Description of the condition
An abdominal aortic aneurysm (AAA) is an abnormal dilatation of the aorta as it passes below the renal arteries to the point of bifurcation, where it forms the left and right common iliac arteries. The clinical definition of AAA varies, although a maximum infrarenal measurement (a measurement taken below the renal artery branches) of ≥ 30 mm is commonly used (Wanhainen 2008). The prevalence of AAA is six times greater in men than in women (Pleumeekers 1995), with one study demonstrating a prevalence of 1.3% in women and 7.6% in men (Scott 2002). Apart from male gender, other risk factors for AAA include smoking, increased age and family history of AAA (Blanchard 2000). Conclusive evidence from several studies has shown smoking to be associated with AAA (Badger 2009; Greenhalgh 2008; Wilmink 1999). One study (Wilmink 1999) estimated that the risk of AAA is seven-fold in smokers and three-fold in ex-smokers compared with age-matched nonsmokers, and another study reported that 90% of participants with AAA were smokers (Greenhalgh 2008). Increased age has been consistently shown as a significant risk factor (Lloyd 2010; Singh 2001). One population-based study of 6386 men and women reported no AAA in participants younger than 48 years of age but from this age onward the prevalence increased linearly in both men and women (Singh 2001). Family history is another known risk factor for AAA. One study reported that 9% to 12% of first-degree relatives of a participant with an AAA will develop an aneurysm (van Vlijmen-van Keulen 2002).
The decision to operate on an AAA is made when the risk of rupture is greater than the risk associated with the operation, and burden of co-morbidity is increasingly important (Ohrlander 2011). The UK Small Aneurysm Trial estimated that the annual rupture rate is 0.3% for AAAs < 4 cm in diameter, 1.5% for 4.0 cm to 4.9 cm AAAs, and 6.5% for 5.0 cm to 5.9 cm AAAs (Brown 1999). In general, the American Heart Association and the UK Aneurysm Screening Programme recommend that patients with infrarenal AAAs measuring ≥ 55 mm should undergo repair to eliminate the risk of rupture (Hirsch 2005). AAAs can be repaired using an open or endovascular approach. Open repair with graft placement is a major procedure and may be preferred when patients are fit because complications are fewer and patients do not routinely require follow-up. Endograft repair involving stent placement (EVAR) is associated with a lower postoperative risk and is therefore considered when the patient is a high surgical risk or has coexisting medical conditions. The major risks in repairing an AAA are perioperative cardiac events, infection and death. The 30-day mortality has been estimated at 5% in elective open surgical AAA repair compared with 1.7% with EVAR (Greenhalgh 2004; Prinssen 2004). However, a recent study showed no significant difference in survival at five years in participants who had undergone open repair compared with EVAR (Brown 2011). Patients with an infrarenal AAA of 30 mm to 54 mm are monitored by ultrasound or computed tomography (CT) scans every three, six or 12 months for detection of possible expansion and the need for repair. These patients are considered for statin therapy to reduce vascular risk, decrease the risk of rupture and reduce aneurysm growth rates (Davis 2008). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have also been proposed to reduce aneurysmal growth (Hackam 2006).
Studies have shown that even after successful surgical repair of an AAA, participants had a poorer survival rate than healthy controls (de Bruin 2013; De Martino 2013; Timmers 2013). A Dutch cohort study measured a survival rate of 59% 10 years after open AAA repair, and patients had a poorer health-related quality of life than age-matched controls (Timmers 2013). Another Dutch study compared statin use in patients undergoing AAA repair and found that while statins were associated with fewer cardiovascular deaths, several risk factors remained that were associated with poor survival after AAA repair including age > 70 years, a history of cardiac disease, and moderate to severe tobacco use (de Bruin 2013). A further study of 2637 patients undergoing AAA repair determined that although five-year survival rates were similar between open and EVAR repair groups, advanced age ≥ 75 years, coronary artery disease, unstable angina or recent myocardial infarction, oxygen-dependent chronic obstructive pulmonary disease, and estimated glomerular filtration rate < 30 mL/min/1.73 m
A recent study conducted in Australia demonstrated an association between AAA thrombus volume and subsequent cardiovascular events (Parr 2011). AAA thrombus products are released into the circulation where they have the potential to stimulate leukocytes and produce other changes that might promote atherosclerotic plaque activation and acute coronary and cerebrovascular events (Morange 2006; Parry 2009; Smith 2005; Takagi 2009).
AAA size and growth have been found to be associated with local generation of inflammation markers such as interleukin-6, matrix metalliproteinase-2 (MMP-2) and MMP-9 (Schouten 2006). Inflammation also seems to be important in perioperative adverse cardiac events. Larger AAA size is independently associated with an increased incidence of perioperative cardiovascular complications after elective infrarenal AAA repair (Schouten 2006).
