Dual antiplatelet therapy versus single antiplatelet ...

Cardiovascular Revascularization Medicine xxx (2018) xxx–xxx

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Cardiovascular Revascularization Medicine

Dual antiplatelet therapy versus single antiplatelet therapy after transaortic valve replacement: Meta-analysis☆ Abdulah Alrifai a,⁎, Mohamad Soud b, Amjad Kabach c, Yash Jobanputra a, Abdulrahman Masrani d, Saleh El Dassouki e, M. Chadi Alraies f, Zaher Fanari g a

University of Miami/JFK Medical Center, Atlantis, FL, USA MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA Creighton University, School of Medicine, Omaha, NE, USA d Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, USA e Jackson Memorial Hospital/University of Miami, Miller School of Medicine, Division of Cardiovascular Medicine, Miami, FL, USA f Wayne State University, Detroit Medical Center, Detroit, MI, USA g Heartland Cardiology/Wesley Medical Center, University of Kansas School of Medicine, Wichita, KS, USA b c

a r t i c l e

i n f o

Article history: Received 29 January 2018 Received in revised form 9 March 2018 Accepted 9 March 2018 Available online xxxx Keywords: Transcatheter aortic valve replacement Antiplatelet Dual antiplatelet therapy Bleeding

a b s t r a c t Background: The current guidelines recommend empirical therapy with DAPT of aspirin and clopidogrel for six months after TAVR. This recommendation is based on expert consensus only. Giving the lack of clear consensus on treatment strategy following TAVR. Goal of this meta-analysis is to assess the efficacy and safety of monoantiplatelet therapy (MAPT) versus dual antiplatelet therapy (DAPT) following transcatheter aortic valve replacement (TAVR). Methods and Materials: We performed a meta-analysis from randomized clinical trials (RCTs) and prospective studies that tested DAPT vs. MAPT for all-cause mortality and major bleeding of 603 patients. The primary efficacy outcomes were 30 days mortality and stroke. The primary safety outcomes were major bleeding and major vascular complications. Results: We included 603 patients from 4 studies. The use of MAPT was associated with similar mortality rate (5.9% vs. 6.6%; RR = 0.92; 95% CI 0.49–1.71; P = 0.68) and stroke rate compared with DAPT (1.3% vs. 1.3%; RR 1.04; 95% CI 0.27 to 4.04; P = 0.81). There was no difference in major vascular complication (4.2% vs. 8.9%; RR 0.52; 95% CI 0.23 to 1.18; P = 0.17) or minor vascular complication (4.2% vs. 7.3%; RR 0.58; 95% CI 0.25 to 1.34; P = 0.14). However, MAPT was associated with significantly less risk of major bleeding (4.9% vs. 14.5%; RR 0.37; 95% CI 0.20 to 0.70; P b 0.01) but no difference in minor bleeding (4.2% vs. 3.6%; RR 1.16; 95% CI 0.43 to 3.10; P = 0.85). Conclusion: MAPT use after TAVR is associated with lower rates of major bleeding compared with DAPT with no significant difference in mortality, stroke or vascular complications. © 2018 Elsevier Inc. All rights reserved.

1. Background Transcatheter aortic valve replacement (TAVR) has emerged as a feasible and safe alternative to conventional surgical management of severe aortic stenosis (AS) in high and intermediate risk patients [1]. While improved technology and growing experience with TAVR led to

☆ Authorship declaration: All authors listed above meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors, and in agreement with the manuscript. ⁎ Corresponding author at: University of Miami Miller School of Medicine Regional Campus, 5301 Congress Avenue, Atlantis, FL 33462, USA. E-mail address: [email protected] (A. Alrifai).

continuous improvement in outcomes, TAVR is still associated with potentially serious ischemic and bleeding complications that can affect morbidity and mortality and leads to worse long-term prognosis [2–4]. To avoid ischemic complications, full-dose anticoagulation is usually administered during the TAVR procedure in addition to dual antiplatelet therapy following the procedure. It is a widely accepted practice to empirically use dual-antiplatelet therapy (DAPT) with clopidogrel in addition to acetylsalicylic acid (ASA). However; this approach is still lacking evidence-based support and is associated with a higher rate of bleedings particularly in elderly TAVR patients with multiple co-morbidities [5]. The currently recommended use of DAPT after TAVR is mainly based on expert consensus rather than clear clinical evidence. The current American College of Cardiology/American Heart Association (ACC/AHA) recommends

https://doi.org/10.1016/j.carrev.2018.03.008 1553-8389/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Alrifai A, et al, Dual antiplatelet therapy versus single antiplatelet therapy after transaortic valve replacement: Metaanalysis, Cardiovascular Revascularization Medicine (2018), https://doi.org/10.1016/j.carrev.2018.03.008

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A. Alrifai et al. / Cardiovascular Revascularization Medicine xxx (2018) xxx–xxx

empirical therapy with ASA and clopidogrel for six months after TAVR (Class IIb) [7]. Giving the lack of data supporting antiplatelet management following TAVR, we performed meta-analysis of studies comparing monoantiplatelet therapy (MAPT) with DAPT following TAVR.

