Canadian Journal of Cardiology 31 (2015) 775e784
Systematic Review/Meta-analysis
Comparison of Dual-antiplatelet Therapy to Mono-antiplatelet Therapy After Transcatheter Aortic Valve Implantation: Systematic Review and Meta-analysis Sumeet Gandhi, MD,a Jon-David R. Schwalm, MD, MSc,b James L. Velianou, MD,b Madhu K. Natarajan, MD, MSc,b and Michael E. Farkouh, MD, MScc a b
Department of Medicine, Division of Cardiology, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, Division of Cardiology, and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada c
Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Background: Postetranscatheter aortic valve implantation (TAVI) dualantiplatelet therapy (DAPT) with acetylsalicylic acid and clopidogrel is common practice to reduce ischemic complications despite the lack of clinical trial evidence demonstrating superiority over mono-antiplatelet therapy (MAPT). Methods: A systematic search was conducted to retrieve studies that investigated DAPT vs MAPT in patients who have undergone TAVI. Outcomes of interest included both ischemic and bleeding events at 30 days and 6 months. Results: Four studies met inclusion criteriae2 randomized control trials and 2 observational studies, with 286 patients in the DAPT group and 354 patients in the MAPT group. For the primary outcome of a combined end point of 30-day major stroke, spontaneous myocardial infarction (MI), all-cause mortality, and combined lethal and major bleeding, there was a trend toward increased harm in the DAPT group
rapie antiplaquettaire (BTAP) par l’acide Introduction : La bithe tylsalicylique et le clopidogrel après l’implantation valvulaire aorace ter (IVAC) est une pratique fre quente pour re duire les tique par cathe mique en de pit du manque de donne es complications d’origine ische montrant sa supe riorite par rapport à la provenant d’essais cliniques de rapie antiplaquettaire (MTAP). monothe thodes : Nous avons mene une recherche syste matique pour Me tudes qui avaient examine la BTAP vs la MTAP chez les extraire les e sultats d’inte rêt ont inclus les patients ayant subi l’IVAC. Les re ve nements ische miques et les e ve nements he morragiques à 30 jours e et à 6 mois. sultats : Quatre e tudes ont re pondu aux critères d’inclusion Re atoires et 2 e tudes observationnelles totalisant (2 essais cliniques ale 286 patients dans le groupe BTAP et 354 patients dans le groupe valuation principal d’un critère de MTAP). Pour ce qui est du critère d’e
Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement in patients considered at very high surgical risk.1 Despite the high success rate for device implantation, ischemic and bleeding complications are not uncommon, with a 5% incidence of 30-day stroke, a 17% incidence of major bleeding, and a negligible risk of 30-day myocardial infarction (MI).2 The empirical use of dual-antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and clopidogrel after TAVI is controversial, driven by the theoretical risk of thrombus formation on the aortic valve
prosthesis secondary to denuded native valve leaflets compressed behind the prosthetic valve. DAPT may also benefit by accelerating neointimal tissue growth and endothelialization incorporating the prosthesis within the aortic wall.3 Despite the lack of clinical trials demonstrating superiority of DAPT over mono-antiplatelet therapy (MAPT), DAPT after TAVI is embedded in common practice, with variation in the duration of therapy after the procedure. Guideline recommendations from the American College of Cardiology/American Heart Association recommend empirical therapy with ASA and clopidogrel for 6 months after TAVI (class IIb, level of evidence C).4 Similarly, the Canadian Cardiovascular Society recommends 1-3 months of DAPT after TAVI and to avoid adjunctive anticoagulation for fear of a risk of bleeding.1 To assess the benefits of DAPT, we performed a systematic review and meta-analysis of studies comparing DAPT with MAPT in patients who have undergone TAVI.
Received for publication December 25, 2014. Accepted January 19, 2015. Corresponding author: Dr Sumeet Gandhi, Hamilton General Hospital, North Wing, Room 8N-01, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. Tel.: þ1-416-801-1447; fax: þ1-905-577-1481. E-mail: [email protected] See page 783 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.01.014 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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(29%) compared with the MAPT group (16%), with an odds ratio (OR) of 1.88 (P ¼ 0.05). Secondary outcome analysis revealed that there was no significant difference between groups regarding 30-day stroke, 30-day spontaneous MI, and 30-day all-cause mortality. Patients who received DAPT had a significant increase in combined 30-day lethal and major bleeding (OR, 2.62; P ¼ 0.008). Further analysis revealed that increased adverse events were driven by observational studies, with no difference in outcomes between groups in randomized controlled trials. Conclusions: DAPT in patients who have undergone TAVI demonstrated no benefit over MAPT in reduction of ischemic events, with a trend toward increased harm because of bleeding. Future considerations should be given to MAPT with clopidogrel alone, as well as the omission of clopidogrel loading before the procedure.
de l’accident vasculaire ce re bral à 30 jours, de jugement combine , de la mortalite toutes causes l’infarctus du myocarde (IM) spontane e d’he morragie mortelle et confondues, et de l’incidence combine morragie majeure, nous avons observe une tendance à l’augd’he mentation du risque dans le groupe BTAP (29 %) par rapport au groupe (RIA) de 1,88 (P ¼ MTAP (16 %), et un ratio d’incidence approche valuation secondaire a re ve le qu’il 0,05). L’analyse du critère d’e rence significative entre les groupes concernant n’existait aucune diffe re bral à 30 jours, l’IM spontane à 30 jours et la l’accident vasculaire ce toutes causes confondues à 30 jours. Les patients qui mortalite une augmentation significative de recevaient la BTAP ont montre e de l’he morragie mortelle et de l’he morragie l’incidence combine majeure à 30 jours (RIA, 2,62; P ¼ 0,008). D’autres analyses ont ve le que l’augmentation des e ve nements inde sirables avait e te re e par des e tudes observationnelles, qui n’ont montre aucune souleve rence dans les re sultats entre les groupes des essais cliniques diffe atoires. ale Conclusions : La BTAP chez les patients ayant subi l’IVAC n’a montre aucun avantage par rapport à la MTAP sur la re duction des de ve nements d’origine ische mique, mais a plutôt montre une tendance e s par l’he morragie. Nous devà l’augmentation des dommages cause rons nous pencher sur la MTAP par le clopidogrel seul, ainsi que sur l’omission de la dose de charge du clopidogrel avant l’intervention.
Methods
independently by 2 investigators, with discrepancies resolved by a third investigator.
