Abdominal aortic aneurysm expansion rate: Effect of size and beta-adrenergic blockade

Abdominal aortic aneurysm expansion rate: Effect of size and beta-adrenergic blockade Gregory R. Gadowski, MD, David B. Pilcher, MD, and Michael A. Ricci, MD, Burlington, Vt. Purpose: The purpose of this study was to investigate the hypothesis that abdominal aortic aneurysm (AAA) expansion may be slowed by -adrenergic antagonists. Methods: One hundred twenty-one patients with infrarenal AAA were monitored with serial aortic ultrasound examinations. Eighty-three patients received no -blockers (group I), and 38 patients received -blockers (group II). Values are expressed as mean ± SD. Results: The me'\d follow-up was 43 ± 29 months with 5.5 ± 3.4 ultrasound examinations per patient. The expansion rate among all AAA was 0.38 ± 0.44 cm/yr. Large aneurysms (5 cm) expanded significantly faster than small aneurysms (p = 0.02) in patients not treated with -blockers. Among patients with large AAA, those receiving -blockers had a significantly reduced mean expansion rate; 0.36 ± 0.20 versus 0.68 ± 0.64 cm/yr, (p < 0.05). Although rupture rates were lower in group I (5%) versus group II (13%), this difference was not statistically significant. Thirty-four patients in a poor-risk category with AAA were monitored greater than 5 cm in diameter. Ten of these AAA ruptured. The mean expansion rate was significantly greater in those patients with ruptured AAA versus those patients with AAA that did not rupture; 0.82 ± 0.74 versus 0.42 ± 0.41 cm/yr (p = 0.04). Conclusions: In patients not undergoing -blocker therapy, large AAA expand at a significantly greater rate than smaller AAA. Large aneurysms that rupture show more rapid expansion than those AAA that do not rupture. We have demonstrated a significantly reduced rate of expansion of large AAA in patients receiving -blockade. (J VAse SURG 1994;19:727-31.) Large abdominal aortic aneurysms (AAA), more than 5 cm in diameter, have an approximate risk of rupture of 30% within 5 years. Although elective surgical resection is the preferred treatment, care of patients with smaller aneurysms or those with medical contraindications to surgery is less well defined. In those situations, nonoperative measures that would retard AAA enlargement or prevent rupture would be beneficial. The suggestion that pharmacologic therapy might slow AAA expansion was first made by Leach and coworkers2 in 1988. In their retrospective study, From the Department of Surgery, University of Vermont College of Medicine, Burlington. Presented at the Third Annual Winter Meeting of the Peripheral Vascular Surgery Society, Brekenridge, Colo. January 25,1993. Reprint requests: David B. Pilcher, MD, Department of Surgery, University Health Center, 1 S. Prospect St., Burlington, VT 0540l. Copyright 1994 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter. 0741-5214/94/$3.00 + 0 24/1/51145 they found that -adrenergic blockade significantly reduced rapid AAA expansion and, in general, tended to slow aneurysm growth. This clinical observation is especially intriguing in light of growing experimental evidence suggesting that -blockers delay or prevent aneurysm formation. 3-6 In this clinical study, we have investigated the hypothesis that -adrenergic blockade reduces the rate of AAA expansion. MATERIALS AND METHODS From 1977 to 1991, all patients with AAA less than 5 cm in size or with medical contraindications to surgery were prospectively monitored with serial ultrasound examinations. Aneurysms less than 3.0 cm in diameter as measured in the sagittal anteroposterior plane by ultrasonography were excluded in this study. Serial ultrasonography measurements were performed every 3 to 12 months. Inclusion in the study required a total follow-up of at least 6 months and two or more ultrasound examinations. Data collection also included the patient's age at study entry, complete medical history, and blood pressure recordings at the time of each ultrasound 727

728 Gadowski, Pilcher, and Ricci JOURNAL OF VASCULAR SURGERY April 1994 (cm/yr) 1 I_GROUP I DGROUP III UJ 0.8 p=0.02 * a: o a: 0.6 0.4 0.2 o 3.0-3.9 em 4.0-4.9 em ANEURYSM DIAMETER p<0.05 ** - 5.0 em Fig. 1. AAA expansion rates of group I (no (3-bloeker) and group II «(3-bloeker) classified by aneurysm size. Asterisk represents large (;;e: 5 em) versus small «5 em) AM, group 1. Double asterisk represents group I versus group II, large AAA. measurement. Follow-up was obtained until the point of AAA rupture, patient death, elective AAA repair, or the most recent ultrasound examination results. The decision to undergo surgery was made on an individual basis and was usually based on AAA growth to greater than S cm in diameter. Patients were divided into two groups: those who did not receive any f3-blockers during the entire period of study (group I), and those who received f3-blockers (group II). Only patients receiving continuous f3-blocker therapy during the entire period of study were included in group II. Most patients receiving f3-blockers were receiving these drugs for long-term therapy of hypertension or coronary artery disease. Nine patients were given f3-blockers specifically to retard AAA expansion. Patients were classified according to AAA size as follows: 3.0 to 3.9 cm, 4.0 to 4.9 cm, S.O cm or greater. Linear AAA expansion rates were calculated within each size classification. Statistical analysis was performed with one-way analysis of variance for group comparisons, Student's t test for continuous variables, chi-squared analysis for categorical variables, and linear regression analysis. A p value of less than O.OS was considered significant. Data are expressed as the mean ± standard deviation. RESULTS During a IS-year period, 121 patients met the study criteria listed above. The study population consisted of 71 % men with a mean age of 68 ± 9 years. Mean follow-up was 43 ± 29 months and the mean number of ultrasound examinations per patient was S.6 ± 3.4. Thirteen patients had aneurysm rupture (11%). Overall AAA expansion rate for the entire population was 0.38 ± 0.44 cm/yr. No correlation was found between AAA expansion rate and patient age, sex, systolic blood pressure, diastolic blood pressure, pulse pressure, or mean arterial pressure. In the nine patients given f3-blockers specifically for their MA, blood pressure before and after the initiation of therapy was not significantly altered. Characteristics for group I and group II are shown in Table I. Overall the rate of expansion of aneurysms in group I was 0.44 ± 0.42 cm/yr, compared with group II, which was 0.30 ± 0.31 cm/yr (p = 0.07). In group I, 31 (60%) patients had expansion rates that exceeded the population mean of 0.38 cm/yr, compared with six (19%) patients in group II (p = 0.03). Expansion rate categorized by AAA size are depicted in Fig. 1. There were no significant differences in sex, age, number of examinations, follow-up, or blood pressure between patients in separate size categories. Large aneurysms (S cm) expanded significantly faster than smaller aneurysms in group I, however, this was not true for patients in group II. Among AAA of S cm or greater, a significant difference in growth rate between group I and group II was also observed (Fig. 1). AAA rupture occurred in 11 patients in group I (13%) and two patients in group II (S%); however, this difference was not statistically significant (p = 0.33). A total of 34 patients with AAA S cm or larger were treated without operation because of medical contraindications to surgery or refusal to undergo surgery. Ten of these patients had AAA that ruptured, including two patients receiving f3-blockers. Mean AAA diameter at the time of rupture was 6.9 ± 0.9 cm in the untreated patients, and was 7.2 and 6.S cm in the two patients on f3-blockers. The mean expansion rate of aneurysms that subsequently ruptured was significantly greater than that of nonruptured AAA in this subset of 34 patients: 0.82 ± 0.74 cm/yr vs. 0.42 ± 0.41 cm/yr, p = 0.04. Within group II, most patients received nonselective 131/132 blockade with propranolol. The remaining patients received the 131 selective drugs metoprolol and atenolol. Patients treated with propranolol had a significantly lower mean growth rate than those treated with selective f3-blockers (Table II).

JOURNAL OF VASCULAR SURGERY Volume 19, Number 4 Gaduwski, Pilcher, and Ricci 729 Table I. Characteristics of group I (no l3-blocker) versus group II (l3-blocker) Group I n = 83 Group II n = 38 p Value Age (years) Sex (% male) Initial size (cm) No. examinations/patient Follow-up (mo) BP systolic (mm Hg) BP diastolic (mm Hg) MAP (mmhg) Rupmre (No.) Expansion rate (cm/yr) 68 ± 8 71% 4.0 ± 0.7 5.2 ± 3.0 43 ± 29 151 ± 20 84 ± 13 105 ± 18 11 (13%) 0.44 ± 0.42 67 ± 10 74% 4.0 ± 0.8 5.9 ± 3.6 43 ± 30 154 ± 18 84 ± 10 107 ± 10 2 (5%) 0.30 ± 0.39 0.56 0.97 0.27 0.43 0.52 0.33 0.07 BP, Blood pressure; iwap, mean arterial pressure. Table II. Comparison of propranolol versus 131 selective drugs within group II Drug No. Dose (mg/day) Initial AAA size (em) Expansion rate (em/yr) Propranolol Atenolol Metoprolol 21 10 7 92 ± 38 68 ± 30 80 ± 21 4.4 ± 0.8* 4.6 ± u.8* 0.20 ± 0.23t 0.42 ± 0.37t *p = 0.34. tp = 0.03. DISCUSSION There is currently no pharmacologic therapy that has been clearly shown to be clinically effective in preventing abdominal aortic aneurysm enlargement and rupture. In contrast to atherosclerotic aneurysms of the aorta, established treatment of aortic dissection includes l3-blockade, which lowers blood pressure as well as the rate of rise of the aortic pressure wave (dp/dt), effectively reducing the extent of the dissection, risk of rupture, and dilation of the aortic root. 7,8 According to the Law of LaPlace, arterial hypertension increases aortic wall tension and has clinically been related to an increased rate of AAA rupture. 