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Cochrane Database of Systematic Reviews Protocol - Intervention

Continuation versus discontinuation of antiplatelet therapy for bleeding and ischaemic events in adults undergoing non‐cardiac surgery

Authors' declarations of interest

Version published: 08 March 2017 Version history

https://doi.org/10.1002/14651858.CD012584

This is not the most recent version

view the current version 18 July 2018
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Abstract

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

To compare the effects of continuation versus discontinuation of antiplatelet therapy on the occurrence of bleeding and ischaemic events in non‐cardiac surgical patients.

Background

Description of the condition

Platelets play a major role in the pathogenesis of atherosclerotic and thrombotic diseases. Drugs intended to prevent or treat these diseases are widely used. Antiplatelet agents are recommended for people with myocardial infarction and acute coronary syndromes, transient ischaemic attack or stroke, and for those in whom coronary stents have been inserted (NICE 2010). Many patients are prescribed two antiplatelet drugs (typically aspirin plus another drug), especially after acute coronary syndromes and coronary artery stenting. In the latter context, these drugs are needed to prevent clots from forming and blocking the stent until normal vascular endothelium grows over the metal of the stent. Stents of different types (‘bare metal’ or ‘drug‐eluting’) require different durations of treatment; for instance, dual antiplatelet therapy with aspirin and clopidogrel is recommended for at least one month after insertion of a bare metal stent, and for at least 12 months after insertion of a drug‐eluting stent (Levine 2016). Interfering with platelet function naturally increases risk of bleeding, but in general this risk is low enough to be acceptable (Sorensen 2009).

In the year after stent insertion, about 4% of people will have to undergo non‐cardiac surgery (Berger 2010). Such procedures carry increased risk of an adverse outcome, as both myocardial infarction (Hawn 2013; Wijeysundera 2012) and significant bleeding (Singla 2012) are more likely. However, premature discontinuation of dual antiplatelet therapy can be fatal (Korte 2011) in patients with coronary stents. On the other hand, dual antiplatelet therapy used for the treatment of atrial fibrillation or for primary prevention of cardiac or cerebrovascular events can be stopped before surgery is performed without major consequences (Oprea 2013).

Description of the intervention

Commonly used antiplatelet agents fall into three pharmacological classes: thromboxane A2 inhibitors (aspirin), thienopyridines (clopidogrel, prasugrel and ticlopidine) and cyclopentyltriazolopyrimidines (ticagrelor).

Aspirin irreversibly inhibits the enzyme cyclo‐oxygenase 1, leading to loss of platelet aggregation. This effect persists for the lifespan of the platelet, which is 7 to 10 days (Oprea 2013). The remaining drugs act on the P2Y12 receptor on the platelet surface, preventing it from binding with adenosine diphosphate (ADP) and thus inhibiting aggregation (Oprea 2013). Again, for clopidogrel, this effect is irreversible and lasts as long as the platelet itself. Thus it is necessary to discontinue these agents for at least one week to allow their effects to wear off. Ticagrelor, on the other hand, is a reversible antagonist at the ADP receptor, although reversal of its clinical effect may not be straightforward.

How the intervention might work

The patient on antiplatelet agents undergoing surgery is therefore at risk for two types of complications: bleeding and thrombosis. Which carries greater risk will depend on the indications for the antiplatelet agent and on the type of surgery proposed; these and other factors can be incorporated into a ‘matrix’ to help balance the risks for an individual patient (Korte 2011; Rossini 2014). Discontinuing the antiplatelet agent may make thrombotic problems such as myocardial infarction more likely; on the other hand, performing surgery when antiplatelet drugs are still active in the body is likely to increase bleeding. To complicate matters, the haemodynamic instability caused by severe bleeding may in itself lead to myocardial ischaemia and infarction (Devereaux 2016). Some recent studies (e.g. Mantz 2011, Oscarsson 2010) have investigated the effects of continuing or discontinuing aspirin during the perioperative period; results demonstrate no difference in the number of bleeding events (Mantz 2011; Oscarsson 2010) but a reduction in the number of major adverse cardiac events when aspirin is continued during the perioperative period (Oscarsson 2010).

Why it is important to do this review

Current recommendations are to usually continue antiplatelet therapy for patients with a coronary artery stent (Fleisher 2014; Oprea 2013) and that very low bleeding risk procedures may be undertaken without stopping dual antiplatelet therapy (Keeling 2016). However, very recent evidence suggests that the relationship between continuation of antiplatelet agents and reduced thrombotic complications might not be as simple as one might suppose (Wasowicz 2016). Given this uncertainty and the large numbers of people affected worldwide, a systematic review of available high‐quality evidence is necessary. The results of this review may inform clinical guidelines and may have implications for the costs of health care.

Objectives

To compare the effects of continuation versus discontinuation of antiplatelet therapy on the occurrence of bleeding and ischaemic events in non‐cardiac surgical patients.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials (RCTs) including quasi‐randomized studies (e.g. studies in which participants are assigned by alternation, date of birth or medical record number).

We will exclude cluster trials.

