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. 2017 Feb 2;2017(2):CD012534. doi: 10.1002/14651858.CD012534

Antiplatelet and anticoagulant agents for primary prevention of thrombosis in individuals with antiphospholipid antibodies

Malgorzata M Bala 1,✉, Elzbieta M Paszek 2, Dorota Wloch‐Kopec 3, Wiktoria Lesniak 4, Anetta Undas 5
PMCID: PMC6464540

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of antiplatelet and anticoagulant agents versus placebo or no intervention or other intervention for the development of thrombosis in people with antiphospholipid (aPL) antibodies but who have not had a thrombotic event.

Background

Description of the condition

Antiphospholipid syndrome (APS), also known as Hughes syndrome, is an autoimmune condition triggered by antiphospholipid (aPL) antibodies that have prothrombotic activity. The aPL antibodies are a heterogeneous group of antibodies directed against certain proteins in blood, such as protein C (Chen 2010), and on platelet cell membranes (annexin V (Rand 2008)), tissue factor and others (Chen 2010). The risk of prothrombotic activity varies depending on the type of antibodies, which include: anticardiolipin (aCL) antibodies, anti‐beta2‐glycoprotein I (anti‐β2GPI) antibodies and lupus anticoagulant (LA) (Sebastiani 1999). According to the literature, aPL antibodies are found in approximately 1% to 5% of the general population, in 6% (interquartile range (IQR) 2% to 13%) of women who present with pregnancy complications, in 9% of women with spontaneous abortion, in 9.5% (IQR 5.3% to 13.8%) of patients with deep vein thrombosis, in 11% (IQR 4% to 23%) of patients with myocardial infarction and in 13.5% (IQR 6.8% to 23.3%) of patients with ischaemic stroke (Amengual 2015; Andreoli 2013; Gomez‐Puerta 2014). The aPL antibodies can be detected in people who have various conditions, such as autoimmune diseases and most commonly lupus erythematosus (SLE) (Abu‐Shakra 1995), or during diagnostic processes that investigate foetal deaths, premature births and recurrent spontaneous abortions (Miyakis 2006). The isolated presence of aPL antibodies is insufficient to diagnose APS. According to the modified criteria by Miyakis 2006, a patient is required to meet at least one clinical criterion related to either a vascular thrombosis or an obstetric complication, as well as the presence of one or more specified aPL antibody on two or more occasions at least 12 weeks apart. It is unclear if individuals who have aPL antibodies present in their circulating blood but have not experienced any thrombotic clinical events should receive primary prophylaxis. Empson 2005 conducted a Cochrane systematic review that addresses this issue in pregnant women with prior miscarriage and aPL antibodies, and showed that combined unfractionated heparin (UFH) and aspirin may reduce pregnancy loss by 54%. More recently another systematic review, Amengual 2015, assessed the effect of acetylsalicylic acid in asymptomatic women who were positive for aPL antibodies and had no history of recurrent miscarriage or intrauterine foetal death. Amengual 2015 did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent obstetric complications in otherwise healthy women with aPL antibodies during their first pregnancy.

Description of the intervention

Antiplatelet drugs inhibit platelet function, mostly platelet aggregation, which reduces the probability of thrombus formation (Depta 2015; Weitz 2012). The most commonly used antiplatelet agent is acetylsalicylic acid, which is also known as aspirin. Anticoagulants are agents that interfere with blood coagulation and thereby reduce fibrinogen polymerisation and blood clot formation.

In standard practice, antiplatelet agents (aspirin, clopidogrel, prasugrel and ticagrelor) are used in patients with coronary artery disease (Montalescot 2013; Roffi 2016; Windecker 2014), or peripheral artery disease (Alonso‐Coello 2012), to prevent thrombus formation.

Anticoagulant agents (vitamin K antagonists (VKA); warfarin, acenocoumarol) and non‐vitamin K antagonists called direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) (Ageno 2012; Kearon 2016)) are used to prevent thrombus formation in patients with atrial fibrillation (Lip 2014), to treat venous thromboembolism (Kearon 2016), after implantation of an artificial heart valve (Whitlock 2012), and in the primary prevention of thromboembolic complications in patients with knee or hip replacement surgery (Gomez‐Outes 2012).

Low molecular weight heparins (LMWHs) and, less often, UFH are also used to treat and prevent thrombotic events (Garcia 2012; Vandvik 2012), e.g. in patients immobilised because of a medical condition (Kahn 2012), or surgery (Douketis 2012), in patients with cancer (Farge 2016), or pregnant women with thrombophilia (Bates 2012).

