Alpha‐2 adrenergic agonists for the prevention of cardiovascular complications among patients undergoing cardiac or non‐cardiac surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective:
To determine the efficacy and safety of alpha‐2 adrenergic agonists for reducing mortality and cardiovascular complications following cardiac and non‐cardiac surgery.
Secondary objectives:
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To compare the efficacy and safety of clonidine, mivazerol, and dexmedetomidine for reducing mortality and cardiovascular complications following cardiac and non‐cardiac surgery.
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To compare the efficacy and safety of alpha‐2 adrenergic agonists for reducing mortality and cardiovascular complications following cardiac, vascular non‐cardiac, and non‐vascular non‐cardiac surgery.
Background
Cardiovascular complications are associated with increased mortality, morbidity, and healthcare costs following cardiac and non‐cardiac surgery . Approximately 4.5% of individuals undergoing cardiac surgery (AHA 2001) will sustain a postoperative myocardial infarction (Carrier 2000). The latter are associated with increased in‐hospital mortality following cardiac surgery (Chaitman 1983; Force 1990). Approximately 30% of patients undergoing non‐cardiac surgery either have, or are at risk for, coronary artery disease (Mangano 1990). Cardiovascular complications following non‐cardiac surgery are also associated with increased short‐ and long‐term mortality (Mangano 1992). The direct health costs of these cardiac events has been estimated at US $20 billion (Mangano 1995).
The surgical stress response plays an important role in the pathogenesis of cardiovascular complications during the perioperative period (Halter 1977; Roizen 1988). We define the perioperative period as the interval from immediately preceding to 30 days following a surgical procedure. The alpha‐2 adrenergic agonists currently used in clinical practice (i.e. clonidine, dexmedetomidine, mivazerol) are able to attenuate this response; specifically, they have been shown to inhibit central sympathetic outflow (Muzi 1992), reduce peripheral release of norepinephrine (Ellis 1994), dilate post‐stenotic coronary vessels (Heusch 1985), and reduce the severity of hemodynamic abnormalities (Talke 1995; McSPI 1997).
Nonetheless, these beneficial pharmacological actions have, as yet, not been translated into conclusive evidence for the reduction of perioperative mortality or major cardiovascular complications. In the recent 2002 ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Non‐cardiac Surgery (Eagle 2002), alpha‐2 agonists were conferred a Grade IIb recommendation. The latter is indicated when evidence for a therapy's efficacy is conflicting and less well established (Eagle 2002). Furthermore, the recommendation was itself based primarily on one study (Oliver 1999).
A comprehensive systematic review is therefore warranted to better define the limits of existing knowledge on perioperative alpha‐2 agonist use. A prior study did attempt to address this question, but had several important limitations (Nishina 2002). This meta‐analysis of clonidine use during surgery concluded that it caused a statistically significantly reduction in myocardial ischaemia. However, the review was underpowered (664 patients in seven studies) to show effects on death or infarction, searched only English language literature, and excluded other alpha‐2 agonists. Inclusion of other alpha‐2 agonists would have significantly improved the study's power given that mivazerol and dexmedetomidine have been evaluated in trials of up to 1,900 patients (Oliver 1999). In addition, the meta‐analysis did not consider the relationship between alpha‐2 agonists' treatment effects and other interventions that may themselves reduce perioperative cardiovascular complications: beta‐blockers (Mangano 1996; Poldermans 1999) and neuraxial anaesthesia or analgesia (Beattie 2001; Rodgers 2000).
There is therefore justification for a new systematic review to determine the efficacy of alpha‐2 agonists in preventing perioperative mortality and cardiovascular complications, while addressing the limitations of the prior meta‐analysis.
Objectives
Primary objective:
To determine the efficacy and safety of alpha‐2 adrenergic agonists for reducing mortality and cardiovascular complications following cardiac and non‐cardiac surgery.
Secondary objectives:
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To compare the efficacy and safety of clonidine, mivazerol, and dexmedetomidine for reducing mortality and cardiovascular complications following cardiac and non‐cardiac surgery.
