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Optimal duration of dual antiplatelet therapy following percutaneous coronary intervention: Protocol for an
umbrella review
Journal: BMJ Open
Manuscript ID bmjopen-2016-015421
Article Type: Protocol
Date Submitted by the Author: 02-Dec-2016
Complete List of Authors: Elliott, Jesse; University of Ottawa Heart Institute, Kelly, Shannon; University of Ottawa, Department of Epidemiology and Community Medicine; Ottawa Hospital Research Institute, Medicine
Bai, Zemin; University of Ottawa Heart Institute Liu, Wenfei; University of Ottawa Heart Institute Skidmore, Becky; Independent Information Specialist Boucher, Michel ; Canadian Agency for Drugs and Technologies in Health (CADTH), So, DYF; University of Ottawa, Wells, George ; Ottawa Hospital Research Institute
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Evidence based practice
Keywords: Dual antiplatelet therapy, Percutaneous intervention, Umbrella review
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Optimal duration of dual antiplatelet therapy following percutaneous coronary
intervention: Protocol for an umbrella review
Word count: 1694
Jesse Elliott, Shannon Kelly, Zemin Bai, Wenfei Liu, Becky Skidmore, Michel Boucher, Derek
So, George A Wells
Jesse Elliott MSc,
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario, Canada
jelliott@ottawaheart.ca
Shannon Kelly MSc,
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, Canada
skelly@ottawaheart.ca
Zemin Bai, MSc
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario, Canada
abai@ottawaheart.ca
Wenfei Liu, MSc
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, Canada
wliu088@uottawa.ca
Becky Skidmore, MLS, Independent Information Specialist,
Ottawa, Ontario, Canada
bskidmore@rogers.com
Michel Boucher, B. Pharm, MSc, Grad Dipl. Bus Adm, RPh
Canadian Agency for Drugs and Technologies in Health (CADTH),
Ottawa, Ontario, Canada
MichelB@cadth.ca
Derek So, MD FRCPC FACC
Division of Cardiology, University of Ottawa Heart Institute,
Ottawa, Ontario, Canada
dso@ottawaheart.ca
George A. Wells, PhD*
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Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, K1Y4W7
gawells@ottawaheart.ca
*Corresponding author
ABSTRACT
Introduction: Although dual antiplatelet therapy (DAPT) is routinely given to patients after
percutaneous coronary intervention (PCI) with stenting, the optimal duration is unknown. Recent
evidence indicates there may be benefits in extending the duration beyond 12 months but such
decision may increase the risk of bleeding. Clinicians and policy makers require a
comprehensive overview of the literature assessing the optimal duration of DAPT.
Methods and analysis: We will perform a comprehensive search of the published and grey
literature for systematic reviews involving randomized controlled trials assessing the optimal
duration of DAPT following PCI with stenting. The intervention of interest is extended DAPT
(beyond 12 months) compared with short-term DAPT (6-12 months). Studies will be selected for
inclusion by two reviewers, and the quality will be assessed. The primary outcome is death (all-
cause and cardiovascular). Secondary outcomes will be bleeding (major, minor, gastrointestinal),
urgent target vessel revascularization, major adverse cardiovascular events, myocardial
infarction, stroke, and stent thrombosis. Outcomes will be assessed while on DAPT and after
withdrawal of DAPT. Data will be summarized with respect to the number of included studies,
number of participants, effect estimates, and heterogeneity. Data will be reported separately
based on patient demographics, procedural parameters (e.g. stent types, lesion complexity,
concurrent disease) and clinical presentation (e.g. acute coronary syndromes, infarct type).
Ethics and dissemination: Our umbrella review aims to provide a comprehensive overview of
the benefits and harms associated with extending DAPT beyond 12 months following PCI with
stenting. The results of this review will inform clinical and policy decisions regarding the
optimal treatment duration and reimbursement of DAPT following PCI with stenting. Results
will be disseminated through a peer-reviewed publication and conference presentations. Ethics
approval is not required for this study.
Registration: PROSPERO no. CRD42016047735
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Keywords: dual antiplatelet therapy, duration, percutaneous intervention, umbrella review.
Abbreviations:
BMS = bare metal stent
DAPT = dual anti-platelet therapy
DES = drug-eluting stent
PCI = percutaneous coronary intervention
STRENGTHS AND LIMITATIONS OF THIS STUDY
• This protocol was designed following guidelines for umbrella reviews from Joanna Briggs
Institute and reported following the Preferred Reporting Items for Systematic review and Meta-
Analyses (PRISMA) guidelines.
• The results of this review will inform policy decisions regarding the reimbursement of DAPT
following PCI with stenting and will be useful for shared decision making, providing information
to clinicians and patients about the potential tradeoffs between risks and benefits of extended
DAPT.
• As with other umbrella reviews, the quality of our findings will depend on the quality of the
included systematic reviews.
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BACKGROUND
Dual antiplatelet therapy (DAPT), the combination of a P2Y12 inhibitor with acetylsalicylic acid
(ASA), is routinely given following percutaneous coronary intervention (PCI) with stenting with
the aim of preventing stent thrombosis and major adverse cardiovascular events.[1] Guidelines
currently recommend for DAPT for 6 to 12 months;[1-3] however, the optimal duration of
DAPT remains controversial. Extending DAPT beyond 12 months may reduce the risk of late
stent thrombosis but may increase the risk of bleeding.[4] Clinicians must balance the potential
risks and benefits in determining the optimal duration of DAPT, and, in some jurisdictions,
reimbursement of P2Y12 inhibitors after PCI may be limited to 12 months by some public
payers.
The association between DAPT duration and clinical outcomes has been assessed in many
systematic reviews and meta-analyses,[5-8] yet the optimal duration of DAPT remains a
controversial topic, and clinicians and policy makers require a comprehensive overview of the
depth and strength of the evidence base. To this end, we will perform a comprehensive umbrella
review to collect and assess information from previous systematic reviews that have investigated
the optimal duration of DAPT following PCI with stenting. We will seek to answer to following
questions using the findings of high-quality systematic reviews: What are the benefits and harms
of extended DAPT (> 12 mo v. 6 to 12 mo) following PCI with stenting? Are there subgroups of
patients based on demographics, angiographic parameters, or clinical presentation for whom the
optimal duration of DAPT is different? Does the optimal duration of DAPT depend on the type
of stent implanted (bare-metal stent [BMS] or drug-eluting stent [DES])? Is there a rebound
effect after withdrawal of DAPT?
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METHODS AND ANALYSIS
This umbrella review was designed using the methodology guidelines for umbrella reviews
provided by the Joanna Briggs Institute.[9] As well, we followed the Preferred Reporting Items
for Systematic review and Meta-Analyses (PRISMA) guidelines[10] and the extension for
protocols.[11] The completed PRISMA-P checklist is available (Supplementary File 1). This
protocol is registered with PROSPERO (No. CRD42016047735).
Search strategy
We will search for systematic reviews that included randomized controlled trials (RCTs)
evaluating different durations of DAPT following PCI with stenting. The search strategy
(Supplementary File 2) was developed and tested by an experienced medical information
specialist using an iterative process in consultation with the review team. The search strategy has
been reviewed by another senior information specialist using the Peer Review of Electronic
Search Strategies (PRESS) checklist.[12] Embase and Ovid MEDLINE, including Epub Ahead
of Print and In-Process & Other Non-Indexed Citations, will be searched using the OVID
platform. We will also search the Cochrane Library on Wiley and PubMed for the most recent
and unindexed citations. Grey literature from major health technology assessment sources and
clinical practice guidelines sources will be searched using CADTH’s Grey Matters Light.[13]
The search strategies involve a combination of controlled vocabulary (e.g., “Stents”,
“Percutaneous Coronary Intervention”, “Purinergic P2Y Receptor Antagonists”) and keywords
(e.g., “DES”, “PCI”, “dual antiplatelet therapy”). Vocabulary and syntax will be adjusted across
databases. Because of the depth of the literature base and the timeline of the project, results will
be limited to those published between 2011 and August 2016.
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Inclusion criteria
We set the inclusion criteria for this umbrella review following the PICO (population,
intervention, comparison, outcome) criteria:
Population: Adult patients who have undergone PCI with any type of stent and who are
receiving DAPT.
Intervention: DAPT following PCI with stenting for an extended duration (more than 12
months) DAPT may involve any type of P2Y12 inhibitor (clopidogrel, prasugrel,
ticagrelor) in combination with ASA.
Comparison: DAPT for 6 or 12 months.
Outcomes: The primary outcome is death (cardiovascular and all cause). Secondary
outcomes will be bleeding (major or minor, as defined by TIMI or BARC classifications;
gastrointestinal bleeding), urgent target vessel revascularization, major adverse
cardiovascular events, myocardial infarction, stroke, and stent thrombosis. Studies will
not be included or excluded on the basis of reported outcomes.
Study designs: Systematic evidence syntheses that included RCTs comparing different durations
of DAPT following PCI. To be eligible for inclusion, studies must have used a systematic
process to literature searching and study selection. If both RCTs and non-randomized studies are
included, the effect estimates from RCTs must be reported separately.
No language restrictions will be used during the screening or study selection process. Because of
the short timeline of this project, we will extract data only from foreign-language studies that can
be translated within the timeline of the project. All foreign language studies eligible for inclusion
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will be listed in an appendix to the final publication.
Because our aim is to summarize data from high-quality systematic reviews, studies must meet
the following criteria in addition to the PICO criteria. First, studies must report using a
comprehensive search strategy involving two or more electronic databases; second, they must
provide an explicit statement describing the inclusion criteria applied to candidate RCTs; and
third, they must have critically appraised the quality and/or risk of bias of the included RCTs and
report the outcome of that process.
