Single vs Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation: A Systematic Review

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1 Reviews Single vs Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation: A Systematic Review Address for correspondence: Dr. Arden Barry, 0G1.01 WMC, Street NW, Edmonton, Alberta T6G 2B7, Canada, arden.barry@ualberta.ca Ricky D. Turgeon, BSc(Pharm), PharmD, ACPR and Arden R. Barry, BSc, BSc(Pharm), PharmD, ACPR Doctor of Pharmacy Student, Faculty of Pharmaceutical Sciences (Turgeon), University of British Columbia, Vancouver, British Columbia, Canada; Clinical Academic Colleague, Faculty of Pharmacy and Pharmaceutical Sciences (Barry), University of Alberta, and Clinical Pharmacist and Practice Leader, Pharmacy Services, Mazankowski Alberta Heart Institute, Alberta Health Services, Edmonton, Alberta, Canada There is wide variability in prescribing of antiplatelet regimens following transcatheter aortic valve implantation (TAVI). The objective of this review was to evaluate published and unpublished reports regarding the efficacy and safety of dual antiplatelet therapy (DAPT) compared with a single antiplatelet agent in patients undergoing TAVI. We searched MEDLINE, CENTRAL, Embase, and unpublished sources of literature from inception to December 2014 using terms synonymous with TAVI and DAPT. We included randomized controlled trials (RCTs) and cohort or case-control studies that compared DAPT with a single antiplatelet agent post-tavi. Four articles met the inclusion criteria (2 RCTs, 2 cohort studies), of which all were deemed to be at high risk of bias, for a total of 662 patients. Compared with a single antiplatelet agent, DAPT did not significantly reduce all-cause mortality (risk ratio: 1.22, 95% confidence interval: , I 2 = 0%). Due to selective outcome reporting and variable follow-up, other outcomes of interest could not be meta-analyzed; however, evaluation of individual studies demonstrated no significant reduction in thrombotic events with DAPT and a similar or higher risk of bleeding. Current evidence, though limited by low methodological quality, suggests a lack of benefit and potential harm with DAPT compared with a single antiplatelet agent in patients post-tavi. Therefore, clinicians should evaluate the use of DAPT in patients post-tavi on a case-by-case basis until more robust evidence is available to guide practice. Introduction In the Western world, aortic stenosis (AS) is generally considered to be a disease of the elderly, affecting only approximately 0.4% of the general population but up to 12.4% of individuals age >75 years. 1,2 Progressive calcification and resulting narrowing of the aortic valve annulus is the most common cause of AS in the elderly. 3 Prognosis of AS is similar to that of an age-matched population until the onset of symptoms. 3 If left untreated, mean survival following onset of angina, syncope, and clinical heart failure is 5, 3, and 2 years, respectively. 3 Until recently, surgical aortic valve replacement was the only modality by which to correct AS. However, recent advances in percutaneous interventions have led to the adoption of transcatheter aortic valve implantation (TAVI). In the pivotal randomized Placement of Aortic Transcatheter Valves (PARTNER) trials, TAVI with a The authors have no funding, financial relationships, or conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article. Received: March 10, 2015 Accepted with revision: April 24, 2015 SAPIEN valve (Edwards Lifesciences Corp., Irvine, CA) reduced mortality, rehospitalization, and symptom burden compared with medical management in inoperable patients and demonstrated noninferiority compared with surgical aortic valve replacement in high-risk surgical candidates at up to 2 years. 4,5 Similar data exist for the CoreValve self-expanding valve (Medtronic, Minneapolis, MN). 6 A current area of controversy in post-tavi care is the optimal regimen and duration of antiplatelet therapy following implantation. In the landmark PARTNER trials, investigators encouraged, but did not require, use of dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and clopidogrel for 3 or 6 months post-tavi. 4 6 However, this recommendation was based on expert consensus. Most patients who undergo TAVI are elderly with multiple comorbidities, and thus they are at high risk for both thrombotic and bleeding events. Surveys of prescribing practice show a high level of variability in DAPT duration, even within a single country, which illustrates the lack of standard of care and need for research into the benefits and risks of DAPT following TAVI. 7,8 The objective of this study was to perform a comprehensive systematic review and meta-analysis to assess 629 DOI: /clc Wiley Periodicals, Inc.

