Skip to main content
SpringerLink
Log in

Adverse Gastrointestinal Events with Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors: