A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair
Amy E Hackmann, Brian G Rubin, Luis A Sanchez, Patrick A Geraghty, Robert W Thompson, John A Curci, Amy E Hackmann, Brian G Rubin, Luis A Sanchez, Patrick A Geraghty, Robert W Thompson, John A Curci
Abstract
Background: The late durability of endovascular aneurysm repair (EVAR) has been limited by progressive aortic degeneration believed to be mediated by matrix metalloproteases (MMP). The goal of this study was to evaluate the effect of a MMP inhibitor, doxycycline, on EVAR.
Methods: Patients undergoing EVAR were randomized to doxycycline (100 mg twice daily) or placebo for 6 months following the procedure. Clinical data, blood samples, and computed tomography (CT) scans were obtained preoperatively, postoperatively (blood only), and at 1- and 6-month follow-up. Forty-four subjects were analyzed based on intention-to-treat.
Results: Plasma MMP-9 decreased significantly below baseline in the doxycycline (N = 20) treated patients at 6 months (-16.4% +/- 20.7%, P < .05) while there was a nonsignificant increase in the placebo (N = 24) group (128.1% +/- 73.5%). This was primarily related to changes between 1 and 6 months. In patients with endoleaks at 6 months, plasma MMP-9 increased in 83% of the placebo treated patients, but in only 14% of the doxycycline treated group (P < .03). Among endoleak-free patients with AneuRx or Excluder endografts, doxycycline treatment resulted in greater decreases in maximum aortic diameter than placebo treatment (-13.3% +/- 3.3% vs -3.8% +/- 3.0%, P < .05). Furthermore, doxycycline treatment significantly reduced the aortic neck dilatation at 6 months in Excluder treated patients.
Conclusion: There is evidence of persistent MMP release representing ongoing aortic degradation after endografting which can be inhibited by doxycycline therapy. In analyses based on the endograft used, treatment with doxycycline also demonstrated evidence of increased aortic dimensional stability, a surrogate marker for long-term success of EVAR. Although encouraging, these results require confirmation in larger patient populations. Doxycycline should undergo more thorough evaluation as a potential adjuvant treatment to improve the results of EVAR, particularly in certain subgroups.
Figures
![Figure 1. Study enrollment data](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2564857/bin/nihms67806f1.jpg)
![Figure 2. Correlation between pre-operative MMP-9 and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2564857/bin/nihms67806f2.jpg)
![Figure 3. Effect of doxycycline treatment on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2564857/bin/nihms67806f3.jpg)
Figure 4. Effect of doxycycline treatment on…
Figure 4. Effect of doxycycline treatment on aortic neck diameter among patients with Excluder endograft
Figure 5. Effect of doxycycline therapy on…
Figure 5. Effect of doxycycline therapy on the circulating levels of MMP-9
The mean levels…
- New results with 100 Excluder cases.Ghotbi R, Sotiriou A, Mansur R. Ghotbi R, et al. J Cardiovasc Surg (Torino). 2010 Aug;51(4):475-80. J Cardiovasc Surg (Torino). 2010. PMID: 20671631
- Analysis of EndoAnchors for endovascular aneurysm repair by indications for use.de Vries JP, Ouriel K, Mehta M, Varnagy D, Moore WM Jr, Arko FR, Joye J, Jordan WD Jr; Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry ANCHOR Trial. de Vries JP, et al. J Vasc Surg. 2014 Dec;60(6):1460-7.e1. doi: 10.1016/j.jvs.2014.08.089. Epub 2014 Oct 3. J Vasc Surg. 2014. PMID: 25284629
- Determination of Endograft Apposition, Position, and Expansion in the Aortic Neck Predicts Type Ia Endoleak and Migration After Endovascular Aneurysm Repair.Schuurmann RCL, van Noort K, Overeem SP, van Veen R, Ouriel K, Jordan WD Jr, Muhs BE, 't Mannetje YW, Reijnen MMPJ, Fioole B, Ünlü Ç, Brummel P, de Vries JPM. Schuurmann RCL, et al. J Endovasc Ther. 2018 Jun;25(3):366-375. doi: 10.1177/1526602818764616. Epub 2018 Mar 26. J Endovasc Ther. 2018. PMID: 29575993
- The use of endoanchors in repair EVAR cases to improve proximal endograft fixation.Avci M, Vos JA, Kolvenbach RR, Verhoeven EL, Perdikides T, Resch TA, Espinosa G, Böckler D, De Vries JP. Avci M, et al. J Cardiovasc Surg (Torino). 2012 Aug;53(4):419-26. J Cardiovasc Surg (Torino). 2012. PMID: 22854521
- Influence of different self-expanding stent-graft types on remodeling of the aortic neck after endovascular aneurysm repair.Oberhuber A, Schwarz A, Hoffmann MH, Klass O, Orend KH, Mühling B. Oberhuber A, et al. J Endovasc Ther. 2010 Dec;17(6):677-84. doi: 10.1583/10-3172.1. J Endovasc Ther. 2010. PMID: 21142472
- Metalloproteinases and their inhibitors in neurological disease.Lopez-Navarro ER, Gutierrez J. Lopez-Navarro ER, et al. Naunyn Schmiedebergs Arch Pharmacol. 2022 Jan;395(1):27-38. doi: 10.1007/s00210-021-02188-x. Epub 2021 Dec 1. Naunyn Schmiedebergs Arch Pharmacol. 2022. PMID: 34851449 Review.