How the intervention might work

The presence of aPL antibodies is associated with an increased risk of thrombus formation with all its consequences (Giannakopoulos 2007; Giannakopolous 2013). People who had a thrombotic event and meet criteria of antiphospholipid syndrome are recommended to receive anticoagulation (Ruiz‐Irastorza 2011). The benefits of antiplatelet (aspirin) use in the context of primary prevention of cardiovascular events has been shown (Guirguis‐Blake 2016) and anticoagulants have been examined in the primary prevention of several prothrombotic conditions (MRCGPRF 1998; Rasmussen 2012). Therefore it is assumed that antiplatelet and anticoagulant agents may decrease the incidence of thrombus formation based on their mechanism of action (Cuadrado 2014; Erkan 2007). Aspirin, a commonly used antiplatelet agent, acts through inhibition of platelet cyclooxygenase 1 (COX‐1), which leads to blockade of the production of thromboxane A2 (TXA2) (Warner 2011), while clopidogrel, another commonly used antiplatelet agent, acts through blockade of P2Y receptors on platelets thus reducing their function (Wijeyeratne 2011). UFH and LMWHs are administered intravenously or subcutaneously and form complexes with antithrombin molecules, which leads to the neutralisation of factor Xa and deactivation of thrombin (Garcia 2012). Additionally, UFH directly inhibits thrombin activity. VKA are oral antagonists of vitamin K. They reduce the production of coagulation factors II, VII, IX and X and proteins C and S (Ageno 2012). Among DOAC there are direct thrombin inhibitors (dabigatran), which block the catalytic site or the substrate recognition site in the thrombin molecule, and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), which cause factor Xa inhibition that is not mediated by antithrombin (Ageno 2012).

The administration of all anticoagulants is generally associated with a high risk of bleeding. VKAs are potentially teratogenic and require regular international normalised ratio (INR) monitoring (Torbicki 2008). Important UFH side effects are heparin‐induced thrombocytopaenia (HIT) (Linkins 2012), and osteopaenia (Rajgopal 2008). LMWHs, for which the most common complications are bleeding, allergic reactions and injection site reactions, are associated with lower risk of HIT (Junqueira 2012; Martel 2005), and some studies also indicated lower risk of major bleeding compared to UFH (Alikhan 2014).

Why it is important to do this review

The issue of secondary prevention of thrombosis in patients with APS has been or will be addressed by other Cochrane reviews. One Cochane review addressed the prevention of recurrent miscarriage in patients with aPL (Empson 2005). One Cochrane protocol considers using antiplatelets or anticoagulants to prevent recurrent peripheral vascular thrombosis (Islam 2016). We have also published a Cochrane protocol on secondary prevention of recurrent thrombosis, particularly ischaemic stroke, in patients with APS (Bala 2016). However, we have not identified any Cochrane review that addresses the issue of primary prevention of thrombosis in individuals with aPL antibodies, while there is at least one randomised controlled trial (RCT) that has investigated this issue (Erkan 2007). Two recently published systematic reviews partly addressed this issue (Arnaud 2014; Qushmaq 2014). Arnaud 2014 assessed the effect of acetylsalicylic acid and included all types of study designs (RCTs and observational studies, both prospective and retrospective), and Qushmaq 2014 considered all primary prophylactic interventions but included all types of study designs and excluded studies published in languages other than English. This Cochrane review will present a broader scope of studies, including those that assess antiplatelet agents other than acetylsalicylic acid, as well as anticoagulants.

Objectives

To assess the effects of antiplatelet and anticoagulant agents versus placebo or no intervention or other intervention for the development of thrombosis in people with antiphospholipid (aPL) antibodies but who have not had a thrombotic event.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

People of any age with no history of thrombosis (as defined by the antiphospholipid syndrome (APS) Sapporo classification criteria (Wilson 1999), or updated Sydney classification criteria (Miyakis 2006), but with antiphospholipid (aPL) antibodies confirmed on at least two separate measurements (time period between measurement as defined in the criteria current when the study was done), including lupus anticoagulant (LA), anti‐beta‐2‐glycoprotein I (anti‐β2GPI) antibodies and anticardiolipin (aCL) antibodies (all detected using the assays recommended at the time when the study was conducted).

