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Cochrane Database of Systematic Reviews Protocol - Intervention

Immediate versus delayed treatment for recently symptomatic carotid artery stenosis

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Abstract

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

To assess the risks and benefits of performing very early cerebral revascularization (within two days) compared with delayed treatment (after two days) for individuals with recently symptomatic carotid artery stenosis.

Background

Description of the condition

Annually, approximately 15 million people have a stroke worldwide, and 5.5 million of them die as a result of the event (Mackay 2004). Approximately 88% of all strokes are ischemic (Park 2012), and thromboembolism from an atheromatous plaque in the extracranial carotid artery has been determined to be the sole cause of stroke or a transient ischemic attack (TIA) in about 8% (Flaherty 2013; Park 2012). The risk of developing a future cerebrovascular ischemic event is related to inadequate cerebral blood perfusion as a result of hemodynamic stenosis, or plaque rupture and obstruction of smaller, more distally located blood vessels (Mokin 2013). In people with a recent cerebral or ocular ischemic episode, in whom the relevant (i.e. symptomatic) carotid artery is patent, but the atheroma has caused a stenosis, some type of revascularization procedure may be required. According to different guidelines, surgical revascularization is recommended for people with symptomatic 50% to 99% carotid artery stenosis (Brott 2011; Kakisis 2012; Ricotta 2011). Carotid revascularization can be achieved by carotid endarterectomy or carotid artery stenting. The effectiveness of carotid endarterectomy for stroke prevention in people with symptomatic extracranial carotid disease has been established in randomized controlled trials (RCTs) (Rothwell 2003). Angioplasty with stenting has emerged as an alternative, less invasive therapeutic method of treating all patients with carotid disease, with the increased risk of periprocedural stroke or death limited to older patients (Bonati 2012).

Description of the intervention

Since the 1950s, when carotid endarterectomy was introduced as an option for treatment and prevention of stroke, the number of procedures has increased (Rerkasem 2011). Carotid revascularization can reestablish adequate blood flow by removal of a critical carotid stenosis; this can be accomplished by surgical or endovascular treatment. Surgical options comprise conventional and eversion carotid endarterectomy. Conventional carotid endarterectomy is achieved by a longitudinal carotid arteriotomy with patch angioplasty (Antonopoulos 2011; Ricotta 2011), whereas eversion carotid endarterectomy involves a transection of the internal carotid artery and reimplantation into the common carotid artery (Antonopoulos 2011). Clamping of the carotid arteries is required for removal of the plaque in both techniques (Kakisis 2012).

Furthermore, endovascular treatment may be a useful alternative to carotid endarterectomy. Carotid artery stenosis can be treated after a catheter inserted into the femoral artery is advanced, and after the target vessel lesion has been crossed, by deploying a self‐expanding stent to cover the entire lesion (Kakisis 2012).

How the intervention might work

The timing of revascularization of symptomatic internal carotid artery stenosis has changed over the years. Rothwell 2003 showed greater benefit of surgery when performed within 14 days of the last symptomatic event. However, no definite time lag has been observed between occurrence of the neurologic event and surgery. Early revascularization is beneficial for symptomatic patients because this intervention may prevent a disabling or fatal stroke, but an early intervention may increase perioperative risk of stroke and death from carotid revascularization (Capoccia 2012; Imai 2005; Rantner 2011).

An ischemic stroke recurrence and perioperative risks of revascularization have very different mechanisms (Rerkasem 2011). The presumption is that early revascularization will improve perfusion to a large territory at risk surrounding an infarct core (i.e. the penumbra), will recruit brain areas before cell death occurs, and will prevent new embolic events (Capoccia 2011; Ricotta 2011). Major concerns about early revascularization after TIA or stroke include the following.

  • Transformation of the preexisting infarct core into a hemorrhagic lesion as a result of reperfusion/hyperperfusion injury (Ferrero 2014; Tsivgoulis 2014).

  • Increased vulnerability of recently infarcted brain tissue to periprocedural cerebral ischemia induced by carotid clamping or profoundly decreased blood pressure (Tsivgoulis 2014).

  • Increased vulnerability of carotid plaques in the early phase of cerebral ischemia and thus hazardous removal without distal embolization (Strömberg 2012; Tsivgoulis 2014).