- Aortic Aneurysms, Chronic Kidney Disease and Metalloproteinases.Andreucci M, Provenzano M, Faga T, Michael A, Patella G, Mastroroberto P, Serraino GF, Bracale UM, Ielapi N, Serra R. Andreucci M, et al. Biomolecules. 2021 Jan 30;11(2):194. doi: 10.3390/biom11020194. Biomolecules. 2021. PMID: 33573220 Free PMC article. Review.
- Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?Dalhoff A. Dalhoff A. Infection. 2021 Feb;49(1):29-56. doi: 10.1007/s15010-020-01536-y. Epub 2020 Dec 23. Infection. 2021. PMID: 33367978 Free PMC article. Review.
- A Novel Hybrid Drug Delivery System for Treatment of Aortic Aneurysms.Yoshimura K, Aoki H, Teruyama C, Iijima M, Tsutsumi H, Kuroda S, Hamano K. Yoshimura K, et al. Int J Mol Sci. 2020 Aug 2;21(15):5538. doi: 10.3390/ijms21155538. Int J Mol Sci. 2020. PMID: 32748844 Free PMC article.
- Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections.Grant JS, Stafylis C, Celum C, Grennan T, Haire B, Kaldor J, Luetkemeyer AF, Saunders JM, Molina JM, Klausner JD. Grant JS, et al. Clin Infect Dis. 2020 Mar 3;70(6):1247-1253. doi: 10.1093/cid/ciz866. Clin Infect Dis. 2020. PMID: 31504345 Free PMC article. Review.
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Aged
- Aorta / drug effects*
- Aorta / enzymology
- Aorta / pathology
- Aorta / surgery
- Aortic Aneurysm, Abdominal / diagnostic imaging
- Aortic Aneurysm, Abdominal / drug therapy*
- Aortic Aneurysm, Abdominal / enzymology
- Aortic Aneurysm, Abdominal / surgery
- Aortography / methods
- Biomarkers / blood
- Blood Vessel Prosthesis Implantation / adverse effects
- Blood Vessel Prosthesis Implantation / instrumentation*
- Blood Vessel Prosthesis*
- Dilatation, Pathologic
- Doxycycline / therapeutic use*
- Female
- Foreign-Body Migration / enzymology
- Foreign-Body Migration / etiology
- Humans
- Inflammation Mediators / blood
- Male
- Matrix Metalloproteinase 9 / blood
- Matrix Metalloproteinase Inhibitors*
- Prosthesis Failure
- Protease Inhibitors / therapeutic use*
- Time Factors
- Tomography, X-Ray Computed
- Treatment Outcome
- Biomarkers
- Inflammation Mediators
- Matrix Metalloproteinase Inhibitors
- Protease Inhibitors
- Matrix Metalloproteinase 9
- Doxycycline
- Full Text Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4. Effect of doxycycline treatment on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2564857/bin/nihms67806f4.jpg)
Figure 5. Effect of doxycycline therapy on…
Figure 5. Effect of doxycycline therapy on the circulating levels of MMP-9
The mean levels…
- New results with 100 Excluder cases.Ghotbi R, Sotiriou A, Mansur R. Ghotbi R, et al. J Cardiovasc Surg (Torino). 2010 Aug;51(4):475-80. J Cardiovasc Surg (Torino). 2010. PMID: 20671631
- Analysis of EndoAnchors for endovascular aneurysm repair by indications for use.de Vries JP, Ouriel K, Mehta M, Varnagy D, Moore WM Jr, Arko FR, Joye J, Jordan WD Jr; Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry ANCHOR Trial. de Vries JP, et al. J Vasc Surg. 2014 Dec;60(6):1460-7.e1. doi: 10.1016/j.jvs.2014.08.089. Epub 2014 Oct 3. J Vasc Surg. 2014. PMID: 25284629
- Determination of Endograft Apposition, Position, and Expansion in the Aortic Neck Predicts Type Ia Endoleak and Migration After Endovascular Aneurysm Repair.Schuurmann RCL, van Noort K, Overeem SP, van Veen R, Ouriel K, Jordan WD Jr, Muhs BE, 't Mannetje YW, Reijnen MMPJ, Fioole B, Ünlü Ç, Brummel P, de Vries JPM. Schuurmann RCL, et al. J Endovasc Ther. 2018 Jun;25(3):366-375. doi: 10.1177/1526602818764616. Epub 2018 Mar 26. J Endovasc Ther. 2018. PMID: 29575993
