Vasodilators in the treatment of patients with acute myocardial infarction undergoing percutaneous coronary intervention
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To study the impact of adenosine and verapamil on AMI participants who are undergoing PPCI.
Background
Description of the condition
Acute myocardial infarction (AMI), one of major cause of mortality worldwide, can be defined from different perspective related to clinical, electrocardiographic, cardiac biomarker and pathological characteristics (Thygesen 2007). It is estimated that more than three million people have acute ST‐elevation myocardial infarction (STEMI) each year, while more than four million have non‐ST‐elevation myocardial infarction (White 2008). And about one third of myocardial infarcted patients die before they reach the hospital to receive any effective treatment (Huikuri 2001). Rapid reperfusion of the infarcted coronary artery in STEMI is required which can be carried out by pharmacological or mechanical therapy where primary percutaneous coronary intervention (PPCI) is accepted as superior to fibrinolysis (Keeley 2003; Weaver 1997; Zijlstra 1993) and is associated with normal epicardial flow in more than 90% of patients (Boersma 2006; Simes 1995). Fewer than 30% of PPCI patients had door‐to‐balloon in less than 90 minutes according to National Registry of Myocardial Infarction and less than five per cent of interhospital transferred patients had undergone PPCI within 90 minutes after first medical contact (Boersma 2006). Although there is restoration of epicardial coronary flow after PPCI, impaired myocardial perfusion is frequently observed, known as no‐reflow phenomenon. The pathogenetic components of no‐reflow are very complicated and including variable combination of distal atherothrombotic embolization, ischaemic injury, reperfusion related injury and susceptibility of coronary microcirculation to injury (Niccoli 2009). The diagnosis of this phenomenon can be assessed by angiography, electrocardiography, myocardial contrast echocardiography and cardiac magnetic resonance (Niccoli 2009), and its prevalence range from 5‐50% after PPCI depending on the methods used to assess it (Eeckhout 2001; Rezkalla 2008). The angiographic no‐reflow can be defined as thrombolysis in myocardial infarction (TIMI) flow grade <3 or 3 with myocardial blush grade (MBG) 0 to 1 (Niccoli 2009). More importantly, AMI with no‐reflow is strongly associated with poor clinical outcomes (Henriques 2003; Morishima 1995). The participant we interest for this review is a PPCI not a fibrinolytic participant.
Description of the intervention
In order to improve myocardial perfusion or prevent the incidence of no‐reflow after PPCI, many drugs have been tried clinically as adjunctive treatment to PPCI (Kunadian 2008) for years including adenosine and verapamil. Both have vasodilatory effects and have been commonly studied (Kunadian 2008; Wilson 1990).
Adenosine, an endogenous nucleoside, have vasodilatory actions including both arteries & arterioles mediated through adenosine A2A & A2B receptor (Forman 2006). It also reduces the release of vasoconstrictors by inhibiting the activation of neutrophils & platelets, prevents the endothelial damage and microvascular spasm, which contribute to cardioprotective effect and anti‐thrombotic effect of adenosine (Berne 1980; Minamino 1998). In addition, it can decrease the free radical formation, thereby limiting the degree of myocardial injury (Forman 2006). Moreover, it acts as an antiarrhythmic agent by blocking AV node via adenosine A1 receptor, and also have inhibitory effects in the central nervous system (Mustafa 2009). Dipyridamole, an inhibitor of adenosine deaminase, can potentiate the action of adenosine (Wilson 1990). Because of extremely short half‐life of intravascular adenosine (one‐two seconds in human), the duration of its adverse effects are limited (Forman 2006). The adverse effects of intracoronary adenosine in AMI participants are hypotension (14.3%), bradycardia (20%), second degree AV block (18.5%) & bronchospasm (0.6%). Fortunately, these adverse effects disappear within two‐three minutes (Fokkema 2009).
Verapamil, a calcium channel blocker, can decrease oxygen demand by lowering heart rate and arterial pressure, and improve myocardial perfusion by relieving microvascular spasm (Taniyama 1997), and may subsequently reduce infarct size. Furthermore, verapamil may have a direct effect on calcium flux across the sarcolemmal membrane or within the intracellular compartments by enhancing calcium homeostasis, which could provide the protective action on reversibly injured myocardial cells, in addition to the vasodilatory effect and inhibitory effect on platelet aggregation in the setting of AMI (Ikeda 1981; Taniyama 1997). It has been used as an antiarrhythmic agent due to its action on AV node (Akhtar 1989; Singh 1987) AV block. Side effects are more common in verapamil when compared with adenosine (Vijayalakshmi 2006).