Study selection
The eligibility criteria will be applied to each title and abstract identified in the literature search
by two independent reviewers in a standardized manner. All records identified by at least one
author as potentially relevant will be obtained in full-text format. The eligibility criteria will then
be applied to the full-text records, and a final decision made for inclusion. Conflicts will be
resolved by discussion. The reviewers will not be blinded to study authors or centre of
publication prior to study selection. Study screening and assessment of eligibility will be
facilitated and standardized through the use of DistillerSR (Evidence Partners), an online
systematic review software.
Quality assessment
Two independent reviewers will apply the AMSTAR (A MeaSurement Tool to Assess
systematic Reviews)[14] checklist to each included study, and any disagreements will be
resolved by consensus. Only reviews meeting a minimum quality threshold will be included in
the summary of findings. We will not use a numerical score on the AMSTAR checklist to define
“high quality”; instead, the following criteria must be met: use of a comprehensive search
strategy involving two or more electronic databases; use of an explicit statement describing the
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inclusion criteria applied to candidate RCTs; use of a formal critical appraisal or quality
assessment process for all included studies and report the outcome of that process; report
findings on outcomes of interest using details on the study and patient characteristics of two or
more studies; and provide the direction of the findings from any pooled analyses (narrative or
meta-analysis) carried out, including direction of effect and any statistical significance. Any
included reviews that do not meet these minimum requirements will remain included; however,
no data will be extracted.
In the event that included reviews report significantly overlapping lists of included studies
reporting the same outcome(s), we will report findings from the higher quality, more recent
review with the largest number of studies.
Data collection
All information will be collected using piloted and standardized data abstraction forms in
DistillerSR. Extraction forms will be developed following the Joanna Briggs Institute’s
recommended extraction items.[9] Data will be extracted from each included systematic review
by one reviewer and verified by a second reviewer. Any disagreements will be resolved by
consensus when possible; otherwise, the judgment of a third reviewer will be considered final.
The original, primary publication for each included review will be used for data extraction,
except where multiple publications for a unique review are found. Multiple publications for a
unique review (e.g., supplemental online appendices, companion publications of specific
outcomes or populations from the original study) will be handled by extracting the most recently
adjudicated data for each outcome specified a priori in this protocol.
The data extracted will include specific details about the included RCTs (e.g., study population,
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the durations of DAPT investigated) and the review methods (e.g., number of databases
searched, search date, and any date, location, or language restrictions on the search). Patient
characteristics (e.g., age, sex, smoking status, diabetes, prior MI, history of heart failure) will
also be extracted from the included reviews, if reported. We plan to extract the effect estimates
for the outcomes of interest for the whole population and for any subgroups, as well as the
method of synthesis (e.g., meta-analysis, network meta-analysis). The authors’ overall
conclusion or recommendation will also be extracted. Outcome data will be extracted for the
period while patients were on DAPT and after withdrawal of DAPT.
Subgroups
If available, effect estimates will be extracted separately for clinically important subgroups based
on patient demographics (e.g., age, sex, smoking status, diabetes, prior MI, history of heart
failure), procedural parameters (e.g., vein graft intervention, stent type, lesion complexity,
concurrent disease), and clinical presentation (e.g., acute coronary syndrome (ACS) v. no ACS;
ST-elevation myocardial infarction [STEMI] v. non-STEMI). If subgroup data are not available
from the included SRs, we will extract such data from the RCTs identified from the included
SRs.
Data summary
The aim of this umbrella review is to present a summary of the existing research syntheses that
have addressed the optimal duration of DAPT. The findings will be summarized from the most
recent high-quality systematic reviews using a narrative approach. A tabular summary of review
characteristics (year of publication, county of origin, number of included studies, setting and/or
context, and interventions) will be provided. Outcome data will be summarized with respect to
number of included studies, number of participants, effect estimates, and heterogeneity. Data for
subgroups will be presented separately. Strengths and limitations of the included studies, as
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assessed by AMSTAR, will also be presented.
ETHICS AND DISSEMINATION
In this umbrella review, we will undertake a comprehensive review of previously published
systematic reviews assessing the optimal duration of DAPT. Using evidence from this review,
we expect to make a conclusion regarding the benefits and harms associated with extending
DAPT beyond 12 months following PCI with stenting. As well, we aim to determine whether
there are subgroups of patients who would benefit from shorter or longer DAPT. The results of
our review will be of interest to clinicians, policy makers, and patients. We plan to disseminate
our findings through peer-reviewed journal publication and conference presentations. This
review does not require ethical approval.
DECLARATIONS
Authors' contributions: JE, SK, MB, DS, and GW designed the study. BS designed and will
execute the search strategy. JE drafted the protocol, which was revised by all authors. All authors
have approved the version of the manuscript submitted for publication.
Consent for publication: Not applicable
Funding: This work is funded by the Canadian Institutes of Health Research, Drug Safety and
Effectiveness Network. The funder had no role in the design of the study.
Competing interests: None declared
ADDITIONAL MATERIALS
Supplementary File 1: PRISMA-P checklist
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Supplementary File 2: Search strategy
REFERENCES
1 Levine GN, Bates ER, Mauri L, et al. 2016 ACC/AHA guideline focused update on duration of
dual antiplatelet therapy in patients with coronary artery disease. A report of the American
College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
Circulation 2016;133.
2 The Task Force on Myocardial Revascularization of the European Society of Cardiology
(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2014 ESC/EACTS
Guidelines on myocardial revascularization. Eur Heart J 2014;35(37):2541–619.
3 Tanguay JF, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian cardiovascular
society guidelines for the use of antiplatelet therapy. Can J Cardiol 2013;29(11):1334–45.
4 Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy
after Drug-Eluting Stents. N Engl J Med 2014;371(23):2155–66.
5 Liu M, Chen J, Huang D, Ke J, Tang W, Wu W. Optimal duration of dual antiplatelet therapy
after drug-eluting stent implantation: a meta-analysis of 3 randomized controlled trials. J
Cardiovasc Pharmacol 2014;64(1):41–6.
6 Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy after
percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised
controlled trials. BMJ 2015;350:h1618.
7 Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended
duration dual antiplatelet therapy after drug-eluting stent implantation: A pairwise and Bayesian
network meta-analysis of randomised trials. Lancet 2015;385(9985):2371–82.
8 Palmerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy
after drug-eluting stent implantation: An individual patient data pairwise and network meta-
analysis. J Am Coll Cardiol 2015;65(11):1092–102.
9 Aromataris E, Fernandez R, Godfrey C, Holly C, Khalil H, Tungpunkom P. Methodology for
JBI Mixed Methods Systematic Reviews 2014.
http://joannabriggs.org/assets/docs/sumari/ReviewersManual-Methodology-JBI_Umbrella
Reviews-2014.pdf (accessed15 Aug 2016).
10 Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred Reporting Items for Systematic
Reviews and Meta-Analyses: The PRISMA Statement (Reprinted from Annals of Internal
Medicine). Phys Ther 2009;89(9):873–80.
11 Moher D, Shamseer L, Clarke M, et al. Preferred Reporting Items for Systematic Review and
Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4(1):1.
12 McGowan J, Sampson M, Lefebvre C. An evidence based checklist for the Peer Review of
Electronic Search Strategies (PRESS EBC). Evid Based Libr Inf Pract 2010;5(1):149–54.
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13 Canadian Agency for Drugs and Technologies in Health. Grey Matters Light.
www.cadth.ca/sites/default/files/is/cadth_Handout_greymatters
_light_e.pdf (accessed 15 Aug 2016).
14 Shea BJ, Grimshaw JM, Wells G a, et al. Development of AMSTAR: a measurement tool to
assess the methodological quality of systematic reviews. BMC Med Res Methodol 2007;7:10.