Study selection This meta-analysis was performed in accordance with PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) recommendations.5 A systematic search was conducted to retrieve studies that investigated DAPT compared with MAPT in patients who have undergone TAVI. We searched for candidate articles in PubMed, MEDLINE, EMBASE, and Cochrane databases from 1950-November 2014 using OVID software with the “explode” feature. The following keywords were used: (transcatheter aortic valve implantation, transcatheter aortic valve replacement, TAVI) and (clopidogrel, ADP receptor inhibitor, antiplatelet, antithrombotic). The electronic search has been archived and is available on request. In addition, reference lists of any studies meeting inclusion criteria were reviewed manually to identify additional relevant publications. An electronic search of abstracts available online were also reviewed from the annual congresses of the Canadian Cardiovascular Congress, European Society of Cardiology, American College of Cardiology and the American Heart Association. Inclusion/exclusion criteria Studies were included if they met the following criteria: (1) observational studies and randomized controlled trials, (2) included patients with severe aortic stenosis undergoing TAVI who were not eligible for surgical aortic valve replacement, (3) compared DAPT (ASA or clopidogrel, or both) to MAPT (ASA or clopidogrel alone), and (4) were published as full articles in the English language. Eligibility assessment and data extraction were carried out
Study outcomes The primary outcome was the combined end point of 30day stroke, spontaneous myocardial infarction, all-cause mortality, and combined lethal and major bleeding. Secondary outcomes of interest included 30-day major stroke, 30-day spontaneous MI, 30-day all-cause mortality, 30-day combined lethal and major bleeding, 6-month major stroke, 6-month MI, 6-month all-cause mortality, and 6-month combined lethal and major bleeding. Data extraction and study quality Quality assessment was carried out independently by 2 investigators using the Newcastle-Ottawa Quality Assessment Scale for observational studies and the Jadad score for randomized studies. Discrepancies in interpretation of data and inclusion of studies was resolved by consultation with the senior author. Statistical analysis The meta-analysis was conducted by combining the odds ratios of individual studies into a pooled risk ratio using a random-effects model.6 Summary relative risk ratios were calculated and are reported with 95% confidence intervals. A P value < 0.05 was deemed to be indicative of a statistically significant difference. We tested for heterogeneity using the c2 test and the I2 test. Funnel plots were constructed to subjectively assess for publication bias. Analyses were performed with RevMan, version 5.1, (Review Manager [RevMan], version 5.1. Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
Gandhi et al. Antiplatelet Therapy After TAVI
Results Search results Figure 1 outlines the search strategy. Our search strategy yielded 138 results, 69 of which were duplicate studies that were removed. Sixty-nine studies were screened, 48 of which were excluded on review of the title and abstract. A further 17 studies were excluded after careful review of the full text (7 observational studies that did not report the outcome of interest,7-13 9 review articles,14-22 and 1 meta-analysis23). Thus, 4 studies with 640 patients were eligible for inclusion in the systematic review.24-27 Characteristics of included studies Details of eligible studies, including patient and procedural characteristics, are outlined in Table 1 and Table 2, respectively.24-27 Two randomized trials and 2 prospective studies were included, with patients enrolled from May 2009June 2012. All studies met the inclusion criteria. In the DAPT group, patients received ASA 75-100 mg/d and clopidogrel 75 mg/d. Stabile et al.26 treated patients with either clopidogrel
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75 mg/d or ticlopidipine 500 mg/d as the second antiplatelet agent. In 3 studies, patients in the DAPT group received loading doses of clopidogrel 300 mg before the procedure.24,25,27 In the MAPT group, all 4 studies treated patients with ASA 75-100 mg/d; in the study by Durand et al.,24 patients were treated with either ASA 75 mg/d or clopidogrel 75 mg/d as monotherapy.24-27 Three studies included patients with atrial fibrillation.24,25,27 All 4 studies included patients who underwent transfemoral TAVI; 1 study included patients who underwent transapical TAVI and 1 study included patients who underwent a subclavian TAVI approach.24-27 Regarding the type of prosthetic aortic valve, 1 study used the SAPIEN system (Edwards Lifesciences, Irvine, CA),26 1 study used both the SAPIEN and CoreValve system (Medtronic, Minneapolis, MN),24 and 2 studies used the CoreValve system exclusively.25,27 Two studies defined bleeding according to the Valve Academic Research Consortium: overt bleeding either associated with a drop in hemoglobin of at least 3 g/dL or requiring transfusion of 2-3 units of whole blood/red blood cells or causing hospitalization or permanent injury or requiring surgery.25,26 Life-threatening bleeding was defined as fatal bleeding, bleeding in a critical organ, bleeding causing hypovolemic shock or hypotension requiring vasopressors or surgery, or overt bleeding with a drop of hemoglobin of at least 5 g/dL or requiring transfusion of at least 5 units of whole blood/red blood cells. The remaining 2 studies provided data on life-threatening major and minor bleeding; however, they did not provide a definition.24,27 The quality of included studies was deemed adequate for inclusion in the meta-analysis (Table 1). Patient characteristics Our analysis included 4 studiesd286 patients in the DAPT group and 354 patients in the MAPT group.24-27 A total of 640 patients were included in the analysis. The mean age was 82.2 years, and 57% of the patients were women. The prevalence of atrial fibrillation (18%), chronic kidney disease (8.1%), and previous MI (13%) was low. Almost all patients had a previous diagnosis of hypertension (99%), approximately half had dyslipidemia (52%) and known coronary artery disease (47%), and one quarter had diabetes mellitus (24%). Patients included were considered at high surgical risk with a mean EuroSCORE of 21.5 and a mean Society of Thoracic Surgeons (STS) score of 7.9.28,29 Results
Figure 1. Study flow chart showing literature search strategy and selection process for inclusion in systematic review.
A summary of meta-analysis outcomes is shown in Table 3. Regarding the primary outcome of a combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding, there was a trend toward increased harm in the DAPT group (29%) compared with the MAPT group (16%) (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.00-3.56; P ¼ 0.05; I2, 56%) (Fig. 2). When specifically assessing outcomes in randomized vs nonrandomized studies, we observed an increase in the primary outcome in the DAPT group for nonrandomized studies (OR, 3.02; 95% CI, 1.91-4.76; P < 0.00001; I2, 0%); however, there was no difference in randomized studies (OR, 0.98; 95% CI, 0.46-2.11; P ¼ 0.97; I2, 0%). Sensitivity analysis
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Table 1. Study characteristics Study (y) Study type Enrollment date Location Inclusion
Exclusion
DAPT group
TAVI device
Durand (2014)
Randomized trial April 2010-April 2011 Single centre, Italy 1. Severe AS: echocardiographically derived AVA < 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mm Hg or peak jet velocity > 4.0 m/s 2. Cardiac symptoms: NYHA functional class II, syncope 3. High surgical risk: predicted operative mortality 15% or STS score 10 1. Aortic annular diameter on echocardiography < 18 mm or > 25mm 2. Aortic dissection, or iliac-femoral dimensions or disease precluding safe sheath insertion 3. Untreated coronary artery disease requiring revascularization 4. Severe aortic regurgitation or mitral regurgitation (> 3þ), or prosthetic valve 5. Acute myocardial infarction within 1 mo 6. Upper gastrointestinal bleeding within 3 mo 7. Cerebrovascular accident or transient ischemic attack within 6 mo 8. Any cardiac procedure, other than balloon aortic valvuloplasty, within 1 mo or within 6 mo of drug-eluting stent placement 9. Indication for oral anticoagulation therapy (ie, atrial fibrillation) 10. Aspirin intolerance/allergy 11. Thienopyridine intolerance/allergy
Prospective study January 2010-December 2011 France, 2 TAVI registries, 3 centres, France 1. Patients with symptomatic severe AS who were not candidates for surgical AV replacement because of coexisting illness 2. AVA < 0.8 cm2, mean aortic gradient 40mm Hg or a peak aortic jet velocity 4.0 m/s 3. NYHA functional class II, III, or IV
Prospective study December 2007-June 2012 Single centre, United Kingdom All patients who underwent TAVI
All patients included in the registry
None
1. ASA 80 mg/d 2. Clopidogrel 75 mg/d or ticlodipine 500 mg BID Duration: 6 mo ASA 75-160 mg/d Duration: 6 mo
1. ASA 75 mg/d 2. clopidogrel 300 mg loading then clopidogrel 75 mg/d Duration: 1-6 mo ASA 75 mg/d or clopidogrel 75 mg/ d (without clopidogrel loading dose) Duration: 1-6 mo 1. SAPIEN, transfemoral or transapical route 2. CoreValve (Medtronic) transfemoral or subclavian route
1. ASA 75 mg/d 2. Clopidogrel 300 mg loading then 75 mg/d Duration: 6 mo ASA 300 mg loading then ASA 75 mg/d Duration: 6 mo
Vascular disease that precluded access Severe deformation of the chest Intracardiac thrombus Unprotected stenosis of the left main coronary artery not amenable to PCI 5. MI within 7 days 6. Prosthetic heart valve 7. Active infection 8. Leukopenia 9. Coagulopathy 10. Active bleeding 11. Acute anemia (Hb < 9 mg/dL) 12. Aorta could not be fully dilated with a 23-mm aortic valvuloplasty balloon 13. Aortic annulus size < 19 mm or > 24mm 14. Liver cirrhosis 15. Recurrent pulmonary embolism 16. Porcelain aorta 17. Respiratory failure 18. History of radiotherapy to mediastinum 19. Severe connective tissue disease 20. Previous PCI or MI requiring DAPT 21. Need for oral anticoagulation therapy 22. Allergy or intolerance to study drugs 1. ASA 100 mg/d 2. Clopidogrel 300 mg loading then 75 mg/d Duration: 3 mo ASA 100 mg/d Duration: 3 mo
CoreValve
CoreValve
SAPIEN (Edwards Lifesciences)
Poliacikova (2013)
Ussia (2011) Randomized trial May 2009-August 2010 Single centre, Italy 1. Severe symptomatic AS with AVA < 1 cm2 2. Refused for standard AV replacement
1. 2. 3. 4.
