraction, AS aortic stenosis, MR mitral regurgitation Deﬁned as aortic valve mean gradient \ 40 mmHg, left ventricular ejection fraction \ 50%, and aortic valve area \1cm when fewer antithrombotic agents are used, omitting an anticoagulant in patients with atrial ﬁbrillation (or another indication for OAC) signiﬁcantly increases the risk of throm- boembolism, which often has more serious clinical consequences than bleeding. The relatively low number of patients, espe- cially in the TT group, is an important limita- tion of our study. Additionally, patients in the TT and SAC groups had higher rates of atrial ﬁbrillation/ﬂutter and an indication for OAC, which could have led to confounding by indi- cation despite our use bootstrap resampling. Patients were categorized based on antithrom- Fig. 1 Kaplan–Meier time-to-event curves for the primary botic regimen at the latest time of follow-up, composite endpoint of death, myocardial infarction, and results could differ if an intention-to-treat stroke, or major bleeding stratiﬁed by treatment group. analysis was carried out. The patients we studied TAVR transcatheter aortic valve replacement, HR hazard represent a high-risk cohort, as evidenced by ratio, CI conﬁdence interval, AP antiplatelet therapy, SAC the large burden of co-morbidities and high single antiplatelet plus anticoagulant therapy, TT triple 2-year mortality rate. Thus, our results may not therapy be applicable to lower-risk patients. Lastly, our study is observational in nature, and random- after TAVR, which is consistent with ﬁndings ized trials are needed to determine the optimal from other studies of patients undergoing TAVR antithrombotic regimen after TAVR in patients with and without an indication for anticoagu- [17, 18] and surgical aortic valve replacement . We did not observe a beneﬁt on ischemic lation. The recently reported aspirin versus aspirin ? clopidogrel following transcatheter endpoints with regimens using 2 or 3 antithrombotics compared to AP alone, as rates aortic valve implantation (ARTE) trial demon- of MI and stroke were similar among the three strated that aspirin monotherapy reduced risk treatment groups, but the study was not pow- of bleeding, without increasing the risk of MI or ered to do so. In addition to higher rates of stroke, compared to DAPT in TAVR patients bleeding with TT and SAC, we observed a higher . Ongoing trials include ATLANTIS mortality rate with these treatment strategies (NCT02664649), AUREA (NCT01642134), AVA- TAR (NCT02735902), ENVISAGE-TAVR compared to AP. Importantly, our analysis shows that these effects persisted over a period (NCT02943785), GALILEO (NCT02556203), POPular-TAVI (NCT02247128), and TICTAVR of 2 years. However, while bleeding is reduced (NCT02817789). The results of these trials will 76 Cardiol Ther (2018) 7:71–77 likely inform future guidelines and clinical 1964 Helsinki declaration and its later amend- decision-making. ments or comparable ethical standards. Informed consent was obtained from all indi- vidual participants included in the study. CONCLUSIONS Data Availability. The datasets during and/ In a consecutive series of patients from our or analyzed during the current study are avail- institution undergoing TAVR between 2009 and able from the corresponding author on reason- 2014, treatment with triple therapy or a single able request. antiplatelet agent plus an oral anticoagulant was associated with an increased risk of the Open Access. This article is distributed composite of death, MI, stroke, or major under the terms of the Creative Commons bleeding at 2 years compared to treatment with Attribution-NonCommercial 4.0 International antiplatelet therapy alone, even after multi- License (http://creativecommons.org/licenses/ variable adjustment. Further prospective inves- by-nc/4.0/), which permits any noncommercial tigations to determine the optimal use, distribution, and reproduction in any antithrombotic regimen in TAVR patients are medium, provided you give appropriate credit awaited. to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. ACKNOWLEDGEMENTS We thank the participants of the study. REFERENCES Funding. No funding or sponsorship was 1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, received for this study or publication of this Svensson LG, et al. Transcatheter aortic-valve article. implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597–607. Authorship. All named authors meet the International Committee of Medical Journal 2. Smith CR, Leon MB, Mack MJ, Miller DC, Moses Editors (ICMJE) criteria for authorship for this JW, Svensson LG, et al. 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Cardiology and Therapy – Springer Journals
Published: May 19, 2018
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