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1
PRISMAPRISMAPRISMAPRISMA----P 2015 ChecklistP 2015 ChecklistP 2015 ChecklistP 2015 Checklist
This checklist has been adapted for use with protocol submissions to Systematic Reviews from Table 3 in Moher D et al: : : : Preferred reporting
items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015 4444:1
Section/topic # Checklist item Information reported Page
number(s) Yes No
ADMINISTRATIVE INFORMATION
Title
Identification 1a Identify the report as a protocol of a systematic review 1
Update 1b If the protocol is for an update of a previous systematic review, identify as such NA
Registration 2 If registered, provide the name of the registry (e.g., PROSPERO) and registration number in the Abstract
2
Authors
Contact 3a Provide name, institutional affiliation, and e-mail address of all protocol authors; provide physical mailing address of corresponding author
1
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 10
Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments
NA
Support
Sources 5a Indicate sources of financial or other support for the review 10
Sponsor 5b Provide name for the review funder and/or sponsor 10
Role of sponsor/funder
5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 10
INTRODUCTION
Rationale 6 Describe the rationale for the review in the context of what is already known 4
Objectives 7
Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO)
4
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2
Section/topic # Checklist item Information reported Page
number(s) Yes No
METHODS
Eligibility criteria 8 Specify the study characteristics (e.g., PICO, study design, setting, time frame) and report characteristics (e.g., years considered, language, publication status) to be used as criteria for eligibility for the review
6
Information sources 9 Describe all intended information sources (e.g., electronic databases, contact with study authors, trial registers, or other grey literature sources) with planned dates of coverage
5
Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated
Supplemental File 2
STUDY RECORDS
Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 7
Selection process 11b State the process that will be used for selecting studies (e.g., two independent reviewers) through each phase of the review (i.e., screening, eligibility, and inclusion in meta-analysis)
7
Data collection process
11c Describe planned method of extracting data from reports (e.g., piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators
8
Data items 12 List and define all variables for which data will be sought (e.g., PICO items, funding sources), any pre-planned data assumptions and simplifications
6,9
Outcomes and prioritization
13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale
6
Risk of bias in individual studies
14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis
7
DATA
Synthesis
15a Describe criteria under which study data will be quantitatively synthesized NA
15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data, and methods of combining data from studies, including any planned exploration of consistency (e.g., I
2, Kendall’s tau)
NA
15c Describe any proposed additional analyses (e.g., sensitivity or subgroup analyses, meta-regression)
9
15d If quantitative synthesis is not appropriate, describe the type of summary planned 9
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3
Section/topic # Checklist item Information reported Page
number(s) Yes No
Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (e.g., publication bias across studies, selective reporting within studies)
NA
Confidence in cumulative evidence
17 Describe how the strength of the body of evidence will be assessed (e.g., GRADE) NA
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Additional File 2
DAPT PCI
Final Strategies
2016 Aug 12
OVID
Database: Embase <1980 to 2016 Week 32>, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid
MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:
--------------------------------------------------------------------------------
1 exp Stents/ (190875)
2 (stent or stents or stented or stenting).tw,kw. (201982)
3 (DES or DESs).tw,kw. (70216)
4 (Strecker* or Supremo* or WallFlex* or Wallstent*).tw,kw. (3902)
5 or/1-4 (300274) [STENTS]
6 ((dual or double) adj (antiplatelet* or anti-platelet*)).tw,kw. (9238)
7 (DAPT or DAPTs).tw,kw. (3105)
8 6 or 7 (10825) [DAPT PT 1]
9 Platelet Aggregation Inhibitors/ (61484)
10 (antiplatelet* or anti-platelet*).tw,kw. (62043)
11 (platelet* adj2 inhibit*).tw,kw. (34284)
12 thrombocyte aggregation inhibit*.tw,kw. (264)
13 Purinergic P2Y Receptor Antagonists/ (1565)
14 ((P2Y or P2Y1 or P2Y12 or P2Y2) adj (receptor antagonist* or purinoceptor antagonist*)).tw,kw. (1339)
15 (ADP receptor adj (antagonist* or blocker*)).tw,kw. (665)
16 (adenosine diphosphate receptor adj (antagonist* or blocker*)).tw,kw. (152)
17 clopidogrel*.tw,kw. (28081)
18 (clopilet or grepid or iscover or PCR 4099 or PCR4099 or plavix or SC 25989C or SC 25990C or SR 25989 or zopya or
zylagren or zyllt).tw,kw. (3218)
19 (duocover or duoplavin).tw,kw. (11)
20 clopidogrel.rn. (46154)
21 Prasugrel Hydrochloride/ (6357)
22 (prasugrel or CS 747 or CS747 or effient or efient or LY 640315 or LY640315).tw,kw. (4607)
23 prasugrel.rn. (5348)
24 ticagrelor.tw,kw. (3509)
25 (AZD 6140 or AZD6140 or brilinta or brilique or possia).tw,kw. (691)
26 ticagrelor.rn. (3951)
27 Aspirin/ (201606)
28 asa.tw,kw. (56611)
29 aspirin.tw,kw. (140513)
30 ("2-(Acetyloxy)benzoic Acid" or acetylsalicylic acid or acetysal or acylpyrin or aloxiprimum or colfarit or dispril or easprin
or ecotrin or endosprin or magnecyl or micristin or polopirin or polopiryna or solprin or solupsan or zorprin).tw,kw. (18867)
31 ("2 acetoxybenzoate" or "8-hour bayer" or acenterine or acesal or acetan or acetard or aceticil or aceticyl or acetonyl or
acetophen or acetosal or acetosalicylic acid or acetosalin or acetosalum or acetyl salicylate or acetyl salicylic acid or acetylic
salicylic acid or acetylin or acetylo or acetylon or acetylosalicylic acid or acetylsal or acetylsalicyclic acid or acetylsalicyl or
acetylsalicylate or acetylsalicylic acid or acetylsalycic acid or acetylsalycylic acid or acetysal or acidulatum or acidum acetyl
salicylicum or acidum acetylosalicylicum or acidum acetylsalicylicum).tw,kw. (22012)
32 (actorin or acylpyrine or acytosal or adiro or alabukun or alasil or albyl-e or alka seltzer or alkaspirin or anasprin or andol or
anopyrin or ansin or anthrom or aptor or arthralgyl or asaflow or asaphen or asapor or asatard or asawin or aspec or aspent or
aspex or aspilets or aspirem or aspirgran or aspirina or aspirine or aspirinine or aspirisucre or aspisol or aspo cid or aspro or
asrina or asrivo or asta or asteric or astrix).tw,kw. (3438)
33 (bebesan or biprin or bokey or boxazin or breoprin or bufferin or cafenol or caprin or cardioaspirina or caspirin or catalgine
or catalgix or cemerit or cemirit or claradin or claragine or comoprin or contrheuma).tw,kw. (439)
34 (darosal or dispirin or dolean or dolean or dusil or ecasil or ecosprin or egalgic or emocin or empirin or encaprin or encine
or endosprin or entaprin or entericin or enteroprin or enterosarine or enterospirine or entrophen or eskotrin or euthermine or
extren).tw,kw. (186)
35 (genasprin or globentyl or godamed or gotosan or helicon or idotyl or infatabs or istopirin or istopyrine or ivepirine or
juvepirine or keypo or kilios or "mcn r 358" or measurin or mejoral or melabon or micropyrin or mikristin or miniasal or
mycristin).tw,kw. (271)
36 (naspro or novasen or nu seal or nu seals or nuseal? or ortho acetoxybenzoate or ortho acetoxybenzoic or ostoprin or
pancemol or paracin or paynocil or pengo or platet 300 cleartab or plewin or polopiryna or premaspin or primaspan or proprin or
pyronoval).tw,kw. (137)
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37 (reumyl or rhodine or rhonal or ronal or salacetin or salacetogen or saletin or salisalido or sargepirine or soldral or solpyron
or solucetyl or solupsa or spren).tw,kw. (162)
38 (tapal or temagin or tevapirin or "th 2152" or thrombo-aspilets or treupahlin or treuphalin or tromalyt or tromcor or turivital
or verin or vitalink or xaxa or zero-order release).tw,kw. (1718)
39 aspirin.rn. (40892)
40 or/9-39 (379020)
41 Drug Combinations/ (115854)
42 Drug Therapy, Combination/ (200510)
43 Combined Modality Therapy/ (205183)
44 ((combination* or combine* or combining) adj2 (agent or agents or drug or drugs)).tw,kw. (62908)
45 ((combination* or combine* or combining) adj2 (therap* or treatment*)).tw,kw. (262970)
46 ((dual or double) adj2 (therap* or treatment*)).tw,kw. (24189)
47 or/41-46 (734986)
48 40 and 47 (22994) [DAPT PT 2]
49 8 or 48 (25717) DAPT PT 1 & 2]
50 5 and 49 (7359) [STENTS AND DAPT]
51 Adolescent/ not (exp Adult/ and Adolescent/) (1028571)
52 exp Child/ not (exp Adult/ and exp Child/) (2731326)
53 exp Infant/ not (exp Adult/ and exp Infant/) (1507636)
54 or/51-53 (3534744)
55 50 not 54 (7340) [CHILD-ONLY ONLY REMOVED]
56 exp Animals/ not (exp Animals/ and Humans/) (13628610)
57 55 not 56 (4777) [ANIMAL-ONLY REMOVED]
58 (comment or editorial or interview or letter or news or newspaper article).pt. (3189325)
59 57 not 58 (4505) [OPINION PIECES REMOVED]
60 limit 59 to yr="2011-current" (2397) [DATE LIMIT]
61 limit 60 to systematic reviews [Limit not valid in Embase; records were retained] (1126)
62 meta analysis.pt. (72334)
63 exp meta-analysis as topic/ (43504)
64 (meta-analy* or metanaly* or metaanaly* or met analy* or integrative research or integrative review* or integrative
overview* or research integration or research overview* or collaborative review*).tw. (231753)
65 (systematic review* or systematic overview* or evidence-based review* or evidence-based overview* or (evidence adj3
(review* or overview*)) or meta-review* or meta-overview* or meta-synthes* or rapid review* or "review of reviews" or
technology assessment* or HTA or HTAs).tw. (271308)
66 exp Technology assessment, biomedical/ (21604)
67 (cochrane or health technology assessment or evidence report).jw. (34056)
68 ((indirect* or mixed or multi-treatment*) adj2 compar*).tw. (8594)
69 ((network* or network-based) adj (MA or MAs)).kw,tw. (11)
70 or/62-69 (502953)
71 60 and 70 (177)
72 61 or 71 (1148) [REVIEWS]
73 exp Guidelines as Topic/ (504541)
74 exp Clinical Protocols/ (219109)
75 Guideline.pt. (15919)
76 Practice Guideline.pt. (21735)
77 standards.fs. (609295)
78 Consensus Development Conference.pt. (10113)
79 Consensus Development Conference, NIH.pt. (756)
80 (guideline* or standards or recommendation*).ti. (239243)
81 (expert consensus or consensus statement* or consensus conference* or practice parameter* or position statement* or
policy statement* or CPG or CPGs).tw. (93481)
82 or/73-81 (1404586)
83 60 and 82 (166) [GUIDELINES]
84 72 or 83 (1233) [REVIEWS OR GUIDELINES]
85 84 use ppez (257) [MEDLINE RECORDS]
86 exp stent/ (190875)
87 (stent or stents or stented or stenting).tw,kw. (201982)
88 (DES or DESs).tw,kw. (70216)
89 (Strecker* or Supremo* or WallFlex* or Wallstent*).tw,kw. (3902)
90 or/86-89 (300274) [STENTS]
91 ((dual or double) adj (antiplatelet* or anti-platelet*)).tw,kw. (9238)
92 (DAPT or DAPTs).tw,kw. (3105)
93 acetylsalicylic acid plus clopidogrel/ (322)
94 (duocover or duoplavin).tw,kw. (11)
95 or/91-94 (11094) [DAPT PT 1]
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96 antithrombocytic agent/ (34172)
97 (antiplatelet* or anti-platelet*).tw,kw. (62043)
98 (platelet* adj2 inhibit*).tw,kw. (34284)
99 thrombocyte aggregation inhibit*.tw,kw. (264)
100 purinergic P2Y receptor antagonist/ (1720)
101 ((P2Y or P2Y1 or P2Y12 or P2Y2) adj (receptor antagonist* or purinoceptor antagonist*)).tw,kw. (1339)
102 (ADP receptor adj (antagonist* or blocker*)).tw,kw. (665)
103 (adenosine diphosphate receptor adj (antagonist* or blocker*)).tw,kw. (152)
104 clopidogrel/ (45790)
105 (clopidogrel or clopilet or grepid or iscover or PCR 4099 or PCR4099 or plavix or SC 25989C or SC 25990C or SR 25989
or zopya or zylagren or zyllt).tw,kw. (30159)
106 clopidogrel.rn. (46154)
107 prasugrel/ (6357)
108 (prasugrel or CS 747 or CS747 or effient or efient or LY 640315 or LY640315).tw,kw. (4607)
109 prasugrel.rn. (5348)
110 ticagrelor/ (4114)
111 ticagrelor.tw,kw. (3509)
112 (AZD 6140 or AZD6140 or brilinta or brilique or possia).tw,kw. (691)
113 ticagrelor.rn. (3951)
114 acetylsalicylic acid/ (212507)
115 asa.tw,kw. (56611)
116 aspirin.tw,kw. (140513)
117 ("2-(Acetyloxy)benzoic Acid" or acetylsalicylic acid or acetysal or acylpyrin or aloxiprimum or colfarit or dispril or
easprin or ecotrin or endosprin or magnecyl or micristin or polopirin or polopiryna or solprin or solupsan or zorprin).tw,kw.