Types of interventions

We will include studies that compare any antiplatelet or anticoagulant agents, or their combinations, at any dose and administered using any mode of delivery with placebo, no intervention or other intervention (such as hydroxychloroquine), with each other or with studies that compare two different doses of the same drug.

Types of outcome measures

Primary outcomes

  1. Any acute arterial or venous thrombosis diagnosed based on the APS Sapporo classification criteria (Wilson 1999), or updated Sydney classification criteria (Miyakis 2006), which would be confirmed by objectively validated methods, including but not limited to deep vein thrombosis, pulmonary embolism, myocardial infarction, ischaemic stroke, transient ischaemic attack, peripheral thromboembolism or obstetrical failure.

  2. Bleeding based on definitions of minor or major bleeding (Schulman 2005).

  3. Total mortality.

We will analyse any acute arterial and venous thrombosis events combined and also separately by the type of event (such as myocardial infarction, deep vein thrombosis etc.).

Secondary outcomes

  1. Quality of life as measured by a validated questionnaire.

  2. Adverse event other than bleeding, for example gastrointestinal (GI) disturbances, urticaria, other allergic reactions, dizziness, peptic ulcer, insomnia or headache.

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist (CIS) will search the Cochrane Vascular Specialised Register. In addition the CIS will search CENTRAL in the Cochrane Register of Studies (CRS) (www.metaxis.com/CRSWeb/Index.asp). See Appendix 1 for details of the search strategy which will be used to search the CRS. The Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE, Embase, CINAHL and AMED, and by handsearching relevant journals. The full list of the databases, journals and conference proceedings that have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Vascular module in the Cochrane Library (www.cochranelibrary.com).

The CIS will search the following trial databases for details of ongoing and unpublished studies.

  1. World Health Organization (WHO) International Clinical Trials Registry (ICTRP) (http://apps.who.int/trialsearch/).

  2. ClinicalTrials.gov (http://clinicaltrials.gov/).

  3. ISRCTN Register (www.isrctn.com/).

Searching other resources

We will check the references of included studies, systematic reviews, health technology assessments and practice guidelines relevant to the topic of this review. We will contact experts in the field, including PL Meroni (Milan), MA Khamashta (London), PG de Groot (Utrecht) and P de Moerloose (Geneva), and manufacturers of the brand‐name drugs (mainly direct oral anticoagulants (DOAC)) for additional studies.

Data collection and analysis

Selection of studies

We will use the Covidence software for abstract and full text screening (Covidence 2017). We will eliminate duplicate records of the same study using appropriate software. We will divide work between two pairs of review authors (EMP and MMB, DWK and WL). In each pair, one of the review authors is an active clinician and another one is an experienced review author. The review authors in the above mentioned two pairs will each independently screen the titles and abstracts of the search results against the eligibility criteria and we will resolve any discrepancies by discussion. If it impossible to resolve within a pair, a third review author will act as an arbiter (AU). We will retrieve and select the full‐text articles of studies that appear to fulfil inclusion criteria. We will resolve any discrepancies by discussion. If it is not possible to resolve within a pair, a third review author (AU) will act as an arbiter. We will screen the gathered reports for multiple publications of the results of the same study. We will assess the following aspects: time, location, the study authors, the number of participants, the baseline data, the doses and frequencies of drug administration. If necessary, we will contact the authors of the reports or studies, or both, to clarify or add any important information. We will include studies based on the data we collect in the described process. We will list all studies we exclude after full‐text assessment in a 'Characteristics of excluded studies' table. We will display the study selection process in a PRISMA study flow diagram.

Data extraction and management

We will collect data on study design and methods, population intervention, outcomes and results of the included studies. We will use and prepare the Cochrane Vacular data extraction template in Covidence if sufficient form adjustment options are available (Covidence 2017); otherwise we will use the Cochrane Vascular template spreadsheet for data extraction. We will pilot test a data collection form first, in case we need to add, erase or rephrase some additional fields or options. In the case of multiple reports being available for the same study, we will extract data from all of those reports into a single data collection form.

Two pairs of review authors will independently extract the data as outlined above. We will discuss the disagreements and, if impossible to solve within a pair, we will ask a third review author (AU) for their opinion. If we are unable to reach agreement, we will describe this in the review.

Assessment of risk of bias in included studies

We will use the Cochrane 'Risk of bias' assessment tool, as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two pairs of review authors (EMP and MMB, DWK and WL) will independently apply the tool to each included study. We will resolve any disagreements through discussion or, if necessary, we will consult a third review author (AU).