On one hand, the danger of delaying investigation and treatment after a TIA or a nondisabling stroke depends on the early risk of ischemic recurrence (Lovett 2003; Rantner 2011). Early risk of stroke after a TIA or a non‐disabling stroke is around 3.1% to 5.2% within 48 hours; this increases to 8.3% to 11.2% at 14 days (Giles 2007; Johansson 2013; Marnane 2011). On the other hand, the risk of hemorrhagic transformation or of dislodging a thrombus is a matter of major concern during the early intervention. All major adverse events and vascular complications that occur within 30 days of the procedure are attributed to the procedure. Within 30 days of endarterectomy, the risk of death or stroke is 2.4% to 7.6% within 48 hours, and 0.8% to 6.9% at 14 days (Halm 2009; Johansson 2013; Rantner 2013; Sharpe 2013).

In addition, angioplasty has a periprocedural stroke and death risk of 7.1% within 48 hours of a neurologic event, and 2.8% to 8.1% at 14 days (Rantner 2013; Wach 2014). The theoretical benefit of early angioplasty is that it provides the possibility of reopening a critical stenosis with rare reduction in cerebral blood flow (Imai 2005). However, angioplasty within the first few days of a neurologic event may carry excessive risk of mobilization of a thrombus (Rantner 2013).

Why it is important to do this review

The inability to predict which patients may have neurologic worsening during the first 24 to 48 hours after stroke may explain the variation in management of acute stroke among physicians and institutions (Battocchio 2012; Ferrero 2014).

In the UK, current guidelines recommend that carotid intervention ideally should be performed within two days for symptomatic severe carotid stenosis in stable patients (Capoccia 2011; Strömberg 2012). In the USA, it is recommended that carotid endarterectomy should be performed within two weeks of the neurologic event, and urgent revascularization may be considered for stable patients who have limited areas of infarct with a large penumbra (Ricotta 2011).

Analysis of RCTs is necessary to determine whether increased risk of recurrent events outweighs the increased risk of an earlier intervention. Reliable data on risk of surgery or angioplasty in relation to timing of the intervention are necessary if clinicians are to plan surgery or angioplasty most effectively, to adjust risks for case‐mix, and to understand the mechanisms of operative stroke.

Objectives

To assess the risks and benefits of performing very early cerebral revascularization (within two days) compared with delayed treatment (after two days) for individuals with recently symptomatic carotid artery stenosis.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs that compare early intervention versus delayed revascularization in people with recently symptomatic carotid artery stenosis (14 or fewer days from onset of symptoms). We will include studies only if data on clinically significant endpoints, such as ischemic stroke, hemorrhagic stroke, or death, are available.

Types of participants

We plan to include people who had suffered a recent neurologic (TIA or stroke) event ipsilateral to stenosis of 50% to 99% in the carotid artery. We will define a stroke as any cerebrovascular or retinal event with symptoms lasting longer than 24 hours (Rerkasem 2011; Rothwell 2003), and a TIA as a focal neurologic deficit lasting 24 hours (Ferrero 2014; Giles 2007). We will define a nondisabling stroke as a stroke that resulted in no disability of functional significance (modified Rankin score < 3) (Brott 2011; Rerkasem 2011; Rothwell 2003).

Brain imaging that demonstrates a new lesion involving a different anatomic site or vascular territory from the index event can be used to support the diagnosis of perioperative stroke. We will classify strokes as disabling or nondisabling (as defined by trial authors), fatal or nonfatal, or contralateral, ipsilateral, hemorrhagic, or ischemic.

Types of interventions

All techniques aimed at revascularization in symptomatic carotid artery stenosis, including but not confined to:

  • percutaneous transluminal balloon angioplasty and stenting;

  • carotid endarterectomy; and

  • carotid eversion.

We will include randomized studies comparing early intervention (within two days) versus delayed treatment (after two days).

Types of outcome measures

Primary outcomes

  • The combined outcome of any stroke or death occurring within 30 days of surgery or endovascular treatment.

Secondary outcomes

  • Myocardial infarction within 30 days of surgery.

  • Myocardial infarction within 30 days of endovascular treatment.

  • All strokes during the follow‐up period and perioperative deaths.

  • Duration of procedures, length of hospital stay, and procedure‐related costs (if data are available).

  • Significant local complications related to revascularization, such as access site hematoma, infection, cranial nerve palsy, or pseudoaneurysm formation.

Myocardial infarction is defined by the presence of two of the following criteria.

  • Specific cardiac enzymes more than twice the upper limit of normal.

  • History of chest discomfort lasting at least 30 minutes.

  • Development of specific abnormalities on a standard 12‐lead electrocardiogram (ECG).

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We will search for relevant trials published in all languages and will arrange translation of trial reports if required.

Electronic searches

We will search the Cochrane Stroke Group trials register and the following electronic databases and trials registers.

We developed the MEDLINE search strategy with the help of the Cochrane Stroke Group Trials Search Co‐ordinator and will modify it for use with the other databases.