Types of participants

We will include adults who have been taking antiplatelet therapy for at least two weeks and are scheduled for elective surgery. Antiplatelet therapy may be prescribed as single or dual therapy to include all antiplatelet agents, such as aspirin, clopidogrel, prasugrel, ticlopidine or ticagrelor.

We will include participants scheduled for all surgeries except cardiac surgical patients, who require different clinical management. Participants will have at least one cardiac risk factor.

Types of interventions

We will include studies that compare perioperative continuation of antiplatelet agents (i.e. continuation of dual or single agent therapy during the preoperative, intraoperative and postoperative periods) with discontinuation of antiplatelet therapy for five days or longer before surgery.

We will include studies that administer a placebo or no treatment during the discontinuation phase. We will exclude studies that continue only one agent in a dual therapy.

Types of outcome measures

We aim to establish whether risk of bleeding is affected by continuation of antiplatelet therapy. We will therefore collect data on two measures of bleeding: the number of patients requiring transfusion of any blood product owing to blood loss during or after surgery; and the number of patients requiring additional surgical intervention for blood loss. Both continuation and discontinuation of antiplatelets may increase the risk of ischaemic events, and we will collect composite data on ischaemic events. We will record ischaemic events for a follow‐up period of 30 days and will record the number of deaths at two time points: the longest follow‐up time point reported by study authors up to six months, and the longest follow‐up time point reported by study authors up to 30 days.

Primary outcomes

  1. All‐cause mortality at longest follow‐up

  2. All‐cause mortality within 30 days

Secondary outcomes

  1. Blood loss requiring transfusion of blood products (intraoperatively and postoperatively)

  2. Blood loss requiring further surgical intervention

  3. Risk of ischaemic events: peripheral thrombosis, cerebral infarction, myocardial infarction within 30 days

Search methods for identification of studies

Electronic searches

We will search for eligible trials in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; most recent issue), MEDLINE (via Ovid) (from 1946 to the present) and Embase (via Ovid) (from 1974 to the present). We will apply the Cochrane highly sensitive filter for RCTs in MEDLINE and Embase. We have provided our search strategy for MEDLINE in Appendix 1. We will adapt this strategy for searching other databases and will include any publications that report on study data, including abstracts. We will not restrict language of publication.

We will also search the trial registers (www.clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (www.who.int/ictrp/network/en/)) for ongoing trials.

Searching other resources

We will undertake backward citation tracking of any potentially relevant reviews identified during database searches. We will also carry out forward and backward citation tracking of any studies identified for inclusion. We will carry out grey literature searching through OpenGrey (available at www.opengrey.eu./).

Data collection and analysis

We (Sharon Lewis (SL) and Andrew Smith (AS)) will independently carry out all data collection and analysis before comparing results and reaching consensus. We will consult with a third review author (Phil Alderson (PA)) to resolve conflicts when necessary.

Selection of studies

We will use reference management software (Endnote) to collate the results of searches and to remove duplicates. We will use Covidence software (Covidence) to screen results of the search from titles and abstracts, identify potentially relevant studies and consider whether they meet the inclusion criteria (see Criteria for considering studies for this review). We will include abstracts at this stage. However, we will include these in the review only if they contain sufficient information and relevant results that include denominator figures for each intervention/comparison group. We will record the number of papers retrieved at each stage and will report this information using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow chart (Liberati 2009). We will report in the review brief details of closely related but excluded papers.

Data extraction and management

We will use Covidence software (Covidence) to extract data from individual studies. A basic template of the data extraction forms is available at www.covidence.org. We will adapt the template to include the following information.

  1. Methods ‐ type of study design; setting; dates of study; funding sources.

  2. Participants ‐ number of participants randomized to each group; baseline characteristics; type of surgery; type of antiplatelet therapy and duration of administration.

  3. Interventions/Comparison ‐ type of control (placebo or no treatment); time of discontinuation of antiplatelet therapy before surgery.

  4. Outcomes ‐ all relevant review outcomes measured and reported by study authors.

  5. Outcome data ‐ results of outcome measures.

We will consider the applicability of information from individual studies and the generalizability of data to our intended study population (i.e. the potential for indirectness in our review). If we identify associated publications from the same study, we will create a composite dataset from all eligible publications.

Assessment of risk of bias in included studies

Two review authors (SL and AS) will independently assess study quality, study limitations and extent of potential bias using the Cochrane 'Risk of bias' tool (Higgins 2011). We will consider the following domains.

  1. Sequence generation (selection bias).

  2. Allocation concealment (selection bias).

  3. Blinding of participants, personnel and outcome assessors (performance and detection bias).

  4. Incomplete outcome data (attrition bias).

  5. Selective outcome reporting (reporting bias).

  6. Other.

For each domain, we will judge whether study authors have made sufficient attempts to minimize bias in their study design. We will make judgements using one of three measures ‐ high, low or unclear risk of bias. We will record this information in 'Risk of bias' tables and will present a summary 'Risk of bias' figure.

Measures of treatment effect

To calculate risk ratios, we will collect dichotomous data for outcomes related to mortality, number of patients requiring transfusion of blood products or additional surgery for blood loss and number of patients having an ischaemic event.