9 Recent experimental studies have confirmed the long held clinical suspicion that hypertension also accelerates AAA expansion. 10,11 By controlling blood pressure, it seems logical that l3-blockers might inhibit AAA expansion. Limited clinical data exists regarding the influence of l3-adrenergic blockade upon the expansion rate of AAA. In a small retrospective study, Leach and coworkers2 monitored 27 patients with AAA, 12 of whom were undergoing l3-blocker therapy, over a mean period of 34 months. The expansion rate for the latter group was 0.17 cm/yr; for those not receiving l3-blockers the rate was 0.44 cm/yr. This comparison did not reach statistical significance (p = 0.09). However, rapid aneurysm expansion, which the authors define as a rate more than the mean expansion rate for the entire study (> 0.32 cm/yr), occurred in only 1 of 12 patients receiving l3-blockade (8%) compared with eight of 15 patients (53%) not receiving l3-blockers (p = 0.013). Leach et al. 2 also showed a weak correlation between blood pressure and AAA expansion rate. However, in this study we were unable to demonstrate any significant correlation between systolic, diastolic, mean, or pulse pressures and AAA expansion rate. Furthermore, we could not demonstrate a difference in systolic, diastolic, or mean arterial pressures in patients receiving l3-blockers compared with untreated patients. Unfortunately, other hemodynamic variables affected by l3-blockers such as dp/dt are difficult to routinely assess in a clinical setting and were not investigated in this study. Nevertheless, if l3-blockers do indeed stabilize AAA, the mechanism is not clearly related to their hemodynamic effects. Experimental evidence suggests that the effect of propranolol on limiting aneurysm formation may be independent of changes in blood pressure and dp /dt, and may involve changes in aortic wall connective tissue metabolism. Brophy and coworkers 3 demonstrated that propranolol could delay the formation of aneurysms in the blotchy mouse, a strain that develops spontaneous aortic aneurysms. They subsequently showed increases of 147% in skin elastin and 54% in skin collagen when the mice were treated with

730 Gadowski, Pilcher, and Ricci JOURNAL OF VASCULAR SURGERY April 1994 propranolol. 12 Although this suggested to the authors a direct effect of propranolol treatment on tissue matrix metabolism, no direct study of aortic tissue was undertaken nor were hemodynamic parameters measured. Simpson and Boucek 13 have investigated drug effects in turkeys fed B-aminopropionitrile fumarate (BAPN), an inhibitor of lysyl oxidase, the enzyme that catalyzes an essential step in the formation of elastin and collagen cross-links. Broad-breasted white turkeys that spontaneously develop hypertension, tachycardia, and atherosclerosis by 5 weeks of age also develop dissecting aneurysms when fed BAPN. BAPN has no hemodynamic effects, decreases aortic ring tensile strength and results in a death from aneurysm rupture of 44%. Nonspecific /3-blockade with propranolol decreased heart rate, blood pressure, and dp /dt while increasing aortic tensile strength and limiting aortic rupture to 1%. The /31 selective drugs practolol and sotalol had similar hemodynamic effects but resulted in 13 % and 5 % rupture rates, respectively. On the basis of these differences, the authors suggest a direct action of propranolol on aortic elastin and collagen. Other studies from this group have suggested a direct dose-response relationship between propranolol and aortic tensile strength and increased elastin crosslinking, but not between the /31 selective drugs and these characteristics. S Similarly, in our study, propranolol was associated with a decreased AAA expansion rate when compared with the /31 selective drugs metoprolol and atenolol. It remains to be shown whether this phenomenon is attributable to the /32 effects of propranolol on vascular smooth muscle or some other unique property of the drug. Inhibiting /32 receptors in bronchiolar smooth muscle may exacerbate obstructive pulmonary disease, which is a potential disadvantage in the use of propranolol versus the /31 cardioselective antagonists. Our data confirm the work by Leach et al. 2 with a larger patient population and lend support to the hypothesis that /3-blockade retards AAA expansion. Although the overall mean expansion rate differences between the treatment groups did not achieve statistical significance at the 5% level, significantly fewer patients in group II (/3-blocker) had expansion rates above the population mean of 0.38 cm/yr. Additionally, among large AAA, expansion rate in patients treated with /3-blocker was significantly less than in untreated patients. Interestingly, our data also suggest that in patients not receiving /3-blockers, AAA expand more rapidly as they enlarge. This phenomenon has been previously observed in work by Nevitt et al.,14 and in a recent study by Limet et al. 1S In the latter study, the authors suggest that AAA expansion is actually better described by an exponential growth curve rather than a linear curve. Rapid AAA expansion (> 0.5 cm/yr) has been believed to represent AAA instability and a high risk for rupture. 