Searching other resources

In an effort to identify further published, unpublished, and ongoing trials, we will:

  • search the reference lists of identified studies and reviews;

  • contact study authors and experts in the field;

  • contact relevant pharmaceutical companies; and

  • use Science Citation Index Cited Reference Search for forward tracking of important articles.

Data collection and analysis

Selection of studies

Two review authors (VV and NC) will independently screen titles and abstracts of the references obtained as a result of our searching activities and will exclude obviously irrelevant reports. We will retrieve full‐text articles for the remaining references, and two review authors (VV and NC) will independently screen the full‐text articles, will identify studies for inclusion, and will identify and record reasons for exclusion of ineligible studies. We will resolve disagreements through discussion; if required, we will consult a third review author (JCCBS) for resolution. We will collate multiple reports on the same study, so that each study, not each reference, is the unit of interest in the review. We will record the selection process and will complete a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram.

Data extraction and management

We plan that two review authors will independently extract the following data from eligible studies and will record this information on standard data extraction forms.

  • Participants: sample size, age, sex, number of participants originally allocated to each treatment group, diagnostic criteria used for carotid stenosis, number of participants in each group with early or delayed intervention.

  • Intervention: time interval from onset of symptoms of TIA/stroke to randomization and from randomization to surgery, type of anesthesia, technique of carotid endarterectomy, technique of angioplasty, any other major vascular surgery.

  • Outcomes: number of participants in each group with outcome events, including stroke, myocardial infarction, and death.

  • Withdrawals and adverse effects.

  • Length of follow‐up.

  • Additional important information.

We will resolve disagreements between review authors by discussion.

Assessment of risk of bias in included studies

Two review authors (VV and NC) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements by discussion or by involving another review author (JCCBS). We will assess risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We will grade the risk of bias for each domain as high, low, or unclear and will provide information from the study report together with a justification for our judgment in the 'Risk of bias' tables.

Measures of treatment effect

For dichotomous variables, we will calculate risk ratios (RRs) and 95% confidence intervals (CIs). For continuous data, we will calculate mean differences (MDs) and 95% CIs between treatment groups if studies report exactly the same outcomes. If similar outcomes are reported on different scales, we will calculate the standardized mean difference (SMD) and the 95% CI. The most appropriate way of summarizing time‐to‐event data is to use methods of survival analysis while expressing the intervention effect as a hazard ratio; we will extract these data directly from the results of studies (Higgins 2011).

Unit of analysis issues

We will base the unit of analysis on the individual participant (unit to be randomized for interventions to be compared) (i.e. the number of observations in the analysis should match the number of individuals randomly assigned).

Dealing with missing data

For missing or unavailable data, we will contact study authors to request additional information. If we receive no response, irrespective of the type of data, we will report dropout rates in the 'Characteristics of included studies' tables of the review, and we will use intention‐to‐treat analysis (Higgins 2011).

Assessment of heterogeneity

We will qualify inconsistency among pooled estimates by using the I² statistic: ((Q ‐ df)/Q) × 100% test, where Q is the Chi² statistic and df represents the degree of freedom. This examines the percentage of total variation across studies due to heterogeneity rather than to chance (Higgins 2003; Higgins 2011).

The thresholds for interpretation of I² will be as follows.

  • 0% to 25%: low heterogeneity.

  • 25% to 75%: moderate heterogeneity.

  • Greater than 75%: significant heterogeneity (Higgins 2003).

When we find sources of heterogeneity, and when data are sufficient, we will conduct meta‐analyses by subgroups. When no significant heterogeneity is identified, we will compute pooled estimates of the treatment effect for each outcome using a fixed‐effect model. When we detect significant heterogeneity despite subgroup analyses, we will calculate the pooled estimate of treatment effects using random‐effects models.

Data synthesis

Methods of synthesizing studies will depend on quality, design, and heterogeneity. We will explore both clinical and statistical heterogeneity. In the absence of clinical and statistical heterogeneity (I² < 50%), we will apply a fixed‐effect model in pooling the data. When we consider studies to be sufficiently similar, we will conduct a meta‐analysis by pooling appropriate data using RevMan (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

If an adequate number of studies are identified, we plan to perform subgroup analyses according to participant age, participant sex, type of revascularization, degree of stenosis, and initial neurologic severity.

Sensitivity analysis

If an adequate number of studies are identified, we will perform sensitivity analyses based on separation of studies according to risk of bias. We will do this by excluding trials that are most susceptible to bias based on our risk of bias assessment: those with inadequate allocation concealment, high levels of post‐randomization losses or exclusions, and uncertain or unblinded outcome assessment (Deeks 2011).