Statin therapy is associated with aneurysm sac regression after endovascular aortic repair

Statin therapy is associated with aneurysm sac regression after endovascular aortic repair Maxime Raux, MD, Frédéric Cochennec, MD, and Jean-Pierre Becquemin, MD, Créteil, France Background: Several anatomic factors have been identified as predictive of sac behavior after endovascular aneurysm repair (EVAR). The effects of statin therapy on aneurysm sac size reduction remain controversial. This study tested the hypothesis that statin therapy enhances aneurysmal sac regression after EVAR. Methods: This monocentric retrospective study included patients with abdominal aortic aneurysms treated by EVAR using the Zenith (Cook, Bloomington, Ind) graft device. We excluded patients presenting with perioperative sac enlargement factors such as endoleaks, endotension, infectious, inflammatory, ruptured, or anastomotic aneurysms. We prospectively assessed standard clinical and anatomic data, as well as statin use, at the time of EVAR and during follow-up. The primary end point was the decrease in the largest transverse aortic diameter at 24 months compared with the preoperative diameter. Results: Among 166 patients treated by a Zenith device and meeting the inclusion criteria, 120 were identified as statin users and 46 as nonstatin users, with comparable characteristics. At 24 months of follow-up, statin group patients had a greater aneurysm sac reduction (25% vs 14%; P < .0001). At a threshold of 5 mm in diameter regression, statin use was a positive factor of retraction (odds ratio, 7.93; 95% confidence interval, 3.22-15.52; P < .0001). Multivariate analysis revealed statin use was an independent predictive factor of sac regression (adjusted odds ratio, 9.39; 95% confidence interval, 3.45-25.56). Conclusions: This study showed that statin use was predictive of sac regression after EVAR with the Zenith graft device. This effect needs to be confirmed by larger randomized trials or by large population evaluation. ( J Vasc Surg 2012;55: 1587-92.)

To date, the benefits of statin therapy on morbidity and mortality of patients with high cardiovascular risk factors are no longer questioned. Statins (3-hydroxyl-3methylglutaryl coenzyme A reductase inhibitors) reduce triglyceride, total cholesterol, and low-density lipoprotein levels and increase the high-density lipoprotein level.1 Large trials and studies have shown a beneficial role of long-term statin therapy on cardiovascular mortality and morbidity rates,2,3 stroke prevention,4 and on peripheral arterial diseases.5 Furthermore, statins have demonstrated many biologic effects, also known as pleiotropic effects, including anti-inflammatory activity,6 decreasing proteases activity involved in aneurysm disease,7,8 and improvement of endothelial function.9,10 There is evidence that abdominal aortic aneurysm (AAA) formation is associated with inflammation, endothelial dysfunction, and proteolysis as a consequence of a gap between proteases and their inhibitors in the arterial wall, resulting in destruction of the elastic media.11,12 The ability of statins to reduce these biologic adverse effects might From the Department of Vascular Surgery, Henri Mondor Hospital, University of Paris XII. Author conflict of interest: none. Reprint requests: Maxime Raux, MD, Department of Vascular Surgery, Henri Mondor Hospital, University of Paris XII, 51 ave du Maréchal de Lattre de Tassigny, 94000 Créteil, France (e-mail: raux.maxime@ gmail.com). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright © 2012 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.12.040

explain why many studies have suggested beneficial effects on postoperative outcomes13 or on AAA evolution.14-17 The latter still remains controversial. In a recent metaanalysis, Twine et al18 found no influence of statin therapy on AAA expansion rate. Endovascular aneurysm repair (EVAR) has become a mainstay of AAA treatment. Three randomized trials19-21 and studies of international registries22 have demonstrated the short-term benefits of EVAR over open surgical repair. The aim of EVAR is to prevent rupture by reducing the pressure on the arterial wall. One of the consequences of this effect is a retraction of the sac. Anatomic predictive factors of sac retraction have been identified,23 but no study so far has demonstrated beneficial effects of drugs on sac regression after EVAR. We hypothesized that statins may accelerate aneurysm sac regression after EVAR. The aim of this study was to investigate the correlation between statin use and aneurysm sac regression. METHODS According to French legislation, no informed consent was required from patients participating in this observational retrospective study. Patient selection. Between January 2000 and August 2009, 957 patients who underwent EVAR for AAAs at our institution (Henri Mondor Hospital, Assistance Publique Hôpitaux de Paris, France) were registered prospectively in a computerized database. Because the type of stent graft has been identified as a predictive factor of shrinkage,24 we only included patients treated with the Zenith device (Cook, Bloomington, Ind). It was the most commonly used device at our institution. Indications for EVAR were in agreement 1587

