AHA thoracic aortic aneurysm review 2011

Jovin, MD An aneurysm is defined as a localized dilatation of a vessel of⬎50% of the normal diameter and includes all layers of the given vessel.1Aortic aneurysms are divided into thorac

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Medical Therapy of Thoracic Aortic Aneurysms

Are We There Yet?

Peter Danyi, MD; John A Elefteriades, MD; Ion S Jovin, MD

An aneurysm is defined as a localized dilatation of a

vessel of⬎50% of the normal diameter and includes all

layers of the given vessel.1Aortic aneurysms are divided into

thoracic aortic aneurysms (TAAs), thoracoabdominal aortic

aneurysms (a thoracic aneurysm extending into the

abdo-men), and abdominal aortic aneurysms (AAAs) Abdominal

aortic aneurysms are reportedly more common than TAAs

Demographic studies have suggested that among peopleⱖ65

years of age, the prevalence of AAA is⬇2.5%.2Occurring at

a rate of 4.5 to 5.9 per 100 000 person-years, TAAs are less

common.3 Aortic aneurysms (TAA and AAA together)

re-main the 13th leading cause of mortality in Western

coun-tries4 and are probably responsible for 15 000 to 30 000

deaths per year in the United States.5TAAs are classified into

4 general anatomic categories: ascending aortic aneurysms

(60%), aortic arch aneurysms (10%), descending aortic

an-eurysms (40%), and thoracoabdominal anan-eurysms (10%) It is

important to understand the development, pathogenesis, and

clinical course of aortic aneurysms and to develop strategies

that reduce its occurrence, progression, and mortality This

review summarizes our present understanding of the available

medical therapies for aortic aneurysms and attempts to

determine whether medical therapy for TAA is currently a

viable option We focus on TAAs whenever possible;

how-ever, it should be mentioned that the available literature for

TAA is limited, and most of the preclinical data are obtained

from AAA animal models Therefore, we use AAA data with

the caveat that it is unclear that extrapolating from AAA data

leads to correct conclusions regarding TAA There is

signif-icant heterogeneity in the aorta and aortic aneurysms in terms

of their epidemiology, structure, mechanics, and biochemical

systems.6 Although animal models of TAAs have been

described7,8and studied intensively, it is unclear how relevant

they are to the basic and clinical pathology in humans

because they involve either a genetic defect that has not been

described in humans or the surgical creation of thoracic

aneurysms, respectively

Origin

Aortic aneurysm is an area of medial degeneration of a focal

portion of the aorta that may or may not be accompanied by

inflammation Extensive extracellular matrix degradation

leads to localized weakening and dilatation of the aortic wall

In most cases, destruction of the elastic tissue of the media is found on histology Several potential mechanisms have been proposed that lead to the final pathway of tunica media destruction

Etiologic factors include genetic disease or mutations such

as Marfan syndrome in which mutations in the gene encoding

fibrillin-1 (FBN1) have been described.9 More than 800

FBN1 mutations that are associated with Marfan syndrome

have been identified Most mutations occur within repeated epidermal growth factor–like domains and lead to enhanced proteolytic degradation and malfunction of fibrillin-1 Marfan syndrome affects about 1 in 5000 humans Aortic dissections and aneurysms have also been reported in people with other

FBN1 sequence variations without exhibiting other Marfan

properties Other genetic diseases include Ehlers-Danlos syndrome, familial aortic dissection, and Loeys-Dietz syn-drome Ehlers-Danlos syndrome can be classified into 11 types and results in skin hyperelasticiy Type IV Ehlers-Danlos patients are at greater risk of aortic rupture owing to

a defective synthesis of type III collagen; normal aorta is rich

in type III collagen The prevalence of Ehlers-Danlos syn-drome is also⬇1 in 5000 Familial aortic dissection results in aneurysm and dissection of the aorta at a young age.10 Loeys-Dietz syndrome was recently identified in patients with mutations in the transforming growth factor-␤ receptors