Description of the intervention
Pharmacological therapy to reduce cardiovascular risk factors such as hypertension and hypercholesterolaemia.
How the intervention might work
As people with AAA have increased cardiovascular risks, pharmacological therapy may reduce cardiovascular mortality and nonfatal cardiovascular events.
Why it is important to do this review
Two Cochrane systematic reviews on the effectiveness of surgical treatment of AAA have been conducted. Dillon 2007 compared endovascular versus open surgical repair, and Filardo 2012 examined immediate repair versus routine ultrasound surveillance. A third recently published review (Rughani 2012) examines the effectiveness of medical treatments in terms of the expansion rate of small abdominal aortic aneurysms. However, these reviews have focused on treatment of AAA rather than on treatment of vascular risk factors associated with cardiovascular mortality in participants with AAA.
Acquired risk factors such as hypertension and hypercholesterolaemia are often reversible through pharmacological therapy. Given the increased risk of mortality with AAA, it is important to determine which prophylaxis is most effective in preventing cardiovascular death in people with AAA. To date, no systematic review has been conducted to study the effectiveness of medical treatments in reducing cardiovascular mortality in people with AAA. This review provides evidence on the most effective medical treatment for this important problem.
To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA).
Criteria for considering studies for this review
Types of studies
Randomised controlled trials in which participants with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment. We included published studies and studies in progress, if preliminary results were available. Non-English studies were eligible and we sought translations, where appropriate, for inclusion in the review.
Types of participants
Men and women of any age with AAA > 30 mm in diameter as measured by standardised techniques such as ultrasound examination or CT. Participants who have undergone endovascular or open surgical repair for AAA were also included. In participants who had an AAA repair, the time period included in this review was the postoperative rather than the surveillance phase. We only included mixed population studies where data on the subset of participants with AAA were available.
Types of interventions
- Antiplatelet therapy (e.g. aspirin, clopidogrel, ticlopidine, cilostazol or any other antiplatelet drugs)
- Antihypertensive drugs (e.g. calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers (β-blockers), or any other antihypertensive drugs)
- Lipid-lowering therapy (e.g. statins)
- Combination treatment (e.g. antiplatelet drug plus antihypertensive or statin) versus single treatment
- Combination treatment versus no treatment
Where possible, we planned to compare one intervention with another treatment, a different regimen of the same treatment, placebo, or no treatment. We included any type, method, duration, timing, mode of delivery, and dose of medical treatment. Studies in which participants were not treated with a specific regimen but were given numerous medications were not included as it would not be possible to attribute outcomes or side effects to one particular regimen.
This review concerns medical interventions in which the principal actions are to modify cardiovascular risk factors. Therefore, the review authors did not include any alternative treatments for which the primary purpose was to treat the aneurysm itself, for example to reduce growth rates or prevent rupture, or both.
Types of outcome measures
- All-cause mortality
- Cardiovascular mortality (fatal myocardial infarction, fatal stroke, other vascular deaths)
- Nonfatal cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or transient ischaemic attack (TIA))
- AAA-related death
- Major amputation
- Quality of life
- Drug-related morbidity
- Drug-related mortality
Outcomes specific to the aneurysm itself (for example change in size, rupture rates) were not included.
Search methods for identification of studies
We sought translations of any non-English trials.
The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched their Specialised Register (last searched April 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3) in The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).
The following trial databases were searched by the TSC for details of ongoing and unpublished studies using the terms abdominal aneurysm:
- World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/);
- ClinicalTrials.gov (http://clinicaltrials.gov/);
- Current Controlled Trials (http://www.controlled-trials.com/).
Searching other resources
We reviewed the reference lists of relevant studies.
Data collection and analysis
Selection of studies
One review author (LR) used the selection criteria to identify trials for inclusion and assessed the titles and abstracts of all identified studies for relevance and design. The second review author (EA) independently confirmed this selection. Any disagreements were resolved by discussion. We planned to include any studies that were published in duplicate only once in the review.
Data extraction and management
Two review authors (LR, EA) independently extracted the data. Information about the trial design; AAA definition and measurement methods; baseline characteristics of patients; treatment type, method, duration, timing, mode of delivery, and dose were recorded. All-cause mortality and cardiovascular mortality data were recorded as the primary outcome measures. Information on non-cardiovascular events and adverse events was collected in accordance with the secondary outcome measures. We planned to contact the study authors for further information if clarification was required. We resolved any disagreements in data extraction and management by discussion.