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ASA group
Stabile (2014)
Jadad score: 2 Newcastle Ottawa scale: 6 Jadad score: 2 Quality assessment
AS, aortic stenosis; ASA, acetylsalicylic acid; AV, aortic valve; AVA, aortic valve area; AVG, AV gradient; BID, twice daily; DAPT, dual-antiplatelet therapy; EF, ejection fraction; Hb, hemoglobin; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons; TAVI, transcatheter aortic valve implantation.
Primary end point: composite of death from any cause, MI, major stroke, urgent or emergency conversion to surgery, and life-threatening bleeding Primary end point not specified Clinical end points of cardiovascular death, major vascular complications, minor vascular complications, major stroke, minor stroke, acute MI, all-cause mortality, life-threatening or disabling bleeding, acute kidney injury Study end points
Primary end point: combination of 30-d mortality, major stroke, life-threatening bleeding, MI, and major vascular complications at 30 d Secondary end points: 30-d transfusion, any vascular complications, any stroke, any bleeding, acute kidney injury, and success rates Newcastle Ottawa scale: 5
Primary end points: (1) combined end point of all-cause mortality, acute coronary event or stroke and (2) combined end point of all-cause mortality, acute coronary event, stroke, or major bleeding
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demonstrated similar results when each individualized study was removed. The incidence of 30-day stroke was low in the DAPT and MAPT groups, 2.4% and 1.4%, respectively, with no significant difference between the 2 groups (OR, 1.44; 95% CI, 0.42-4.94; P ¼ 0.56; I2, 0%) (Fig. 3). The occurrence of 30day spontaneous MI was rared0.3% in the DAPT group and 0.8% in the MAPT group (OR, 0.59; 95% CI, 0.09-4.07; P ¼ 0.59; I2, 0%) (Fig. 4). Similarly, there was no significant difference in 30-day mortality in the DAPT group (7.3%) in comparison with the MAPT group (6.2%) (OR, 1.20; 95% CI, 0.64-2.25; P ¼ 0.57; I2, 0%) (Fig. 5). Patients who received DAPT had a significant increase in combined 30-day lethal and major bleedingd18.5% in the DAPT group and 7.1% in the MAPT group (OR, 2.62; 95% CI, 1.29-5.33; P ¼ 0.008; I2, 40%) (Fig. 6). When specifically assessing outcomes in randomized and nonrandomized studies, we observed increased 30-day combined lethal and major bleeding in the DAPT group for nonrandomized studies (OR, 3.84; 95% CI, 1.79-8.26; P < 0.00006; I2, 37%); however, there was no difference in randomized studies (OR, 1.30; 95% CI, 0.46-3.64; P ¼ 0.62; I2, 0%). Outcomes at 6 months in patients who received both DAPT and MAPT were similar. Comparing DAPT to MAPT, there was no difference in 6-month major stroke (OR, 0.98; 95% CI, 0.21-4.59; P ¼ 0.98; P ¼ 0.98; I2, 0%), 6-month MI (OR, 3.79; 95% CI, 0.39-37.03; P ¼ 0.25; I2, 0%), and 6-month all-cause mortality (OR, 1.31; 95% CI, 0.57-2.98; P ¼ 0.53; I2, 0%). Patients in the DAPT group experienced increased 6-month combined lethal and major bleeding (14.3% vs 6.2%; OR, 2.55; 95% CI, 1.02-6.40; P ¼ 0.05; I2, 1%). Sensitivity analysis demonstrated similar results when each individualized study was removed. Funnel plots did not reveal any evidence of publication bias (Fig. 7). Analysis for fixed-effects model is shown in Supplemental Figure S1. Discussion The results of our study show that DAPT compared with MAPT in patients who have undergone TAVI demonstrated a trend toward an increase in the primary outcome measure of combined 30-day stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding; this was driven by increased events in observational studies alone, with no difference in randomized studies. For the secondary outcome measures, there was increased risk of 30-day and 6-month combined lethal and major bleeding. There was no observed benefit in reduction in 30-day and 6-month major stroke, spontaneous MI, and all-cause mortality. Further analysis revealed that these end points were driven by nonrandomized studies; there was no overall difference in ischemic and bleeding outcomes in randomized studies. We have provided a detailed analysis with differentiation between randomized and nonrandomized studies; this differentiation clearly demonstrates that adverse outcomes with DAPT are driven by nonrandomized studies. We declined to use the end points of minor bleeding or minor stroke and transient ischemic attack because we believe that this would provide a more robust analysis of serious adverse outcomes. The patients included in this analysis were elderly, with
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Table 2. Patient and procedure characteristics Stabile (2014) Study (Y) No. of patients Age (y) Female (%) EuroSCORE (%) STS score (%) Diabetes (%) Dyslipidemia (%) Hypertension (%) Previous CAD Previous MI Previous CABG Previous stroke Peripheral artery disease Atrial fibrillation Pacemaker Chronic kidney disease (creatinine > 200 mmol/L) EF (mean SD) EF < 30% (%) PAP mean (mm Hg) AV mean gradient (mm Hg)
Poliacikova (2013)
MAPT
DAPT
MAPT
DAPT
60 81.1 4.8 36 (60) 25.1 12 10.4 6.8 17 (28.3) e 57 (95.0) e e e e e e e e
60 80.2 5.7 44 (66.7) 23.34 8.15 9.7 5.1 15 (25.0) e 57 (95.0) e e e e e e e e
164 82.7 6.3 74 (45.1) 20.0 12.4 7.4 6.1 40 (24.4) 97 (59.1) 116 (70.7) 82 (50) 22 (13.4) 30 (18.3) 13 (7.9) 28 (17.1) 37 (23) 18 (11) 12 (7.3)
128 84.6 5.8 78 (60.9) 20.2 11.6 6.9 4.0 30 (23.4) 55 (43) 90 (70.3) 39 (30.5) 14 (10.9) 10 (7.8) 12 (9.4) 10 (7.8) 45 (35.2) 10 (7.8) 11 (8.6)
51.5 11.0 8 (13.0) 51.3 12.1 63.6 14.1
52.4 14.4 7 (11.6) 52.64 13.54 59.4 15.4
54.4 13.6 2 (1.2) 44.1 12.8 50.1 15.2
60.5 14.0 0 44.6 14.1 48.3 19.5
e
e
7 (11.7) 32 (53.3) 31 (35.0) 60 e e
6 (10.0) 35 (58.3) 19 (31.7) 60 e e
60 (100) e 34 (56.7) 26 (43.3) e e e e e 14 (23.3) 1 (1.7)
60 (100) e 34 (56.7) 23 (43.3) e e e e e 13 (21.3) 2 (3.3)
0.61 0.16 III 131 (79.9) (NYHA III/IV)
0.63 0.14 99 (77.4) (NYHA III/IV)
92 (56.1) 13 (7.9)
46 (35.9) 8 (6.3)
138 24 2 64 159 110 60 44 6 54 16 35 3
(84.1) (14.6) (0.7) (45.7) (97) (67.1) (54.5) (40) (2.5) (32.9) (29.6) (64.8) (5.6) e 98 (59.8)
98 30 2 3 122 128 60 68 6
(76.6) (23.4) (1.2) (3.1) (95.3) (100) (46.9) (53.1) (5.5) 0 0 0 0 e 0
MAPT
Ussia (2011) DAPT
MAPT
DAPT
58 81.6 6.3 36 (44.8) e e 16 (27.6) e e 37 (63.8) e 17 (29.3) e e 16 (27.6) e 3 (5.2)
39 81 4 23 (59) 21 16 73 8 (21) e 31 (80) e 4 (10) 4 (10) 4 (10) 4 (10) 6 (15) 1 (3) 5 (13)
40 80 6 20 (50) 23 15 85 13 (33) e 35 (88) e 7 (18) 2 (5) 2 (5) 3 (8) 4 (10) 4 (10) 6 (15)
e EF < 50%, 14 (15.4) e Peak gradient 79.0 24.3 0.71 0.22 e
e 10 (17.2) e 93.8 27.7
54 8 e e 57 18
51 12 e e 52 6
0.67 0.17 e
0.6 0.3 23 (59) (NYHA III/IV)
0.6 0.2 26 (65) (NYHA III/IV)
e e
e e
e e 39 (100) 0
e e 38 (95) 2 (5)
90 (98.9) e e e e e e e e 20 (22) e
55 (94.8) e e e e e e e e 16 (27.6) e
36 (92) e e e e e 12 (31) 27 (69) e 9 (23) e
38 (95) e e e e e 23 (56) 17 (43) e 12 (30) e
82 42 16 50 19 10 5
91 6.9 (46.2) e e (17.6) e e (54.9) e (20.9) e e (11) e (5.5)
AS, aortic stenosis; ASA, acetylsalicylic acid; AV, aortic valve; AVG, AV gradient; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual-antiplatelet therapy; EF, ejection fraction; MAPT, mono-antiplatelet therapy; MI, myocardial infarction; PAP, pulmonary artery pressure; PCI, percutaneous coronary intervention; SD, standard deviation; STS, Society of Thoracic Surgeons.
