bmj open€¦ · optimal duration of dual antiplatelet therapy following percutaneous coronary...

For peer review only

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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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

[email protected]

Shannon Kelly MSc,

Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,

40 Ruskin Street, Ottawa, Ontario, Canada

[email protected]

Zemin Bai, MSc



[email protected]

Wenfei Liu, MSc



[email protected]

Becky Skidmore, MLS, Independent Information Specialist,


[email protected]

Michel Boucher, B. Pharm, MSc, Grad Dipl. Bus Adm, RPh

Canadian Agency for Drugs and Technologies in Health (CADTH),


[email protected]

Derek So, MD FRCPC FACC

Division of Cardiology, University of Ottawa Heart Institute,


[email protected]

George A. Wells, PhD*

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40 Ruskin Street, Ottawa, Ontario, K1Y4W7

[email protected]

*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


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


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)




90 or/86-89 (300274) [STENTS]



93 acetylsalicylic acid plus clopidogrel/ (322)


95 or/91-94 (11094) [DAPT PT 1]

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96 antithrombocytic agent/ (34172)




100 purinergic P2Y receptor antagonist/ (1720)




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)


107 prasugrel/ (6357)



110 ticagrelor/ (4114)




114 acetylsalicylic acid/ (212507)

115 asa.tw,kw. (56611)


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)






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



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)










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)




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]


142 exp juvenile/ not (exp juvenile/ and exp adult/) (1888506)




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)


152 (editorial or letter).pt. (2809807)


154 journal conference abstract.pt. (2314692)

155 153 not 154 (7714) [CONFERENCE ABSTRACTS REMOVED]


157 meta-analysis/ (185535)

158 "systematic review"/ (111422)

159 "meta analysis (topic)"/ (28213)




(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)




166 or/157-165 (541812)

167 156 and 166 (383) [REVIEWS]

168 exp practice guideline/ (394445)




171 or/168-170 (636803)

172 156 and 171 (288) [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


BMJ Open on M

ay 26, 2020 by guest. Protected by copyright.

http://bmjopen.bm

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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,



[email protected]

Shannon Kelly MSc,



[email protected]

Zemin Bai, MSc



[email protected]

Wenfei Liu, MSc



[email protected]

Becky Skidmore, MLS, Independent Information Specialist,


[email protected]

Michel Boucher, B. Pharm, MSc, Grad Dipl. Bus Adm, RPh

Canadian Agency for Drugs and Technologies in Health (CADTH),


[email protected]

Derek So, MD FRCPC FACC

Division of Cardiology, University of Ottawa Heart Institute,


[email protected]

George A. Wells, PhD*

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40 Ruskin Street, Ottawa, Ontario, K1Y4W7

[email protected]

*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

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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)




5 or/1-4 (300274) [STENTS]



8 6 or 7 (10825) [DAPT PT 1]

9 Platelet Aggregation Inhibitors/ (61484)




13 Purinergic P2Y Receptor Antagonists/ (1565)




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)



21 Prasugrel Hydrochloride/ (6357)






27 Aspirin/ (201606)

28 asa.tw,kw. (56611)


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)






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



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)










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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)




47 or/41-46 (734986)

48 40 and 47 (22994) [DAPT PT 2]

49 8 or 48 (25717) DAPT PT 1 & 2]





54 or/51-53 (3534744)

55 50 not 54 (7340) [CHILD-ONLY ONLY REMOVED]

56 exp Animals/ not (exp Animals/ and Humans/) (13628610)


58 (comment or editorial or interview or letter or news or newspaper article).pt. (3189325)



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)




(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)




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)




82 or/73-81 (1404586)

83 60 and 82 (166) [GUIDELINES]


85 84 use ppez (257) [MEDLINE RECORDS]

86 exp stent/ (190875)




90 or/86-89 (300274) [STENTS]



93 acetylsalicylic acid plus clopidogrel/ (322)


95 or/91-94 (11094) [DAPT PT 1]

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96 antithrombocytic agent/ (34172)




100 purinergic P2Y receptor antagonist/ (1720)




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)


107 prasugrel/ (6357)



110 ticagrelor/ (4114)




114 acetylsalicylic acid/ (212507)

115 asa.tw,kw. (56611)


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)






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



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)










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)




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]


142 exp juvenile/ not (exp juvenile/ and exp adult/) (1888506)




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)


152 (editorial or letter).pt. (2809807)


154 journal conference abstract.pt. (2314692)

155 153 not 154 (7714) [CONFERENCE ABSTRACTS REMOVED]


157 meta-analysis/ (185535)

158 "systematic review"/ (111422)

159 "meta analysis (topic)"/ (28213)




(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)




166 or/157-165 (541812)

167 156 and 166 (383) [REVIEWS]

168 exp practice guideline/ (394445)




171 or/168-170 (636803)

172 156 and 171 (288) [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


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


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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3


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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