2. Method Meta-analysis was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) guidelines (the PRISMA statement). We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception until July 30, 2017 using the keywords (transcatheter aortic replacement or transcatheter aortic valve implantation i.e. TAVR or TAVI) and (antiplatelet therapy or antiplatelet or ADP receptors inhibitor or clopidogrel or antithrombotic or DAPT). References of selected articles and reviews were manually reviewed for potential relevant citations. To be included in the meta-analysis, studies have to make head to-head comparisons of DAPT vs. MAPT in TAVR patients; all randomized controlled trials and observational studies that fulfilled the inclusion criteria were included. We included only completed, published, unconfounded trials. The inclusion criteria were studies only if they met the following: (1) randomized controlled clinical trials or prospective analysis (2) compared DAPT to MAPT in TAVR patients. (3) Included only patients with severe aortic valve stenosis (4). Were in English language and published online in a peer-reviewed journal. Two investigators (AA and AM) independently reviewed the titles/abstracts, assessed study eligibility, and extracted the data. Disagreements were resolved by consensus or resolved by the senior author. The following data were extracted from each eligible study: name of trial, first author, year of publication, patient profile, number of patients, age, characteristics of the population (gender, diabetes mellitus, hypertension, smoking, dyslipidemia, previous myocardial infarction, coronary artery disease, peripheral vascular disease, porcelain aorta, congestive heart failure, previous stroke, prior CABG, prior COPD, atrial fibrillation), and echocardiogram characteristics mean gradient (mm Hg), indexed aortic valve area (cm 2 /m 2 ), Aortic annulus diameter (mm), left ventricle ejection fraction. The absolute numbers of events were extracted for the measures of risk. The bias risk of randomized controlled trials was assessed by Jadad scale [15]. The quality of observational studies was assessed by the Newcastle-Ottawa Scale criteria [16]. The primary efficacy outcomes were 30 days mortality and stroke. The primary safety outcomes were major bleeding and major vascular complications. Secondary safety outcomes included minor bleeding and minor vascular complications. Outcomes in included studies were defined according Valve Academic Research Consortium criteria (VARC) and (VARC2) [17,18]. [MCA1] Results were extracted from intention-to-treat (ITT) data and expressed as a relative risk (RR) with accompanying 95% confidence intervals. If investigators didn't explicitly provide RR values, they were independently calculated using study data. P-values of b0.05 were deemed to be indicative of a statistically significant difference. Metaanalyses were then pursued for all outcomes of interest using both random-effects and fixed-effects modeling. The I2 statistic and forest plots were used to assess the degree of heterogeneity. Causes of heterogeneity were subsequently explored via subgroup analyses and meta regression. Sensitivity analyses were used to assess the impact of excluding studies based on methodological quality. Funnel plots were used to assess for publication bias. The analysis was performed using R v3.3.1 statistical software (Foundation for Statistical Computing, Vienna, Austria).