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Aortic valve area (cm2) NYHA class II (%) III (%) IV (%) Previous ASA (%) treatment Previous clopidogrel treatment (%) Access transfemoral transapical subclavian surgical cutdown Device success (%) SAPIEN device 23 mm (%) 26 mm (%) 29 mm (%) CoreValve device 26 mm (%) 29 mm (%) 31 mm (%) PCI before index procedure (%) General anesthesia (%)
Durand (2014)
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Table 3. Summary of meta-analysis outcomes (DAPT vs MAPT) Outcomes Combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding 30-d major stroke 30-d spontaneous MI 30-d all-cause mortality 30-d lethal and major bleeding 6-mo major stroke 6-mo spontaneous MI 6-mo all-cause mortality 6-mo lethal and major bleeding
Analysis
Odds ratio
95% CI
I2
P value
Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fix effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects
1.88 2.24 1.44 1.68 0.59 0.59 1.20 1.19 2.62 3.08 0.98 0.96 3.79 3.78 1.31 1.30 2.55 2.55
1.00-3.56 1.52-3.29 0.42-4.94 0.56-5.08 0.09-4.07 0.09-4.04 0.64-2.25 0.64-2.22 1.29-5.33 1.86-5.10 0.21-4.59 0.21-4.31 0.39-37.03 0.39-36.95 0.57-2.98 0.58-2.93 1.02-6.40 1.03-6.32
56% 56% 0% 0% 0% 0% 0% 0% 40% 40% 0% 0% 0% 0% 0% 0% 1% 1%
0.05 < 0.0001 0.56 0.36 0.59 0.59 0.57 0.57 0.008 < 0.0001 0.98 0.95 0.25 0.25 0.53 0.52 0.05 0.04
CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, mono-antiplatelet therapy; MI, myocardial infarction.
multiple medical comorbidities and at high risk for surgical mortality (by EuroSCORE and STS score), so our analysis is comparable to real-life patients undergoing TAVI, who may not be represented in large-scale randomized trials. There are several implications from our analysis because it opens further areas of research to be explored for post-TAVI antiplatelet regimens. The results of this study do not show a clear benefit of DAPT after TAVI, but further validation is required. The prospective study by Durand et al. included patients in the MAPT group who received either ASA or clopidogrel compared with DAPT.24 Although specific outcomes are not available, monotherapy with clopidogrel after TAVI may be enough to combat the risk of thromboembolism and should be assessed in future studies. In their randomized trial, Stabile et al.26 did not give patients a loading
dose of clopidogrel 300 mg before the procedure; their incidence of combined lethal and major bleeding was significantly lower than the 3 other studies combined (7.5% vs 13%). The omission of clopidogrel loading before TAVI may offset the immediate and 30-day risk of bleeding. The ARTE (Aspirin versus Aspirin and Clopidogrel Following Transcatheter Aortic Valve Implantation) trial is an ongoing randomized control trial comparing DAPT (aspirin 80 mg/d and clopidogrel 75 mg/d) to MAPT (aspirin, 80 mg/d) for a total of 6 months’ duration. The primary outcome measure will be a composite end point of death, MI, ischemic stroke/transient ischemic attack, or life-threatening/major bleeding, with end points at 30 days and 12 months. The results of this study hopefully will resolve the issue of DAPT vs MAPT efficacy after TAVI.
Figure 2. Forrest plot for combined end point of 30-day major stroke, spontaneous myocardial infarction (MI), all-cause mortality, and combined lethal and major bleeding showing pooled data from studies, with the odds ratio of the development of the combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding in dual-antiplatelet therapy vs monoantiplatelet therapy. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
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Figure 3. Forrest plot for 30-day major stroke from pooled data from all studies, showing the odds ratio of the development of stroke in dualantiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
Figure 4. Forrest plot for 30-day spontaneous myocardial infarction (MI) of pooled data from studies, showing the odds ratios for the development of spontaneous MI in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
Figure 5. Forrest plot for 30-day all-cause mortality, showing pooled data from studies with the odds ratios for the development of all-cause mortality in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
Gandhi et al. Antiplatelet Therapy After TAVI
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Figure 6. Forrest plot for combined 30-day lethal and major bleeding, with pooled data from studies showing the odds ratios for the development of combined lethal and major bleeding in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
caused by increased bleeding, with no observed benefit in reduction of 30-day and 6-month major stroke, spontaneous MI, and all-cause mortality. The trend toward increased harm is driven by observational studies, with no significant difference in randomized trials. The optimal antiplatelet regimen after TAVI is currently being studied in the ARTE trial. Future consideration should also be given to monotherapy with clopidogrel after TAVI, as well as omission of clopidogrel loading before the procedure. Disclosures The authors have no conflicts of interest to disclose. References Figure 7. Funnel plot for publication bias; the primary outcome did not show publication bias.
There are several limitations to this meta-analysis. Our study included both randomized and retrospective observational studies with variable patient inclusion/exclusion criteria and different prosthetic aortic valve types; this may introduce a selection bias. For the primary outcome measure, only 4 studies were included with 640 patients without patient-level data, which may limit study power and the ability to detect statistically significant findings. Specifically, this may underestimate the benefit of DAPT therapy to reduce ischemic outcomes such as major stroke and spontaneous MI. The pooled analysis cannot control for patient characteristics, clinical variables, and procedural outcomes that may account for increased bleeding and mortality. Only 18% of patients in our analysis had atrial fibrillation, which represents a group at high risk for the development of thromboembolism, in which MAPT alone may not be suitable.
Conclusions DAPT in comparison with MAPT in patients who have undergone TAVI suggested a trend toward increased harm
1. Webb J, Rodes-Cabau J, Fremes S, et al. Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement. Can J Cardiol 2012;28:520-8. 2. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607. 3. Noble S, Asgar A, Cartier R, Virmani R, Bonan R. Anatomo-pathological analysis after CoreValve Revalving system implantation. Eurointervention 2009;5:78-85. 4. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57-185. 5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS One 2009;6:e1000097. 6. Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects metaanalyses. BMJ 2011;342:d549. 7. Seiffert M, Conradi L, Terstesse AC, et al. Blood transfusion is associated with impaired outcome after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2015;85:460-7. 8. Czerwinska-Jelonkiewicz K, Witkowski A, Dabrowski M, et al. Antithrombotic therapydpredictor of early and long-term bleeding
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complications after transcatheter aortic valve implantation. Arch Med Sci 2013;9:1062-70. 9. Griese DP, Reents W, Diegeler A, Kerber S, Babin-Ebell J. Simple, effective and safe vascular access site closure with the double-ProGlide preclose technique in 162 patients receiving transfemoral transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;82:E734-41. 10. Schwerg M, Baldenhofer G, Dreger H, et al. Complete atrioventricular block after TAVI: when is pacemaker implantation safe? Pacing Clin Electrophysiol 2013;36:898-903. 11. Godino C, Pavon AG, Mangieri A, Margonato A. Aortic valvuloplasty as bridging for TAVI in high-risk patients with Heyde’s syndrome: a case report. Case Rep Med 2012;2012:946764. 12. Stepinska J, Czerwinska K, Witkowski A, et al. Risk factors for bleeding complications in patients undergoing transcatheter aortic valve implantation (TAVI). Cardiol J 2013;20:125-33. 13. Salinas P, Moreno R, Calvo L, et al. Clinical and prognostic implications of atrial fibrillation in patients undergoing transcatheter aortic valve implantation. World J Cardiol 2012;4:8-14. 14. Collet JP, Montalescot G. Antithrombotic and antiplatelet therapy in TAVI patients: a fallow field? Eurointervention 2013;(9 suppl):S43-7. 15. Delewi R, Piek JJ. Antiplatelet therapy following TAVI: time to randomise. Neth Heart J 2014;22:62-3. 16. Meier P, Timmis A. Almanac 2012: Interventional Cardiology. The National Society Journals present selected research that has driven recent advances in clinical cardiology. Hellenic J Cardiol 2013;54:242-54. 17. Rodes-Cabau J, Dauerman HL, Cohen MG, et al. Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events. J Am Coll Cardiol 2013;62:2349-59. 18. Fusari M. Clopidogrel, aspirin and proton pump inhibition after percutaneous valve implants: an update. Curr Pharm Des 2013;19: 3932-45. 19. Gerber RT, Osborn M, Mikhail GW. Delayed mortality from aortic dissection post transcatheter aortic valve implantation (TAVI): the tip of the iceberg. Catheter Cardiovasc Interv 2010;76:202-4. 20. Gonyea EF. The abnormal pupil in Cheyne-Stokes respiration. Case report. J Neurosurg 1990;72:810-2.
Canadian Journal of Cardiology Volume 31 2015 21. Lynch DR Jr, Dantzler D, Robbins M, Zhao D. Considerations in antithrombotic therapy among patients undergoing transcatheter aortic valve implantation. J Thromb Thrombolysis 2013;35:476-82. 22. Meier P, Timmis A. Almanac 2012: interventional cardiology: the national society journals present selected research that has driven recent advances in clinical cardiology. Heart Dec 2012;98:1701-9. 23. Aryal MR, Karmacharya P, Pandit A, et al. Dual versus single antiplatelet therapy in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Heart Lung Circ 2015;24:185-92. 24. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014;113:355-60. 25. Poliacikova P, Cockburn J, de Belder A, Trivedi U, Hildick-Smith D. Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantationdcomparison of regimes. J Invasive Cardiol 2013;25:544-8. 26. Stabile E, Pucciarelli A, Cota L, et al. SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. Int J Cardiol 2014;174:624-7. 27. Ussia GP, Scarabelli M, Mule M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2011;108:1772-6. 28. Nashef SA, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16:9-13. 29. O’Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2disolated valve surgery. Ann Thorac Surg 2009;88(1 suppl):S23-42.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2015.01.014.
Systematic Review/Meta-analysis
Comparison of Dual-antiplatelet Therapy to Mono-antiplatelet Therapy After Transcatheter Aortic Valve Implantation: Systematic Review and Meta-analysis Sumeet Gandhi, MD,a Jon-David R. Schwalm, MD, MSc,b James L. Velianou, MD,b Madhu K. Natarajan, MD, MSc,b and Michael E. Farkouh, MD, MScc a b
Department of Medicine, Division of Cardiology, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, Division of Cardiology, and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada c
Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Background: Postetranscatheter aortic valve implantation (TAVI) dualantiplatelet therapy (DAPT) with acetylsalicylic acid and clopidogrel is common practice to reduce ischemic complications despite the lack of clinical trial evidence demonstrating superiority over mono-antiplatelet therapy (MAPT). Methods: A systematic search was conducted to retrieve studies that investigated DAPT vs MAPT in patients who have undergone TAVI. Outcomes of interest included both ischemic and bleeding events at 30 days and 6 months. Results: Four studies met inclusion criteriae2 randomized control trials and 2 observational studies, with 286 patients in the DAPT group and 354 patients in the MAPT group. For the primary outcome of a combined end point of 30-day major stroke, spontaneous myocardial infarction (MI), all-cause mortality, and combined lethal and major bleeding, there was a trend toward increased harm in the DAPT group
rapie antiplaquettaire (BTAP) par l’acide Introduction : La bithe tylsalicylique et le clopidogrel après l’implantation valvulaire aorace ter (IVAC) est une pratique fre quente pour re duire les tique par cathe mique en de pit du manque de donne es complications d’origine ische montrant sa supe riorite par rapport à la provenant d’essais cliniques de rapie antiplaquettaire (MTAP). monothe thodes : Nous avons mene une recherche syste matique pour Me tudes qui avaient examine la BTAP vs la MTAP chez les extraire les e sultats d’inte rêt ont inclus les patients ayant subi l’IVAC. Les re ve nements ische miques et les e ve nements he morragiques à 30 jours e et à 6 mois. sultats : Quatre e tudes ont re pondu aux critères d’inclusion Re atoires et 2 e tudes observationnelles totalisant (2 essais cliniques ale 286 patients dans le groupe BTAP et 354 patients dans le groupe valuation principal d’un critère de MTAP). Pour ce qui est du critère d’e
Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement in patients considered at very high surgical risk.1 Despite the high success rate for device implantation, ischemic and bleeding complications are not uncommon, with a 5% incidence of 30-day stroke, a 17% incidence of major bleeding, and a negligible risk of 30-day myocardial infarction (MI).2 The empirical use of dual-antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and clopidogrel after TAVI is controversial, driven by the theoretical risk of thrombus formation on the aortic valve
prosthesis secondary to denuded native valve leaflets compressed behind the prosthetic valve. DAPT may also benefit by accelerating neointimal tissue growth and endothelialization incorporating the prosthesis within the aortic wall.3 Despite the lack of clinical trials demonstrating superiority of DAPT over mono-antiplatelet therapy (MAPT), DAPT after TAVI is embedded in common practice, with variation in the duration of therapy after the procedure. Guideline recommendations from the American College of Cardiology/American Heart Association recommend empirical therapy with ASA and clopidogrel for 6 months after TAVI (class IIb, level of evidence C).4 Similarly, the Canadian Cardiovascular Society recommends 1-3 months of DAPT after TAVI and to avoid adjunctive anticoagulation for fear of a risk of bleeding.1 To assess the benefits of DAPT, we performed a systematic review and meta-analysis of studies comparing DAPT with MAPT in patients who have undergone TAVI.
Received for publication December 25, 2014. Accepted January 19, 2015. Corresponding author: Dr Sumeet Gandhi, Hamilton General Hospital, North Wing, Room 8N-01, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. Tel.: þ1-416-801-1447; fax: þ1-905-577-1481. E-mail: [email protected] See page 783 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.01.014 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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(29%) compared with the MAPT group (16%), with an odds ratio (OR) of 1.88 (P ¼ 0.05). Secondary outcome analysis revealed that there was no significant difference between groups regarding 30-day stroke, 30-day spontaneous MI, and 30-day all-cause mortality. Patients who received DAPT had a significant increase in combined 30-day lethal and major bleeding (OR, 2.62; P ¼ 0.008). Further analysis revealed that increased adverse events were driven by observational studies, with no difference in outcomes between groups in randomized controlled trials. Conclusions: DAPT in patients who have undergone TAVI demonstrated no benefit over MAPT in reduction of ischemic events, with a trend toward increased harm because of bleeding. Future considerations should be given to MAPT with clopidogrel alone, as well as the omission of clopidogrel loading before the procedure.
de l’accident vasculaire ce re bral à 30 jours, de jugement combine , de la mortalite toutes causes l’infarctus du myocarde (IM) spontane e d’he morragie mortelle et confondues, et de l’incidence combine morragie majeure, nous avons observe une tendance à l’augd’he mentation du risque dans le groupe BTAP (29 %) par rapport au groupe (RIA) de 1,88 (P ¼ MTAP (16 %), et un ratio d’incidence approche valuation secondaire a re ve le qu’il 0,05). L’analyse du critère d’e rence significative entre les groupes concernant n’existait aucune diffe re bral à 30 jours, l’IM spontane à 30 jours et la l’accident vasculaire ce toutes causes confondues à 30 jours. Les patients qui mortalite une augmentation significative de recevaient la BTAP ont montre e de l’he morragie mortelle et de l’he morragie l’incidence combine majeure à 30 jours (RIA, 2,62; P ¼ 0,008). D’autres analyses ont ve le que l’augmentation des e ve nements inde sirables avait e te re e par des e tudes observationnelles, qui n’ont montre aucune souleve rence dans les re sultats entre les groupes des essais cliniques diffe atoires. ale Conclusions : La BTAP chez les patients ayant subi l’IVAC n’a montre aucun avantage par rapport à la MTAP sur la re duction des de ve nements d’origine ische mique, mais a plutôt montre une tendance e s par l’he morragie. Nous devà l’augmentation des dommages cause rons nous pencher sur la MTAP par le clopidogrel seul, ainsi que sur l’omission de la dose de charge du clopidogrel avant l’intervention.