1 and 2 This disease is phenotypically similar to Marfan syndrome, and patients also develop TAAs and dissections at

an early age.11The common congenital anomaly of bicuspid aortic valve, which affects 2% of the population, has been associated with TAA From family studies, it is estimated that

⬇20% of TAAs are due to genetic diseases The common method of inheritance seems to be autosomal dominant.12In AAAs, the genetic predisposition is reported to be between 12% and 19%.13

Among other risk factors, smoking has the strongest association with both TAA and AAA, with a relative risk of

5 for the presence of AAA.14Current smoking by itself is estimated to be responsible for 0.4-mm/y additional growth rate of aortic aneurysms.15Dyslipidemia and hypertension are less powerful risk factors, considered to be associated mainly with the occurrence of AAA, although newer data suggest that hypertension may actually be more closely associated with TAA,16and is certainly a risk factor for dissection Men

From Virginia Commonwealth University (P.D., I.S.J.) and McGuire VAMC (P.D., I.S.J.), Richmond, VA, and Yale University, New Haven, CT (J.A.E., I.S.J.).

Correspondence to Ion S Jovin, MD, 1201 Broad Rock Blvd 111J, Richmond, VA 23249 E-mail isjovin@yahoo.com

(Circulation 2011;124:1469-1476.)

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.006486

1469 by guest on September 16, 2015

http://circ.ahajournals.org/

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are more often affected than women Advanced age,

hyper-tension, chronic obstructive lung disease, and coronary artery

disease are also associated risk factors for both TAA and

AAA,2although it should be noted that not all studies identify

hypertension and coronary artery disease as risk factors for

AAA They are not only risk factors for the presence of

aneurysm, but also dominant determinants of aneurysm

growth and rupture.17 Uncommon causes include bacterial

endocarditis or infection of a laminal clot (from

Staphylococ-cus aureus and S epidermidis, Salmonella, and StreptococStaphylococ-cus

species), as well as syphilis, Takayasu arteritis, and giant-cell

arteritis (temporal arteritis) Dissection is also considered a

risk factor for thoracic aneurysm, and patients who undergo

thoracic dissection repair are at some risk of forming

aneu-rysms in other segments of their thoracic aorta.18,19However,

it is unclear whether dissection is a true risk factor or

dissection was the first manifestation of the aneurysmal

disease Diabetes mellitus may be associated more closely

with AAA than with TAA,16although several other studies

actually suggest an inverse association between diabetes and

AAA (ie, patients with diabetes mellitus are less likely to

develop AAA).2

Pathophysiology

All of the above causes and risk factors exert their effects

through localized inflammatory changes, culminating in

deg-radation of extracellular matrix and apoptosis of vascular

smooth muscle cells, which used to be described as cystic

medial necrosis but is now more accurately called medial

degeneration of the aortic wall Medial degeneration is a

nonspecific degenerative condition that provides the

ana-tomic background for dissection.20The precise pathogenesis

that leads to these changes is not fully understood One

mechanism that has been proposed is the development of

reactive oxygen species that activate matrix

metalloprotei-nases (MMPs), thereby causing an imbalance between MMPs

and their inhibitors (tissue inhibitors of metalloproteinases)

Found to be important in the pathogenesis of both TAAs and

AAAs, MMPs are a family of zinc endopeptidases that are

responsible for the degradation of the extracellular matrix in

aortic aneurysms.21Matrix metalloproteinase-2 is produced

in mesenchymal cells; MMP-9 is produced in macrophages These are required elements of aneurysm formation.22 Ejiri et al23 demonstrated the role of NADH/NADPH oxidase in the development of reactive oxygen species and its effect in the development of TAA Angiotensin II has also been implicated in the development of aortic aneurysms through its NADH/NADPH activation in vascular smooth muscle cells.24Transforming growth factor-␤ has been seen