16 Those large AAA (> 5 cm) that went on to rupture had a significantly greater expansion rate than those that did not rupture. Therefore it intuitively follows that a reduction in the expansion rate by /3-blocker therapy might ultimately decrease the rate of rupture of large AAA. Although the incidence of rupture was lower in the /3-blocker group, this difference did not achieve statistical significance, possibly caused by a relatively small sample size. In summary our study of 121 patients with AAA shows a significantly reduced expansion rate in patients with large AAA (2: 5 cm) receiving /3-adren ergic antagonists. The clinical utility of /3-blockade in AAA could be important in the nonoperative treatment in patients with serious medical risks or contraindications for surgery. Although /3-blockade has clear benefit in patients with acute aortic dissection, the possible benefit of preventing AAA rupture remains to be shown. To clearly define the effect of /3-blockade in AAA expansion and to provide better criteria for clinical indications further study is needed. The results presented here combined with those previously published emphasize the need for a randomized clinical trial. REFERENCES 1. Ernst CB. Current concepts: abdominal aortic aneurysm. N Eng J Med 1993;328:1167-72. 2. Leach SD, Toole AL, Stern H, DeNatale RW, Tilson MD. Effect of j3-adrenergic blockade on the growth rate abdominal aortic aneurysms. Arch Surg 1988;123:606-9. 3. Brophy CM, Tilson JE, Tilson MD. Propranolol delays the formation of aneurysms in the male Blotchy mouse. J Surg Res 1988;44:687-91. 4. Simpson CF, Boucek RJ, Noble NL. Influence of do, 1-, and dl-propranolol and practolol on j3-aminopropionirtiie induced aortic rupture of turkeys. Toxicol Appl Pharmacal 1976;38: 169-75. 5. Boucek RJ, Gunja-Smith Z, Noble NL, Simpson CF. Modulation by propranolol of the Iysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey. Biochem Pharmacol 1983;32:275-80. 6. Siaiby J, Ricci MA, Gadowski GR, Hendley ED, Pilcher DB. Propranolol reduces the size of aortic aneurysms in hypertensive rats. Surg For 1993;44:343-4. 7. Wheat MW, Jr. Acute dissecting aneurysms of the aorta: diagnosis and treatment. Am Heart J 1988;99:373-87. 8. Pyeritz RE. Propranolol retards aortic root dilation in the Marfan syndrome. Circulation 1983;68(suppl 3):365.

JOURNAL OF VASCULAR SURGERY Volume 19, Number 4 Gadowski, Pilcher, and Ricci 731 9. SpittelJA, Jr. Hypertension and arterial aneurysms. J Am Coli CardioI1983;1:533-40. 10. Gadowski GR, Ricci MA, Hendley ED, Pilcher DB. Hypertension accelerates the growth of experimental aortic aneurysms. J Surg Res 1993;54:431-6. 11. Andijar S, Osborne-Pellegrin M, Coutard M, Jean-Baptiste M. Arterial hypertension and aneurysmal dilation. Kidney Int 1992;41 (suppl 37):S-61-66. 12. Brophy CM, Tilson JE, Tilson MD. Propranolol stimulates the crosslinking of matrix components in skin from the aneurysm prone Blotchy mouse. J Surg Res 1989;46:330-2. 13. Simpson CF, Boucek RJ. The J3-aminopropionitrile fed turkey: a model for detecting potential drug action on arterial tissue. Cardiovasc Res 1983;17:26-32. 14. Nevitt MP, Ballard DJ, Hallett JW, Jr. Prognosis of abdominal aortic aneurysms: a population based study. N Eng J Med 1989;321:1009-14. 15. Limet R, Sakalihassan N, Adelin A. Determination of the expansion rate and incidence of rupture of abdominal aortic aneurysms. J VAse SURG 1991;14:540-8. 16. Bernstein EF, Dilley RB, Goldberger LE, Gosink BB, Leopold GR. Growth rates of small abdominal aortic aneurysms. Surgery 1976;80:765-73. Submitted June 15, 1993; accepted Aug 26, 1993. BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF VASCULAR SURGERY for 1994 are available to subscribers only. They may be purchased from the publisher at a cost of $76.00 for domestic, $97.32 for Canadian, and $92.00 for international subscribers for Vol. 19 (January to June) and Vol. 20 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Subscription Services, Mosby-Year Book, Inc., 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, USA. In the United States call toll free (800)325-4177, ext. 4351. In Missouri or foreign countries call (314)453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.