Assessment of risk of bias in included studies
Two review authors (LR, EA) independently used the Cochrane Collaboration's tool (Higgins 2011) for assessing risk of bias for the included study. This tool provides a protocol for judgements on sequence generation, allocation methods, blinding, incomplete outcome data, selective outcome reporting, and any other relevant biases. We resolved any disagreements by discussion.
Measures of treatment effect
We planned to base the analysis on intention-to-treat data from the individual clinical trials. As the primary and secondary outcomes are all binary measures, we computed odds ratios (ORs) using a fixed-effect model. We calculated the 95% confidence intervals (CIs) of the effect sizes.
Unit of analysis issues
The unit of analysis was the individual patient. However, as the trial involved repeat measurements on patients at different points in time it was prone to unit of analysis errors (Deeks 2011). Therefore, for the purpose of this review, we chose cardiovascular mortality at five years as the primary endpoint. We planned to include outcomes at longer follow-up periods as secondary outcomes if reported.
Dealing with missing data
We sought information about dropouts, withdrawals, and other missing data. If not reported, we attempted to contact the study authors.
Assessment of heterogeneity
The inclusion of studies on a wide range of medical treatments was likely to result in a high degree of heterogeneity. We therefore planned to assess the heterogeneity between pooled studies by using the Chi
We planned to perform the Chi
Assessment of reporting biases
We planned to assess reporting biases such as publication bias using funnel plots (Sterne 2011). Only one study was included in this review, which was at a low risk of reporting bias, therefore this was not completed.
Two review authors (LR, EA) independently extracted the data. One review author (LR) entered the data into RevMan. The second review author (EA) cross-checked data entry, and we resolved any discrepancies by consulting the source publication.
We used a fixed-effect model to meta-analyse the data.
Subgroup analysis and investigation of heterogeneity
Where possible, we planned to analyse clinically relevant subgroups based on drug and participant groupings including the following.
- Diameter of aneurysm.
- Type of repair (e.g. endovascular versus surgical).
- Type of repair (e.g. endovascular or surgical) versus no repair.
- Year of publication.
However, as only one study with 227 patients was included in this review, it was not possible to perform subgroup analyses.
We planned to conduct a sensitivity analysis by excluding studies at a high risk of bias to measure the effect on the results. However, as only one study was included in this review it was not possible to conduct a sensitivity analysis.
Description of studies
Results of the search
See: Figure 1
|Figure 1. Study flow diagram.|
One study met the inclusion criteria (Yang 2006). The included study was a double-blind, randomised, placebo-controlled trial which measured the effects of metoprolol on the incidence of cardiac complications at 30 days and six months after vascular surgery. The study included 496 patients who underwent procedures including abdominal aortic repair and infrainguinal or axillofemoral revascularisation. A subgroup of 227 patients had an abdominal aortic repair. Although outcome data for the AAA subgroup were not presented in the full report, these data were obtained through personal communication with the study author and statistician. Of the 227 AAA patients, 111 were randomised to metoprolol and 116 were randomised to a placebo. The doses of metoprolol were as follows: 100 mg in patients weighing ≥ 75 kg, 50 mg for patients weighing between 40 and 75 kg, and 25 mg for those weighing ≤ 40 kg. Beta-blocker therapy was commenced preoperatively on the day of surgery and continued for the duration of the hospital stay. Within two hours post surgery, the study drug was administered orally or intravenously for 15 minutes (metoprolol 1 mg/mL or saline at 0.2 mL/kg, diluted with 20 mL of saline). Study medication was continued intravenously every six hours or orally twice a day for five days or until hospital discharge, whichever occurred sooner. Intravenous study drug was converted to oral as soon as oral intake was tolerated. Thirty-day and six-month follow-ups were done by telephone for discharged patients. The primary outcome was defined as a composite of cardiac complications at 30 days post operation including: cardiac death, nonfatal myocardial infarction (MI), congestive heart failure (CHF), unstable angina, and dysrhythmia requiring treatment, defined as atrial fibrillation or ventricular dysrhythmias. In the presence of more than one outcome, the first outcome was recorded. Secondary study outcomes included study drug discontinuation (due to bronchospasm, hypotension or bradycardia), amputation and intraoperative hypotension or bradycardia.