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with the French National Agency of Health Accreditation and Evaluation criteria.25,26 We also treated EVAR patients who refused open repair but who met the anatomic requirements of the American consensus document, published in 1997.27 We excluded data of patients who did not meet the criteria of treatment success proposed by the American Vascular Surgery Society in 2002: absence of aneurysmrelated death, rupture or surgical conversion, stent graft migration or failure, type I and III endoleaks, and type II endoleaks responsible for aneurysmal growth.28 To limit confounding factors, we excluded all patients presenting any type of endoleak identified during follow-up. We also excluded patients treated for thoracoabdominal aneurysm, infectious, or inflammatory aneurysm, ruptured aneurysm, isolated iliac aneurysm, or anastomotic pseudoaneurysm. Data collection. As part of conventional care after EVAR, patients automatically received a computer-generated notification of each appointment, including computed tomography (CT) scan prescription with the date of the examination. Follow-up information, including clinical screening, duplex scan, and CT angiography, performed at 1, 6, 12, 18, and 24 months, and yearly thereafter, were prospectively collected in a specific database (Logit, Fontenay sous Bois, France). End points. We compared the CT scan obtained before treatment and at the 24-month follow-up. We measured the maximal transverse aneurysm diameter, the maximal diameter of the common iliac arteries, the maximal diameter of the infrarenal aorta (proximal neck diameter), and the proximal neck length, which have been shown to influence sac size regression in previous studies.23,29 The end point was aneurysm sac regression, expressed as a decrease of the preoperative largest diameter. We analyzed two regression thresholds of 5 and 10 mm in maximal aortic diameter. CT scans were reviewed by the vascular surgeon in charge of the patient and by a vascular radiologist, who had to agree on the measurements before data were entered in the database. Measurements were performed on a Netvantage Windows Volume Show 3 platform (Infragistics, Elstree, United Kingdom). We studied the influence on sac regression of statin therapy, of duration of statin therapy, and of anatomic factors. If statins were introduced before surgery, the choice of the drug was respected and was not modified during the study. We considered as statin users only the patients taking statins every day during the study period, starting the day of surgery or before. Changes in the dose or molecule (type of statin) were exclusion criteria. An exclusion criterion for the no statin-user patients was statin therapy before the procedure and/or previous statin taking. Statistical analysis. Statistical analysis was done with Stata 10 software (StataCorp, College Station, Tex). Quantitative data are presented as means ⫾ standard deviations and qualitative data as percentages. Quantitative variables were compared using the Student t-test. Qualitative variables were compared using ␹2 or Fischer exact test when n

957 EVAR TAA Juxtarenal Infectious Inflammatory Ruptured aneurysms

665 Cook

597 AAA (Zenith endograft)

Death = 163 Lost follow up = 88 346 patients Endoleaks = 180 166 patients (clinical success criteria)

No statin n = 46

Statins n = 120 Pre op n = 52

Per op n = 68

Fig. Flow chart shows patient selection. AAA, Abdominal aortic aneurysm; EVAR, endovascular aneurysm repair; TAA, thoracoabdominal aneurysm.

⬍ 5 (level of significance P ⬍ .05). A multivariate analysis by logistic regression included factors assessed in the univariate analysis with P ⬍ .1. Demographic and anatomic factors that have been associated with sac size modifications in the literature were forced into logistic regression to not neglect confounding factors. RESULTS Demographics. Among the 957 patients who underwent EVAR, 665 were treated with a Zenith endograft. After exclusion of complex aneurysms (thoracoabdominal aneurysms, pararenal aneurysms), ruptured aneurysms, conversion, and inflammatory or infectious aneurysms, 597 consecutive patients were suitable for the study. To limit confounding factors, we excluded endoleaks (29.9%) because they influence sac behavior. Among the 417 remaining patients, 163 died during the study period, and 88 were lost to follow-up (Fig). Finally, 166 patients were suitable for analysis. The control group comprised 46 patients who never had statin therapy pre-EVAR and were not given statin therapy postoperatively. The statin group comprised 120 patients. In 52 patients, statin therapy has been previously introduced before the procedure, and 68 started therapy the day before the intervention. Introduction of long-term preoperative statin therapy was not controlled in this study, but an anesthesiologist controlled the relevance of statin therapy in each patient at least 1 month before surgery. Maximum duration of preoperative therapy was 20 years (average duration of treatment, 7 years). All cases of statin introduction before surgery were in accordance with French Health Products