How the intervention might work
Reperfusion related injury after PPCI has been associated with high activated neutrophil count, activation and aggregation of platelet and can result in damages of endothelial, plugging of capillaries and production of oxygen free radicals and release of potent vasoconstrictors such as thromboxane‐A2, endothelin‐1 and others inflammatory mediators. These can subsequently contribute to sustained spasm of the coronary microcirculation (Niccoli 2009). Also, calcium overload in myocytes can be observed. To treat and prevent the no‐reflow phenomenon, adenosine and verapamil have been used as pharmacological strategies (Niccoli 2010) since they are effective on different mechanisms of no‐reflow by inducing vasodilation, antithrombotic effects, anti‐inflammatory effects, decreasing free radicals production and calcium overload in myocytes respectively. Adenosine is safe and feasible in AMI participants as adjunct to PPCI and can decrease the incidence of no‐reflow (Marzilli 2000). Similarly, verapamil can reverse the no‐reflow after PPCI (Werner 2002).
According to European Society of Cardiology guidelines for AMI (Van de Werf 2008), adenosine and verapamil have been demonstrated as treatment for no‐reflow with class of recommendation IIb and level of evidence B&C respectively.
Why it is important to do this review
Firstly, AMI with no‐reflow after PPCI is difficult to treat and is strongly associated with poor clinical in‐hospital and long term outcomes. Secondly, randomised controlled trials of adenosine and verapamil on AMI participants who are undergoing PPCI have been studied clinically for many years (Fokkema 2009; Grygier 2011; Marzilli 2000; Micari 2005; Petronio 2005; Taniyama 1997), however, their efficacy on this patient group has not been systematically reviewed to date. This review is needed to summarise the available evidence to provide important clinical guidance for no‐reflow with AMI after PPCI.
Objectives
To study the impact of adenosine and verapamil on AMI participants who are undergoing PPCI.
Methods
Criteria for considering studies for this review
Types of studies
We will select randomised controlled trials only.
Types of participants
Participants who are diagnosed with AMI undergoing PPCI, irrespective of age, sex and ethnic group, will be included in our review. Because our interest is to study the impact of vasodilators (adenosine or verapamil only) on PPCI patients, AMI participants who received fibrinolysis during accident and emergency stage will be excluded. In addition, as asthma, renal impairment, malignant disease and haemodynamic instability may influence the outcomes of interest, studies that included patients with these conditions will be excluded.
Types of interventions
Comparison: adenosine or verapamil versus placebo.
We will include trials in which adenosine or verapamil compared to placebo regardless of dosage, frequency and duration. Route of administration can be either intravenous or intracoronary.
Types of outcome measures
Because case‐specific event rate can not be available for every study at the same time point, we define short‐term as 4‐6 weeks and long‐term as 6‐18 months.
Primary outcomes
1. Death‐all cause at short‐term and long‐term
2. Non‐fatal myocardial infarction at short‐term and long‐term
Secondary outcomes
1.Thrombolysis In Myocardial Infarction (TIMI) flow grade <3 after PPCI & at short term (or discharge)
2. Myocardial Blush Grade (MBG) 0 to 1 after PPCI & at short term (or discharge)
3. Adverse events of specific interest including hypotension, bradycardia and AV block (all type of AV block)
4. Economic outcome: Treatment cost (US$)
5. Quality of life
Search methods for identification of studies
Electronic searches
Randomised controlled trials will be searched for in the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE and EMBASE. No language or date restrictions will be applied. We will also search Web of Science and BIOSIS. Non English papers will be translated in attempt to assess it fully. China National Knowledge Infrastructure (CNKI) will also be searched . Detail of the search strategy that will be used to search MEDLINE, using the Cochrane sensitivity‐maximising RCT filter, Lefebvre, 2011), can be seen in Appendix 1 and for CNKI can be seen in Figure 1.
Searching other resources
The Clinical Trials registers Clinical Trials.gov, Current Controlled Trials, Australian & New Zealand Clinical Trials Registry and the WHO International Clinical Trials Registry Platform (WHO ICTRP) will be searched. Reference lists of identified studies will be examined for obtaining additional trials. Where appropriate, handsearching from Journal of the American Journal of Cardiology will be carried out from 2000 to 2010. And we will contact the authors of relevant articles to ask for more sources of information when necessary.
