Pharmacological treatment of vascular risk factors for reducing mortality and cardiovascular events in patients with abdominal aortic aneurysm

  • Review
  • Intervention

Authors


Abstract

Background

Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in patients with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in patients with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA.

Objectives

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).

Search methods

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and CENTRAL (2013, Issue 3). Reference lists of relevant articles were also checked.

Selection criteria

Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality.

Data collection and analysis

Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion. Only one study was included in the review, therefore meta-analysis could not be performed.

Main results

One randomised controlled study was included in the review. A subgroup of 227 patients with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. The study was deemed to be at a generally low risk of bias.

Authors' conclusions

Due to the limited number of trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials examining many types of prophylaxis with long-term follow-up are required before firm conclusions can be made.

Résumé scientifique

Traitement pharmacologique des facteurs de risque vasculaire pour réduire la mortalité et les événements cardio-vasculaires chez les patients atteints d'anévrisme de l'aorte abdominale

Contexte

La prophylaxie pharmacologique s'est révélée être efficace pour réduire le risque d'événements cardio-vasculaires chez les patients atteints de maladie occlusive artérielle athéroscléreuse. Cependant, le rôle de la prophylaxie chez les patients atteints d'anévrisme de l'aorte abdominale (AAA) reste incertain. Plusieurs études ont montré que malgré une réparation fructueuse, les patients atteints d'AAA présentent une aggravation du taux de survie par rapport aux témoins sains. Les personnes atteintes d'AAA ont une prévalence accrue de la maladie coronarienne et du risque d'événements cardio-vasculaires. Malgré cette association, l'efficacité de la prophylaxie pharmacologique dans la réduction du risque cardio-vasculaire chez les personnes atteintes d'AAA est peu connue.

Objectifs

Déterminer l'efficacité à long terme des antihypertenseurs, des médicaments antiplaquettaires ou des médicaments hypolipidémiants dans la réduction de la mortalité et des événements cardio-vasculaires chez les personnes atteintes d'anévrisme de l'aorte abdominale (AAA).

Stratégie de recherche documentaire

Le registre des essais du groupe Cochrane sur les maladies vasculaires périphériques a effectué des recherches dans le registre spécialisé (dernière recherche en avril 2013) et CENTRAL (2013, numéro 3). Les références bibliographiques des articles pertinents ont également été examinées.

Critères de sélection

Les essais contrôlés randomisés dans lesquels les personnes atteintes d'AAA ont été aléatoirement assignées à un traitement prophylactique par rapport à un autre, à un schéma thérapeutique différent du même traitement, à un placebo, ou à l'absence de traitement, étaient éligibles pour inclusion dans cette revue. Les principaux critères de jugement incluaient la mortalité toutes causes confondues et la mortalité cardio-vasculaire.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné des études, évalué la qualité et extrait les données. Les désaccords ont été résolus par discussion. Une seule étude a été incluse dans la revue, c'est pourquoi une méta-analyse n'a pas pu être réalisée.

Résultats principaux

Une étude contrôlée randomisée a été incluse dans la revue. Un sous-groupe de 227 patients atteints d'AAA a reçu soit le métroprolol (n = 111), soit un placebo (n = 116). Aucune preuve démontrait clairement si le métroprolol réduisait la mortalité toutes causes confondues (rapport des cotes (RC) 0,17, intervalle de confiance (IC) à 95% 0,02 à 1,41), les décès cardio-vasculaires (RC 0,20, IC à 95% 0,02 à 1,76), les décès liés aux AAA (RC 1,05, IC à 95% 0,06 à 16,92) ou augmentait les événements cardiovasculaires non mortels (RC 1,44, IC à 95% 0,58 à 3,57), 30 jours après l'opération. De plus, six mois après l'opération, les effets estimés étaient compatibles aux effets bénéfiques et néfastes pour la mortalité toutes causes confondues (RC 0,71, IC à 95% 0,26 à 1,95), les décès cardio-vasculaires (RC 0,73, IC à 95% 0,23 à 2,39) et les événements cardiovasculaires non mortels (RC 1,41, IC à 95% 0,59 à 3,35). Les effets indésirables des médicaments ont été rapportés pour l'ensemble de la population de l'étude et n'étaient pas disponibles pour le sous-groupe des participants atteints d'AAA. L'étude a été considérée comme étant généralement à faible risque de biais.

