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Original Research |

Doxycycline for Stabilization of Abdominal Aortic Aneurysms: A Randomized Trial

C. Arnoud Meijer, MD; Theo Stijnen, PhD; Martin N.J.M. Wasser, MD, PhD; Jaap F. Hamming, MD, PhD; J. Hajo van Bockel, MD, PhD; Jan H.N. Lindeman, MD, PhD, for the Pharmaceutical Aneurysm Stabilisation Trial Study Group*
[+] Article and Author Information

* For a list of collaborators for the Pharmaceutical Aneurysm Stabilisation Trial Study Group, see Appendix 1.


From Leiden University Medical Center, Leiden, the Netherlands.

Note: All authors had full access to all of the data in the study that were stored on the servers of the data center of the surgical department and take responsibility for the integrity of the data and accuracy of the data analysis.

Acknowledgment: The authors thank the members of the data center of the surgical department of the Leiden University Medical Center for logistic support during patient enrollment and follow-up: Marjolijn Duijm-de Carpentier, Wil Planje, Linda Verhoeff, and Richard E. Zwaan. They also thank the local trial coordinators and research nurses for their dedication on site: Maria Nooren, Karin de Vlaming, Thea G.C.M Laghuwitz, Margreth Huschka, and Anja Brussee. In addition, they thank Linda M. van der Hulst for her help with pharmaceutical matters; Elma Meershoek-Klein Kranenbarg and Chantal te Marvelde for design and development of the database; Rob van Wissen for his advice and technical support of the ultrasonogram measurements; and Roula Tsonaka for her help with the sensitivity analyses.

Grant Support: By the Netherlands Organisation for Health Research and Development (grant 40-41200-98-052) and the NutsOhra Fund (project SNO-T-0701-061).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2533.

Reproducible Research Statement: Study protocol, statistical code, and data set: Available from Dr. Lindeman (e-mail, Lindeman@LUMC.nl).

Requests for Single Reprints: Jan H.N. Lindeman, MD, PhD, Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail, Lindeman@LUMC.nl.

Current Author Addresses: Drs. Meijer, Hamming, van Bockel, and Lindeman: Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

Dr. Stijnen: Department of Medical Statistics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

Dr. Wasser: Department of Radiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

Author Contributions: Conception and design: T. Stijnen, M.N.J.M. Wasser, J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Analysis and interpretation of the data: C.A. Meijer, T. Stijnen, J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Drafting of the article: C.A. Meijer, T. Stijnen, J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Critical revision of the article for important intellectual content: C.A. Meijer, T. Stijnen, M.N.J.M. Wasser, J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Final approval of the article: C.A. Meijer, T. Stijnen, M.N.J.M. Wasser, J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Provision of study materials or patients: J.F. Hamming, J.H. van Bockel.

Statistical expertise: T. Stijnen.

Obtaining of funding: J.F. Hamming, J.H. van Bockel, J.H.N. Lindeman.

Administrative, technical, or logistic support: C.A. Meijer, J.H. van Bockel, J.H.N. Lindeman.

Collection and assembly of data: C.A. Meijer, J.H.N. Lindeman.


Ann Intern Med. 2013;159(12):815-823. doi:10.7326/0003-4819-159-12-201312170-00007
Text Size: A A A

Background: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans.

Objective: To test whether doxycycline inhibits AAA progression in humans.

Design: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345)

Setting: 14 Dutch hospitals.

Patients: 286 patients with small AAAs between October 2008 and June 2011.

Intervention: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months.

Measurements: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery.

Results: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan–Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, −0.4% [CI, −9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92).

Limitations: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect.

Conclusion: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair.

Primary Funding Source: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.

Figures

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Appendix Figure.

Bland–Altman plot showing the agreement between paired ultrasonogram readings when testing the reproducibility.

AAA = abdominal aortic aneurysm.

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Figure 1.

Study flow diagram.

For the primary and secondary outcomes, data were available for all 286 patients. Adverse effects included aneurysm rupture, death, and other serious adverse effects as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; treatment-emergent adverse effects; and other reasons for study withdrawal. Growth estimates were calculated with linear mixed model analysis that was based on all available diameter measurements from the 286 patients in the trial, including those who had surgery or withdrew from the study for other reasons.

* One patient who died after rupture is listed under rupture only.

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Figure 2.

Estimated mean growth curves based on linear mixed model analysis for aneurysm growth during 18-mo follow-up.

Bars represent upper- and lower-limit mean growth; data and P values are presented in Table 2.

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Figure 3.

Kaplan–Meier estimates for cumulative incidence of elective surgery during 18-mo follow-up.

Among patients randomly assigned to receive either doxycycline or placebo, no benefit with respect to elective surgery or time to repair was found. Twenty-one patients in the doxycycline group had elective surgery vs. 22 in the placebo group. Censored for other reasons for study withdrawal.

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