Nine studies, for which full text reports were obtained, were excluded from the review. Two studies (Durazzo 2004; POBBLE Trial) had AAA subgroups but did not present specific outcome data for these patients. The author of one study (Durazzo 2004) confirmed through personal communication that these data were not available. The authors of the POBBLE Trial could not be contacted. Three studies (Cesanek 2008; Mangano 1996; POISE Study) did not report AAA subgroups. Authors of the POISE Study confirmed that outcome data for AAA patients were not available, but the other two study authors did not respond (Cesanek 2008; Mangano 1996). One study (Mackey 2006) was not a randomised controlled trial but a prospective study measuring the incidence of myocardial injury in vascular surgery patients. In two studies (Kouvelos 2013; Neilipovitz 2012) participants were taking co-medications and therefore results could not be attributed to one particular drug. Finally, the DECREASE Study was excluded as the integrity of the data was questionable. In a report released by Erasmus MC Follow Up Committee in 2012 the principal investigator admitted that written informed consent was not obtained for every patient and that the data were collected in a negligent manner (http://www.erasmusmc.nl/5663/135857/3675250/3706798/Integrity_report_2012-10.pdf?lang=en).
Risk of bias in included studies
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
Random sequence generation was performed in blocks of four by a study statistician and therefore judged to be at a low risk of bias. However, the authors did not report the methods used to conceal allocation of treatment and therefore the risk of selection bias was unclear.
All study participants, investigators, caretakers and data outcome evaluators of Yang 2006 were blinded to treatment. Furthermore, blinding was maintained throughout the study, even if study medication was discontinued.
Incomplete outcome data
The two treatment groups in Yang 2006 were well-balanced with respect to baseline characteristics, completion of the study protocol and discontinuation of treatment. Furthermore, all missing data were accounted for and reported.
Yang 2006 specified their hypothesis using results from previously published work. Primary and secondary outcomes were clearly stated and data on all outcomes were reported.
Other potential sources of bias
The Yang 2006 study was deemed to be at low risk of other potential sources of bias.
Effects of interventions
As only one study (Yang 2006) met the inclusion criteria, pooling of data and meta-analysis was not possible. Therefore, individual estimates from the study are reported in a narrative synthesis. The included study did not measure mortality at five years but at two shorter time points of 30 days and six months post operation. Results indicated no clear evidence that metoprolol reduced all-cause or cardiovascular mortality at 30 days: the incidence of all-cause mortality was 1/111 in the metoprolol group and 6/116 in the placebo group (OR 0.17, 95% CI 0.02 to 1.41) while the incidence of cardiovascular mortality at 30 days was 1/111 and 5/116 in the metoprolol and placebo groups respectively (OR 0.20, 95% CI 0.02 to 1.76). One participant in each treatment group died of causes related to AAA (OR 1.05, 95% CI 0.06 to 16.92). Nonfatal cardiovascular events occurred in 12/111 in the metoprolol group and 9/116 in the placebo group at 30 days (OR 1.44, 95% CI 0.58 to 3.57). At six months, metoprolol did not significantly reduce the rate of all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95) or cardiovascular deaths (OR 0.73, 95% CI 0.23 to 2.39). The incidence of AAA-related death was not measured at six months. The incidence of nonfatal cardiovascular events was similar between the two treatment groups at six months (OR 1.41, 95% CI 0.59 to 3.35). No participant had to undergo an amputation. Quality of life was not reported.
Yang 2006 reported on adverse events in the form of study drug discontinuation (due to bronchospasm, hypotension or bradycardia) and intraoperative hypotension or bradycardia. However, data on study drug discontinuation and the incidence of intraoperative hypotension or bradycardia were not available for the subgroup of AAA patients. In the overall study of 496 patients, the study authors reported that the incidence of intraoperative complications was significantly higher in the metoprolol group (P < 0.01). Hypotension occurred in 54% of metoprolol patients (46% required treatment) compared to 41% of placebo patients (34% required treatment). Bradycardia occurred in 35% and 10% of metoprolol and placebo patients, respectively, of whom 22% and 7% required treatment. However, given that these outcomes are based on a population of patients who had undergone vascular surgery for other conditions, the results could not be generalised to participants with AAA.
Summary of main results
Only one study was identified that fulfilled eligibility criteria for inclusion in this review. The study was a randomised controlled trial in which 496 patients undergoing non-cardiac vascular surgery received either metoprolol or placebo (Yang 2006). Data on a subgroup of 227 patients who underwent AAA repair were received from the study author. Results of the study indicate that metoprolol is not associated with a reduction in the rate of all-cause or cardiovascular mortality at either 30 days or six months. No participant had to undergo an amputation. Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA.