Conclusions des auteurs

En raison du nombre limité d'essais, il n'existe pas suffisamment de preuves pour apporter des conclusions concernant l'efficacité de la prophylaxie dans la réduction de la mortalité cardio-vasculaire et des événements cardio-vasculaires chez les personnes atteintes d'AAA. D'autres essais contrôlés randomisés de bonne qualité examinant de nombreux types de prophylaxie avec un suivi à long terme sont nécessaires avant que des conclusions définitives puissent être apportées.

Plain language summary

Medical treatment of vascular risk factors for reducing mortality and cardiovascular events in people with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a potentially life-threatening condition where the aorta enlarges and can ultimately burst leading to massive internal bleeding. Current guidelines recommend that AAAs ≥ 55 mm should be surgically repaired as at this size the risk of rupture outweighs the risk of surgical repair. AAAs between 30 and 54 mm in size are not as high risk and are generally monitored by regular scans to check for further enlargement. Recent research has shown that even after the aneurysm is repaired, the survival rate in people with AAA is poorer than in people without AAA. In the majority of cases, the cause of death is a cardiovascular event such as a heart attack or a stroke. Conditions such as high blood pressure or high cholesterol increase the risk of cardiovascular death. However, both conditions can be reversed through medical treatment. Given the increased risk of mortality with AAA, it is important to determine which medical treatment is most effective in preventing cardiovascular death in people with AAA.

In this review, the effectiveness of medical treatment to treat vascular risk factors and reduce cardiovascular deaths and events in people with an AAA was studied. After searching for all relevant studies, one study was found in which a subgroup of 227 people with AAA were randomised to receive the beta-blocker metoprolol or a placebo. The results from the included study were imprecise for all causes of death and death from cardiovascular disease or nonfatal cardiovascular events at 30 days or six months after AAA repair. Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. The study was deemed to be at a generally low risk of bias.

Research with larger and longer duration trials is needed to determine which treatment is most effective. At present people with AAA are offered a wide range of pharmacological treatment including antiplatelet drugs, antihypertensives and lipid-lowering drugs. Future trials should test available drugs to find the most effective strategy, whether that be one single drug or a combination of treatments. In addition, the acceptability of such interventions needs to be assessed and future studies should measure adverse side effects associated with these drugs and their impact on quality of life.

Résumé simplifié

Traitement médical des facteurs de risque vasculaire pour réduire la mortalité et les événements cardio-vasculaires chez les patients atteints d'anévrisme de l'aorte abdominale

L'anévrisme de l'aorte abdominale (AAA) est une affection potentiellement mortelle où l'aorte s'élargit et peut finalement éclater conduisant à une hémorragie interne massive. Les directives actuelles recommandent que les AAA ≥ à 55 mm doivent être réparés chirurgicalement, car à cette taille, le risque de rupture surpasse le risque de la réparation chirurgicale. Les AAA entre 30 et 54 mm ne sont pas à risque aussi élevé et sont généralement suivis par des échographies régulières pour vérifier l'élargissement. Les récentes recherches ont montré que, même une fois l'anévrisme réparé, le taux de survie chez les personnes atteintes d'AAA est plus mauvais que chez les personnes sans AAA. Dans la majorité des cas, la cause de décès est un événement cardio-vasculaire tel qu'une crise cardiaque ou un AVC. Des affections telles qu'une tension artérielle élevée ou un cholestérol élevé augmentent le risque de décès cardio-vasculaire. Cependant, les deux pathologies peuvent être traitées par un traitement médical. Étant donné le risque accru de mortalité avec l'AAA, il est important de déterminer le traitement médical le plus efficace dans la prévention des décès cardio-vasculaire chez les personnes atteintes d'AAA.

Dans cette revue, l'efficacité du traitement médical pour traiter les facteurs de risque vasculaire et réduire les décès et les évènements cardio-vasculaires chez les personnes atteintes d'un AAA a été étudiée. Après avoir recherché toutes les études pertinentes, une étude a été trouvée dans laquelle un sous-groupe de 227 personnes atteintes d'AAA a été randomisé pour recevoir le bêtabloquant de métoprolol ou un placebo. Les résultats de l'étude incluse étaient imprécis pour toutes les causes de décès et de décès de maladie cardiovasculaire ou d'événements cardiovasculaires non mortels à 30 jours ou à six mois après la réparation d'AAA. Les effets indésirables des médicaments ont été rapportés pour l'ensemble de la population d'étude et n'étaient pas disponibles pour le sous-groupe des participants atteints d'AAA. L'étude a été considérée comme étant généralement à faible risque de biais.