We will assess the risk of bias in the following domains (Higgins 2011).

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding of participants and personnel.

  4. Blinding of outcome assessment.

  5. Incomplete outcome data.

  6. Selective outcome reporting.

  7. Other bias.

We will grade the risk of bias as high, low or unclear for each domain and we include a justification for our judgment in the 'Risk of bias' tables. We will judge the trials as at low risk of bias if they have low risk of bias in each of the 'Risk of bias' domains; in other cases we will judge them as at high risk of bias. We will take the 'Risk of bias' assessment into account when we interpret the data.

Measures of treatment effect

We will calculate the risk ratio (RR) and 95% confidence interval (CI) for all the primary endpoints (death, any thrombosis, bleeding), as well as the secondary endpoints described as 'other' (i.e. GI disturbances or allergic reactions). For the quality of life indicators, we will determine the mean difference or standardised mean difference values and 95% CIs, depending on the use of the same or different scales in the included studies.

Unit of analysis issues

The participant will be the unit of analysis. If an included study has a mixture of units of analysis, we will adjust them to one common unit. We will discuss any unusual issues within the review author team and we will adjust the methods outlined in the published protocol accordingly. If any cross‐over studies meet the inclusion criteria of the review, we will only include the first period of such study in our analyses.

Dealing with missing data

In the case of missing data, we will contact the authors of the original reports for the missing data or for the reasons why they excluded the data. For the data missing at random, we will only analyse the available data. We will analyse the potential impact of missing data on the results using sensitivity analyses and we will discuss this in the review.

Assessment of heterogeneity

Since we will assess the effects of the introduction of several different drugs, we expect there to be clinical diversity. We will estimate statistical heterogeneity visually (overlap of CIs derived from single studies) and by using the Chi2 test, with a significance level of P = 0.10. We will also calculate the percentage of variability that stems from heterogeneity (I2 statistic).

Assessment of reporting biases

In order to minimize the reporting bias we plan to search multiple sources (see the 'Search methods for identification of studies' section). We will visually assess funnel plots in order to screen for small study effects, if there are at least 10 included studies included in the meta‐analysis(Higgins 2011).

Data synthesis

As we mentioned in the 'Assessment of heterogeneity' section, we expect the heterogeneity to be significant. Therefore, we will perform meta‐analyses using a random‐effects model. If we are unable to pool the data due to considerable heterogeneity, as defined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will summarise the findings in the form of tables, figures and text. We will use Review Manager 5 (RevMan 5) to perform analyses (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We will analyse the effect of the antiplatelet and anticoagulant agents separately. Provided that the number of studies included in the analysis is sufficient (at least 10 included studies), we will analyse the effects of the interventions in relation to different subgroups of antiplatelets and anticoagulants and, if the basic material provides such information, the presence of additional risk factors of thrombosis (such as smoking, the use of contraception/hormone replacement therapy, obesity, neoplasms and heart failure). If possible we will analyse the effects in the subgroups according to the type of antibodies present as well as number of types of antibodies present, e.g.one two or three types of antibodies.

Sensitivity analysis

We will assess the following.

  1. The impact of risk of bias on study results: we will analyse the results of studies that are at low risk of bias vs. studies that are at high risk of bias (see the 'Assessment of risk of bias in included studies' section).

  2. The impact of missing data: we will perform analyses by the "best case scenario" (when all participants with missing data in intervention group will be assumed to have good outcome and all participants with missing data in the control group will be assumed to have poor outcome) and by the "worst case scenario" (when all participants with missing data in intervention group will be assumed to have poor outcome and all participants with missing data in the control group will be assumed to have good outcome) and will compare the results of trials that have no missing data with trials that have missing data.

'Summary of findings' tables

Two review authors will independently assess the quality of the evidence using the GRADE approach, as specified by the Cochrane Handbook for Systematic Reviews of Interventions, Higgins 2011, and by Atkins 2004. We will summarise the quality of the evidence in 'Summary of findings' tables (separately for anticoagulants and antiplatelets) using GRADEpro Guideline Development Tool (GDT) (GRADEpro GDT 2014). In the 'Summary of findings' table we will include all of the pre‐specified outcomes (primary and secondary, see the 'Types of outcome measures' section). In case of composite outcomes we will present results for the composite and also for the individual aspects of the composite.