(18867)
118 ("2 acetoxybenzoate" or "8-hour bayer" or acenterine or acesal or acetan or acetard or aceticil or aceticyl or acetonyl or
acetophen or acetosal or acetosalicylic acid or acetosalin or acetosalum or acetyl salicylate or acetyl salicylic acid or acetylic
salicylic acid or acetylin or acetylo or acetylon or acetylosalicylic acid or acetylsal or acetylsalicyclic acid or acetylsalicyl or
acetylsalicylate or acetylsalicylic acid or acetylsalycic acid or acetylsalycylic acid or acetysal or acidulatum or acidum acetyl
salicylicum or acidum acetylosalicylicum or acidum acetylsalicylicum).tw,kw. (22012)
119 (actorin or acylpyrine or acytosal or adiro or alabukun or alasil or albyl-e or alka seltzer or alkaspirin or anasprin or andol
or anopyrin or ansin or anthrom or aptor or arthralgyl or asaflow or asaphen or asapor or asatard or asawin or aspec or aspent or
aspex or aspilets or aspirem or aspirgran or aspirina or aspirine or aspirinine or aspirisucre or aspisol or aspo cid or aspro or
asrina or asrivo or asta or asteric or astrix).tw,kw. (3438)
120 (bebesan or biprin or bokey or boxazin or breoprin or bufferin or cafenol or caprin or cardioaspirina or caspirin or
catalgine or catalgix or cemerit or cemirit or claradin or claragine or comoprin or contrheuma).tw,kw. (439)
121 (darosal or dispirin or dolean or dolean or dusil or ecasil or ecosprin or egalgic or emocin or empirin or encaprin or encine
or endosprin or entaprin or entericin or enteroprin or enterosarine or enterospirine or entrophen or eskotrin or euthermine or
extren).tw,kw. (186)
122 (genasprin or globentyl or godamed or gotosan or helicon or idotyl or infatabs or istopirin or istopyrine or ivepirine or
juvepirine or keypo or kilios or "mcn r 358" or measurin or mejoral or melabon or micropyrin or mikristin or miniasal or
mycristin).tw,kw. (271)
123 (naspro or novasen or nu seal or nu seals or nuseal? or ortho acetoxybenzoate or ortho acetoxybenzoic or ostoprin or
pancemol or paracin or paynocil or pengo or platet 300 cleartab or plewin or polopiryna or premaspin or primaspan or proprin or
pyronoval).tw,kw. (137)
124 (reumyl or rhodine or rhonal or ronal or salacetin or salacetogen or saletin or salisalido or sargepirine or soldral or
solpyron or solucetyl or solupsa or spren).tw,kw. (162)
125 (tapal or temagin or tevapirin or "th 2152" or thrombo-aspilets or treupahlin or treuphalin or tromalyt or tromcor or
turivital or verin or vitalink or xaxa or zero-order release).tw,kw. (1718)
126 acetylsalicylic acid.rn. (158374)
127 or/96-126 (374118)
128 acetylsalicylic acid/cb [Drug Combination] (21253)
129 antithrombocytic agent/cb [Drug Combination] (2370)
130 clopidogrel/cb [Drug Combination] (9274)
131 prasugrel/cb [Drug Combination] (533)
132 purinergic P2Y receptor antagonist/cb [Drug Combination] (27)
133 ticagrelor/cb [Drug Combination] (414)
134 drug combination/ (56206)
135 ((combination* or combine* or combining) adj2 (agent or agents or drug or drugs)).tw,kw. (62908)
136 ((combination* or combine* or combining) adj2 (therap* or treatment*)).tw,kw. (262970)
137 ((dual or double) adj2 (therap* or treatment*)).tw,kw. (24189)
138 or/128-137 (401125)
139 127 and 138 (36893) [DAPT PT 2]
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140 95 or 139 (39770) [DAPT PTS 1 AND 2]
141 90 and 140 (10221) [STENTS AND DAPT]
142 exp juvenile/ not (exp juvenile/ and exp adult/) (1888506)
143 Adolescent/ not (exp Adult/ and Adolescent/) (1028571)
144 exp Child/ not (exp Adult/ and exp Child/) (2731326)
145 exp Infant/ not (exp Adult/ and exp Infant/) (1507636)
146 or/142-145 (3570214)
147 141 not 146 (10178) [CHILD-ONLY REMOVED]
148 exp animal experimentation/ or exp models animal/ or exp animal experiment/ or nonhuman/ or exp vertebrate/
(42570215)
149 exp human/ or exp human experimentation/ or exp human experiment/ (33622929)
150 148 not 149 (8948879)
151 147 not 150 (10112) [ANIMAL-ONLY REMOVED]
152 (editorial or letter).pt. (2809807)
153 151 not 152 (9580) [OPINION PIECES REMOVED]
154 journal conference abstract.pt. (2314692)
155 153 not 154 (7714) [CONFERENCE ABSTRACTS REMOVED]
156 limit 155 to yr="2011-current" (3949) [DATE LIMIT]
157 meta-analysis/ (185535)
158 "systematic review"/ (111422)
159 "meta analysis (topic)"/ (28213)
160 (meta-analy* or metanaly* or metaanaly* or met analy* or integrative research or integrative review* or integrative
overview* or research integration or research overview* or collaborative review*).tw. (231753)
161 (systematic review* or systematic overview* or evidence-based review* or evidence-based overview* or (evidence adj3
(review* or overview*)) or meta-review* or meta-overview* or meta-synthes* or "review of reviews" or technology assessment*
or HTA or HTAs).tw. (270915)
162 biomedical technology assessment/ (20495)
163 (cochrane or health technology assessment or evidence report).jw. (34056)
164 ((indirect* or mixed or multi-treatment*) adj2 compar*).tw. (8594)
165 ((network* or network-based) adj (MA or MAs)).kw,tw. (11)
166 or/157-165 (541812)
167 156 and 166 (383) [REVIEWS]
168 exp practice guideline/ (394445)
169 (guideline* or standards or recommendation*).ti. (239243)
170 (expert consensus or consensus statement* or consensus conference* or practice parameter* or position statement* or
policy statement* or CPG or CPGs).tw. (93481)
171 or/168-170 (636803)
172 156 and 171 (288) [GUIDELINES]
173 167 or 172 (618) [REVIEWS OR GUIDELINES]
174 173 use emez (492) [EMBASE RECORDS]
175 85 or 174 (749) [MEDLINE AND EMBASE RECORDS]
176 remove duplicates from 175 (593) [TOTAL UNIQUE RECORDS]
177 176 use ppez (247) [MEDLINE UNIQUE RECORDS]
178 176 use emez (346) [EMBASE UNIQUE RECORDS]
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Optimal duration of dual antiplatelet therapy following percutaneous coronary intervention: Protocol for an
umbrella review
Journal: BMJ Open
Manuscript ID bmjopen-2016-015421.R1
Article Type: Protocol
Date Submitted by the Author: 30-Jan-2017
Complete List of Authors: Elliott, Jesse; University of Ottawa Heart Institute, Kelly, Shannon; University of Ottawa, Department of Epidemiology and Community Medicine; Ottawa Hospital Research Institute, Medicine
Bai, Zemin; University of Ottawa Heart Institute Liu, Wenfei; University of Ottawa Heart Institute Skidmore, Becky; Independent Information Specialist Boucher, Michel ; Canadian Agency for Drugs and Technologies in Health (CADTH), So, DYF; University of Ottawa, Wells, George ; Ottawa Hospital Research Institute
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Evidence based practice
Keywords: Dual antiplatelet therapy, Percutaneous intervention, Umbrella review
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on M
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j.com/
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Optimal duration of dual antiplatelet therapy following percutaneous coronary
intervention: Protocol for an umbrella review
Word count: 2082
Jesse Elliott, Shannon Kelly, Zemin Bai, Wenfei Liu, Becky Skidmore, Michel Boucher, Derek
So, George A Wells
Jesse Elliott MSc,
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario, Canada
jelliott@ottawaheart.ca
Shannon Kelly MSc,
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, Canada
skelly@ottawaheart.ca
Zemin Bai, MSc
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario, Canada
abai@ottawaheart.ca
Wenfei Liu, MSc
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, Canada
wliu088@uottawa.ca
Becky Skidmore, MLS, Independent Information Specialist,
Ottawa, Ontario, Canada
bskidmore@rogers.com
Michel Boucher, B. Pharm, MSc, Grad Dipl. Bus Adm, RPh
Canadian Agency for Drugs and Technologies in Health (CADTH),
Ottawa, Ontario, Canada
MichelB@cadth.ca
Derek So, MD FRCPC FACC
Division of Cardiology, University of Ottawa Heart Institute,
Ottawa, Ontario, Canada
dso@ottawaheart.ca
George A. Wells, PhD*
Page 1 of 20
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Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, Ontario, K1Y4W7
gawells@ottawaheart.ca
*Corresponding author
ABSTRACT
Introduction: Although dual antiplatelet therapy (DAPT) is routinely given to patients after
percutaneous coronary intervention (PCI) with stenting, the optimal duration is unknown. Recent
evidence indicates there may be benefits in extending the duration beyond 12 months but such
decisions may increase the risk of bleeding. Our objective is to provide a comprehensive
overview of the literature for clinicians and policy makers via an umbrella review assessing the
optimal duration of DAPT.