Des recherches supplémentaires à plus grande échelle et des essais à plus longue durée sont nécessaires afin de déterminer le traitement le plus efficace. À l'heure actuelle, un large éventail de traitement pharmacologique est proposé aux personnes atteintes d'AAA, y compris les médicaments antiplaquettaires, les antihypertenseurs et les médicaments hypolipidémiants. Les futurs essais devront tester les médicaments disponibles afin de déterminer la stratégie la plus efficace, qu'il s'agisse d'un médicament unique ou d'une combinaison de traitements. De plus, l'acceptabilité de ces interventions doit être évaluée et les futures études devraient mesurer les effets secondaires indésirables associés à ces médicaments et leur impact sur la qualité de vie.

Notes de traduction

Traduit par: French Cochrane Centre 15th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Background

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 m2 were associated with poor survival at five years (De Martino 2013).

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.   

Objectives

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).

Methods

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

Primary outcomes
  • All-cause mortality

  • Cardiovascular mortality (fatal myocardial infarction, fatal stroke, other vascular deaths)

Secondary outcomes
  • 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.

Electronic searches

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:

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 Chi2 test regarding the characteristics and quality of included studies (Deeks 2011).

We planned to perform the Chi2 test to assess heterogeneity in identified subgroups, and we planned to use the I2 statistic to measure the degree of inconsistency between studies. An I2 statistic result > 50% may represent moderate to substantial heterogeneity (Deeks 2011). Only one study met the inclusion criteria for the review and therefore it was not necessary to measure the heterogeneity between studies.

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.

Data synthesis

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.

  • Diabetes.

  • Year of publication.

However, as only one study with 227 patients was included in this review, it was not possible to perform subgroup analyses.

Sensitivity analysis

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.

Results

Description of studies

Results of the search

See: Figure 1

Figure 1.

Study flow diagram.

Included studies

See: Characteristics of included studies

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.

Excluded studies

See: Characteristics of excluded studies

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

See: 'Risk of bias' table in Characteristics of included studies and Figure 2 and Figure 3

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.

Allocation

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.

Blinding

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.

Selective reporting

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.

Discussion

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.

Authors' conclusions

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.

Acknowledgements

Thanks to Karen Welch (TSC), Cochrane Peripheral Vascular Disease Group, for conducting the search for the studies.

Data and analyses

Download statistical data

Comparison 1. Metoprolol versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality, 30 days1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Cardiovascular death, 30 days1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3 AAA-related death, 30 days1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Nonfatal cardiovascular event, 30 days1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
5 All-cause mortality, 6 months1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Cardiovascular death, 6 months1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
7 Nonfatal cardiovascular event, 6 months1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Metoprolol versus placebo, Outcome 1 All-cause mortality, 30 days.

Analysis 1.2.

Comparison 1 Metoprolol versus placebo, Outcome 2 Cardiovascular death, 30 days.

Analysis 1.3.

Comparison 1 Metoprolol versus placebo, Outcome 3 AAA-related death, 30 days.

Analysis 1.4.

Comparison 1 Metoprolol versus placebo, Outcome 4 Nonfatal cardiovascular event, 30 days.

Analysis 1.5.

Comparison 1 Metoprolol versus placebo, Outcome 5 All-cause mortality, 6 months.

Analysis 1.6.

Comparison 1 Metoprolol versus placebo, Outcome 6 Cardiovascular death, 6 months.

Analysis 1.7.