Unit of analysis issues

If multi‐arm studies compare different antiplatelet agents or include dual and single agent therapies versus a control, we will include both comparison groups but will split the data for the control group, using a 'halving' method to avoid double‐counting, as recommended by Higgins 2011. We will collect risk of ischaemic events as composite data. We will report the number of participants who have had at least one ischaemic event and will pay attention to how study authors report this outcome to avoid a unit of analysis issue in which a participant may have more than one different event.

Dealing with missing data

We will assess whether all measured outcomes have been reported by study authors by comparing, when possible, published reports with protocols or clinical trial registration documents that have been prospectively published.

We will assess whether all randomized individuals are included in outcome data. We will contact study authors to request any missing outcome data that are not explained. If we are unable to obtain these data, we will report data only as presented in the published report, to include intention‐to‐treat data. We will not combine unexplained incomplete data in a meta‐analysis but will report these data narratively.

In the Discussion section, we will discuss the potential impact of missing data on the findings of our review.

Assessment of heterogeneity

We will assess whether there is evidence of inconsistency within our results through consideration of heterogeneity. We will assess clinical heterogeneity by comparing differences in study design, participants, interventions and outcomes in our included studies using the data we have collected during data extraction. We will assess statistical heterogeneity by calculating the Chi2 P value or the I2 statistic. We will judge any heterogeneity above an I2 of 60% and a Chi2 P value of 0.05 or less to indicate moderate to substantial statistical heterogeneity (Higgins 2011).

As well as looking at the statistical results, we will consider point estimates and overlap of confidence intervals (CIs). If the CIs overlap, the results are more consistent. However, combined studies may show a large consistent effect but with significant heterogeneity. We will therefore interpret heterogeneity with caution (Guyatt 2011).

Assessment of reporting biases

We will attempt to source published protocols for each of our included studies using clinical trials registers. We will compare published protocols with published study results to assess the risk of selective reporting bias. If we identify sufficient studies (i.e. more than 10) (Higgins 2011), we will generate a funnel plot to assess risk of publication bias in the review; an asymmetrical funnel plot may indicate potential publication of only positive results (Egger 1997).

Data synthesis

We will complete meta‐analysis for outcomes for which we have comparable effect measures from more than one study and when measures of heterogeneity indicate that pooling of results is appropriate. We will use RevMan (RevMan 5.3) to perform meta‐analysis.

For each outcome, we will calculate risk ratios using the summary data presented in each trial report. We will use a Mantel‐Haenszel effects model, unless events are extremely rare (1 per 1000), in which case we will use Peto odds ratios (Higgins 2011). We will use a fixed‐effect statistical model. If evidence suggests moderate statistical or clinical heterogeneity, we will investigate this by performing subgroup analyses, as below, and will analyse data using a random‐effects model to incorporate unexplained heterogeneity.

Subgroup analysis and investigation of heterogeneity

We aim to use subgroup analysis to address potential differences in the population group for which the risk‐benefit ratios may differ according to continuation or discontinuation of the drug; whether participants have been taking a single or dual antiplatelet therapy; and whether they have coronary stents. We also aim to address whether there is an optimum point at which antiplatelets can be discontinued; patients whose therapy has been discontinued earlier than five days may be at increased risk of ischaemic events.

We will perform subgroup analyses as follows.

  1. Single antiplatelet treatment versus dual therapy.

  2. Coronary stents versus no coronary stents.

  3. Discontinuation of antiplatelet agents within five days before surgery versus discontinuation at more than five days before surgery.

Sensitivity analysis

We will explore potential effects of decisions made as part of the review process as follows.

  1. We will exclude all studies that we judge to be at high or unclear risk of selection bias.

  2. We will conduct meta‐analysis using the alternate meta‐analytical effects model (fixed‐effect or random‐effects).

We will compare effect estimates from the above results with effect estimates from the main analysis. We will report differences that alter interpretation of the effect.

We will perform sensitivity analysis on all of our outcomes.

Summary of findings table and GRADE

The GRADE approach incorporates assessment of indirectness, study limitations, inconsistency, publication bias and imprecision. We will make these assessments at each stage of our analysis as detailed above (Data collection and analysis; Assessment of risk of bias in included studies; Assessment of heterogeneity; Assessment of reporting biases; Data synthesis, respectively). This approach gives an overall measure of how confident we can be that our estimate of effect is correct (Guyatt 2008).

We will use the principles of the GRADE system to give an overall assessment of evidence related to each of the following outcomes.

  1. All‐cause mortality at longest follow‐up.

  2. All‐cause mortality within 30 days.

  3. Blood loss requiring transfusion of blood products.

  4. Blood loss requiring further surgical intervention.

  5. Risk of ischaemic events: peripheral thrombosis, cerebral infarction, myocardial infarction.

Two review authors (SL and AS) will independently use GRADEpro software (available at http://www.guidelinedevelopment.org/) to create a 'Summary of findings' table for each comparison. We will reach consensus and will resolve disagreements by consulting a third review author, if required.