Methods
independently by 2 investigators, with discrepancies resolved by a third investigator.
Study selection This meta-analysis was performed in accordance with PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) recommendations.5 A systematic search was conducted to retrieve studies that investigated DAPT compared with MAPT in patients who have undergone TAVI. We searched for candidate articles in PubMed, MEDLINE, EMBASE, and Cochrane databases from 1950-November 2014 using OVID software with the “explode” feature. The following keywords were used: (transcatheter aortic valve implantation, transcatheter aortic valve replacement, TAVI) and (clopidogrel, ADP receptor inhibitor, antiplatelet, antithrombotic). The electronic search has been archived and is available on request. In addition, reference lists of any studies meeting inclusion criteria were reviewed manually to identify additional relevant publications. An electronic search of abstracts available online were also reviewed from the annual congresses of the Canadian Cardiovascular Congress, European Society of Cardiology, American College of Cardiology and the American Heart Association. Inclusion/exclusion criteria Studies were included if they met the following criteria: (1) observational studies and randomized controlled trials, (2) included patients with severe aortic stenosis undergoing TAVI who were not eligible for surgical aortic valve replacement, (3) compared DAPT (ASA or clopidogrel, or both) to MAPT (ASA or clopidogrel alone), and (4) were published as full articles in the English language. Eligibility assessment and data extraction were carried out
Study outcomes The primary outcome was the combined end point of 30day stroke, spontaneous myocardial infarction, all-cause mortality, and combined lethal and major bleeding. Secondary outcomes of interest included 30-day major stroke, 30-day spontaneous MI, 30-day all-cause mortality, 30-day combined lethal and major bleeding, 6-month major stroke, 6-month MI, 6-month all-cause mortality, and 6-month combined lethal and major bleeding. Data extraction and study quality Quality assessment was carried out independently by 2 investigators using the Newcastle-Ottawa Quality Assessment Scale for observational studies and the Jadad score for randomized studies. Discrepancies in interpretation of data and inclusion of studies was resolved by consultation with the senior author. Statistical analysis The meta-analysis was conducted by combining the odds ratios of individual studies into a pooled risk ratio using a random-effects model.6 Summary relative risk ratios were calculated and are reported with 95% confidence intervals. A P value < 0.05 was deemed to be indicative of a statistically significant difference. We tested for heterogeneity using the c2 test and the I2 test. Funnel plots were constructed to subjectively assess for publication bias. Analyses were performed with RevMan, version 5.1, (Review Manager [RevMan], version 5.1. Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
Gandhi et al. Antiplatelet Therapy After TAVI
Results Search results Figure 1 outlines the search strategy. Our search strategy yielded 138 results, 69 of which were duplicate studies that were removed. Sixty-nine studies were screened, 48 of which were excluded on review of the title and abstract. A further 17 studies were excluded after careful review of the full text (7 observational studies that did not report the outcome of interest,7-13 9 review articles,14-22 and 1 meta-analysis23). Thus, 4 studies with 640 patients were eligible for inclusion in the systematic review.24-27 Characteristics of included studies Details of eligible studies, including patient and procedural characteristics, are outlined in Table 1 and Table 2, respectively.24-27 Two randomized trials and 2 prospective studies were included, with patients enrolled from May 2009June 2012. All studies met the inclusion criteria. In the DAPT group, patients received ASA 75-100 mg/d and clopidogrel 75 mg/d. Stabile et al.26 treated patients with either clopidogrel
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75 mg/d or ticlopidipine 500 mg/d as the second antiplatelet agent. In 3 studies, patients in the DAPT group received loading doses of clopidogrel 300 mg before the procedure.24,25,27 In the MAPT group, all 4 studies treated patients with ASA 75-100 mg/d; in the study by Durand et al.,24 patients were treated with either ASA 75 mg/d or clopidogrel 75 mg/d as monotherapy.24-27 Three studies included patients with atrial fibrillation.24,25,27 All 4 studies included patients who underwent transfemoral TAVI; 1 study included patients who underwent transapical TAVI and 1 study included patients who underwent a subclavian TAVI approach.24-27 Regarding the type of prosthetic aortic valve, 1 study used the SAPIEN system (Edwards Lifesciences, Irvine, CA),26 1 study used both the SAPIEN and CoreValve system (Medtronic, Minneapolis, MN),24 and 2 studies used the CoreValve system exclusively.25,27 Two studies defined bleeding according to the Valve Academic Research Consortium: overt bleeding either associated with a drop in hemoglobin of at least 3 g/dL or requiring transfusion of 2-3 units of whole blood/red blood cells or causing hospitalization or permanent injury or requiring surgery.25,26 Life-threatening bleeding was defined as fatal bleeding, bleeding in a critical organ, bleeding causing hypovolemic shock or hypotension requiring vasopressors or surgery, or overt bleeding with a drop of hemoglobin of at least 5 g/dL or requiring transfusion of at least 5 units of whole blood/red blood cells. The remaining 2 studies provided data on life-threatening major and minor bleeding; however, they did not provide a definition.24,27 The quality of included studies was deemed adequate for inclusion in the meta-analysis (Table 1). Patient characteristics Our analysis included 4 studiesd286 patients in the DAPT group and 354 patients in the MAPT group.24-27 A total of 640 patients were included in the analysis. The mean age was 82.2 years, and 57% of the patients were women. The prevalence of atrial fibrillation (18%), chronic kidney disease (8.1%), and previous MI (13%) was low. Almost all patients had a previous diagnosis of hypertension (99%), approximately half had dyslipidemia (52%) and known coronary artery disease (47%), and one quarter had diabetes mellitus (24%). Patients included were considered at high surgical risk with a mean EuroSCORE of 21.5 and a mean Society of Thoracic Surgeons (STS) score of 7.9.28,29 Results
Figure 1. Study flow chart showing literature search strategy and selection process for inclusion in systematic review.
A summary of meta-analysis outcomes is shown in Table 3. Regarding the primary outcome of a combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding, there was a trend toward increased harm in the DAPT group (29%) compared with the MAPT group (16%) (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.00-3.56; P ¼ 0.05; I2, 56%) (Fig. 2). When specifically assessing outcomes in randomized vs nonrandomized studies, we observed an increase in the primary outcome in the DAPT group for nonrandomized studies (OR, 3.02; 95% CI, 1.91-4.76; P < 0.00001; I2, 0%); however, there was no difference in randomized studies (OR, 0.98; 95% CI, 0.46-2.11; P ¼ 0.97; I2, 0%). Sensitivity analysis
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Table 1. Study characteristics Study (y) Study type Enrollment date Location Inclusion
Exclusion
DAPT group
TAVI device
Durand (2014)
Randomized trial April 2010-April 2011 Single centre, Italy 1. Severe AS: echocardiographically derived AVA < 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mm Hg or peak jet velocity > 4.0 m/s 2. Cardiac symptoms: NYHA functional class II, syncope 3. High surgical risk: predicted operative mortality 15% or STS score 10 1. Aortic annular diameter on echocardiography < 18 mm or > 25mm 2. Aortic dissection, or iliac-femoral dimensions or disease precluding safe sheath insertion 3. Untreated coronary artery disease requiring revascularization 4. Severe aortic regurgitation or mitral regurgitation (> 3þ), or prosthetic valve 5. Acute myocardial infarction within 1 mo 6. Upper gastrointestinal bleeding within 3 mo 7. Cerebrovascular accident or transient ischemic attack within 6 mo 8. Any cardiac procedure, other than balloon aortic valvuloplasty, within 1 mo or within 6 mo of drug-eluting stent placement 9. Indication for oral anticoagulation therapy (ie, atrial fibrillation) 10. Aspirin intolerance/allergy 11. Thienopyridine intolerance/allergy
Prospective study January 2010-December 2011 France, 2 TAVI registries, 3 centres, France 1. Patients with symptomatic severe AS who were not candidates for surgical AV replacement because of coexisting illness 2. AVA < 0.8 cm2, mean aortic gradient 40mm Hg or a peak aortic jet velocity 4.0 m/s 3. NYHA functional class II, III, or IV
Prospective study December 2007-June 2012 Single centre, United Kingdom All patients who underwent TAVI
All patients included in the registry
None
1. ASA 80 mg/d 2. Clopidogrel 75 mg/d or ticlodipine 500 mg BID Duration: 6 mo ASA 75-160 mg/d Duration: 6 mo
1. ASA 75 mg/d 2. clopidogrel 300 mg loading then clopidogrel 75 mg/d Duration: 1-6 mo ASA 75 mg/d or clopidogrel 75 mg/ d (without clopidogrel loading dose) Duration: 1-6 mo 1. SAPIEN, transfemoral or transapical route 2. CoreValve (Medtronic) transfemoral or subclavian route
1. ASA 75 mg/d 2. Clopidogrel 300 mg loading then 75 mg/d Duration: 6 mo ASA 300 mg loading then ASA 75 mg/d Duration: 6 mo
Vascular disease that precluded access Severe deformation of the chest Intracardiac thrombus Unprotected stenosis of the left main coronary artery not amenable to PCI 5. MI within 7 days 6. Prosthetic heart valve 7. Active infection 8. Leukopenia 9. Coagulopathy 10. Active bleeding 11. Acute anemia (Hb < 9 mg/dL) 12. Aorta could not be fully dilated with a 23-mm aortic valvuloplasty balloon 13. Aortic annulus size < 19 mm or > 24mm 14. Liver cirrhosis 15. Recurrent pulmonary embolism 16. Porcelain aorta 17. Respiratory failure 18. History of radiotherapy to mediastinum 19. Severe connective tissue disease 20. Previous PCI or MI requiring DAPT 21. Need for oral anticoagulation therapy 22. Allergy or intolerance to study drugs 1. ASA 100 mg/d 2. Clopidogrel 300 mg loading then 75 mg/d Duration: 3 mo ASA 100 mg/d Duration: 3 mo
CoreValve
CoreValve
SAPIEN (Edwards Lifesciences)
Poliacikova (2013)
Ussia (2011) Randomized trial May 2009-August 2010 Single centre, Italy 1. Severe symptomatic AS with AVA < 1 cm2 2. Refused for standard AV replacement
1. 2. 3. 4.