Comparison 1 Metoprolol versus placebo, Outcome 7 Nonfatal cardiovascular event, 6 months.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Vascular Surgical Procedures] explode all trees11204
#2vascular near/3 surg*:ti,ab,kw (Word variations have been searched)1291
#3non-cardiac near/3 surg*:ti,ab,kw (Word variations have been searched)75
#4non-cardiac near/3 surg*:ti,ab,kw (Word variations have been searched)75
#5noncardiac near/3 surg*148
#6infrarenal near/3 surg*53
#7MeSH descriptor: [Aortic Aneurysm, Abdominal] explode all trees537
#8aneurysm* near/4 (abdom* or thoracoabdom* or thoraco-abdom* or aort*)1026
#9(aort* near/3 (ballon* or dilat* or bulg* or expan*))74
#10AAA400
#11#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #1012754
#12MeSH descriptor: [Leg] explode all trees and with qualifiers: [Blood supply - BS, Surgery - SU]1231
#13MeSH descriptor: [Amputation] explode all trees304
#14(atherosclero* or arteriosclero* or PVD or PAOD or PAD)17338
#15(arter* or carotid) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)5373
#16(vascular) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)1382
#17(vein*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)719
#18(veno*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)981
#19(peripher*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)1366
#20peripheral near/3 dis*3274
#21arteriopathic12
#22(claudic* or hinken*)1445
#23(isch* or CLI)16925
#24dysvascular*16
#25leg near/4 (obstruct* or occlus* or steno* or block* or obliter*)179
#26limb near/4 (obstruct* or occlus* or steno* or block* or obliter*)233
#27(lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* or block* or obliter*)140
#28(aort* or iliac or femoral or popliteal or femoro* or fempop* or crural) near/3 (obstruct* or occlus*)328
#29MeSH descriptor: [Arterial Occlusive Diseases] explode all trees and with qualifiers: [Drug therapy - DT]1809
#30MeSH descriptor: [Hypertension] explode all trees and with qualifiers: [Drug therapy - DT]9210
#31MeSH descriptor: [Heart Diseases] explode all trees and with qualifiers: [Drug therapy - DT]13297
#32MeSH descriptor: [Cardiovascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]27872
#33MeSH descriptor: [Pulmonary Veno-Occlusive Disease] explode all trees and with qualifiers: [Drug therapy - DT]0
#34MeSH descriptor: [Vascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]22701
#35MeSH descriptor: [Peripheral Vascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]611
#36CVD or CHD2533
#37cardiovascular near/2 disease*9389
#38coronary near/2 disease*14222
#39heart near/2 disease*10405
#40heart near/2 failure10411
#41heart next attack515
#42myocardial next infarct*15595
#43angina8426
#44((aort* or mitral) near/2 stenosis):ti,ab,kw (Word variations have been searched)432
#45Arrythmia:ti,ab,kw (Word variations have been searched)18
#46hyperten*:ti,ab,kw (Word variations have been searched)26735
#47MeSH descriptor: [Cerebrovascular Disorders] explode all trees and with qualifiers: [Drug therapy - DT]2027
#48MeSH descriptor: [Carotid Artery Diseases] explode all trees and with qualifiers: [Drug therapy - DT]170
#49MeSH descriptor: [Stroke] explode all trees and with qualifiers: [Drug therapy - DT]776
#50stroke:ti,ab,kw (Word variations have been searched)18137
#51#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50108008
#52cerebrovascular$ or *cerebral or CVA or cerebellar or brain$ or vertebrobasilar or intracranial or parenchymal or intraventricular or subarachnoid or infratentorial or supratentorial:ti,ab,kw (Word variations have been searched)27327
#53haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm or infarct$ or isch?emi$ or thrombo$ or emboli$ or dis*:ti,ab,kw (Word variations have been searched)283777
#54#52 and #5316637
#55transient isch?emic attack:ti,ab,kw (Word variations have been searched)248
#56TIA:ti,ab,kw (Word variations have been searched)386
#57MeSH descriptor: [Hyperlipidemias] explode all trees and with qualifiers: [Drug therapy - DT]2728
#58hypercholesterol* or hyper-cholesterol*:ti,ab,kw (Word variations have been searched)3915
#59hyperlipid* or hyper-lipid*:ti,ab,kw (Word variations have been searched)2532
#60MeSH descriptor: [Adrenergic beta-Agonists] explode all trees1609
#61(adrenergic near/3 (antagonist* or block*))6868
#62(betablocker* or beta-blocker* or β-blocker)4691
#63acebutolol or atenolol or Tenormin or alprenolol3241