Acknowledgements

We thank Mr Mateusz Swierz for help in preparing the Background section of this protocol and Dr Karsten Juhl Jørgensen for comments on the draft protocol.

Appendices

Appendix 1. Cochrane Register of Studies (CRS) search strategy

#1 MESH DESCRIPTOR Antiphospholipid Syndrome
#2 MESH DESCRIPTOR Antibodies, Antiphospholipid EXPLODE ALL TREES
#3 (aPL antibodies):TI,AB,KY
#4 APS :TI,AB,KY
#5 (Hughes syndrome):TI,AB,KY
#6 (antiphospholipid near2 syndrome):TI,AB,KY
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6
#8 MESH DESCRIPTOR Thrombosis
#9 MESH DESCRIPTOR Thromboembolism
#10 MESH DESCRIPTOR Venous Thromboembolism
#11 MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES
#12 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol* or microembol*):TI,AB,KY
#13 MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES
#14 (PE or DVT or VTE):TI,AB,KY
#15 ((vein* or ven*) near thromb*):TI,AB,KY
#16 (blood near3 clot*):TI,AB,KY
#17 (pulmonary near3 clot*):TI,AB,KY
#18 (lung near3 clot*):TI,AB,KY
#19 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18
#20 MESH DESCRIPTOR Anticoagulants EXPLODE ALL TREES
#21 (anticoagul* or anti‐coagu*):TI,AB,KY
#22 MESH DESCRIPTOR Heparin EXPLODE ALL TREES
#23 *parin*:TI,AB,KY
#24 UFH:TI,AB,KY
#25 LMWH:TI,AB,KY
#26 LMH:TI,AB,KY
#27 (Ariven or Arteven or Calcilean or Hepalean or Hepathrom or Leparan or Lipo‐Hepin or Liquaemin or Liquemin or Pabyrin or Pularin or Thromboliquine or Vetren ):TI,AB,KY
#28 (Clexane or klexane or lovenox ):TI,AB,KY
#29 (Fragmin):TI,AB,KY
#30 (Innohep):TI,AB,KY
#31 clivarin* :TI,AB,KY
#32 (danaproid or danaparoid):TI,AB,KY
#33 (antixarin):TI,AB,KY
#34 (Zibor or cy 222 or embolex or monoembolex):TI,AB,KY
#35 (rd 11885 or RD1185):TI,AB,KY
#36 (Kabi‐2165 or Kabi 2165):TI,AB,KY
#37 (emt‐966 or emt966 or emt‐967 or emt977 or pk‐10169 or pk10169):TI,AB,KY
#38 (fr‐860 or fr860 or cy‐216 or cy216):TI,AB,KY
#39 (kb101 or lomoparan or orgaran ):TI,AB,KY
#40 (fluxum or lohepa or lowhepa):TI,AB,KY
#41 (op 2123 or op2123):TI,AB,KY
#42 (ave 5026 or ave5026 ):TI,AB,KY
#43 (M118 or RO‐1):TI,AB,KY
#44 *coumar*:TI,AB,KY
#45 (*warfarin or (vitamin near/3 antagonist*)):TI,AB,KY
#46 (VKA or phenindione or Sinthrome or nicoumalone or phenprocoumon or Marcoumar or Marcumar or Falithrom or AVK or phenprocoumon* or aldocumar or carfin or jantoven or kumatox or lawarin or marevan or prothromadin or sofarin or tedicumar or tintorane or waran or warfant or warfilone or warnerin):TI,AB,KY
#47 MESH DESCRIPTOR Antithrombins EXPLODE ALL TREES
#48 MESH DESCRIPTOR Hirudin Therapy
#49 (thrombin near3 inhib*):TI,AB,KY
#50 hirudin*:TI,AB,KY
#51 (dabigatran or Pradaxa or Rendix):TI,AB,KY
#52 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048):TI,AB,KY
#53 (ximelagatran or Exanta or Exarta or melagatran):TI,AB,KY
#54 (AZD0837 or AZD‐0837):TI,AB,KY
#55 (S35972 or S‐35972):TI,AB,KY
#56 MESH DESCRIPTOR Factor Xa Inhibitors
#57 (Factor X* near4 (antag* or inhib* or block*)):TI,AB,KY
#58 (FX* near4 (antag* or inhib* or block*)):TI,AB,KY
#59 (10* near4 (antag* or inhib* or block*) ):TI,AB,KY
#60 (rivaroxaban or Xarelto):TI,AB,KY
#61 (Bay‐597939 or Bay597939):TI,AB,KY
#62 (betrixaban or PRT054021):TI,AB,KY
#63 apixaban:TI,AB,KY
#64 (BMS‐562247 or BMS‐562247 or ELIQUIS):TI,AB,KY