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ASA group
Stabile (2014)
Jadad score: 2 Newcastle Ottawa scale: 6 Jadad score: 2 Quality assessment
AS, aortic stenosis; ASA, acetylsalicylic acid; AV, aortic valve; AVA, aortic valve area; AVG, AV gradient; BID, twice daily; DAPT, dual-antiplatelet therapy; EF, ejection fraction; Hb, hemoglobin; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons; TAVI, transcatheter aortic valve implantation.
Primary end point: composite of death from any cause, MI, major stroke, urgent or emergency conversion to surgery, and life-threatening bleeding Primary end point not specified Clinical end points of cardiovascular death, major vascular complications, minor vascular complications, major stroke, minor stroke, acute MI, all-cause mortality, life-threatening or disabling bleeding, acute kidney injury Study end points
Primary end point: combination of 30-d mortality, major stroke, life-threatening bleeding, MI, and major vascular complications at 30 d Secondary end points: 30-d transfusion, any vascular complications, any stroke, any bleeding, acute kidney injury, and success rates Newcastle Ottawa scale: 5
Primary end points: (1) combined end point of all-cause mortality, acute coronary event or stroke and (2) combined end point of all-cause mortality, acute coronary event, stroke, or major bleeding
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demonstrated similar results when each individualized study was removed. The incidence of 30-day stroke was low in the DAPT and MAPT groups, 2.4% and 1.4%, respectively, with no significant difference between the 2 groups (OR, 1.44; 95% CI, 0.42-4.94; P ¼ 0.56; I2, 0%) (Fig. 3). The occurrence of 30day spontaneous MI was rared0.3% in the DAPT group and 0.8% in the MAPT group (OR, 0.59; 95% CI, 0.09-4.07; P ¼ 0.59; I2, 0%) (Fig. 4). Similarly, there was no significant difference in 30-day mortality in the DAPT group (7.3%) in comparison with the MAPT group (6.2%) (OR, 1.20; 95% CI, 0.64-2.25; P ¼ 0.57; I2, 0%) (Fig. 5). Patients who received DAPT had a significant increase in combined 30-day lethal and major bleedingd18.5% in the DAPT group and 7.1% in the MAPT group (OR, 2.62; 95% CI, 1.29-5.33; P ¼ 0.008; I2, 40%) (Fig. 6). When specifically assessing outcomes in randomized and nonrandomized studies, we observed increased 30-day combined lethal and major bleeding in the DAPT group for nonrandomized studies (OR, 3.84; 95% CI, 1.79-8.26; P < 0.00006; I2, 37%); however, there was no difference in randomized studies (OR, 1.30; 95% CI, 0.46-3.64; P ¼ 0.62; I2, 0%). Outcomes at 6 months in patients who received both DAPT and MAPT were similar. Comparing DAPT to MAPT, there was no difference in 6-month major stroke (OR, 0.98; 95% CI, 0.21-4.59; P ¼ 0.98; P ¼ 0.98; I2, 0%), 6-month MI (OR, 3.79; 95% CI, 0.39-37.03; P ¼ 0.25; I2, 0%), and 6-month all-cause mortality (OR, 1.31; 95% CI, 0.57-2.98; P ¼ 0.53; I2, 0%). Patients in the DAPT group experienced increased 6-month combined lethal and major bleeding (14.3% vs 6.2%; OR, 2.55; 95% CI, 1.02-6.40; P ¼ 0.05; I2, 1%). Sensitivity analysis demonstrated similar results when each individualized study was removed. Funnel plots did not reveal any evidence of publication bias (Fig. 7). Analysis for fixed-effects model is shown in Supplemental Figure S1. Discussion The results of our study show that DAPT compared with MAPT in patients who have undergone TAVI demonstrated a trend toward an increase in the primary outcome measure of combined 30-day stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding; this was driven by increased events in observational studies alone, with no difference in randomized studies. For the secondary outcome measures, there was increased risk of 30-day and 6-month combined lethal and major bleeding. There was no observed benefit in reduction in 30-day and 6-month major stroke, spontaneous MI, and all-cause mortality. Further analysis revealed that these end points were driven by nonrandomized studies; there was no overall difference in ischemic and bleeding outcomes in randomized studies. We have provided a detailed analysis with differentiation between randomized and nonrandomized studies; this differentiation clearly demonstrates that adverse outcomes with DAPT are driven by nonrandomized studies. We declined to use the end points of minor bleeding or minor stroke and transient ischemic attack because we believe that this would provide a more robust analysis of serious adverse outcomes. The patients included in this analysis were elderly, with
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Table 2. Patient and procedure characteristics Stabile (2014) Study (Y) No. of patients Age (y) Female (%) EuroSCORE (%) STS score (%) Diabetes (%) Dyslipidemia (%) Hypertension (%) Previous CAD Previous MI Previous CABG Previous stroke Peripheral artery disease Atrial fibrillation Pacemaker Chronic kidney disease (creatinine > 200 mmol/L) EF (mean SD) EF < 30% (%) PAP mean (mm Hg) AV mean gradient (mm Hg)
Poliacikova (2013)
MAPT
DAPT
MAPT
DAPT
60 81.1 4.8 36 (60) 25.1 12 10.4 6.8 17 (28.3) e 57 (95.0) e e e e e e e e
60 80.2 5.7 44 (66.7) 23.34 8.15 9.7 5.1 15 (25.0) e 57 (95.0) e e e e e e e e
164 82.7 6.3 74 (45.1) 20.0 12.4 7.4 6.1 40 (24.4) 97 (59.1) 116 (70.7) 82 (50) 22 (13.4) 30 (18.3) 13 (7.9) 28 (17.1) 37 (23) 18 (11) 12 (7.3)
128 84.6 5.8 78 (60.9) 20.2 11.6 6.9 4.0 30 (23.4) 55 (43) 90 (70.3) 39 (30.5) 14 (10.9) 10 (7.8) 12 (9.4) 10 (7.8) 45 (35.2) 10 (7.8) 11 (8.6)
51.5 11.0 8 (13.0) 51.3 12.1 63.6 14.1
52.4 14.4 7 (11.6) 52.64 13.54 59.4 15.4
54.4 13.6 2 (1.2) 44.1 12.8 50.1 15.2
60.5 14.0 0 44.6 14.1 48.3 19.5
e
e
7 (11.7) 32 (53.3) 31 (35.0) 60 e e
6 (10.0) 35 (58.3) 19 (31.7) 60 e e
60 (100) e 34 (56.7) 26 (43.3) e e e e e 14 (23.3) 1 (1.7)
60 (100) e 34 (56.7) 23 (43.3) e e e e e 13 (21.3) 2 (3.3)
0.61 0.16 III 131 (79.9) (NYHA III/IV)
0.63 0.14 99 (77.4) (NYHA III/IV)
92 (56.1) 13 (7.9)
46 (35.9) 8 (6.3)
138 24 2 64 159 110 60 44 6 54 16 35 3
(84.1) (14.6) (0.7) (45.7) (97) (67.1) (54.5) (40) (2.5) (32.9) (29.6) (64.8) (5.6) e 98 (59.8)
98 30 2 3 122 128 60 68 6
(76.6) (23.4) (1.2) (3.1) (95.3) (100) (46.9) (53.1) (5.5) 0 0 0 0 e 0
MAPT
Ussia (2011) DAPT
MAPT
DAPT
58 81.6 6.3 36 (44.8) e e 16 (27.6) e e 37 (63.8) e 17 (29.3) e e 16 (27.6) e 3 (5.2)
39 81 4 23 (59) 21 16 73 8 (21) e 31 (80) e 4 (10) 4 (10) 4 (10) 4 (10) 6 (15) 1 (3) 5 (13)
40 80 6 20 (50) 23 15 85 13 (33) e 35 (88) e 7 (18) 2 (5) 2 (5) 3 (8) 4 (10) 4 (10) 6 (15)
e EF < 50%, 14 (15.4) e Peak gradient 79.0 24.3 0.71 0.22 e
e 10 (17.2) e 93.8 27.7
54 8 e e 57 18
51 12 e e 52 6
0.67 0.17 e
0.6 0.3 23 (59) (NYHA III/IV)
0.6 0.2 26 (65) (NYHA III/IV)
e e
e e
e e 39 (100) 0
e e 38 (95) 2 (5)
90 (98.9) e e e e e e e e 20 (22) e
55 (94.8) e e e e e e e e 16 (27.6) e
36 (92) e e e e e 12 (31) 27 (69) e 9 (23) e
38 (95) e e e e e 23 (56) 17 (43) e 12 (30) e
82 42 16 50 19 10 5
91 6.9 (46.2) e e (17.6) e e (54.9) e (20.9) e e (11) e (5.5)