#64betaxolol or bisoprolol or bupranolol919
#65carvedilol or Coreg or carteolol or celiprolol1073
#66esmolol or labetalol or Normodyne or Trandate923
#67metoprolol or nadolol or nebivolol2826
#68oxprenolol or penbutolol or pindolol1330
#69Visken or practolol or propranolol or Inderal4445
#70sotalol or timolol2166
#71MeSH descriptor: [Antihypertensive Agents] explode all trees6120
#72antihypertensive11422
#73*nitrate or thiazide4576
#74bendrofluazide199
#75bendroflumethiazide300
#76hydrochrlothiazide3
#77MeSH descriptor: [Calcium Channel Blockers] explode all trees2551
#78calcium near/3 antagonist*2427
#79calcium near/3 blocker*4020
#80calcium near/3 inhibit*574
#81amlodipine or amrinone or azelnidipine1707
#82bencyclan* or bepridil154
#83cilnidipine or cinnarizine or conotoxin*256
#84daropidine or diltiazem1497
#85efonidipine or felodipine or fendiline or flunarizine981
#86gallopamil or isradipine or lacidopine or lidoflazine619
#87mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine5096
#88perhexiline or prenylamine or verapamil1974
#89magnesium next sulph*474
#90MeSH descriptor: [Angiotensin-Converting Enzyme Inhibitors] explode all trees3557
#91angiotensin near/3 (inhibitors or blocker or antagonist)6537
#92ACE next inhibitor2689
#93captopril or enalapril or lisinopril or perindopril or ramipril6164
#94candesartan646
#95losartan1296
#96telmisartan404
#97valsartan727
#98clonidine2668
#99MeSH descriptor: [Anticholesteremic Agents] explode all trees3884
#100(atorvastatin or cerivastatin or fluvastatin or lovastatin or pravastatin or simvastatin or *statin or lipitor or baycol or lescol or mevacor or altocor or pravachol or lipostat or zocor or rosuvastatin):ti,ab,kw7847
#101mevinolin* or monacolin or lipex* or lipitor or lescol*:ti,ab,kw155
#102(compactin or mevastatin or meglutol or crestor or zocor)67
#1033-hydroxy-3-methylglutar*:ti,ab,kw316
#104MeSH descriptor: [Fish Oils] explode all trees1907
#105MeSH descriptor: [Fatty Acids, Omega-3] explode all trees1663
#106fatty near/3 acid7756
#107omega near/3 acid1578
#108*eicosapentanoic or docosahexanoic or docosapentanoic or alpha-linolenic:ti,ab,kw (Word variations have been searched)314
#109*eicosapentaen* or icosapentaenoic or docosahexaeno*1416
#110fish near/3 oil*1434
#111cod near/3 oil70
#112PUFA or EPA or E-EPA or DHA or DPA or ALA2200
#113MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees2678
#114antiplatelet* or anti-platelet* or antiaggreg* or anti-aggreg*:ti,ab,kw1884
#115((platelet or thromboxane or thrombocyte or cyclooxygenase or cyclo-oxygenase or phosphodiesterase or fibrinogen or PAR-1) near/3 (antagonist or inhibitor)):ti,ab,kw5827
#116(gp* or glycoprotein* or protease or P2Y12 or TXA2) near/3 (inhibit*):ti,ab,kw2082
#117(aspirin* or nitroaspirin or ASA or "acetyl salicylic acid*" or "acetylsalicylic acid" or "acetyl-salicylic acid"):ti,ab,kw13510
#118(carbasalate calcium or indobufen or triflusal or Disgren or Grendis or Triflux):ti,ab,kw161
#119abciximab or tirofiban* or eftifibatid or eptifibatide or ReoPro or Integrilin* or Aggrastat:ti,ab,kw875
#120(thienopyrid* or thiophen* or clopidogrel or Plavix or Iscover or prasugrel or Effient or ticlopidine or Ticlid or Ticagrelor or Cangrelor or Elinogrel):ti,ab,kw2839
#121cilostazol or Pletal or d?pyridamol? or Persantin or Triflusal or picotamide:ti,ab,kw1548
#122(picotinamide or suloctidil or sulphinpyrazone):ti,ab,kw84
#123satigrel or sarpolgrelate:ti,ab,kw3
#124(epoprostenol* or iloprost* or ketanserin* or milrinone* or mopidamol*):ti,ab,kw1349
#125(Dispril or Albyl* or Ticlid* or Persantin* or Plavix or Aggrenox or Plasugrel or Ticagrelor or Cangrelor):ti,ab,kw165
#126terutroban15
#127MeSH descriptor: [Antioxidants] explode all trees2941
#128antioxidant or anti-oxidant4805
#129MeSH descriptor: [Fibrinolytic Agents] explode all trees1770
#130#55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 or #99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111 or #112 or #113 or #114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or #124 or #125 or #126 or #127 or #12987424
#131#11 and (#51 or #54 or #130) in Trials (Word variations have been searched)8534
#132MeSH descriptor: [Vascular Diseases] explode all trees52984
#133MeSH descriptor: [Risk Factors] explode all trees16644
#134#7 and #132 and #133 in Trials54
#135#131 or #134 in Trials8543
#136MeSH descriptor: [Cardiac Surgical Procedures] explode all trees10493
#137#135 not #136 in Trials2920