2 Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study flow diagram. the efficacy and safety of DAPT compared with single antiplatelet therapy (SAPT) in adult patients following TAVI. Methods Study Search and Data Sources This systematic review utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. 9 The following databases were searched from inception to December 2014: CENTRAL, Embase, and MEDLINE. Included were all randomized controlled trials (RCTs) and cohort and case-control studies published in any language that evaluated DAPT (defined as ASA in combination with a P2Y12 inhibitor) vs SAPT (ASA or a P2Y12 inhibitor) in adult patients (age 18 years) following TAVI. The search queries for each database used terms synonymous with TAVI and DAPT (see Supporting Information, Appendix A, in the online version of this article). For grey and unpublished literature, completed or ongoing trials were searched using the World Health Organization International Clinical Trials Registry Platform and 10,11 Furthermore, local TAVI experts were contacted to inquire about ongoing or unpublished studies. Finally, a manual search of the references of the included studies was performed. Data Extraction and Quality Assessment Both authors independently performed study selection, data extraction, risk-of-bias assessment, and data analysis. The risk of bias of RCTs was assessed using the Cochrane Collaboration Risk of Bias Tool, which evaluates 6 separate domains of bias that commonly present threats to validity of RCTs. 12 For cohort and case-control studies, the Newcastle- Ottawa Scale was utilized, as it is endorsed by the Cochrane Collaboration to evaluate the quality of nonrandomized clinical trials. 13,14 To minimize the risk of publication bias, a comprehensive search of both published and unpublished literature was performed. To uncover and minimize outcome-reporting bias, the authors of all included studies were contacted to request access to the study protocol and outcome data. Any disagreement was resolved by discussion and consensus. Outcomes All-cause mortality was selected as the primary outcome, as it is objective and a readily available measure of net effect on thrombotic and bleeding events. The following were designated as secondary outcomes: ischemic or thrombotic events (any major adverse coronary or cerebrovascular event [MACCE], myocardial infarction, or stroke) and bleeding events (any severity, life-threatening or major) at longest available follow-up. When available, independently and blindly adjudicated outcomes were sought preferably according to the accepted consensus definitions described by the Valve Academic Research Consortium (VARC). 15 Statistical Analysis Characteristics of the included studies were reported using descriptive statistics. A Mantel-Haenszel random-effects model was utilized to calculate a risk ratio (RR) and 95% confidence interval (CI) for each outcome of interest. Statistical heterogeneity was assessed with the I 2 statistic, and significant heterogeneity was defined as a value >50%. A P value of <0.05 was considered to be statistically significant. Results The search strategy yielded 156 studies after duplicates were removed, and 4 met the inclusion criteria (Figure 1) Attempts to obtain trial protocols or unpublished data from authors of all 4 studies were unsuccessful. Two RCTs and 2 quasi-experimental studies enrolling a total of 662 patients were available as full text. Of the 2 quasiexperimental studies, one was a before-and-after study at a single center, whereas the other prospectively compared center-wide adoption of DAPT or SAPT post-tavi. Table DOI: /clc Wiley Periodicals, Inc.