in elevated levels in certain aneurysmal segments, notably in Marfan syndrome and other inherited diseases.25 Transform-ing growth factor-␤ has been associated with thickening of the aortic wall and the fragmentation and disarray of elastic fibers.25In a recent study, Moran et al26demonstrated the role

of osteoprotegerin in the growth of AAAs Osteoprotegerin is

a member of the tumor necrosis factor receptor family Osteoprotegerin plays a role in vascular disease; its serum level increases in atherosclerosis, and it is associated with AAA size.27 Recombinant human osteoprotegerin inhibits vascular smooth muscle cell proliferation and induces apo-ptosis.26Satoh et al28recently identified cyclophilin A as a key factor in the development of aortic aneurysms via the inflammatory response to angiotensin II through reactive oxygen species It is possible that all of the above-described pathways are part of a common inflammatory cascade.29 Finally, the mitogen-activated protein kinase/extracellular signal-regulated kinase cascade has also been implicated in aneurysm formation This signal transduction pathway is very complex, involves a large number of proteins, and serves to couple intracellular responses to the binding of growth factor

to cell surfaces Inhibition of this pathway with statin and extracellular signal-regulated kinase inhibitors has been shown to reduce AAA formation in experimental models.30

An overview of potential cellular pathways leading to aortic aneurysm is depicted in the Figure

Biomarkers and Genetic Markers

Thoracic aortic aneurysm is a virulent, potentially lethal, but predominantly silent disease There are significant challenges

in diagnosing and following the growth of aneurysms.31

Figure Molecular mechanisms of aneurysm

formation and the effects of different medica-tions Angiotensin promotes aneurysm forma-tion through angiotensin 1 (AT1) receptors Increased angiotensin II causes an increase in reactive oxygen species (ROS) through the NADH/NADPH system, which in turn increases cyclophilin A and matrix metalloproteinase (MMP) levels This promotes inflammatory reac-tion and subsequent medial degenerareac-tion, leading to aneurysm formation Fibrillin gene mutations cause enhanced transforming growth factor (TGF)- ␤ signaling This results in cellular proliferation and matrix degradation probably through signaling via the psmad2 system An-giotensin receptor blockers (ARBs) are thought

to inhibit the above pathways via inhibition of the AT1 receptors Angiotensin-converting enzyme inhibitors (ACEIs) block angiotensin II Statins block the NADH/NADPH system; tetra-cyclines and macrolides reduce MMP activity.

␤-Blockers reduce shear stress on the vessel.

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Recent understanding of the pathophysiology of aneurysmal