AS, aortic stenosis; ASA, acetylsalicylic acid; AV, aortic valve; AVG, AV gradient; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual-antiplatelet therapy; EF, ejection fraction; MAPT, mono-antiplatelet therapy; MI, myocardial infarction; PAP, pulmonary artery pressure; PCI, percutaneous coronary intervention; SD, standard deviation; STS, Society of Thoracic Surgeons.
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Aortic valve area (cm2) NYHA class II (%) III (%) IV (%) Previous ASA (%) treatment Previous clopidogrel treatment (%) Access transfemoral transapical subclavian surgical cutdown Device success (%) SAPIEN device 23 mm (%) 26 mm (%) 29 mm (%) CoreValve device 26 mm (%) 29 mm (%) 31 mm (%) PCI before index procedure (%) General anesthesia (%)
Durand (2014)
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Table 3. Summary of meta-analysis outcomes (DAPT vs MAPT) Outcomes Combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding 30-d major stroke 30-d spontaneous MI 30-d all-cause mortality 30-d lethal and major bleeding 6-mo major stroke 6-mo spontaneous MI 6-mo all-cause mortality 6-mo lethal and major bleeding
Analysis
Odds ratio
95% CI
I2
P value
Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fix effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects Random effects Fixed effects
1.88 2.24 1.44 1.68 0.59 0.59 1.20 1.19 2.62 3.08 0.98 0.96 3.79 3.78 1.31 1.30 2.55 2.55
1.00-3.56 1.52-3.29 0.42-4.94 0.56-5.08 0.09-4.07 0.09-4.04 0.64-2.25 0.64-2.22 1.29-5.33 1.86-5.10 0.21-4.59 0.21-4.31 0.39-37.03 0.39-36.95 0.57-2.98 0.58-2.93 1.02-6.40 1.03-6.32
56% 56% 0% 0% 0% 0% 0% 0% 40% 40% 0% 0% 0% 0% 0% 0% 1% 1%
0.05 < 0.0001 0.56 0.36 0.59 0.59 0.57 0.57 0.008 < 0.0001 0.98 0.95 0.25 0.25 0.53 0.52 0.05 0.04
CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, mono-antiplatelet therapy; MI, myocardial infarction.
multiple medical comorbidities and at high risk for surgical mortality (by EuroSCORE and STS score), so our analysis is comparable to real-life patients undergoing TAVI, who may not be represented in large-scale randomized trials. There are several implications from our analysis because it opens further areas of research to be explored for post-TAVI antiplatelet regimens. The results of this study do not show a clear benefit of DAPT after TAVI, but further validation is required. The prospective study by Durand et al. included patients in the MAPT group who received either ASA or clopidogrel compared with DAPT.24 Although specific outcomes are not available, monotherapy with clopidogrel after TAVI may be enough to combat the risk of thromboembolism and should be assessed in future studies. In their randomized trial, Stabile et al.26 did not give patients a loading
dose of clopidogrel 300 mg before the procedure; their incidence of combined lethal and major bleeding was significantly lower than the 3 other studies combined (7.5% vs 13%). The omission of clopidogrel loading before TAVI may offset the immediate and 30-day risk of bleeding. The ARTE (Aspirin versus Aspirin and Clopidogrel Following Transcatheter Aortic Valve Implantation) trial is an ongoing randomized control trial comparing DAPT (aspirin 80 mg/d and clopidogrel 75 mg/d) to MAPT (aspirin, 80 mg/d) for a total of 6 months’ duration. The primary outcome measure will be a composite end point of death, MI, ischemic stroke/transient ischemic attack, or life-threatening/major bleeding, with end points at 30 days and 12 months. The results of this study hopefully will resolve the issue of DAPT vs MAPT efficacy after TAVI.
Figure 2. Forrest plot for combined end point of 30-day major stroke, spontaneous myocardial infarction (MI), all-cause mortality, and combined lethal and major bleeding showing pooled data from studies, with the odds ratio of the development of the combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding in dual-antiplatelet therapy vs monoantiplatelet therapy. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
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Figure 3. Forrest plot for 30-day major stroke from pooled data from all studies, showing the odds ratio of the development of stroke in dualantiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
Figure 4. Forrest plot for 30-day spontaneous myocardial infarction (MI) of pooled data from studies, showing the odds ratios for the development of spontaneous MI in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
Figure 5. Forrest plot for 30-day all-cause mortality, showing pooled data from studies with the odds ratios for the development of all-cause mortality in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
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Figure 6. Forrest plot for combined 30-day lethal and major bleeding, with pooled data from studies showing the odds ratios for the development of combined lethal and major bleeding in dual-antiplatelet therapy vs monoantiplatelet therapy studies. CI, confidence interval; DAPT, dual-antiplatelet therapy; MAPT, monoantiplatelet therapy.
caused by increased bleeding, with no observed benefit in reduction of 30-day and 6-month major stroke, spontaneous MI, and all-cause mortality. The trend toward increased harm is driven by observational studies, with no significant difference in randomized trials. The optimal antiplatelet regimen after TAVI is currently being studied in the ARTE trial. Future consideration should also be given to monotherapy with clopidogrel after TAVI, as well as omission of clopidogrel loading before the procedure. Disclosures The authors have no conflicts of interest to disclose. References Figure 7. Funnel plot for publication bias; the primary outcome did not show publication bias.
There are several limitations to this meta-analysis. Our study included both randomized and retrospective observational studies with variable patient inclusion/exclusion criteria and different prosthetic aortic valve types; this may introduce a selection bias. For the primary outcome measure, only 4 studies were included with 640 patients without patient-level data, which may limit study power and the ability to detect statistically significant findings. Specifically, this may underestimate the benefit of DAPT therapy to reduce ischemic outcomes such as major stroke and spontaneous MI. The pooled analysis cannot control for patient characteristics, clinical variables, and procedural outcomes that may account for increased bleeding and mortality. Only 18% of patients in our analysis had atrial fibrillation, which represents a group at high risk for the development of thromboembolism, in which MAPT alone may not be suitable.
Conclusions DAPT in comparison with MAPT in patients who have undergone TAVI suggested a trend toward increased harm
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Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2015.01.014.