3 Table 1. Study Characteristics Author Ussia 16 Stabile 17 Poliacikova 18 Durand 19 Methodology RCT RCT Quasi-experimental (before-and-after study) Quasi-experimental (prospective cohort of center-based selection of DAPT or SAPT) No Timeframe DAPT: ; SAPT: Country Italy Italy England France No.ofcenters Inclusion Eligible for TAVI Eligible for TAVI Eligible for TAVI Underwent TAVI Exclusion Patient characteristics Previous PCI or ACS requiring DAPT or need for an OAC Indication for an OAC NR None Mean age, y Female sex, % Valve used CoreValve Sapien XT CoreValve DAPT: Sapien (100%); SAPT: CoreValve (32.9%), Sapien (67.1%) STS score, % NR DAPT: 6.9; SAPT: 7.4 Comorbidities, % Previous stroke 8 NR DAPT: 27.6; SAPT: 17.6 DAPT: 9.4; SAPT: 7.9 Hypertension NR 70.5 Previous PCI 27 NR DAPT: 27.6; SAPT: 22.0 NR PVD 9 NR NR DAPT: 7.8; SAPT: 17.1 CKD 14 NR 5.3 NR DM NR 24 Taking OAC at baseline DAPT: 32.8; SAPT: 28.0 Intervention regimen ASA 100 mg PO once daily + clopidogrel 75 mg PO once daily for 3 mo ASA mg PO once daily + either clopidogrel 75 mg PO once daily or ticlopidine 500 mg PO twice daily for 6 mo daily + clopidogrel 75 mg PO once daily for 6 mo daily for life + clopidogrel 75 mg PO once daily for 1mo Control regimen ASA 100 mg PO once daily for 3 mo ASA mg PO once daily for 6 mo daily for 6 mo daily for life or clopidogrel 75 mg PO once daily for 1mo Abbreviations: ACS, acute coronary syndrome; ASA, acetylsalicylic acid; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; NR, not reported; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; PO, by mouth; PVD, peripheral vascular disease; RCT, randomized controlled trial; SAPT, single antiplatelet therapy; STS, Society of Thoracic Surgeons; TAVI, transcatheter aortic valve implantation. 631 DOI: /clc Wiley Periodicals, Inc.

4 Table 2. Risk of Bias of Included Studies Author RCTs Ussia 16 Stabile 17 Sequence generation Unclear Unclear Allocation concealment Unclear Unclear Blinding: participants High risk Unclear Blinding: personnel High risk Unclear Blinding: outcome assessors Low risk Low risk Incomplete outcome data Low risk Unclear Selective outcome reporting Low risk Unclear Other biases High risk High risk Author Cohort Studies Poliacikova 18 Durand 19 Representativeness: exposed 1/1 1/1 Representativeness: nonexposed 1/1 0/1 Exposure ascertainment 1/1 1/1 Absence of outcome at baseline 1/1 1/1 Comparability of groups 0/2 2/2 Assessment of outcome 1/1 1/1 Length of follow-up 1/1 1/1 Adequacy of follow-up 0/1 1/1 Abbreviations: RCTs, randomized controlled trials. outlines relevant study characteristics. All 4 included studies compared the combination of ASA + clopidogrel (DAPT) with ASA alone. Duration of DAPT ranged from 1 to 6 months, followed by lifelong ASA therapy. Follow-up ranged from 30 days to 6 months post-tavi. All 4 studies classified some or all outcomes according to the VARC definitions. (See Supporting Information, Appendix B, in the online version of this article for data on outcomes of interest at various points of follow-up as reported.) All included studies were deemed to be at high risk of bias (Table 2). Of particular concern, the authors did not report all outcomes at final study follow-up. Further, authors of only 2 studies stated a predefined primary outcome, 16,19 and none of the studies accounted for simultaneous statistical testing of multiple outcomes, either statistically or methodologically. Finally, none of the studies reported a priori sample size estimations for identification of clinically relevant differences. The meta-analysis was only performed for all-cause mortality. It could not be performed for thrombotic and bleeding outcomes due to considerable selective reporting bias and variable follow-up. Therefore, it was reasoned that a meta-analysis of these biased data would produce unreliable and inaccurate estimates of effect and instead report a qualitative description of the outcomes for each individual study. All-Cause Mortality All 4 included studies reported data on death from any cause. Three studies reported mortality at 6 months (range, 5% 13%) and 1 study reported mortality at 1 month (range, 8% 9%) for a median follow-up of 4.75 months. DAPT did not demonstrate a statistically significant reduction in all-cause mortality compared with SAPT (RR: 1.22, 95% CI: , I 2 = 0%; Figure 2). Ischemic or Thrombotic Outcomes Two studies (1 RCT and 1 cohort) reported on the combined endpoint of MACCE at 6 months. 