Overall completeness and applicability of evidence
Currently, there is a severe lack of evidence concerning the effectiveness of pharmacological prophylaxis in the prevention of cardiovascular events in AAA patients. The one study included in this review was relatively small and tested one beta-blocker against a placebo at 30 days and six months follow-up. Therefore, the results of this study are not widely applicable to the AAA population and the follow-up period was relatively short to study mortality and cardiovascular events in such participants. Recent evidence has questioned whether beta-blockers are of any perioperative value and suggests they may be harmful (Bolsin 2013). As there are many different drugs available, it is important to test these drugs, not just against a placebo but also against each other. Furthermore, it is important to establish if a combination of drugs would yield a better outcome than one drug alone.
Quality of the evidence
The quality of reporting in the study was good. With the exception of failing to report the methods used to conceal allocation of treatments, the study authors provided adequate information on the process of randomisation and blinding. As such, the study was deemed to be at a low risk of selection, performance and detection bias. Additionally, authors accounted for all missing data and reported data on all primary and secondary outcomes and therefore minimised the chances of attrition and performance bias.
Potential biases in the review process
None of the authors of this report were involved in any of the included or excluded studies. Furthermore, none have any commercial or other conflict of interest. The search was as comprehensive as possible and all studies were independently assessed for inclusion by two review authors. We are confident that we have included all relevant studies and attempted to reduce bias in the review process. However, the possibility remains that we may have missed studies which have not been published.
Agreements and disagreements with other studies or reviews
This is the first systematic review to measure the effectiveness of pharmacological prophylaxis in reducing cardiovascular morbidity and mortality in AAA patients. One prospective study of AAA patients who were followed up over a median of 4.7 years determined that, in those who survived AAA repair, beta-blocker use was associated with a significantly lower incidence of all-cause mortality (hazard ratio (HR) 0.6, 95% CI 0.5 to 0.9) and cardiovascular mortality (HR 0.7, 95% CI 0.4 to 0.9) (Kertai 2004). After adjusting for clinical risk factors and beta-blocker use, the same study showed that long-term use of statins showed a reduction in both all-cause and cardiovascular mortality (HR 0.4, 95% CI 0.3 to 0.6 and HR 0.3, 95% CI 0.2 to 0.6 respectively). Therefore, it would appear that statins reduce cardiovascular risk regardless of beta-blocker use. However, this was a prospective cohort study with no randomisation and therefore likely to be at high risk of bias.
Implications for practice
From the one study which met our inclusion criteria for this review, we found no evidence that the beta-blocker metoprolol improves the survival rate in patients with AAA. Although the study was of good quality, it was based on a relatively small sample size and therefore no firm conclusions can be drawn from it. There are a wide range of prophylactic treatments for AAA patients which need to be tested for effectiveness and other outcomes such as adverse side effects and quality of life. They also need to be tested at long-term endpoints, such as five years or greater. The introduction of AAA screening programmes in the UK has provided a valuable tool to identify patients with AAA and therefore potentially modify risk factors in those at high cardiovascular risk. However, until adequate evidence regarding the efficacy and acceptability of interventions is available, definitive conclusions cannot be made.
Implications for research
The results of this systematic review confirm the need for large randomised controlled trials with longer follow up (five years or greater) to determine the effectiveness of pharmacological prophylaxis in preventing mortality and cardiovascular events in AAA patients. At present, patients with AAA are offered a wide range of pharmacological prophylaxes including antiplatelet drugs, antihypertensives and lipid-lowering drugs. Future research should test the available drugs to find the most effective strategy, whether that be one drug alone or a combination of treatments. Moreover, the acceptability of such interventions needs to be assessed. Thus, any future studies should also analyse the secondary effects of such interventions, including adverse side effects and quality of life.
Thanks to Karen Welch (TSC), Cochrane Peripheral Vascular Disease Group, for conducting the search for the studies.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. CENTRAL search strategy
Contributions of authors
LR: drafted the protocol, selected studies for inclusion, assessed the quality of studies, performed data analyses, and wrote the review.
EA: contributed to the protocol, selected studies for inclusion, assessed the quality of studies, and contributed to the text of the review.
GS: contributed to both the protocol and the text of the review.
Declarations of interest
Sources of support
- No sources of support supplied
- National Institute for Health Research (NIHR), UK.The authors are supported by a programme grant from the NIHR.
- Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.The PVD Group editorial base is supported by the Chief Scientist Office.
- National Institute for Health Research (NIHR), UK.The PVD Group editorial base is supported by a programme grant from the NIHR.
Medical Subject Headings (MeSH)
Antihypertensive Agents [therapeutic use]; Aortic Aneurysm, Abdominal [*complications; mortality]; Cardiovascular Agents [*therapeutic use]; Cardiovascular Diseases [mortality; *prevention & control]; Cause of Death; Metoprolol [*therapeutic use]; Randomized Controlled Trials as Topic; Risk Factors
MeSH check words
* Indicates the major publication for the study