Methods and analysis: We will perform a comprehensive search of the published and grey
literature for systematic reviews involving randomized controlled trials assessing the optimal
duration of DAPT following PCI with stenting. The intervention of interest is extended DAPT
(beyond 12 months) compared with short-term DAPT (6-12 months). Studies will be selected for
inclusion by two reviewers, and the quality will be assessed. The primary outcomes of interest
are all-cause mortality and cardiovascular mortality. Secondary outcomes will be bleeding
(major, minor, gastrointestinal), urgent target vessel revascularization, major adverse
cardiovascular events, myocardial infarction, stroke, and stent thrombosis. Outcomes will be
assessed while on DAPT and after withdrawal of DAPT. Data will be summarized with respect
to the number of included RCTs, number of participants, effect estimates, and heterogeneity.
Data will be reported separately based on patient demographics, procedural parameters (e.g. stent
types, lesion complexity, concurrent disease) and clinical presentation (e.g. acute coronary
syndromes, infarct type).
Ethics and dissemination: Our umbrella review aims to provide a comprehensive overview of
the benefits and harms associated with extending DAPT beyond 12 months following PCI with
stenting. The results of this review will inform clinical and policy decisions regarding the
optimal treatment duration and reimbursement of DAPT following PCI with stenting. Results
Page 2 of 20
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will be disseminated through a peer-reviewed publication and conference presentations. Ethics
approval is not required for this study.
Registration: PROSPERO no. CRD42016047735
Keywords: dual antiplatelet therapy, duration, percutaneous intervention, umbrella review.
Abbreviations:
BMS = bare metal stent
DAPT = dual anti-platelet therapy
DES = drug-eluting stent
PCI = percutaneous coronary intervention
STRENGTHS AND LIMITATIONS OF THIS STUDY
• This protocol was designed following guidelines for umbrella reviews from Joanna Briggs
Institute and reported following the Preferred Reporting Items for Systematic review and Meta-
Analyses (PRISMA) guidelines.
• The results of this review will inform policy decisions regarding the reimbursement of DAPT
following PCI with stenting and will be useful for shared decision making, providing information
to clinicians and patients about the potential tradeoffs between risks and benefits of extended
DAPT.
• As with other umbrella reviews, the quality of our findings will depend on the quality of the
included systematic reviews.
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BACKGROUND
Dual antiplatelet therapy (DAPT), the combination of a P2Y12 inhibitor with acetylsalicylic acid
(ASA), is routinely given following percutaneous coronary intervention (PCI) with stenting with
the aim of preventing stent thrombosis and major adverse cardiovascular events.[1] Guidelines
currently recommend for DAPT for 6 to 12 months;[1-3] however, the optimal duration of
DAPT remains controversial. DAPT for less than 6 months may be appropriate in some clinical
settings, such as in patients with low risk of stroke but high risk of bleeding, while DAPT for
more than 12 months may be appropriate for patients with high risk of stroke and low risk of
bleeding.[1] Extending DAPT beyond 12 months may reduce the risk of late stent thrombosis but
may increase the risk of bleeding.[4] Clinicians must balance the potential risks and benefits in
determining the optimal duration of DAPT, and, in some jurisdictions, reimbursement of P2Y12
inhibitors after PCI may be limited to 12 months by some public payers.
The association between DAPT duration and clinical outcomes has been assessed in many
systematic reviews and meta-analyses,[5-8] yet the optimal duration of DAPT remains a
controversial topic. Previous meta-analyses have reported an increased risk of death among
patients who received DAPT for more than 12 months following stenting, yet extending DAPT
beyond 12 months may reduce the risk of MI and stent thrombosis.[6,7] These potential benefits
must be balanced against an increased risk of harms, including death and major bleeding.
Clinicians and policy makers require a comprehensive overview of the depth and strength of the
evidence base in order to evaluate the potential benefits and harms associated with extending
DAPT beyond 12 months after stenting. To this end, we will perform a comprehensive umbrella
review to collect and assess information from previous systematic reviews that have investigated
the optimal duration of DAPT following PCI with stenting. We will seek to answer the following
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questions using the findings of high-quality systematic reviews: What are the benefits and harms
of extended DAPT (> 12 mo v. 6 to 12 mo) following PCI with stenting? Are there subgroups of
patients based on demographics, angiographic parameters, or clinical presentation for whom the
optimal duration of DAPT is different? Does the optimal duration of DAPT depend on the type
of stent implanted (bare-metal stent [BMS] or drug-eluting stent [DES])? Is there a rebound
effect after withdrawal of DAPT?
Umbrella review are syntheses of existing systematic reviews and/or meta-analyses and provide
an ideal method to comprehensively review the evidence base and to explore the contradictory
findings of previous reviews.[9] Because a number of previous systematic reviews on this topic
are available and timely evidence is required to inform health policy, undertaking a de novo
systematic review would not be appropriate. An umbrella review design will allow us to explore
the reasons for discrepant findings in previous systematic reviews and to provide clinicians and
policy makers with evidence in a timely manner.
METHODS AND ANALYSIS
This umbrella review was designed using the methodology guidelines for umbrella reviews
provided by the Joanna Briggs Institute.[9] As well, we followed the Preferred Reporting Items
for Systematic review and Meta-Analyses (PRISMA) guidelines[10] and the extension for
protocols.[11] The completed PRISMA-P checklist is available (Supplementary File 1). This
protocol is registered with PROSPERO (No. CRD42016047735).
Search strategy
We will search for systematic reviews that included randomized controlled trials (RCTs)
evaluating different durations of DAPT following PCI with stenting. The search strategy
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(Supplementary File 2) was developed and tested by an experienced medical information
specialist using an iterative process in consultation with the review team. The search strategy has
been reviewed by another senior information specialist using the Peer Review of Electronic
Search Strategies (PRESS) checklist.[12] Embase and Ovid MEDLINE, including Epub Ahead
of Print and In-Process & Other Non-Indexed Citations, will be searched using the OVID
platform. We will also search the Cochrane Library on Wiley and PubMed for the most recent
and unindexed citations. Grey literature from major health technology assessment sources and
clinical practice guidelines sources will be searched using CADTH’s Grey Matters Light.[13]
The search strategies involve a combination of controlled vocabulary (e.g., “Stents”,
“Percutaneous Coronary Intervention”, “Prasugrel Hydrochloride”) and keywords (e.g., “DES”,
“PCI”, “Clopidogrel”). Vocabulary and syntax will be adjusted across databases. Because of the
depth of the literature base and the timeline of the project, results will be limited to those
published between 2011 and August 2016.
Inclusion criteria
We set the inclusion criteria for this umbrella review following the PICO (population,
intervention, comparison, outcome) criteria:
Population: Adult patients who have undergone PCI with any type of stent and who are
receiving DAPT. Patients receiving DAPT in the absence of stenting are beyond the
scope of this review.
Intervention: DAPT following PCI with stenting for an extended duration (more than 12
months). DAPT may involve any type of P2Y12 inhibitor (clopidogrel, prasugrel,
ticagrelor) in combination with ASA.
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Comparison: DAPT for 6 to 12 months. The comparison of less than 6 months of DAPT
to more than 12 months of DAPT is beyond the scope of this review.
Outcomes: The primary outcomes of interest are all-cause mortality and cardiovascular
mortality. Secondary outcomes will be urgent target vessel revascularization, major
adverse cardiovascular events, myocardial infarction, stroke, stent thrombosis, and major,
minor and gastrointestinal bleeding, as defined by the individual study protocols and/or
publications. A range of bleeding classifications and definitions are expected (e.g., TIMI,
BARC, GUSTO, REPLACE).
All outcomes will be assessed based on the definitions applied in the systematic reviews,
with the exception of major bleeding and major adverse cardiovascular events
(depending on components of the composite). Studies will not be included or excluded
on the basis of reported outcomes.
Study designs: Systematic evidence syntheses that included RCTs comparing different durations
of DAPT following PCI. To be eligible for inclusion, studies must have used a systematic
process to literature searching and study selection. If both RCTs and non-randomized studies are
included, the effect estimates from RCTs must be reported separately. If a potentially relevant
systematic review includes RCTs that enrolled both stented and non-stented patients, data must
be reported separately for stented and non-stented patients. Individual RCTs may be eligible for
inclusion to address questions about subgroups if at least 85% of patients received either a drug-
eluting or bare-metal stent. Data will not be extracted from systematic reviews that included
RCTs that enrolled less than 85% stented patients.
No language restrictions will be used during the screening or study selection process. Because of
the short timeline of this project, we will extract data only from foreign-language studies that can
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be translated within the timeline of the project. All foreign language studies eligible for inclusion
will be listed in an appendix to the final publication.
Because our aim is to summarize data from high-quality systematic reviews, studies must meet
the following criteria in addition to the PICO criteria. First, studies must report using a
comprehensive search strategy involving two or more electronic databases; second, they must
provide an explicit statement describing the inclusion criteria applied to candidate RCTs; and
third, they must have critically appraised the quality and/or risk of bias of the included RCTs and
report the outcome of that process.
Study selection
The eligibility criteria will be applied to each title and abstract identified in the literature search
by two independent reviewers in a standardized manner. All records identified by at least one
author as potentially relevant will be obtained in full-text format. The eligibility criteria will then
be applied to the full-text records, and a final decision made for inclusion. Conflicts will be
resolved by discussion. The reviewers will not be blinded to study authors or centre of
publication prior to study selection. Study screening and assessment of eligibility will be
facilitated and standardized through the use of DistillerSR (Evidence Partners), an online
systematic review software.
Quality assessment
Two independent reviewers will apply the AMSTAR (A MeaSurement Tool to Assess
systematic Reviews)[14] checklist to each included study, and any disagreements will be
resolved by consensus. Only reviews meeting a minimum quality threshold will be included in
the summary of findings. We will not use a numerical score on the AMSTAR checklist to define
“high quality”; instead, the following criteria must be met: use of a comprehensive search
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strategy involving two or more electronic databases; use of an explicit statement describing the
inclusion criteria applied to candidate RCTs; use of a formal critical appraisal or quality
assessment process for all included studies and report the outcome of that process; report
findings on outcomes of interest using details on the study and patient characteristics of two or
more studies; and provide the direction of the findings from any pooled analyses (narrative or
meta-analysis) carried out, including direction of effect and any statistical significance. Any
included reviews that do not meet these minimum requirements will remain included; however,
no data will be extracted.
In the event that included reviews report significantly overlapping lists of included studies
reporting the same outcome(s), we will report findings from the higher quality, more recent
review with the largest number of studies.
Data collection
All information will be collected using piloted and standardized data abstraction forms in
DistillerSR. Extraction forms will be developed following the Joanna Briggs Institute’s
recommended extraction items.[9] Data will be extracted from each included systematic review
by one reviewer and verified by a second reviewer. Any disagreements will be resolved by
consensus when possible; otherwise, the judgment of a third reviewer will be considered final.
The original, primary publication for each included review will be used for data extraction,
except where multiple publications for a unique review are found. Multiple publications for a
unique review (e.g., supplemental online appendices, companion publications of specific
outcomes or populations from the original study) will be handled by extracting the most recently
adjudicated data for each outcome specified a priori in this protocol.
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The data extracted will include specific details about the included RCTs (e.g., study population,
the durations of DAPT investigated) and the review methods (e.g., number of databases
searched, search date, and any date, location, or language restrictions on the search). Patient
characteristics (e.g., age, sex, smoking status, diabetes, prior MI, history of heart failure) will
also be extracted from the included reviews, if reported. We plan to extract the effect estimates
for the outcomes of interest for the whole population and for any subgroups, as well as the
method of synthesis (e.g., meta-analysis, network meta-analysis). The authors’ overall
conclusion or recommendation will also be extracted. Outcome data will be extracted for the
period while patients were on DAPT and after withdrawal of DAPT.
Subgroups
If available, effect estimates will be extracted separately for clinically important subgroups based
on patient demographics (e.g., age, sex, smoking status, diabetes, prior MI, history of heart
failure), procedural parameters (e.g., vein graft intervention, left main intervention, stent type,
lesion complexity, concurrent disease), and clinical presentation (e.g., acute coronary syndrome
(ACS) v. no ACS; ST-elevation myocardial infarction [STEMI] v. non-STEMI). If subgroup
data are not available from the included SRs, we will extract such data from the RCTs identified
from the included SRs.
Data summary
The aim of this umbrella review is to present a summary of the existing research syntheses that
have addressed the optimal duration of DAPT. The findings will be summarized from the most
recent high-quality systematic reviews using a narrative approach. A tabular summary of review
characteristics (year of publication, county of origin, number of included studies, setting and/or
context, and interventions) will be provided. Outcome data will be summarized with respect to
number of included studies, number of participants, effect estimates, and heterogeneity. Data for
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all bleeding outcomes will be summarized as appropriate using the similarity of outcome
definitions and classification systems to guide synthesis and/or pooling. Data for subgroups will
be presented separately. Strengths and limitations of the included studies, as assessed by
AMSTAR, will also be presented.
ETHICS AND DISSEMINATION
In this umbrella review, we will undertake a comprehensive review of previously published
systematic reviews assessing the optimal duration of DAPT. Using evidence from this review,
we expect to make a conclusion regarding the benefits and harms associated with extending
DAPT beyond 12 months following PCI with stenting. As well, we aim to determine whether
there are subgroups of patients who would benefit from shorter or longer DAPT. The results of
our review will be of interest to clinicians, policy makers, and patients. We plan to disseminate
our findings through peer-reviewed journal publication and conference presentations. This
review does not require ethical approval.
DECLARATIONS
Authors' contributions: JE, SK, MB, DS, and GW designed the study. BS designed and will
execute the search strategy. JE drafted the protocol, which was revised by all authors. All authors
have approved the version of the manuscript submitted for publication.
Consent for publication: Not applicable
Funding: This work is funded by the Canadian Institutes of Health Research, Drug Safety and
Effectiveness Network. The funder had no role in the design of the study.
Competing interests: None declared
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ADDITIONAL MATERIALS
Supplementary File 1: PRISMA-P checklist
Supplementary File 2: Search strategy
REFERENCES
1 Levine GN, Bates ER, Mauri L, et al. 2016 ACC/AHA guideline focused update on duration of
dual antiplatelet therapy in patients with coronary artery disease. A report of the American
College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
Circulation 2016;133.
2 The Task Force on Myocardial Revascularization of the European Society of Cardiology
(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2014 ESC/EACTS
Guidelines on myocardial revascularization. Eur Heart J 2014;35(37):2541–619.
3 Tanguay JF, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian cardiovascular
society guidelines for the use of antiplatelet therapy. Can J Cardiol 2013;29(11):1334–45.
4 Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy
after Drug-Eluting Stents. N Engl J Med 2014;371(23):2155–66.
5 Liu M, Chen J, Huang D, Ke J, Tang W, Wu W. Optimal duration of dual antiplatelet therapy
after drug-eluting stent implantation: a meta-analysis of 3 randomized controlled trials. J
Cardiovasc Pharmacol 2014;64(1):41–6.
6 Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy after
percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised
controlled trials. BMJ 2015;350:h1618.
7 Fei Y, Tsoi MF, Cheung TT, Cheung BM. Optimal duration of dual antiplatelet therapy after
drug-eluting stent implantation: Meta-analysis of randomized controlled trials. Int J Cardiol.
2016;220:895-900.
8 Palmerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy
after drug-eluting stent implantation: An individual patient data pairwise and network meta-
analysis. J Am Coll Cardiol 2015;65(11):1092–102.
9 Aromataris E, Fernandez R, Godfrey C, Holly C, Khalil H, Tungpunkom P. Methodology for
JBI Mixed Methods Systematic Reviews 2014.
http://joannabriggs.org/assets/docs/sumari/ReviewersManual-Methodology-JBI_Umbrella
Reviews-2014.pdf (accessed15 Aug 2016).
10 Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred Reporting Items for Systematic
Reviews and Meta-Analyses: The PRISMA Statement (Reprinted from Annals of Internal
Medicine). Phys Ther 2009;89(9):873–80.
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11 Moher D, Shamseer L, Clarke M, et al. Preferred Reporting Items for Systematic Review and
Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4(1):1.
12 McGowan J, Sampson M, Lefebvre C. An evidence based checklist for the Peer Review of
Electronic Search Strategies (PRESS EBC). Evid Based Libr Inf Pract 2010;5(1):149–54.
13 Canadian Agency for Drugs and Technologies in Health. Grey Matters Light.
www.cadth.ca/sites/default/files/is/cadth_Handout_greymatters
_light_e.pdf (accessed 15 Aug 2016).
14 Shea BJ, Grimshaw JM, Wells G a, et al. Development of AMSTAR: a measurement tool to
assess the methodological quality of systematic reviews. BMC Med Res Methodol 2007;7:10.
