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

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness of antiplatelet, antihypertensive and/or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm.

Background

Description of the condition

Abdominal aortic aneurysm (AAA) is an abnormal dilatation of the aorta as it passes below the aortic hiatus of the diaphragm 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 also 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 repair. 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). Abdominal aortic aneurysms 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 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 3, 6, 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).

Recent studies have shown that even after successful surgical repair of an abdominal aortic aneurysm, participants had a poorer survival rate than healthy controls (Batt 1999; Hallett 1993; Galland 1998). Hallett (Hallett 1993) conducted a population-based study and reported a five-year survival of only 60% after repair of AAAs greater than 5 cm in diameter compared with the expected survival of 77% of age- and sex-matched controls, with most late deaths due to cardiovascular causes. In a French study (Batt 1999), five-year survival after aneurysm repair was 72% compared with 90% in the same age- and sex-matched population. Similarly, a study in England (Galland 1998) showed that the five-year survival of participants undergoing surveillance with AAAs < 4 cm and 4 cm to 5.5 cm in diameter was 62% and 45%, respectively, compared with 80% in an age- and sex-matched population. Again, a majority of late deaths were the result of cardiovascular events. Thus it would appear that even once the aneurysm is repaired, people are still at risk for experiencing cardiovascular events due to underlying atheroma and vascular risk factors.

A recent study conducted in Australia demonstrated an association between AAA thrombus volume and subsequent cardiovascular events ( Parr 2011). AAA thrombus products are also released into the circulation, where they have the potential to stimulate leukocytes and 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 (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 high mortality rate associated with these largely preventable conditions, 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 CV mortality in people with AAA. This review will provide evidence on the most effective medical treatment for this important problem.   

Objectives

To determine the effectiveness of antiplatelet, antihypertensive and/or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials in which participants with AAA are randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment. We will include published studies and studies in progress, if preliminary results are available. Non-English studies will also be eligible, and we will seek 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 will also be included.

Types of interventions

  • Antiplatelet therapy (e.g. aspirin, clopidogrel, ticlopidine, cilostazol or any other antiplatelets).

  • Antihypertensive drugs (e.g. calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, or any other antihypertensive drugs).

  • Lipid-lowering therapy (e.g. statins).

  • Combination treatment (e.g. antiplatelet plus antihypertensive or statin) versus single treatment.

  • Combination treatment versus no treatment.

We will compare one intervention with another treatment, a different regimen of the same treatment, placebo, or no treatment. We will include any type, method, duration, timing, mode of delivery, and dose of medical treatment.

This review concerns medical interventions in which the principal actions are to modify cardiovascular risk factors. Therefore, the review authors will not include any alternative treatments for which the primary purpose is to treat the aneurysm itself, for example, to reduce growth rates and/or prevent rupture.

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 (e.g. change in size, rupture rates) will not be included.

Search methods for identification of studies

We will seek translations of any non-English trials.

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) will search their Specialised Register and The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, www.thecochranelibrary.com). See Appendix 1 for details of the search strategy that will be used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, and AMED, and through handsearching of relevant journals. The full list of the databases, journals, and conference proceedings that 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 will be searched by the TSC for details of ongoing and unpublished studies:

World Health Organization International Clinical Trials Registry http://apps.who.int/trialsearch/

ClinicalTrials.gov http://clinicaltrials.gov/

Current Controlled Trials http://www.controlled-trials.com/

Searching other resources

We will review all reference lists of identified studies.

Data collection and analysis

Selection of studies

One review author (LR) will use the selection criteria to identify trials for inclusion. The second review author (EA) will independently confirm this selection, and any disagreements will be resolved by discussion.

Data extraction and management

Two review authors (LR, EA) will independently extract the data. We will record information about the trial design, AAA definition and measurement methods, and baseline characteristics of patients, and we will record the treatment type, method, duration, timing, mode of delivery, and dose. We will record all-cause mortality and cardiovascular mortality data as the primary outcome measures. We will collect information on noncardiovascular events and adverse events in accordance with the secondary outcome measures. We will contact authors of included studies for further information if clarification is required. We will resolve any disagreements in data extraction and management by discussion.

Assessment of risk of bias in included studies

Two review authors (LR, EA) will independently use The Cochrane Collaboration’s tool (Higgins 2011) for assessing risk of bias for each of the included studies. 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 will resolve any disagreements by discussion.

Measures of treatment effect

We will base analysis on intention-to-treat data from the individual clinical trials. As the primary and secondary outcomes are all binary measures, we will compute odds ratios (ORs) using a fixed-effect model. We will calculate the 95% confidence intervals (CIs) of the effect sizes.

Unit of analysis issues

The unit of analysis within each trial will be the individual patient. However as the trials will involve repeat measurements on patients at different points in time, they will be prone to unit of analysis errors (Deeks 2011). Therefore, for the purpose of this review, we will choose cardiovascular mortality at five years as the primary end point. Outcomes at longer follow-up periods will be included as secondary outcomes if reported in trials.

Dealing with missing data

We will seek information about dropouts, withdrawals, and other missing data, and if not reported, we will attempt to contact the study authors.

Assessment of heterogeneity

The inclusion of studies on a wide range of medical treatments is likely to result in a high degree of heterogeneity. We plan to assess the heterogeneity between pooled studies by using the Chi2 test regarding characteristics and quality of included studies.

We will perform the Chi2 test to assess heterogeneity in identified subgroups, and we will use the I2 test to measure the degree of inconsistency between studies. An I2 test result > 50% may represent moderate to substantial heterogeneity (Deeks 2011).

Assessment of reporting biases

We will assess reporting biases such as publication bias using funnel plots. There are many reasons for funnel plot asymmetry, and we will consult the Cochrane Handbook for Systematic Reviews of Interventions to aid interpretation of the results (Sterne 2011).

Data synthesis

The review authors will independently extract the data. One review author (LR) will enter the data into RevMan. The second review author (EA) will cross-check data entry, and the authors will resolve any discrepancies by consulting the source publication.

We will use a fixed-effect model to meta-analyse the data.

Subgroup analysis and investigation of heterogeneity

Where possible, we will attempt to analyse clinically relevant subgroups based on drug and participant groupings. Possible groupings include:

  • 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.

Sensitivity analysis

We will perform sensitivity analysis to examine the stability of the results in relation to the quality of included studies. The analyses required will be clarified as the protocol is put into practice.

Appendices

Appendix 1. CENTRAL search strategy

#1        MeSH descriptor: [Vascular Surgical Procedures] explode all trees

#2        vascular near/3 surg*:ti,ab,kw  (Word variations have been searched)

#3        non-cardiac near/3 surg*:ti,ab,kw  (Word variations have been searched)

#4        non-cardiac near/3 surg*:ti,ab,kw  (Word variations have been searched)

#5        noncardiac near/3 surg*

#6        infrarenal near/3 surg*

#7        MeSH descriptor: [Aortic Aneurysm, Abdominal] explode all trees

#8        aneurysm* near/4 (abdom* or thoracoabdom* or thoraco-abdom* or aort*)

#9        (aort* near/3 (ballon* or dilat* or bulg* or expan*))

#10      AAA

#11      #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

#12      MeSH descriptor: [Leg] explode all trees and with qualifiers: [Blood supply - BS, Surgery - SU]

#13      MeSH descriptor: [Amputation] explode all trees

#14      (atherosclero* or arteriosclero* or PVD or PAOD or PAD)

#15      (arter* or carotid) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)

#16      (vascular) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)

#17      (vein*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)

#18      (veno*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)

#19      (peripher*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)

#20      peripheral near/3 dis*

#21      arteriopathic

#22      (claudic* or hinken*)

#23      (isch* or CLI)

#24      dysvascular*

#25      leg near/4 (obstruct* or occlus* or steno* or block* or obliter*)

#26      limb near/4 (obstruct* or occlus* or steno* or block* or obliter*)

#27      (lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* or block* or obliter*)

#28      (aort* or iliac or femoral or popliteal or femoro* or fempop* or crural) near/3 (obstruct* or occlus*)

#29      MeSH descriptor: [Arterial Occlusive Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#30      MeSH descriptor: [Hypertension] explode all trees and with qualifiers: [Drug therapy - DT]

#31      MeSH descriptor: [Heart Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#32      MeSH descriptor: [Cardiovascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#33      MeSH descriptor: [Pulmonary Veno-Occlusive Disease] explode all trees and with qualifiers: [Drug therapy - DT]

#34      MeSH descriptor: [Vascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#35      MeSH descriptor: [Peripheral Vascular Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#36      CVD or CHD

#37      cardiovascular near/2 disease*

#38      coronary near/2 disease*

#39      heart near/2 disease*

#40      heart near/2 failure

#41      heart next attack

#42      myocardial next infarct*

#43      angina

#44      ((aort* or mitral) near/2 stenosis):ti,ab,kw  (Word variations have been searched)

#45      Arrythmia:ti,ab,kw  (Word variations have been searched)

#46      hyperten*:ti,ab,kw  (Word variations have been searched)

#47      MeSH descriptor: [Cerebrovascular Disorders] explode all trees and with qualifiers: [Drug therapy - DT]

#48      MeSH descriptor: [Carotid Artery Diseases] explode all trees and with qualifiers: [Drug therapy - DT]

#49      MeSH descriptor: [Stroke] explode all trees and with qualifiers: [Drug therapy - DT]

#50      stroke:ti,ab,kw  (Word variations have been searched)

#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 #50

#52      cerebrovascular$ 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)

#53      haemorrhage 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)

#54      #52 and #53

#55      transient isch?emic attack:ti,ab,kw  (Word variations have been searched)

#56      TIA:ti,ab,kw  (Word variations have been searched)

#57      MeSH descriptor: [Hyperlipidemias] explode all trees and with qualifiers: [Drug therapy - DT]