3. Results We identified 146 articles in our literature search. The final analysis included 4 studies, 3 randomized control studies and 1 prospective study, which met the inclusion criteria with a total of 603 patients (Fig. 1). We included 603 patients, 301 patients in the MAPT group vs. 302 in the DAPT group. Mean age was similar in both groups. About 61% of the patients were females in the MAPT group vs. 60% in the DAPT group. Almost all patients had normal ejection fraction 51%– 54.4% in MAPT group vs. 51–60.5% in DAPT group. Only high-risk patients were included, STS score of 6.2–0 in MAPT vs. 6.4–9.7 in the DAPT group. Table 1 shows the baseline characteristics of patients in each of the included studies. The DAPT arm in the population included in these trials was given Aspirin and Clopidogrel. The MAPT arm was given ASA (75–160 mg/day) [10–12], ASA 75 mg or Clopidogrel 75 mg [8]. Sapien and CoreValve were used. The duration of the treatment was 6 months except in Ussia's article [12], which was 3 months. All trials were RCTs except Durand article [8], which was prospective and observational. Rodes-cabau and colleagues did not report the events for major vascular complications, minor vascular complications and minor bleeds and thus was not included in the analysis of these variables. The Valve Academic Research Consortium (VARC) consensus document was updated in 2012 as the VARC-2 guidelines. 3 of our 4 studies were performed before 2012 and used the VARC definitions to report outcomes whereas ARTE trial used the VARC-2 guidelines for reporting outcomes. The use of MAPT was associated with similar mortality compared with DAPT (5.9% vs. 6.6%, respectively, RR = 0.92; 95% CI 0.49 to 1.71; P = 0.68) (Fig. 2-A). Similarly, there was no difference in rate of major strokes in both groups (1.3% vs. 1.3%; RR 1.04; 95% CI 0.27 to 4.04; P = 0.81) (Fig. 2-B). MAPT was associated with significantly less risk of major bleeding (4.9% vs. 14.5%; RR 0.37; 95% CI 0.20 to 0.70; P b 0.01; Fig. 3-A). However, there was no difference in major vascular complication (4.2% vs. 8.9%; RR 0.52; 95% CI 0.23 to 1.18; P = 0.17) (Fig. 3 B), minor bleeding (4.2% vs. 3.6%; RR 1.16; 95% CI 0.43 to 3.10; P = 0.85) (Fig. 4-A) or minor vascular complication (4.2% vs. 7.3%; RR 0.58; 95% CI 0.25 to 1.34; P = 0.14) (Fig. 4 B). Table 2. 4. Discussion The findings of this meta-analysis of prospective studies showed that while DAPT did not offer any benefit in reducing rates of all-cause mortality, stroke, minor or major vascular complication, it is associated with increased risk for major bleeding compared with MAPT. Dual antiplatelet therapy is the currently recommended by guidelines, as in the American heart association/American College of Cardiology 2014 guidelines for 6 months. [7] This strategy in theory provide stronger platelet inhibition with the possibly to reduce stroke risk, prosthesis thrombosis, and subsequently mortality. However, this benefit over MAPT is not well established. Also, taking into consideration the adverse outcome of increased bleeding which might counter any benefit that DAPT provide. DAPT for TAVR population who are elderly patients with multiple comorbidities often jeopardize the antithrombotic benefit as it increased risk of bleeding. All studies in this meta-analysis were either randomized or prospective studies. Both Rodés-Cabau et al. [10] and Durand et al. [8] studies were in favor of MAPT in term of reduction in life threatening bleeding with no difference between the two groups in mortality, stroke or myocardial infarction. Stabile et al were able to demonstrate reduction in vascular complication in the MAPT group with no difference of other outcomes between the two groups. Ussia et al. [12] study didn't show any difference between the two groups in outcomes. A meta-analysis done by Gandhi et al. [9] did show a trend toward increase in spontaneous myocardial infarction, all-cause mortality and bleeding in the DAPT group. These finding was driven mostly by observational trials, however, sub-analysis of randomized trials showed no



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Fig. 1. Flow diagram of the study selection process.

significant difference between the two groups. A meta-analysis by Verdoia et al. [13] showed decrease in mortality in favor of DAPT, this study results were mostly powered from a registry analysis by Sherwood et al. [14], the later study did show a decrease in mortality and lower bleeding rates in the DAPT group this finding of lower bleeding in the DAPT group contradict what other randomized and observational studies found. This could be explained by the lack of randomization and small sample size; the results could indicate higher prescription of MAPT in patients with higher risk of bleeding with possible other comorbidities. Hassell et al [6] and Aryal et al [19] showed MAPT associated with no difference in mortality and a trend towards less bleeding, but both meta-analyses included retrospective studies and did not include the most recent RCT. A recent meta-analysis by Ando et al. [20], which did not include prospective studies, also confirmed the same findings. Our current meta-analysis addressed the efficacy and safety of long-term use of DAPT vs. MAPT post TAVR using exclusively prospective data. There are multiple limitations in our meta-analysis; first, as with any other meta-analysis, the results are affected by variation in study design, endpoint definitions, endpoint reporting and possible publication bias.

Second, although we were able to report efficacy outcomes in uniformly fashion, there was some slight variability in clinical endpoints definitions. Main reason for variability was secondary to the fact that while most included trials, used clinical endpoints as were defined according to the Valve Academic Research Consortium (VARC-1) criteria, that was not the case for ARTE trial which used definitions according to (VARC-2) [10]. Few changes and additions have been applied in VARC-2 to improve the interpretation of clinical endpoint definitions and provide further insights on TAVR-related outcomes, which included 1. Immediate procedural death has been added to capture intraprocedural events that result in immediate or consequent death, 2. Stroke assessment has been re-categorized as non-disabling or disabling, detailed documentation of the etiology of strokes and concomitant therapies is needed to provide insights into the multifactorial nature of acute, early, and late strokes; 3. Closure device failure is now a separate category within vascular complications, and if unplanned percutaneous or surgical intervention does not lead to adverse outcomes, these are not considered as a major vascular complication per se; 4. The time for AKI diagnosis has been extended from 72 h to 7 days 5. peri-procedural myocardial infarction is


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Table 1 Baseline characteristics. (Ussia)

(Durand) DAPT n = 40

(Stabile)