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To compare the efficacy and safety of alpha‐2 adrenergic agonists for reducing mortality and cardiovascular complications following cardiac, vascular non‐cardiac, and non‐vascular non‐cardiac surgery.
Methods
Criteria for considering studies for this review
Types of studies
Published randomized controlled trials (RCTs)
Types of participants
Adults above 18 years undergoing surgery (cardiac and non‐cardiac) under general anaesthesia and/or neuraxial anaesthesia. Surgical procedures performed under local anaesthesia or peripheral nerve blockade alone will be excluded, given that such procedures are generally associated with a very low incidence of perioperative mortality and morbidity. Trials exclusively recruiting individuals who are pregnant, organ transplant recipients, or suffering from substance withdrawal will also be excluded. Organ transplantation procedures may be associated with a high incidence of perioperative mortality unrelated to cardiovascular causes, therefore, masking any potential benefit from alpha‐2 agonists. Prior studies have already shown alpha‐2 agonists to be appropriate agents for the management of substance withdrawal (Gowing 2002; Mayo‐Smith 1997).
Types of interventions
Clonidine, mivazerol, and dexmedetomidine administration during any of the following periods: preoperative (within 24 hours of surgery), intraoperative, or postoperative (within 48 hours of surgery). Medication may be administered via intravenous, intramuscular, oral, or transdermal routes. The specific route employed will be documented for each study.
Types of outcome measures
Primary outcomes
Death (all‐cause)
Secondary outcomes
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Cardiac death ‐ sudden death or death resulting from a primarily identifiable cardiac cause
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Myocardial infarction (MI) ‐ definition as per individual study (specific criteria employed will be documented)
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Supraventricular tachyarrhythmia (SVT) ‐ supraventricular tachycardia, atrial fibrillation, or atrial flutter
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Congestive heart failure ‐ clinical diagnosis of congestive heart failure or requirement for intra‐aortic balloon pump support
Side‐Effects from Treatment
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Myocardial ischaemia ‐ as detected on an electrocardiogram (ECG) or transesophageal echocardiogram (specific criteria employed will be documented)
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Bradycardia requiring pharmacological or pacemaker treatment
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Hypotension requiring inotropes or vasopressors
Included trials must report any of the following outcomes: death, MI, or SVT; or the side‐effect: myocardial ischaemia.
Search methods for identification of studies
MEDLINE (1966 to February 2003) will be searched using the following strategy:
(1) MeSH ‐ postoperative complications OR perioperative care OR intraoperative complications
(2) intraoperative OR perioperative OR postoperative
(3) #1 OR #2
(4) MeSH ‐ clonidine OR dexmedetomidine
(5) mivazerol
(6) #4 OR #5
(7) #3 AND #6
The identified studies will then be limited to those identified simultaneously by the highly sensitive search strategy for identifying RCTs in MEDLINE (Dickersin 1994).
EMBASE (1980 to February 2003) will be searched using the following strategy:
(1) MeSH ‐ postoperative complication OR postoperative period OR perioperative period OR intraoperative period OR peroperative care OR peroperative complication OR perioperative period
(2) perioperative OR intraoperative OR postoperative
(3) #1 OR #2
(4) clonidine OR dexmedetomidine OR mivazerol
(5) #3 AND #4
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2002) will be searched using the following strategy:
(1) clonidine OR dexmedetomidine OR mivazerol
(2) perioperative OR preoperative OR postoperative
(3) #1 AND #2
All trials selected for inclusion will be entered into the Science Citation Index to identify any further relevant articles. The bibliographies of all included articles and published reviews will be searched to identify any other potential studies for inclusion. Local content experts will also be consulted.
Authors of published trials will be contacted to provide any additional information required for the proposed analyses (see Methods). No language restriction will be applied.