Data collection and analysis
Selection of studies
The search of trials will be performed by two authors independently. When potentially relevant abstracts are identified, full articles will be retrieved in order to assess whether they meet our inclusion criteria and methodological qualities. Any disagreement will be resolved by discussion between authors. If disagreement still persists, we will consult with third author from our team or other experts until a consensus is reached. A flow diagram (QUOROM statement) will be provided under the guidance from Cochrane Heart Group.
Data extraction and management
Two reviewers will extract data from the related articles independently by using data extraction form. Again, if disagreements cannot be resolved by discussion, third person from our team will be consulted or contact the authors of associated studies to get a clear clarification. The following information will be included in the data extraction form.
1. General information: Record number, trial identification number, date of publication.
2. Characteristics of the included trial: design, allocation concealment, duration.
3. Participants: diagnosis, number of people in the experimental & control group, age, sex, withdrawals/losses to follow up (reason/description)
4. Interventions: dose, route and timing of administration.
5. Outcomes: outcomes which have emphasized in this protocol, length of follow up.
For binary data, total number and number of events in each group will be extracted. And sample sizes, mean and standard deviation of each group will be extracted for continuous data.
Assessment of risk of bias in included studies
Risk of bias of selected trials will be assessed under the guidance of Cocharne Heart Group by using the tool described in Cochrane Handbook for Systematic Review of intervention (Higgins 2011) and by two reviewers independently. Any disagreement will be resolved by discussion between authors or contact the authors of related studies in order to obtain further information. Risk of bias assessment will be presented in tables on the following domains:(Higgins 2011)
1. sequence generation
2. allocation concealment
3. blinding
4. incomplete outcome data
5. selective outcome reporting
6. other bias
The risk of bias for each domain can be categorized as:
YES‐ low risk of bias
NO‐ high risk of bias
UNCLEAR‐ uncertain risk of bias
Measures of treatment effect
The extracted data will be analysed by Review Manger (Revman 5). For dichotomous outcomes, we will determine it by using risk ratio (RR). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). This misinterpretation then leads to an overestimate of the impression of the effect. We will measure for continuous data by using Mean Difference (MD) between groups. If continuous data has been reported using geometric means, we will combine the findings on a log scale and report on the original scale. 95% confidence intervals (CI) & 'P' value will be provided for the comparisons.
Unit of analysis issues
Special issues in the analysis of studies with non‐standard design like cross‐over trials, cluster‐randomised trials and studies with multiple treatment groups will be addressed they meet our inclusion criteria.
For cross‐over trials, a major concern is carry‐over effect. Should there be any cross‐over studies that meet our criteria, we will only use the data from the first phase. For analysis we will be guided by the Cochrane Heart Group.
When a study has more than two treatment groups, if relevant, we will present the additional treatment arms. Where the additional treatment arms are not relevant, they will not be taken into account.
Dealing with missing data
When there is missing data, we will contact the original authors to request for the necessary information. If missing data cannot be obtained, imputation method will be used and sensitivity analysis will be attempted to assess the assumptions made. Intention to treat analysis will be performed for the outcomes.
Assessment of heterogeneity
Clinical heterogeneity will be assessed by considering variability in the participants, interventions and outcomes of studies. Statistical heterogeneity will be carried out by Chi‐squared test and I2 test; where the I2 value ranges between 50% to 90% we will assume the presence of substantial heterogeneity (Higgins 2003, Higgins 2011). The importance of the observed value of I2 depends on magnitude and direction of effects and strength of evidence for heterogeneity (e.g. 'P' value from chi2 test, or a confidence interval for I2).
Assessment of reporting biases
Potential publication bias of selected studies will be investigated by funnel plot (Egger 1997). However, a funnel plot will not be used should there be less than ten studies.
Data synthesis
Each outcome of the included studies will be combined and calculated via Review Manager (Revman5) in an attempt to estimate the overall effect. Mantel‐Haenszel method for fixed effect model will be used except when statistical heterogeneity is observed, where random effects model will be chosen.
Subgroup analysis and investigation of heterogeneity
If clinical heterogeneity is suspected, subgroup analysis will be carried out basing on:
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Patient characteristic (age,sex).
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For adenosine, early administration versus late administration to AMI participants (early means administration <4hr of onset of myocardial infarction symptoms ).
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Route of administration.
Sensitivity analysis
We will perform sensitivity analysis where in doubt of methodological quality or eligibility criteria or publication status of included studies, in order to assess their impact on the overall result. In addition, the comparisons between the combined results of fixed effect model and random effect model will be carried out where necessary.