MAPT n = 164

DAPT n = 128

82.7 ± 6.3 74 (45.1) 97 (59.1) 116 (70.7) 40 (24.4) 28 (17.1) 6 (3.7) – 22 (13.4) 13 (7.9) 56 (34.1) 37 (23) 7.4 ± 6.1

84.6 ± 5.8 78 (60.9) 55 (43) 90 (70.3) 30 (23.4) 10 (7.8) 8 (6.3) – 14 (10.9) 12 (9.4) 26 (20.3) 45 (35.2) 6.9 ± 4

P-value Age, years (mean ±SD) Female HLD HTN DM PAD Porcelain aorta CHF MI/CAD CVA COPD AFib STS score

81 ± 4 23 (59) – 31 (80) 8 (21) 4 (10) 1 (3) 14 (36) 4 (10) 2 (5) 1 (3) 6 (15) 7±3

80 ± 6 20 (50) – 35 (88) 13 (33) 3 (8) 1 (3) 18 (45) 7 (18) 2 (5) 10 (25) 4 (1) 8±5

0.38 0.43 – 0.33 0.23 0.75 1 0.41 0.31 1 0.005 0.0004 0.29

(Rodés-Cabau)

MAPT n = 60

DAPT n = 60

81.1 ± 4.8 36 (60) – 57 (95) 17 (28.3) – – – – – – – 10.4 ± 6.8

80.2 ± 5.7 44 (66.7) – 57 (95) 15 (25) – – – – – – – 9.7 ± 5.1

P-value 0.009 0.007 0.007 0.94 0.84 0.02 0.31 0.52 0.65 0.01 0.02 0.42

MAPT n = 111

DAPT n = 111

79 ± 9 52 (46.8) – 86 (77.5) 36 (32.7) 22 (20) 11 (10.1) – 20 (18.4) – 33 (30) – 6.2 ± 4.4

79 ± 9 41 (36.9) – 87 (79.8) 41 (36.9) 28 (25.2) 18 (16.2) – 26 (23.4) – 28 (25.2) – 6.4 ± 4.6

P-value 0.35 0.45 – 1 0.68 – – – – – – – 0.52

P-value 1 0.14 – 0.87 0.48 0.33 0.16 – 0.32 – 0.45 – 0.74

HLD – hyperlipidemia; HTN – hypertension; CAD – coro-ry artery disease; CHF – congestive heart failure; PAD – peripheral artery disease; CHF – congestive heart failure; MI – myocardial infarction; DM – diabetes mellitus; CVA – cerebral vascular accident; COPD – chronic obstructive pulmonary disease; Afib – atrial fibrillation; STS – the society of thoracic surgery risk score; MAPT – mono-antiplatelet therapy; DAPT – dual anti platelet therapy.

defined by troponin or CK-MB elevation and the troponin threshold has changed from 10× ULN to 15× ULN. Third, we used published event rates for each trial as opposed to individual patient data. Access to individual patient data would have enabled us to perform subgroup analyses and propensity analyses to account for differences in risk to minimize potential bias. Fourth, the small sample number of patients in most of the studies with total patients of 603 could decrease the power of the study, which could reflect on the difference between the two groups. Further studies with longer outcome and larger patient sample are needed to establish the benefit of both strategies.

5. Conclusion As a conclusion, our findings suggest that MAPT use after TAVR is associated with lower risk of major bleeding compared with DAPT with no significant difference in mortality, stroke or vascular complications. These findings are hypothesis generating and driven from relatively small studies. Acknowledgements None.

Fig. 2. The impact of aspirin vs. dual antiplatelet on primary efficacy outcomes after tanscathter aortic valve replacement (A- Impact on mortality, B- Impact on stroke).



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Fig. 3. The impact of aspirin vs. dual antiplatelet on primary safety outcomes after tanscathter aortic valve replacement. (A- Impact on major bleeding, B- Impact on major vascular complications).

Fig. 4. The impact of aspirin vs. dual antiplatelet on secondary safety outcomes after tanscathter aortic valve replacement. (A- Impact on minor bleeding, B- Impact on minor vascular complications).


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Table 2 Summary of meta-analysis outcomes. MAPT

DAPT

Relative risk

P-value

95% CI All-cause mortality Major bleeding Major vascular complications Major stroke Minor bleeding Minor vascular complications

18 (5.9%) 15 (4.9%) 8 (4.2%) 4 (1.3%) 8 (4.2%) 8 (4.2%)

20 (6.6%) 44 (14%) 17 (8.9%) 4 (1.3%) 9 (4.7%) 14 (7.3%)

0.92 (0.49–1.71) 0.36 (0.20–0.64) 0.52 (0.23–1.1) 1.04 (0.27–4.04) 1.1 (0.43–3.10) 0.58 (0.25–1.34)

0.68 b0.01 0.17 0.81 0.85 0.14

MAPT – mono-antiplatelet therapy; DAPT – dual anti platelet therapy

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