- The use of endoanchors in repair EVAR cases to improve proximal endograft fixation.Avci M, Vos JA, Kolvenbach RR, Verhoeven EL, Perdikides T, Resch TA, Espinosa G, Böckler D, De Vries JP. Avci M, et al. J Cardiovasc Surg (Torino). 2012 Aug;53(4):419-26. J Cardiovasc Surg (Torino). 2012. PMID: 22854521
- Influence of different self-expanding stent-graft types on remodeling of the aortic neck after endovascular aneurysm repair.Oberhuber A, Schwarz A, Hoffmann MH, Klass O, Orend KH, Mühling B. Oberhuber A, et al. J Endovasc Ther. 2010 Dec;17(6):677-84. doi: 10.1583/10-3172.1. J Endovasc Ther. 2010. PMID: 21142472
- Metalloproteinases and their inhibitors in neurological disease.Lopez-Navarro ER, Gutierrez J. Lopez-Navarro ER, et al. Naunyn Schmiedebergs Arch Pharmacol. 2022 Jan;395(1):27-38. doi: 10.1007/s00210-021-02188-x. Epub 2021 Dec 1. Naunyn Schmiedebergs Arch Pharmacol. 2022. PMID: 34851449 Review.
- Aortic Aneurysms, Chronic Kidney Disease and Metalloproteinases.Andreucci M, Provenzano M, Faga T, Michael A, Patella G, Mastroroberto P, Serraino GF, Bracale UM, Ielapi N, Serra R. Andreucci M, et al. Biomolecules. 2021 Jan 30;11(2):194. doi: 10.3390/biom11020194. Biomolecules. 2021. PMID: 33573220 Free PMC article. Review.
- Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?Dalhoff A. Dalhoff A. Infection. 2021 Feb;49(1):29-56. doi: 10.1007/s15010-020-01536-y. Epub 2020 Dec 23. Infection. 2021. PMID: 33367978 Free PMC article. Review.
- A Novel Hybrid Drug Delivery System for Treatment of Aortic Aneurysms.Yoshimura K, Aoki H, Teruyama C, Iijima M, Tsutsumi H, Kuroda S, Hamano K. Yoshimura K, et al. Int J Mol Sci. 2020 Aug 2;21(15):5538. doi: 10.3390/ijms21155538. Int J Mol Sci. 2020. PMID: 32748844 Free PMC article.
- Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections.Grant JS, Stafylis C, Celum C, Grennan T, Haire B, Kaldor J, Luetkemeyer AF, Saunders JM, Molina JM, Klausner JD. Grant JS, et al. Clin Infect Dis. 2020 Mar 3;70(6):1247-1253. doi: 10.1093/cid/ciz866. Clin Infect Dis. 2020. PMID: 31504345 Free PMC article. Review.
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Aged
- Aorta / drug effects*
- Aorta / enzymology
- Aorta / pathology
- Aorta / surgery
- Aortic Aneurysm, Abdominal / diagnostic imaging
- Aortic Aneurysm, Abdominal / drug therapy*
- Aortic Aneurysm, Abdominal / enzymology
- Aortic Aneurysm, Abdominal / surgery
- Aortography / methods
- Biomarkers / blood
- Blood Vessel Prosthesis Implantation / adverse effects
- Blood Vessel Prosthesis Implantation / instrumentation*
- Blood Vessel Prosthesis*
- Dilatation, Pathologic
- Doxycycline / therapeutic use*
- Female
- Foreign-Body Migration / enzymology
- Foreign-Body Migration / etiology
- Humans
- Inflammation Mediators / blood
- Male
- Matrix Metalloproteinase 9 / blood
- Matrix Metalloproteinase Inhibitors*
- Prosthesis Failure
- Protease Inhibitors / therapeutic use*
- Time Factors
- Tomography, X-Ray Computed
- Treatment Outcome
- Biomarkers
- Inflammation Mediators
- Matrix Metalloproteinase Inhibitors
- Protease Inhibitors
- Matrix Metalloproteinase 9
- Doxycycline
- Full Text Sources
- Medical
- Miscellaneous
![Figure 5. Effect of doxycycline therapy on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2564857/bin/nihms67806f5.jpg)
Source: PubMed