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

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • 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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Yang 2006

Methods

Study type: Double-blind randomised controlled trial

Study aim: To test the hypothesis that, at 30 days and 6 months after vascular surgery, the perioperative administration of metoprolol reduces the incidence of cardiac complications defined as cardiac death, nonfatal MI, CHF, unstable angina, and dysrhythmias requiring treatment.

Country: Canada

Setting: 3 tertiary care centres: General Campus, Hamilton Health Sciences; Victoria Campus, London Health Sciences; and Kingston General Hospital between 1999 and 2002.

Recruitment: all patients undergoing vascular surgery were screened for eligibility. Elective vascular surgical patients are evaluated by internists, cardiologists, or anaesthesiologists in preoperative clinics. Screening was also undertaken on the wards when applicable

Participants

Inclusion criteria: Patients with American Society of Anesthesiology class 3 or less and undergoing abdominal aortic surgery and infrainguinal or axillofemoral revascularisation

Exclusion criteria: current or recent β-blocker use, current amiodarone use, airflow obstruction requiring treatment, history of CHF, history of atrioventricular block, previous adverse drug reactions to β-blockers, and previous participation in the MaVS study

Gender: Placebo group 184 M/66 F; Metoprolol group 193 M/53 F

Age: Placebo patients mean 65.9 ± 10.0 years; Metoprolol patients mean 66.4± 10.0 years

Co-morbidities:

Prior MI: 30 placebo, 37 metoprolol

Angina: 25 placebo, 18 metoprolol

Diabetes mellitus (DM) on treatment: 37 placebo, 54 metoprolol

Permanent pacemaker: 1 placebo, 0 metoprolol

AAA subgroup: 116 placebo, 111 metoprolol

Interventions

Treatment: Metoprolol administered orally or intravenously. Patients weighing ≥ 75 kg received metoprolol 100 mg; patients weighing between 40 and 75 kg received metoprolol 50 mg; and patients weighing ≤ 40 kg received metoprolol 25 mg OR intravenously at 1 mg/mL for 15 minutes. IV treatment was converted to oral as soon as oral intake was tolerated

Control: Placebo administered orally as tablet or given intravenously as saline 0.2 mL/kg (to a maximum of 15 mL), diluted with 20 mL of saline for 15 minutes

Duration: Metoprolol or placebo given orally 2 hours preoperatively. Within 2 hours of surgery, metoprolol or placebo were give intravenously or orally. IV drug administered over 15 minutes every 6 hours. Oral administration was twice daily. Treatment lasted for 5 days or until hospital discharge, whichever occurred sooner

Co-interventions: Short-acting vasoactive medications including phenylephrine, ephedrine, nitroglycerine, and low-dose dopamine were allowed. Open-label β-blocker use was strongly discouraged except when deemed absolutely necessary by the attending physician. Circumstances for open-label use were generally for rapid heart rate control. Intraoperatively, esmolol, if deemed absolutely necessary, was allowed

Outcomes

Primary outcome: Composite of cardiac complications at 30 days post operation including; cardiac death1, nonfatal MI2, CHF3, unstable angina4, and dysrhythmia requiring treatment defined as atrial fibrillation or ventricular dysrhythmias5

1 Cardiac death was defined as either the ultimate cause of death traceable to an initiating cardiac complication or death in which the cause was not clearly identifiable or was insufficient to account for the demise in a patient who was not expected to succumb at the time of death.