#58      hypercholesterol* or hyper-cholesterol*:ti,ab,kw  (Word variations have been searched)

#59      hyperlipid* or hyper-lipid*:ti,ab,kw  (Word variations have been searched)

#60      MeSH descriptor: [Adrenergic beta-Agonists] explode all trees

#61      (adrenergic near/3 (antagonist* or block*))

#62      (betablocker* or beta-blocker* or β-blocker)

#63      acebutolol or atenolol or Tenormin or alprenolol

#64      betaxolol or bisoprolol or bupranolol

#65      carvedilol or Coreg or carteolol or celiprolol

#66      esmolol or labetalol or Normodyne or Trandate

#67      metoprolol or nadolol or nebivolol

#68      oxprenolol or penbutolol or pindolol

#69      Visken or practolol or propranolol or Inderal

#70      sotalol or timolol

#71      MeSH descriptor: [Antihypertensive Agents] explode all trees

#72      antihypertensive

#73      *nitrate or thiazide

#74      bendrofluazide

#75      bendroflumethiazide

#76      hydrochrlothiazide

#77      MeSH descriptor: [Calcium Channel Blockers] explode all trees

#78      calcium near/3 antagonist*

#79      calcium near/3 blocker*

#80      calcium near/3 inhibit*

#81      amlodipine or amrinone or azelnidipine

#82      bencyclan* or bepridil

#83      cilnidipine or cinnarizine or conotoxin*

#84      daropidine or diltiazem

#85      efonidipine or felodipine or fendiline or flunarizine

#86      gallopamil or isradipine or lacidopine or lidoflazine

#87      mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine

#88      perhexiline or prenylamine or verapamil

#89      magnesium next sulph*

#90      MeSH descriptor: [Angiotensin-Converting Enzyme Inhibitors] explode all trees

#91      angiotensin near/3 (inhibitors or blocker or antagonist)

#92      ACE next inhibitor

#93      captopril or enalapril or lisinopril or perindopril or ramipril

#94      candesartan

#95      losartan

#96      telmisartan

#97      valsartan

#98      clonidine

#99      MeSH descriptor: [Anticholesteremic Agents] explode all trees

#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,kw

#101    mevinolin* or monacolin or lipex* or lipitor or lescol*:ti,ab,kw

#102    (compactin or mevastatin or meglutol or crestor or zocor)

#103    3-hydroxy-3-methylglutar*:ti,ab,kw

#104    MeSH descriptor: [Fish Oils] explode all trees

#105    MeSH descriptor: [Fatty Acids, Omega-3] explode all trees

#106    fatty near/3 acid

#107    omega near/3 acid

#108    *eicosapentanoic or docosahexanoic or docosapentanoic or alpha-linolenic:ti,ab,kw  (Word variations have been searched)

#109    *eicosapentaen* or icosapentaenoic or docosahexaeno*

#110    fish near/3 oil*

#111    cod near/3 oil

#112    PUFA or EPA or E-EPA or DHA or DPA or ALA

#113    MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees

#114    antiplatelet* or anti-platelet* or antiaggreg* or anti-aggreg*:ti,ab,kw

#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,kw

#116    (gp* or glycoprotein* or protease or P2Y12 or TXA2) near/3 (inhibit*):ti,ab,kw

#117    (aspirin* or nitroaspirin or ASA or "acetyl salicylic acid*" or "acetylsalicylic acid" or "acetyl-salicylic acid"):ti,ab,kw

#118    (carbasalate calcium or indobufen or triflusal or Disgren or Grendis or Triflux):ti,ab,kw

#119    abciximab or tirofiban* or eftifibatid or eptifibatide or ReoPro or Integrilin* or Aggrastat:ti,ab,kw

#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,kw

#121    cilostazol or Pletal or d?pyridamol? or Persantin or Triflusal or picotamide:ti,ab,kw

#122    (picotinamide or suloctidil or sulphinpyrazone):ti,ab,kw

#123    satigrel or sarpolgrelate:ti,ab,kw

#124    (epoprostenol* or iloprost* or ketanserin* or milrinone* or mopidamol*):ti,ab,kw

#125    (Dispril or Albyl* or Ticlid* or Persantin* or Plavix or Aggrenox or Plasugrel or Ticagrelor or Cangrelor):ti,ab,kw

#126    terutroban

#127    MeSH descriptor: [Antioxidants] explode all trees

#128    antioxidant or anti-oxidant

#129    MeSH descriptor: [Fibrinolytic Agents] explode all trees

#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 #129

#131    #11 and (#51 or #54 or #130) in Trials (Word variations have been searched)

Contributions of authors

LR: drafted the protocol, will select studies for inclusion, assess the quality of studies, perform data analyses, and write the review.
EA: contributed to the protocol, will select studies for inclusion, assess the quality of studies, and contribute to the text of the review.
GS: contributed to the protocol and will contribute to 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.

Ancillary