disease led to the search for potential biomarkers for both the

presence and growth of aneurysms Indicators of ongoing

thrombosis, inflammatory markers, MMPs, markers of

colla-gen turnover, colla-genetic markers, and other potential markers

have been evaluated,32but the promise of biomarkers has not

been realized.33

As has been noted, a significant portion of TAA disease is

genetic (Marfan syndrome, Loeys-Dietz syndrome, familial

TAA and dissection syndrome, Ehlers-Danlos syndrome type

IV) Mutations have been described in the FBN1 gene,

transforming growth factor-␤ receptor gene type 1 and 2

(TGFBR 1 and 2), and smooth muscle–specific isoforms of

␤-myosin and ␣-actin genes (MYH11 and ACTA2) Recent

data have improved our understanding of the role of genetic

factors in altered smooth muscle cell contraction and the

pathogenesis of TAAs.34The genetic predisposition for AAA

is multifactorial, and recent genome-wide association studies

have shown associations between AAA and loci on

chromo-somes 9p21.335and 9q33.36Genetic testing is available for

family members of TAA patients, but routine screening is not

yet advisable because of cost and practicality; hundreds of

mutations in these genes have been associated with TAA, and

the usefulness of genetic testing has not been proven.37

Clinical Course

The major cause of mortality from aortic aneurysm is

dissection and rupture Most aneurysms are clinically silent

If symptoms are present, they can include heart failure, chest

pain, myocardial ischemia, back pain, and flank pain

Com-pression of branch vessels can produce ischemia in the

corresponding territories According to the law of Laplace, as

the size of the aneurysm increases, the wall tension rises, even

though the relationship is potentially altered by the fact that there

often is compensatory aortic thickening through remodeling,

which may reduce the tension There is a rising incidence of

dissection and rupture with expanding aneurysm size.38Studies

show that the overall incidence of aortic dissection in the general

population is 2.9 to 3.5 per 100 000 person-years.39The growth

rate of aneurysms is estimated to be between 0.1 and 0.4 cm/y,40

making accurate measurements of change and clinical trials

challenging The rates of dissection and rupture of TAAs are

also dependent on aneurysm site (ascending or descending

aorta) In the ascending aorta, we see a steep increase in

complication rates once the aneurysm exceeds 6 cm in

diameter Above that diameter, the rate of aortic dissection

and rupture increases to⬎30% a year In descending aortic

aneurysms, this happens when the diameter reaches 7 cm.41

The 5-year survival from untreated TAAs has been reported

to be between 19.2%42and 64%,3whereas 8-year survival in

AAA has been reported to be 75% to 80%.40

Therapy

The recommended therapy for aortic aneurysms is dependent

on aneurysm-specific factors (size, location, rate of growth,

origin) and patient-specific factors (risk factors,

comorbidi-ties, presence of complications from the aneurysm)

Avail-able therapies are open and endovascular surgeries, medical

therapies, and lifestyle modification

Open and Endovascular Surgical Therapy

Historically, surgical repair of aortic aneurysms was sug-gested after it was noted that most aneurysms rupture before they reach 10-cm diameter.43Current recommendations44are

to repair an ascending TAA at 5.5-cm diameter (5.0 cm in case of Marfan patients) and a descending TAA at 6.0 cm if repaired with open surgical technique and 5.5 cm if repaired with endovascular technique (5.5 cm for Marfan patients) or

if the rate of growth is ⬎1 cm/y Other indications are concurrent aortic insufficiency and surgical emergencies from aneurysm complications.44,45 These recommendations are based on the inherent risk of surgery being lower than the annual risk of aortic rupture for sizes larger than the above size criteria Open surgical repair has a surgical mortality rate

of 5% to 10% for elective TAA repair and up to twice as high for nonelective operations,46with lowest values for ascending aneurysm repair and highest values for thoracoabdominal aneurysm repair Recently, low-risk thoracic aortic surgery has been reported at specialized aortic centers.47The risk of spinal cord ischemia causing paraplegia is 5% to 10%48with open TAA repair in descending operations only

Covered stent grafts have been available in the United States for endovascular aneurysm repair since 2005 Current recommendations are for infrarenal AAA repair and descend-ing TAA repair in aneurysms that are without abdominal extension.49The perioperative mortality and 30-day mortality have been reported to be lower than for open repair,50but the durability of benefit has been questioned A recent systematic review of open versus endovascular TAA repair seems to confirm the lower risk of death with endovascular repair, but those authors cautioned that the quality of the studies was not good.51 A review of survival data on ⬎11 000 Medicare patients with TAAs showed a reduced 30-day mortality but similar 5-year mortality between open and endovascular repair.52Recently, hybrid procedural approaches have been reported in which open and endovascular procedures are used.53From randomized trial data, there is no evidence for a midterm survival benefit when comparing medical and endo-vascular repair for either AAA (Endoendo-vascular Aneurysm Repair-2 [EVAR-2]) or TAAs (Investigation of Stent Grafts

in Aortic Dissection [INSTEAD]) or when comparing open and endovascular repair for AAAs (Dutch Randomized En-dovascular Aneurysm Management [DREAM]).31 The EVAR-2 and DREAM trials were done in patients with AAA and compared conservative therapy with endovascular repair and open repair with endovascular repair, respectively The INSTEAD trial,54 which compared medical therapy with endovascular therapy in patients with aortic type B dissection, showed no benefit of endovascular therapy over medical therapy but was underpowered for the chosen end points and was criticized because of the long period of time allowed from the time of dissection to enrollment and the high crossover rate