2 Nonfatal MI within 3 postoperative deaths diagnosed if ≥ 1 of the following present: chemical evidence of MI or new Q waves > 0.04 s on 2 contiguous leads. Beyond 3 days, nonfatal MI was determined by attending physicians with supporting documentation of hospital chart, troponins, and pre- and postoperative electrocardiograms.

3 Unstable angina diagnosed by attending physician when anginal symptoms necessitated a change in medications, coronary revascularisation, or intensive care admission.

4 Congestive heart failure was diagnosed clinically with the requisite radiographic evidence.

5 Dysrhythmia requiring treatment was defined as one of the following: ventricular fibrillation requiring counter shock, ventricular tachycardia requiring counter shock or medication, or atrial fibrillation > 15 minutes in duration requiring counter shock or medication.

Secondary outcomes:

1. Study drug discontinuation due to bronchospasm, advanced heart blocks, hypotension (systolic BP < 90 mmHg) or bradycardia (50 beats/min)

2. Reoperation or amputation

3. Intraoperative hypotension and bradycardia requiring treatment by the attending anaesthesiologists

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was constructed in blocks of 4 by the study statistician"
Allocation concealment (selection bias)Unclear riskComment: Methods of concealment of allocation are not stated. Insufficient information to permit judgement of low or high risk of selection bias
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "The patients, investigators, and all caretakers were blinded to the study randomisation. Blinding of randomisation was maintained throughout clinical decisions on reducing or discontinuing the study medication"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "All data were collected by the participating centres and evaluated by the adjudication committee in a blinded fashion"
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Completion of the study protocol was similar in the placebo (77.6%) and treatment groups (75.2%). Discontinuation of the study protocol was also similar in the placebo and treatment groups; primary outcome event (30 and 25,respectively); patient/family/physician preference (27 and 14, respectively); open-label β-blockers (24 and 14, respectively); patient death (3 and 0, respectively), atrioventricular block (2 and 3, respectively), bronchospasm (1 and 4, respectively); and other reason (11 and 13, respectively)." 

Comment: All missing data accounted for and similarly balanced across the two treatment groups. Low risk of attrition bias

Selective reporting (reporting bias)Low risk

Quote: "Our results show that the RRR achieved with perioperative metoprolol in the vascular population is smaller than previously reported and is not significant" 

Comment: Authors commented on study results in relation to expected outcomes from other published reports. Furthermore, all of the primary and secondary pre-specified outcomes were reported.

Other biasLow riskThe study appears to be free from other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Cesanek 2008Study examined beta-blocker related complications in patients undergoing vascular surgery. Authors were contacted for outcome data for AAA participants but did not respond to communication
DECREASE Study

The principal investigator of the DECREASE Study was dismissed for misconduct including failing to obtain patient written informed consent and negligent data collection. A full copy of the report issued by the Erasmum Medical Centre can be found here:

http://www.erasmusmc.nl/5663/135857/3675250/3706798/Integrity_report_2012-10.pdf?lang=en

Durazzo 2004A subgroup of 56 participants underwent a AAA repair but specific outcome data for these patients was not presented. Through personal communication, the study author confirmed that these data were not available
Kouvelos 2013Of the 262 participants studied, 66% were taking antiplatelets, 19% anticoagulants, 23% calcium antagonists, 33% ACE inhibitors and 15% were taking angiotensin II receptors prior to randomisation. Outcomes in this study could not be attributed to one specific drug and therefore this study was excluded from this review
Mackey 2006Prospective study which measured the incidence of perioperative myocardial ischaemic injury in high risk vascular surgery patients. Not a randomised controlled trial and no drugs administered
Mangano 1996The study did not report if there was a subgroup of participants with AAA. Attempts were made to contact the author to see if this data was available but contact could not be made
Neilipovitz 2012Patients in this study were taking co-medications (angiotensin drugs, calcium channel blockers, beta blockers, acetylsalicylic acid, clopidogrel) that we planned to assess in this review. Outcomes in this study could not be attributed to one specific drug and therefore this study was excluded from the review
POBBLE TrialOf the 103 participants included in this study, 38% underwent aortic repair. However outcome data for this subgroup was not presented. Attempts were made to retrieve this data but the study authors did not respond to communication
POISE StudyPersonal communication with the author of the study confirmed that data for the AAA participants were not available

Ancillary