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Additional File 2
DAPT PCI
Final Strategies
2016 Aug 12
OVID
Database: Embase <1980 to 2016 Week 32>, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid
MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:
--------------------------------------------------------------------------------
1 exp Stents/ (190875)
2 (stent or stents or stented or stenting).tw,kw. (201982)
3 (DES or DESs).tw,kw. (70216)
4 (Strecker* or Supremo* or WallFlex* or Wallstent*).tw,kw. (3902)
5 or/1-4 (300274) [STENTS]
6 ((dual or double) adj (antiplatelet* or anti-platelet*)).tw,kw. (9238)
7 (DAPT or DAPTs).tw,kw. (3105)
8 6 or 7 (10825) [DAPT PT 1]
9 Platelet Aggregation Inhibitors/ (61484)
10 (antiplatelet* or anti-platelet*).tw,kw. (62043)
11 (platelet* adj2 inhibit*).tw,kw. (34284)
12 thrombocyte aggregation inhibit*.tw,kw. (264)
13 Purinergic P2Y Receptor Antagonists/ (1565)
14 ((P2Y or P2Y1 or P2Y12 or P2Y2) adj (receptor antagonist* or purinoceptor antagonist*)).tw,kw. (1339)
15 (ADP receptor adj (antagonist* or blocker*)).tw,kw. (665)
16 (adenosine diphosphate receptor adj (antagonist* or blocker*)).tw,kw. (152)
17 clopidogrel*.tw,kw. (28081)
18 (clopilet or grepid or iscover or PCR 4099 or PCR4099 or plavix or SC 25989C or SC 25990C or SR 25989 or zopya or
zylagren or zyllt).tw,kw. (3218)
19 (duocover or duoplavin).tw,kw. (11)
20 clopidogrel.rn. (46154)
21 Prasugrel Hydrochloride/ (6357)
22 (prasugrel or CS 747 or CS747 or effient or efient or LY 640315 or LY640315).tw,kw. (4607)
23 prasugrel.rn. (5348)
24 ticagrelor.tw,kw. (3509)
25 (AZD 6140 or AZD6140 or brilinta or brilique or possia).tw,kw. (691)
26 ticagrelor.rn. (3951)
27 Aspirin/ (201606)
28 asa.tw,kw. (56611)
29 aspirin.tw,kw. (140513)
30 ("2-(Acetyloxy)benzoic Acid" or acetylsalicylic acid or acetysal or acylpyrin or aloxiprimum or colfarit or dispril or easprin
or ecotrin or endosprin or magnecyl or micristin or polopirin or polopiryna or solprin or solupsan or zorprin).tw,kw. (18867)
31 ("2 acetoxybenzoate" or "8-hour bayer" or acenterine or acesal or acetan or acetard or aceticil or aceticyl or acetonyl or
acetophen or acetosal or acetosalicylic acid or acetosalin or acetosalum or acetyl salicylate or acetyl salicylic acid or acetylic
salicylic acid or acetylin or acetylo or acetylon or acetylosalicylic acid or acetylsal or acetylsalicyclic acid or acetylsalicyl or
acetylsalicylate or acetylsalicylic acid or acetylsalycic acid or acetylsalycylic acid or acetysal or acidulatum or acidum acetyl
salicylicum or acidum acetylosalicylicum or acidum acetylsalicylicum).tw,kw. (22012)
32 (actorin or acylpyrine or acytosal or adiro or alabukun or alasil or albyl-e or alka seltzer or alkaspirin or anasprin or andol or
anopyrin or ansin or anthrom or aptor or arthralgyl or asaflow or asaphen or asapor or asatard or asawin or aspec or aspent or
aspex or aspilets or aspirem or aspirgran or aspirina or aspirine or aspirinine or aspirisucre or aspisol or aspo cid or aspro or
asrina or asrivo or asta or asteric or astrix).tw,kw. (3438)
33 (bebesan or biprin or bokey or boxazin or breoprin or bufferin or cafenol or caprin or cardioaspirina or caspirin or catalgine
or catalgix or cemerit or cemirit or claradin or claragine or comoprin or contrheuma).tw,kw. (439)
34 (darosal or dispirin or dolean or dolean or dusil or ecasil or ecosprin or egalgic or emocin or empirin or encaprin or encine
or endosprin or entaprin or entericin or enteroprin or enterosarine or enterospirine or entrophen or eskotrin or euthermine or
extren).tw,kw. (186)
35 (genasprin or globentyl or godamed or gotosan or helicon or idotyl or infatabs or istopirin or istopyrine or ivepirine or
juvepirine or keypo or kilios or "mcn r 358" or measurin or mejoral or melabon or micropyrin or mikristin or miniasal or
mycristin).tw,kw. (271)
36 (naspro or novasen or nu seal or nu seals or nuseal? or ortho acetoxybenzoate or ortho acetoxybenzoic or ostoprin or
pancemol or paracin or paynocil or pengo or platet 300 cleartab or plewin or polopiryna or premaspin or primaspan or proprin or
pyronoval).tw,kw. (137)
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37 (reumyl or rhodine or rhonal or ronal or salacetin or salacetogen or saletin or salisalido or sargepirine or soldral or solpyron
or solucetyl or solupsa or spren).tw,kw. (162)
38 (tapal or temagin or tevapirin or "th 2152" or thrombo-aspilets or treupahlin or treuphalin or tromalyt or tromcor or turivital
or verin or vitalink or xaxa or zero-order release).tw,kw. (1718)
39 aspirin.rn. (40892)
40 or/9-39 (379020)
41 Drug Combinations/ (115854)
42 Drug Therapy, Combination/ (200510)
43 Combined Modality Therapy/ (205183)
44 ((combination* or combine* or combining) adj2 (agent or agents or drug or drugs)).tw,kw. (62908)
45 ((combination* or combine* or combining) adj2 (therap* or treatment*)).tw,kw. (262970)
46 ((dual or double) adj2 (therap* or treatment*)).tw,kw. (24189)
47 or/41-46 (734986)
48 40 and 47 (22994) [DAPT PT 2]
49 8 or 48 (25717) DAPT PT 1 & 2]
50 5 and 49 (7359) [STENTS AND DAPT]
51 Adolescent/ not (exp Adult/ and Adolescent/) (1028571)
52 exp Child/ not (exp Adult/ and exp Child/) (2731326)
53 exp Infant/ not (exp Adult/ and exp Infant/) (1507636)
54 or/51-53 (3534744)
55 50 not 54 (7340) [CHILD-ONLY ONLY REMOVED]
56 exp Animals/ not (exp Animals/ and Humans/) (13628610)
57 55 not 56 (4777) [ANIMAL-ONLY REMOVED]
58 (comment or editorial or interview or letter or news or newspaper article).pt. (3189325)
59 57 not 58 (4505) [OPINION PIECES REMOVED]
60 limit 59 to yr="2011-current" (2397) [DATE LIMIT]
61 limit 60 to systematic reviews [Limit not valid in Embase; records were retained] (1126)
62 meta analysis.pt. (72334)
63 exp meta-analysis as topic/ (43504)
64 (meta-analy* or metanaly* or metaanaly* or met analy* or integrative research or integrative review* or integrative
overview* or research integration or research overview* or collaborative review*).tw. (231753)
65 (systematic review* or systematic overview* or evidence-based review* or evidence-based overview* or (evidence adj3
(review* or overview*)) or meta-review* or meta-overview* or meta-synthes* or rapid review* or "review of reviews" or
technology assessment* or HTA or HTAs).tw. (271308)
66 exp Technology assessment, biomedical/ (21604)
67 (cochrane or health technology assessment or evidence report).jw. (34056)
68 ((indirect* or mixed or multi-treatment*) adj2 compar*).tw. (8594)
69 ((network* or network-based) adj (MA or MAs)).kw,tw. (11)
70 or/62-69 (502953)
71 60 and 70 (177)
72 61 or 71 (1148) [REVIEWS]
73 exp Guidelines as Topic/ (504541)
74 exp Clinical Protocols/ (219109)
75 Guideline.pt. (15919)
76 Practice Guideline.pt. (21735)
77 standards.fs. (609295)
78 Consensus Development Conference.pt. (10113)
79 Consensus Development Conference, NIH.pt. (756)
80 (guideline* or standards or recommendation*).ti. (239243)
81 (expert consensus or consensus statement* or consensus conference* or practice parameter* or position statement* or
policy statement* or CPG or CPGs).tw. (93481)
82 or/73-81 (1404586)
83 60 and 82 (166) [GUIDELINES]
84 72 or 83 (1233) [REVIEWS OR GUIDELINES]
85 84 use ppez (257) [MEDLINE RECORDS]
86 exp stent/ (190875)
87 (stent or stents or stented or stenting).tw,kw. (201982)
88 (DES or DESs).tw,kw. (70216)
89 (Strecker* or Supremo* or WallFlex* or Wallstent*).tw,kw. (3902)
90 or/86-89 (300274) [STENTS]
91 ((dual or double) adj (antiplatelet* or anti-platelet*)).tw,kw. (9238)
92 (DAPT or DAPTs).tw,kw. (3105)
93 acetylsalicylic acid plus clopidogrel/ (322)
94 (duocover or duoplavin).tw,kw. (11)
95 or/91-94 (11094) [DAPT PT 1]
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96 antithrombocytic agent/ (34172)
97 (antiplatelet* or anti-platelet*).tw,kw. (62043)
98 (platelet* adj2 inhibit*).tw,kw. (34284)
99 thrombocyte aggregation inhibit*.tw,kw. (264)
100 purinergic P2Y receptor antagonist/ (1720)
101 ((P2Y or P2Y1 or P2Y12 or P2Y2) adj (receptor antagonist* or purinoceptor antagonist*)).tw,kw. (1339)
102 (ADP receptor adj (antagonist* or blocker*)).tw,kw. (665)
103 (adenosine diphosphate receptor adj (antagonist* or blocker*)).tw,kw. (152)
104 clopidogrel/ (45790)
105 (clopidogrel or clopilet or grepid or iscover or PCR 4099 or PCR4099 or plavix or SC 25989C or SC 25990C or SR 25989
or zopya or zylagren or zyllt).tw,kw. (30159)
106 clopidogrel.rn. (46154)
107 prasugrel/ (6357)
108 (prasugrel or CS 747 or CS747 or effient or efient or LY 640315 or LY640315).tw,kw. (4607)
109 prasugrel.rn. (5348)
110 ticagrelor/ (4114)
111 ticagrelor.tw,kw. (3509)
112 (AZD 6140 or AZD6140 or brilinta or brilique or possia).tw,kw. (691)
113 ticagrelor.rn. (3951)
114 acetylsalicylic acid/ (212507)
115 asa.tw,kw. (56611)
116 aspirin.tw,kw. (140513)
117 ("2-(Acetyloxy)benzoic Acid" or acetylsalicylic acid or acetysal or acylpyrin or aloxiprimum or colfarit or dispril or
easprin or ecotrin or endosprin or magnecyl or micristin or polopirin or polopiryna or solprin or solupsan or zorprin).tw,kw.