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Table I. Statin distribution Statins Fluvastatin 80 mg Simvastatin 20 mg 40 mg Atorvastatin 10 mg 20 mg 40 mg 80 mg Rosuvastatin 5 mg 10 mg Pravastatin 10 mg 20 mg 40 mg

No. (%) 4 (3.3) 19 (15.9) 3 (2.5) 15 (12.5) 12 (10) 10 (8.3) 1 (0.8) 18 (15) 12 (10) 3 (2.5) 17 (14.2) 6 (5)

Safety Agency requirements. Statin distribution is detailed in Table I. The minimum follow-up in all patients was 2 years, and no deaths occurred in either group during this interval. Both groups were similar, with no significant difference in clinical variables (Table II), in preoperative largest aneurysm diameter, maximal common iliac diameters, maximal proximal neck diameter, and in proximal neck length (Table III). As well, in the statin group, patients taking statins before the procedure and patients starting to take statins perioperatively were strictly comparable regarding demographics and anatomic variables: age (P ⫽ .31), sex (P ⫽ .99), diabetes (P ⫽ .92), smoking (P ⫽ .78), aneurysm diameter (P ⫽ .85), length and diameter of the proximal neck (P ⫽ .54 and P ⫽ .26), and common iliac diameter (P ⫽ .64). No reinterventions, endograft complications, or aortic-related events were observed. Influence of statin therapy and anatomic factors. The decrease in rate in maximal aortic diameter was 25% in the statin group and 14% in the control group (P ⬍ .0001). In the statin group, treatment duration had no effect on aortic diameter: the decrease in maximal aortic diameter was similar in patients who received statins preoperatively to those who started taking statins in the perioperative course (27% vs 24%; P ⫽ .2). A long-term use (⬎7 years) did not affect the aneurysm reduction compared with patients who took statins for ⬍7 years (25% vs 27%; P ⫽ .59). Primary study end point was AAA sac shrinkage, defined as a decrease of aneurysm maximal diameter from the pre-EVAR CT scan to the post-EVAR CT scan scheduled at the 24-month follow-up. We used a threshold of 5 and 10 mm. We performed univariate analysis of the influence of each factor on AAA shrinkage at 24 months. Statin use (odds ratio [OR], 7.93; 95% confidence interval [CI], 3.22-15.52) and maximal preoperative aneurysm diameter (OR, 1.06; 95% CI, 1.01-1.12; P ⫽ .038) were predictive factors of 5-mm shrinkage, and 10-mm decrease factors were also statin therapy (OR, 3.75; 95% CI, 1.83-7.67) and

the maximal preoperative aortic diameter (OR, 1.05; 95% CI, 1.01-1.1; P ⫽ .02). As anatomic factors such as common iliac artery diameter, maximal aneurysm diameter, neck diameter, and length had an influence on sac behavior in subsequent studies, they were forced into the multivariate analysis. The logistic regression model was adjusted for sex, age, diabetes, and smoking, which confirmed the influence of statin therapy on aneurysm sac regression (Table IV). DISCUSSION This study demonstrates that statin therapy in patients who met the criteria of clinical success after EVAR with a Zenith device was associated with an increase in sac shrinkage at 24 months. Aneurysm diameter is a major criterion of efficacy during the follow-up of EVAR.30 Its changes can alter the follow-up sequences and have implication on the surgical outcomes. The variety of effects explain why statins are currently one of the most studied and prescribed drugs.18 Statin therapy in patients with aortic diseases is known to improve outcomes after EVAR or open repair.13,18 Many studies showed controversial results of statin effects on AAA expansion rate.15-18,31 Previous trials analyzed shrinkage factors of the aneurysm sac after EVAR.23,29,32 In a recent large study, Schanzer et al29 identified independent predictive factors of AAA sac enlargement such as endoleak, age ⬎80 years, aortic neck diameter ⬎28 mm, aortic neck angle ⬎60°, and iliac artery diameter ⬎20 mm. However, to our knowledge, our study is the first that has explored the influence of statin therapy on sac regression. The principal limitations of this study are the lack of randomization and that patients who did not take statins were those who were treated in an earlier period in the study. However, the correlation between statin use and sac regression was strong, which we believe provides convincing clues on the efficacy of the drug. To limit the influence of confounding factors, patients included in the series were strictly selected with many exclusion criteria. First, we focused on patients who underwent EVAR with the Zenith device, because previous studies have shown that sac behavior after EVAR was device-specific24,33 and also because this is the most commonly used device in our institution. Furthermore, we chose the Zenith graft because there was no major change in its structure (stent composition, main body cover) over time, which could have interfered with sac behavior. The study of only one graft reduced the studied population but was deemed mandatory to avoid bias. Instructions for use about aortic neck anatomy (ⱕ60° angulation) were respected. Patients who did not meet criteria of treatment success were excluded. We excluded all types of endoleaks, which are known to be a predictive factor of sac enlargement,32 aneurysm-related death, rupture, device migration or failure, and surgical conversion. Excluding all these events reduced the number of patients available for the study but limited the effect of confounding factors so that the sole effect of statin therapy could be assessed. This reason

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Table II. Main clinical data in non-statin-group and statin-group patients Variablea

Total (n ⫽ 166)

Nonstatin (n ⫽ 46)

Statin (n ⫽ 120)

P

71.5 ⫾ 0.7 160 (96.4) 45 (27.2) 26 (15.7) 9 (5.42) 5 (3) 35 (21.1) 61 (36.7) 93 (56) 28 (16.9) 21 (12.6)

72.9 ⫾ 1.3 44 (95.6) 9 (19.6) 7 (15.22) 2 (4.35) 1 (2.17) 10 (21.7) 13 (28.3) 22 (47.8) 6 (13) 4 (8.7)

70.9 ⫾ 0.8 116 (96.7) 36 (30.2) 19 (15.83) 7 (5.83) 4 (3.33) 35 (20.8) 48 (40) 71 (59.2) 22 (18.3) 17 (14.2)

.18 .75 .16 .92 .52 .57 .9 .16 .19 .41 .25

1 (2.2) 71 (43) 87 (52.7) 2 (1.2)

4 (3.4) 22 (47.8) 22 (47.8) 1 (2.2)

5 (3.0) 49 (41.2) 65 (54.6) 1 (0.8)

Age, years Male Obesity COPD Symptomatic carotid lesionsb End-stage renal failure Coronaropathy Dyslipidemia Hypertensionc Active smoker Diabetes mellitus ASA classification 1 2 3 4

.665

ASA, American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease. a Continuous data are expressed as mean ⫾ standard deviation; categoric data as number (%). b Onset of any cerebrovascular disease, including transient ischemic attack or stroke due to a carotid stenosis. c Blood pressure ⬎140/90 mm Hg or taking one or more antihypertensive drug.

Table III. Preoperative aneurysm anatomical criteria Variables Max transverse diameter Proximal neck Max diameter Length Max common iliac artery diameter

Total, mm Mean ⫾ SD mm

Nonstatin Mean ⫾ SD mm

Statin Mean ⫾ SD mm

P

53.15 ⫾ 8.6

53.8 ⫾ 10.6

52.9 ⫾ 7.8

.54

22.74 ⫾ 4.9 27.4 ⫾ 17.9 18 ⫾ 8.1

23.8 ⫾ 4.1 25.76 ⫾ 10.4 18.25 ⫾ 9.5

.24 .46 .86

23.5 ⫾ 4.3 26.2 ⫾ 12.9 18.2 ⫾ 9.1

SD, Standard deviation.

Table IV. Multivariate analysis of statin use and anatomic factors on sac regressiona Variable Statin use Max external diameter Proximal neck Max diameter Length Max common iliac artery diameter

5-mm regression OR (95% CI)

10-mm regression OR (95% CI)

9.39 (3.45-25.56) 1.08 (1.1-1.15)

4.35 (1.99-9.5) 1.07 (1.02-1.12)

0.97 (0.85-1.11) 0.99 (0.95-1.02)

0.94 (0.87-1.02) 1.03 (1-1.06)

1.03 (0.96-1.11)

0.99 (0.95-1.03)

CI, Confidence interval; OR, odds ratio. a Data adjusted for age, sex, diabetes, and smoking.

probably explains differences between our study and the study of Schanzer et al,29 who underlined the influence of anatomic factors and the respect of companies’ instructions for use. We did not use volumetric assessment. Although seemingly reliable, this method is difficult to apply routinely due to time constraints.34 We then relied on diameter measurements because they are reproducible for changes ⱖ5 mm.32,35,36

We did not evaluate the role of thrombus or plaque within the proximal neck. Previous studies have shown their potential influence on sac shrinkage, as circumferential thrombus in the neck may inhibit shrinkage by pressure transmission through thrombus into the sac.32 Despite the absence of clear relation between total cholesterol and AAA, several studies and meta-analyses have highlighted an influence of statin therapy on aneurysm growth.15-17,31 However, these results are disputed by a recent meta-analysis.18 Depletion of smooth muscle cells, degradation of aortic wall proteins, and inflammation are the principal causes of aneurysm formation, mediated by the proinflammatory matrix metalloproteases (MMPs), especially MMP-2 and MMP-9.37,38 MMP-9, also called gelatinase B, which cleaves elastin, collagen, and fibrinogen, appears to have a fundamental role in aneurysm formation.38 MMP-9 levels decrease after open or endovascular treatment. Patients with persistent elevated MMP-9 levels after EVAR may be at higher risk of endoleaks.39 MMP-2, like MMP-9, cleaves type IV collagen and elastin, two proteases that appear to work synergistically on aneurysm formation.40 Statin therapy reduces their concentration in the aortic wall,7,8,11,12 which constitutes the principal hypothesis of statin efficacy. In the light of our results,

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this inhibition is probably immediate because treatment length has no effect on sac evolution. The wide variety of statins used by patients does not allow us to reach conclusions about the effect of one drug or on one efficient dose. But differences of treatment in the statin group allow us to suppose that there is a positive effect of this therapeutic class, more than a given molecule. No complications of statin use (rhabdomyolysis, hepatitis, or acute liver failure) were documented during followup. Liver enzyme measurements were obtained for each patient before statins were introduced, and a new measure was performed at 3 months to ensure the absence of complications. CONCLUSIONS This study shows a beneficial effect of statins on sac regression, which to our knowledge has not been explored before. We strongly believe that currently, statin therapy should be prescribed after EVAR not only for its role in the prevention of cardiovascular events but also as a way of improving EVAR efficacy. Statin therapy, even begun the day of EVAR, appears to be strongly associated with aneurysm sac regression. Whereas a randomized study seems difficult to undertake, this new pleiotropic effect should be further investigated. If this effect is confirmed, it reinforces the necessity of statin therapy for patients scheduled for EVAR, in addition to benefits on morbidity and mortality. It may improve outcomes and allows lightening of the follow-up. AUTHOR CONTRIBUTIONS Conception and design: MR, JB Analysis and interpretation: MR, FC, JB Data collection: MR, FC, JB Writing the article: MR, JB Critical revision of the article: MR, JB Final approval of the article: JB Statistical analysis: MR, FC Obtained funding: Not applicable Overall responsibility: JB REFERENCES 1. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med 2001;5:378-87. 2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78. 3. Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-9. 4. Amarenco P, Labreuche J, Lavallée P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-todate meta-analysis. Stroke 2004;35:2902-9. 5. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev 2007;4:CD000123. 6. Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005;96:24F-33F.

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34. Lee JT, Aziz IN, Lee JT, Haukoos JS, Donayre CE, Walot I, et al. Volume regression of abdominal aortic aneurysms and its relation to successful endoluminal exclusion. J Vasc Surg 2003;38:1254-63. 35. Cho JS, Dillavou ED, Rhee RY, Makaroun MS. Late abdominal aortic aneurysm enlargement after endovascular repair with the excluder device. J Vasc Surg 2004;39:1236-41; discussion: 1241-2. 36. Wever JJ, Blankensteijn JD, Th M Mali WP, Eikelboom BC. Maximal aneurysm diameter follow-up is inadequate after endovascular abdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg 2000;20:177-82. 37. Elmore JR, Keister BF, Franklin DP, Youkey JR, Carey DJ. Expression of matrix metalloproteinases and TIMPs in human abdominal aortic aneurysms. Ann Vasc Surg 1998;12:221-8. 38. McMillan WD, Tamarina NA, Cipollone M, Johnson DA, Parker MA, Pearce WH. Size matters: the relationship between MMP-9 expression and aortic diameter. Circulation 1997;96:2228-32. 39. Lorelli DR, Jean-Claude JM, Fox CJ, Clyne J, Cambria RA, Seabrook GR, et al. Response of plasma matrix metalloproteinase-9 to conventional abdominal aortic aneurysm repair or endovascular exclusion: implications for endoleak. J Vasc Surg 2002;35:916-22. 40. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002;110:625-32.

Submitted Oct 17, 2011; accepted Dec 13, 2011.