The more recently introduced fenestrated endografts also enable an endovascular approach to thoracoabdominal aortic aneurysms and complex aneurysms However, there is little evidence of the long-term durability and efficacy of this approach

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Medical Therapy

Principles and Goals of Medical Therapy

The goals of medical therapy have traditionally been to

reduce shear stress on the aneurysmal segment of the aorta by

reducing blood pressure and contractility (dP/dt) Although

there is little evidence that cardiovascular risk factor

reduc-tion influences outcome in aortic aneurysm to a great degree,

it has traditionally been recommended that cardiovascular

risk factor reduction takes place More recently, numerous

reports have been published of plausible therapies that aim to

affect the underlying pathophysiological changes in aortic

aneurysms, thus modifying the disease process as opposed to

only trying to delay its complications

Medical Therapy in Acute Aortic Dissection

In acute aortic dissection, appropriate and immediate therapy

is essential with the aim of stabilizing the patient and

improving the clinical outlook The main goals of therapy are

blood pressure control, decrease of shear stress, optimization

of anticoagulation, volume management, and pain control A

detailed discussion is beyond the scope of this article but can

be found in excellent published reviews.55,56

Medical Therapy of Chronic Aortic Aneurysm

␤-Blockers

␤-Blockers may be beneficial for reducing the rate of aortic

dilatation This is thought to be due to the effect of␤-blockers

in reducing left ventricular dP/dt and reducing shear stress In

addition,␤-blockers reduce dP/dt in the aorta and might be

beneficial via this mechanism and the resultant effect on

shear stress in the aorta Several animal studies and other

retrospective clinical studies have also indicated a significant

inhibitory effect of␤-blockers on aneurysm growth rate.57,58

In a small study of 70 patients with Marfan syndrome,

propranolol-treated patients had a 73% lower rate of aortic

dilatation and lower mortality than placebo-treated patients.59

However, later prospective randomized trials of␤-blockers in

patients with AAA failed to show a significant effect,60

although there was a trend favoring propranolol.61 These

trials found a low compliance rate with propranolol (a 42%

discontinuation rate in 1 trial) and a significant negative

effect of propranolol on quality of life At this time, no studies

of␤-blockers in patients with thoracic aortic disease (other

than Marfan patients62) have been published

Tetracyclines/Macrolides

Doxycycline is a nonspecific MMP inhibitor.63This

antibi-otic has been used in conditions with MMP overexpression

(eg, periodontal disease, rheumatoid arthritis).64 In animal

models, doxycycline slowed elastin degradation and

aneu-rysm development.65 In a small series of human subjects,

doxycycline decreased MMP-9 levels66and slowed the rate of

progression of AAA in humans.67The macrolide

roxithromy-cin has also been shown to inhibit the rate of expansion of

AAA in humans, possibly through a similar mechanism.68

Statins

Statin treatment is one of the cornerstone therapies in

cardio-vascular diseases Statins reduce the progression of

athero-sclerosis and improve clinical outcomes In addition to their

lipoprotein-reducing properties, statins have a number of effects called pleiotropic effects For instance, they reduce oxidative stress by blocking the effects of reactive oxygen species on aneurysms This effect is independent of their lipid-lowering properties Statins achieve these results through suppressing the NADH/NADPH oxidase system.23 These effects have been shown in both AAA and TAA specimens Aneurysm expansion rate has also been shown to

be reduced in AAA patients on statins in observational studies,69 but the largest study to date failed to show an association between statin prescription and AAA growth rate.70 At this time, no studies of statins in patients with thoracic aortic disease have been published

Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers

Angiotensin II has been shown to have a number of biological effects on the cardiovascular system It promotes vascular hypertrophy, cell proliferation, production of extracellular matrix, and activation of macrophages, and it activates NADH/NADPH oxidase of vascular smooth muscle cells Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to both stimulate and inhibit MMPs and the degradation of extracellular matrix in aortic aneurysms.71 Losartan, an angiotensin I receptor blocker (ARB), seems to exert its beneficial effect through blocking transforming growth factor-␤, thereby reducing matrix degradation in a Marfan syndrome mouse model.25In Marfan and apolipopro-tein E– deficient mice (in which angiotensin II is infused to induce aneurysm), ARB (losartan) prevents aneurysm forma-tion and ACEIs do not.25However, in other animal models of aneurysm (eg, elastase, ␤-aminopropionitrile monofumarate models), ACEIs prevent aortic dissection and ARB does not.72In 1 small human study, ARB has been shown to slow the rate of progression of TAA in Marfan syndrome.73 However, Hackam et al74 found in their case-control study that ACEIs were protective but ARBs were not protective against AAA rupture, but in that study there was no dose-response effect for ACEIs and little adjustment for potential confounders A recent report of an observational prospective study of AAA patients showed an increased growth rate of AAA diameter from 2.77 to 3.33 mm/y in patients on ACEIs.75In a recent randomized trial, perindopril was shown

to reduce the growth rate of thoracic aortic aneurysms in patients with Marfan syndrome.76The ongoing Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome (MARFANSARTAN) seeks to address the efficacy of losartan in Marfan syndrome.77It appears that the discrepant results of ARB and ACEI efficacy in retarding aneurysm growth rate might stem from the differences among models and point toward multiple different biological path-ways of aortic aneurysm development An overview of studies reporting results of medical therapy of aortic aneu-rysm can be found in the Table

Other Agents

New agents in animal studies that attempted to delay AAA development have targeted oxidative stress, proteolysis, and inflammation.78The clinical efficacy of these approaches in TAA has yet to be tested Transforming growth factor-␤–

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neutralizing antibodies have been used in animal research and

have shown efficacy in delaying or avoiding the development

of TAA in Marfan syndrome.25Transforming growth

factor-␤ antagonism therefore might represent a strategy for at least

some forms of aortic aneurysm Unfortunately, transforming

growth factor-␤–neutralizing antibody treatment in humans is

not yet practical In another study, a c-Jun-N-terminal kinase

inhibitor was used to induce regression of AAA in mice.79

Glucocorticoid, leukocyte-depleting antibody (anti-CD 18),

and indomethacine also have been used,80and early studies

with chymase inhibitors81 and aspirin82 have also shown

promising results Lifestyle modifications such as smoking

cessation are also very important Tobacco use is associated

with a marked increase in general morbidity and mortality

and with a 5-fold relative risk increase for the presence of

AAA.83 Pregnancy is not recommended in patients with

Marfan syndrome, especially if the aortic root is⬎4 cm

Conclusions

Aortic aneurysm is still an incompletely known entity that

affects a significant proportion of the population Multiple

new pathophysiological pathways have been proposed

re-cently; however, the exact mechanisms that can induce

aneurysm formation remain unclear Surgical repair has

relatively high risk because of the usually complex nature of

the procedure; therefore, surgical therapy is generally

re-served until the risk of rupture exceeds that of the surgery

Recent series have documented substantially increased safety

of thoracic surgery, approaching the safety of traditional

cardiac procedures such as coronary artery bypass graft surgery and valve replacement Endovascular repair is a new possibility that confers less early risk to carefully selected patients, but midterm results call into question the durability