(18867)
118 ("2 acetoxybenzoate" or "8-hour bayer" or acenterine or acesal or acetan or acetard or aceticil or aceticyl or acetonyl or
acetophen or acetosal or acetosalicylic acid or acetosalin or acetosalum or acetyl salicylate or acetyl salicylic acid or acetylic
salicylic acid or acetylin or acetylo or acetylon or acetylosalicylic acid or acetylsal or acetylsalicyclic acid or acetylsalicyl or
acetylsalicylate or acetylsalicylic acid or acetylsalycic acid or acetylsalycylic acid or acetysal or acidulatum or acidum acetyl
salicylicum or acidum acetylosalicylicum or acidum acetylsalicylicum).tw,kw. (22012)
119 (actorin or acylpyrine or acytosal or adiro or alabukun or alasil or albyl-e or alka seltzer or alkaspirin or anasprin or andol
or anopyrin or ansin or anthrom or aptor or arthralgyl or asaflow or asaphen or asapor or asatard or asawin or aspec or aspent or
aspex or aspilets or aspirem or aspirgran or aspirina or aspirine or aspirinine or aspirisucre or aspisol or aspo cid or aspro or
asrina or asrivo or asta or asteric or astrix).tw,kw. (3438)
120 (bebesan or biprin or bokey or boxazin or breoprin or bufferin or cafenol or caprin or cardioaspirina or caspirin or
catalgine or catalgix or cemerit or cemirit or claradin or claragine or comoprin or contrheuma).tw,kw. (439)
121 (darosal or dispirin or dolean or dolean or dusil or ecasil or ecosprin or egalgic or emocin or empirin or encaprin or encine
or endosprin or entaprin or entericin or enteroprin or enterosarine or enterospirine or entrophen or eskotrin or euthermine or
extren).tw,kw. (186)
122 (genasprin or globentyl or godamed or gotosan or helicon or idotyl or infatabs or istopirin or istopyrine or ivepirine or
juvepirine or keypo or kilios or "mcn r 358" or measurin or mejoral or melabon or micropyrin or mikristin or miniasal or
mycristin).tw,kw. (271)
123 (naspro or novasen or nu seal or nu seals or nuseal? or ortho acetoxybenzoate or ortho acetoxybenzoic or ostoprin or
pancemol or paracin or paynocil or pengo or platet 300 cleartab or plewin or polopiryna or premaspin or primaspan or proprin or
pyronoval).tw,kw. (137)
124 (reumyl or rhodine or rhonal or ronal or salacetin or salacetogen or saletin or salisalido or sargepirine or soldral or
solpyron or solucetyl or solupsa or spren).tw,kw. (162)
125 (tapal or temagin or tevapirin or "th 2152" or thrombo-aspilets or treupahlin or treuphalin or tromalyt or tromcor or
turivital or verin or vitalink or xaxa or zero-order release).tw,kw. (1718)
126 acetylsalicylic acid.rn. (158374)
127 or/96-126 (374118)
128 acetylsalicylic acid/cb [Drug Combination] (21253)
129 antithrombocytic agent/cb [Drug Combination] (2370)
130 clopidogrel/cb [Drug Combination] (9274)
131 prasugrel/cb [Drug Combination] (533)
132 purinergic P2Y receptor antagonist/cb [Drug Combination] (27)
133 ticagrelor/cb [Drug Combination] (414)
134 drug combination/ (56206)
135 ((combination* or combine* or combining) adj2 (agent or agents or drug or drugs)).tw,kw. (62908)
136 ((combination* or combine* or combining) adj2 (therap* or treatment*)).tw,kw. (262970)
137 ((dual or double) adj2 (therap* or treatment*)).tw,kw. (24189)
138 or/128-137 (401125)
139 127 and 138 (36893) [DAPT PT 2]
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140 95 or 139 (39770) [DAPT PTS 1 AND 2]
141 90 and 140 (10221) [STENTS AND DAPT]
142 exp juvenile/ not (exp juvenile/ and exp adult/) (1888506)
143 Adolescent/ not (exp Adult/ and Adolescent/) (1028571)
144 exp Child/ not (exp Adult/ and exp Child/) (2731326)
145 exp Infant/ not (exp Adult/ and exp Infant/) (1507636)
146 or/142-145 (3570214)
147 141 not 146 (10178) [CHILD-ONLY REMOVED]
148 exp animal experimentation/ or exp models animal/ or exp animal experiment/ or nonhuman/ or exp vertebrate/
(42570215)
149 exp human/ or exp human experimentation/ or exp human experiment/ (33622929)
150 148 not 149 (8948879)
151 147 not 150 (10112) [ANIMAL-ONLY REMOVED]
152 (editorial or letter).pt. (2809807)
153 151 not 152 (9580) [OPINION PIECES REMOVED]
154 journal conference abstract.pt. (2314692)
155 153 not 154 (7714) [CONFERENCE ABSTRACTS REMOVED]
156 limit 155 to yr="2011-current" (3949) [DATE LIMIT]
157 meta-analysis/ (185535)
158 "systematic review"/ (111422)
159 "meta analysis (topic)"/ (28213)
160 (meta-analy* or metanaly* or metaanaly* or met analy* or integrative research or integrative review* or integrative
overview* or research integration or research overview* or collaborative review*).tw. (231753)
161 (systematic review* or systematic overview* or evidence-based review* or evidence-based overview* or (evidence adj3
(review* or overview*)) or meta-review* or meta-overview* or meta-synthes* or "review of reviews" or technology assessment*
or HTA or HTAs).tw. (270915)
162 biomedical technology assessment/ (20495)
163 (cochrane or health technology assessment or evidence report).jw. (34056)
164 ((indirect* or mixed or multi-treatment*) adj2 compar*).tw. (8594)
165 ((network* or network-based) adj (MA or MAs)).kw,tw. (11)
166 or/157-165 (541812)
167 156 and 166 (383) [REVIEWS]
168 exp practice guideline/ (394445)
169 (guideline* or standards or recommendation*).ti. (239243)
170 (expert consensus or consensus statement* or consensus conference* or practice parameter* or position statement* or
policy statement* or CPG or CPGs).tw. (93481)
171 or/168-170 (636803)
172 156 and 171 (288) [GUIDELINES]
173 167 or 172 (618) [REVIEWS OR GUIDELINES]
174 173 use emez (492) [EMBASE RECORDS]
175 85 or 174 (749) [MEDLINE AND EMBASE RECORDS]
176 remove duplicates from 175 (593) [TOTAL UNIQUE RECORDS]
177 176 use ppez (247) [MEDLINE UNIQUE RECORDS]
178 176 use emez (346) [EMBASE UNIQUE RECORDS]
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1
PRISMA-P 2015 Checklist
This checklist has been adapted for use with protocol submissions to Systematic Reviews from Table 3 in Moher D et al: Preferred reporting
items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015 4:1
Section/topic # Checklist item Information reported Page
number(s) Yes No
ADMINISTRATIVE INFORMATION
Title
Identification 1a Identify the report as a protocol of a systematic review 1
Update 1b If the protocol is for an update of a previous systematic review, identify as such NA
Registration 2 If registered, provide the name of the registry (e.g., PROSPERO) and registration number in the Abstract
2
Authors
Contact 3a Provide name, institutional affiliation, and e-mail address of all protocol authors; provide physical mailing address of corresponding author
1
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 10
Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments
NA
Support
Sources 5a Indicate sources of financial or other support for the review 10
Sponsor 5b Provide name for the review funder and/or sponsor 10
Role of sponsor/funder
5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 10
INTRODUCTION
Rationale 6 Describe the rationale for the review in the context of what is already known 4
Objectives 7
Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO)
4
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Section/topic # Checklist item Information reported Page
number(s) Yes No
METHODS
Eligibility criteria 8 Specify the study characteristics (e.g., PICO, study design, setting, time frame) and report characteristics (e.g., years considered, language, publication status) to be used as criteria for eligibility for the review
6
Information sources 9 Describe all intended information sources (e.g., electronic databases, contact with study authors, trial registers, or other grey literature sources) with planned dates of coverage
5
Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated
Supplemental File 2
STUDY RECORDS
Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 7
Selection process 11b State the process that will be used for selecting studies (e.g., two independent reviewers) through each phase of the review (i.e., screening, eligibility, and inclusion in meta-analysis)
7
Data collection process
11c Describe planned method of extracting data from reports (e.g., piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators
8
Data items 12 List and define all variables for which data will be sought (e.g., PICO items, funding sources), any pre-planned data assumptions and simplifications
6,9
Outcomes and prioritization
13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale
6
Risk of bias in individual studies
14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis
7
DATA
Synthesis
15a Describe criteria under which study data will be quantitatively synthesized NA
15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data, and methods of combining data from studies, including any planned exploration of consistency (e.g., I
2, Kendall’s tau)
NA
15c Describe any proposed additional analyses (e.g., sensitivity or subgroup analyses, meta-regression)
9
15d If quantitative synthesis is not appropriate, describe the type of summary planned 9
Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (e.g., publication bias across studies, selective reporting within studies)
NA
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Section/topic # Checklist item Information reported Page
number(s) Yes No
Confidence in cumulative evidence
17 Describe how the strength of the body of evidence will be assessed (e.g., GRADE) NA
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