16,18 Both studies failed to demonstrate a statistically significant reduction in MACCE with DAPT compared with SAPT, though event rates were numerically higher in the DAPT group (18% vs 15%, and 14.5% vs 8.5%, respectively). Additionally, 3 studies (1 RCT and 2 cohort studies) reported separately on 1 coronary or cerebrovascular components of the MACCE composite outcome None of the studies demonstrated a statistically significant difference for any of these comparisons, likely due to low event rates (range, 0.8% 4.7%). Notably, Durand et al demonstrated a 4-fold increase in the incidence of stroke at 30 days with DAPT (4.7% vs 1.2%), but this comparison did not reach statistical significance (P = 0.14). 19 Bleeding Outcomes Three studies evaluated bleeding of any severity (1 RCT and 2 cohorts) The risk of bleeding of any severity at 1 month was statistically significantly higher with DAPT in 1 study (31.2% vs 8.5%; P < ). 19 In the remaining 2 studies, the risk of any bleeding was numerically higher with DAPT, although neither comparison reached statistical significance. 17,18 Major or life-threatening bleeding was assessed in 3 studies (2 RCTs and 1 cohort). 16,17,19 In Durand et al, DAPT demonstrated a significantly higher risk of major bleeding (13.3% vs 2.4%; P < ) as well as life-threatening bleeding (12.5% vs 3.7%; P = 0.005) at 1 month. 19 The 2 remaining studies did not find significantly different rates of major or life-threatening bleeding. 16,17 Discussion Consensus-based international guidelines endorse anywhere from 1 to 6 months of DAPT following TAVI Guideline authors primarily based their recommendations on extrapolation of evidence for DAPT following percutaneous coronary intervention with stent implantation due to the lack of evidence directly comparing different antiplatelet regimens post-tavi. However, key characteristics decrease the likelihood of thrombosis or stenosis of TAVI valves compared with coronary stents, including a larger area and the bioprosthetic nature of the valve vs a drug-eluting metal stent. The best estimates of the proportion of post-tavi patients who experience valve thrombosis and embolism are low, at approximately 1.2% and 1.7%, respectively, although they do not account for the antithrombotic regimen used. 23 Conversely, candidates for TAVI are generally older and have more comorbidities than those undergoing 632 DOI: /clc Wiley Periodicals, Inc.

5 Figure 2. All-cause mortality. Abbreviations: CI, confidence interval; DAPT, dual antiplatelet therapy; M-H, Mantel-Haenszel; SAPT, single antiplatelet therapy. percutaneous coronary intervention, which could lead to a potentially greater risk of bleeding with routine use of DAPT post-tavi. Thus, there is a need for an objective assessment of the potential benefits and risks of DAPT compared with SAPT specifically in TAVI patients. This systematic review identified 4 studies comparing DAPT with SAPT following TAVI. There was no statistically significant reduction in death from any cause with DAPT compared with SAPT. Included studies varied in definitions of thrombotic and bleeding outcomes, as well as timing of reporting, rendering a meta-analysis of these data unreliable. In the absence of other published evidence, a qualitative assessment of these outcomes provides valuable insight regarding the efficacy and safety of DAPT post-tavi. The included studies did not demonstrate a reduction in MACCE (or any individual component) with DAPT compared with SAPT, though event rates were too low to make definitive conclusions. With respect to safety, all 4 studies identified a higher rate of bleeding of any severity with DAPT, though this only reached statistical significance in 1 study. 19 Additionally, the aforementioned study demonstrated a higher rate of both major and life-threatening bleeding with DAPT at 30 days. 19 Though not prespecified outcomes of this review, there was additional evidence to support potential harm with DAPT. The primary outcome of 1 cohort study was a combination of vascular and bleeding events (mortality, major stroke, life-threatening bleeding, myocardial infarction, and major vascular complication), which was significantly lower with SAPT vs DAPT (13.4% vs 23.4%; hazard ratio: 0.51, 95% CI: ). 