Data collection and analysis
Two reviewers (DNW, JSN) will independently carry out literature searches for potentially relevant RCTs. All published full papers and abstracts identified will be assessed independently for inclusion by two reviewers (DNW, JSN). Reason(s) for exclusion will be documented for all excluded studies. Three reviewers (DNW, JSN, WSB) will independently extract data from included studies on to pre‐designed data abstraction forms. One reviewer (DNW) will enter all data into RevMan 4.1.1; another (WSB) will crosscheck the printout against his own data abstraction forms. All disagreements will be resolved by consensus.
The quality of all included trials will be evaluated independently by three reviewers (DNW, JSN, WSB) using the criteria recommended by the Cochrane Anaesthesia Review Group. These criteria emphasize adequacy of allocation concealment, randomisation, blinding, and intention‐to‐treat analysis.
The reviewers will not be blinded to authors, institution, or journal when performing data abstraction or quality assessment.
All statistical analyses will be performed using the RevMan 4.1.1 package. If studies have multiple treatment arms, comparisons will be made, where possible, between alpha‐2 agonists and placebo. Given that all outcomes and side‐effects are dichotomous, all treatment effects will be expressed as pooled relative risks (RR) with 95% confidence intervals. Initially, we will assess for statistical heterogeneity using the Q statistic, with statistically significant heterogeneity being defined p‐values below 0.1. In the absence of statistically significant heterogeneity, pooled RRs will be calculated under the fixed effects model. If there is statistically significant heterogeneity, the random effects model will be used instead; in addition, we will carry out post‐hoc analyses to explain the heterogeneity.
We have planned several subgroup analyses a priori to determine the effect of the specific alpha‐2 agonist employed, type of surgical procedure, and co‐existent therapies on the overall results:
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We will calculate treatment effects of alpha‐2 agonists on death, MI, and ischaemia among patients undergoing specific procedure types: cardiac, vascular non‐cardiac, and non‐vascular non‐cardiac surgery. If a variety of surgical procedures are included in a study, we will attempt to obtain subgroup‐specific results from the authors. If such data are not available, and more than 75% of patients underwent the same class of surgery, the study will be allocated to that specific subgroup. Failing that, the study will be excluded from the procedure subgroup analysis.
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We will calculate treatment effects for each of clonidine, mivazerol, and dexmedetomidine on death, MI, and ischaemia.
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The meta‐analyses will be repeated among patients who received intraoperative neuraxial (epidural or spinal) anaesthesia or analgesia.
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We will compare preoperative beta‐blocker and calcium antagonist use between the alpha‐2 agonist and control arms. Medication use differences will be expressed as RRs.
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The included RCTs will be ranked based on the prevalence of preoperative beta‐blocker use. Trials that do not report beta‐blocker use will be excluded. The top half among the ranked RCTs will be designated as the high beta‐blocker use subgroup. The remainder will be designated as the low beta‐blocker use subgroup. The meta‐analyses will be repeated within the subgroups defined by the prevalence of beta‐blocker use.
A number of sensitivity analyses have been planned to characterize the influence of statistical models, included RCTs, and outcome definitions on the overall results:
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Analyses where the fixed‐effects model was used will be repeated using the random effects model.
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Trials will be removed from the meta‐analyses in increasing order of relative risks (i.e. trials most favouring alpha‐2 agonists will be removed first). We will measure the number of trials that have to be removed to make the treatment effect statistically non‐significant.
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The meta‐analyses will be repeated in double‐blinded RCTs alone.
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We will determine the effect of alpha‐2 agonists on MI using only RCTs that strictly defined MI a priori as either significant new Q waves on ECGs, or significant elevations in enzymatic markers of cardiac injury (MB isoenzyme of creatinine kinase, troponin‐I, troponin‐T).
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The effect of alpha‐2 agonists on myocardial ischaemia will be determined using only RCTs that strictly defined ischaemia a priori as ST segment depression/elevation greater than 1 mm for more than 1 minute.
Funnel plot analyses (Egger 1997) will be carried out to assess for any possible publication bias.
The above protocol has been employed in a published review that was limited to publications before May 2002 (Wijeysundera 2003).