#65 (DU‐176b or DU176b):TI,AB,KY
#66 (PRT‐054021 or PRT054021):TI,AB,KY
#67 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*):TI,AB,KY
#68 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893):TI,AB,KY
#69 edoxaban or lixiana:TI,AB,KY
#70 *ixaban:TI,AB,KY
#71 *axaban:TI,AB,KY
#72 *exaban:TI,AB,KY
#73 etexilate:TI,AB,KY
#74 agatroban:TI,AB,KY
#75 *parinux:TI,AB,KY
#76 MESH DESCRIPTOR Platelet Aggregation Inhibitors EXPLODE ALL TREES
#77 MESH DESCRIPTOR Phosphodiesterase Inhibitors EXPLODE ALL TREES
#78 MESH DESCRIPTOR Tetrazoles
#79 (antiplatelet* or anti‐platelet* or antiaggreg* or anti‐aggreg*):TI,AB,KY
#80 (((platelet or thromboxane or thrombocyte or cyclooxygenase or cyclo‐oxygenase or phosphodiesterase or fibrinogen or PAR‐1) near3 (antagonist or inhibitor))):TI,AB,KY
#81 ((gp* or glycoprotein* or protease or P2Y12 or TXA2) near3 inhibit*):TI,AB,KY
#82 thienopyridine:TI,AB,KY
#83 (ticlopidine or Ticlid):TI,AB,KY
#84 (clopidogrel or Plavix):TI,AB,KY
#85 (Prasugrel or Effient or Efient or Prasita):TI,AB,KY
#86 (ticagrelor or AZD6140 or Brilinta):TI,AB,KY
#87 (elinogrel or PRT060128 or PRT‐060128):TI,AB,KY
#88 (cangrelor or AR‐C6993* or ARC6993*):TI,AB,KY
#89 (SCH530348 or SCH‐530348):TI,AB,KY
#90 E5555:TI,AB,KY
#91 (terutroban or Triplion):TI,AB,KY
#92 (aspirin* or nitroaspirin or ASA):TI,AB,KY
#93 (acetylsalicylic acid):TI,AB,KY
#94 (acetyl salicylic acid*):TI,AB,KY
#95 (triflusal or disgren):TI,AB,KY
#96 (Cilostazol or Pletal or Pletaal):TI,AB,KY
#97 (dipyridamol* or Persantine):TI,AB,KY
#98 (OPC‐13013 or OPC13013):TI,AB,KY
#99 (picotamide or picotinamide):TI,AB,KY
#100 satigrel:TI,AB,KY
#101 vorapaxar:TI,AB,KY
#102 indobufen:TI,AB,KY
#103 #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84 OR #85 OR #86 OR #87 OR #88 OR #89 OR #90 OR #91 OR #92 OR #93 OR #94 OR #95 OR #96 OR #97 OR #98 OR #99 OR #100 OR #101 OR #102
#104 #7 AND #19 AND #103
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Contributions of authors

MMB, EMP and AU developed the concept of the study. All protocol authors contributed to the preparation of this protocol and have agreed upon this final version.

Sources of support

Internal sources

  • Jagiellonian University Medical College, Poland.

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

Declarations of interest

MMB receives honoraria as freelancer from a company doing Health Technology Assessment (HTA) and systematic reviews for various clients (Kleijnen Systematic Reviews Ltd). EMP is an investigator in a clinical trial (a trial on evolozumab (antibody antiPCSK9)) conducted for Amgen Inc. Abbott Vascular paid for her registration fee for the 20th International Congress of the Polish Cardiac Society. DWK is an investigator in a clinical trial (a trial on drug resistant epilepsy) conducted by UCB Pharma. WL has no known conflicts of interest. AU received honoraria for lectures and had travel expenses covered by Bayer, Boehringer Ingelheim, Pfizer and Sabofi‐Aventis relating to anticoagulant therapy in Poland; a total below USD 15,000 per year.

Notes

We have based parts of the Methods section of this protocol on a standard template established by Cochrane Vascular.

New

References

Additional references

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