19 Additionally, 1 RCT demonstrated a numerically higher incidence of major and minor procedure-related complications (eg, access-site hematoma) with DAPT compared with ASA alone (5% vs 0%; P = 0.06). 17 Overall, the quality of evidence for this comparison is low; therefore, an appropriately conducted, adequately powered RCT could substantially alter the approach to antiplatelet therapy in patients post-tavi. There is at least one ongoing trial aimed at addressing this clinical question. The Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Implantation With the Edwards SAPIEN XT Valve (ARTE) trial (NCT ) is an open-label study comparing DAPT vs ASA alone in patients following TAVI. 24 The estimated enrollment is 200 patients, and it is due to be completed in July The addition of data from this trial to unpublished outcome data of existing trials will be critical for identifying the most appropriate post-tavi antiplatelet regimen. Conclusion Limited evidence exists to validate the use of DAPT compared with SAPT following TAVI. Consensus guidelines currently advocate for the use of DAPT for 1 to 6 months post-tavi. The published evidence identified in this review, though limited by low methodological quality, suggests there is no additional benefit with DAPT and potentially an increased risk of harm in the form of bleeding. Therefore, until more evidence is available, clinicians should assess antiplatelet therapy on a case-by-case basis, as opposed to routine use of DAPT, accounting for patient-specific factors such as comorbidities or concurrent therapies that may increase the risk of bleeding. References 1. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet. 2006;368: Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol. 2013;62: Carabello BA, Paulus WJ. Aortic stenosis. Lancet. 2009;373: Makkar RR, Fontana GP, Jilaihawi H, et al; PARTNER Trial Investigators. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis [published correction appears in NEnglJ Med. 2012;367:881]. N Engl J Med. 2012;366: Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med. 2012;366: Adams DH, Popma JJ, Reardon MJ, et al; US CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a selfexpanding prosthesis. N Engl J Med. 2014;370: Nijenhuis VJ, Stella PR, Baan J, et al. Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals. Neth Heart J. 2013;22: Hasmi I, Wipder A, More R, et al. Lack of consensus on antithrombotic therapy in patients undergoing TAVI: an online survey from UK TAVI operators. Heart. 2014;100(suppl 3):A Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e World Health Organization. International Clinical Trials Registry Platform. Accessed September 23, US National Institutes of Health. ClinicalTrials.gov. clinicaltrials.gov. Accessed September 23, DOI: /clc Wiley Periodicals, Inc.

6 12. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d Wells G, Shea B, O Connell D, et al; Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed September 18, Higgins JP, Green S. Tools for assessing methodological quality or risk of bias in non-randomized studies. In: Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version The Cochrane Collaboration; Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011;57: Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. 2011;108: 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: Poliacikova P, Cockburn J, de Belder A, et al. Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation comparison of regimes. J Invasive Cardiol. 2013;25: 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: Webb J, Rodés-Cabau J, Fremes S, et al. Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement. Can J Cardiol. 2012;28: Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease. Chest. 2012;141(2 suppl):e576s e600s. 22. Nishumura RA, Otto CM, Bonow RO, et al 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 [published corrections appear in Circulation. 2014;129:e651 and Circulation. 2014;130:e120]. Circulation. 2014;129:e521 e Généreux P, Head SJ, Van Mieghem NM, et al. Clinical outcomes after transcatheter aortic valve replacement using Valve Academic Research Consortium definitions: a weighted meta-analysis of 3519 patients from 16 studies. J Am Coll Cardiol. 2012;59: Aspirin versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation: the ARTE Trial. trials.gov/ct2/show/nct Accessed September 22, DOI: /clc Wiley Periodicals, Inc.