of endovascular repairs of degenerative aneurysms

To improve patient safety and outcome, it is imperative to find treatments that delay or even stop the progression of aneurysm disease The ideal treatment would of course be one that reverses aneurysm formation Multiple medications have been tried that are known to act on 1 or more of the proposed pathophysiological pathways of aortic aneurysm develop-ment Only 2 randomized prospective trials have been carried out so far, both in patients with Marfan syndrome Both trials were relatively small, and only 1 study had clinical end points Some treatment options (eg, ACEI, ARB,␤-blockers) have shown conflicting results, most likely because of the multiple causes of aneurysm formation However, as our understanding of the disease improves, it is conceivable that

we will have better medical therapies to slow the progression

of thoracic aortic disease To do so, we must be willing to randomize patients in clinical trials, and we must also consider relevant clinical end points rather than focusing solely on aneurysm expansion Recently, the heterogeneity of the aorta itself has been raised as a plausible reason for the difference in aneurysm pathology and clinical course.6 Al-though it seems reasonable to treat patients with aneurysms the same way that any other patients are treated in terms of cardiovascular risk factors and prevention, the starting of medications solely to prevent aortic aneurysm expansion is

Table Clinical Studies of Medical Therapy for Aortic Aneurysms

Shores et al 59 Marfan syndrome; randomized, prospective

study; ⬇10-y mean follow-up

Propranolol 32 Treated, 38

control subjects

Propranolol caused significantly reduced aortic root dilatation Gadowski et al 57 Infrarenal AAA; observational, prospective

study; 43-mo mean follow-up

␤-blocker 38 Treated, 83

control subjects

Patients with large aneurysms on

␤-blockers had significantly lower AAA

expansion rate Leach et al 58 AAA; observational, retrospective study;

34-mo mean follow-up

␤-blocker 12 on ␤-blocker, 15

not on ␤-blocker

Patients on ␤-blocker had significantly lower AAA expansion rate Propranolol Aneurysm

Trial Investigators 61

AAA; prospective, randomized, double-blind study; 2.5-y mean follow-up

Propranolol 276 on propranolol,

272 on placebo

Propranolol did not significantly affect small AAA growth; high discontinuation rate of propranolol Lindholt et al 60 AAA; randomized, controlled study; 2-y

follow-up

Propranolol 54 Asymptomatic

patients

Increased mortality in propranolol group; only 22% could be treated Baxter et al 66 AAA; prospective, observational study;

6-mo phase II study

Doxycycline 36 Patients Doxycycline was safe and caused

MMP-9 level decrease Mosorin et al 67 AAA; randomized, placebo controlled,

double-blind study; 18-mo follow-up

Doxycycline 17 on doxycycline,

15 on placebo

Aneurysm expansion rate was significantly lower in the doxycycline

group Vammen et al 68 AAA; randomized, double-blind study;

1.5-y mean follow-up

Roxithromycin 43 on roxithromycin,

49 on placebo

4 wk of therapy reduced AAA expansion

rate Sweeting et al 75 AAA; prospective, observational study;

1.9-y mean follow-up

ACEI 169 on ACEI, 1532

not on ACEI

Patients on ACEI had a faster AAA growth rate than patients not on ACEI Ferguson et al 70 AAA; observational, prospective study; 5-y

median follow-up

Statins 394 on statins, 258

not on statins

Statins were not associated with reduced AAA growth rate Gambarin 62 Marfan syndrome; open-label phase III

study

Losartan, nebivolol 291 patients Ongoing

AAA indicates abdominal aortic aneurysm; MMP, matrix metalloproteinase; and ACEI, angiotensin-converting enzyme inhibitor.

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endorsed by the most recent guidelines44 as a reasonable

option, even though an argument can be made that we should

wait until we have a more thorough understanding of the

etiologic diversity of aneurysm formation and of the risks and

benefits of each treatment.31

Disclosures

None.

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K EY W ORDS : aneurysm 䡲 aorta 䡲 aortic aneurysm, abdominal 䡲 drug therapy䡲 aorta, thoracic 䡲 aortic aneurysm, thoracic

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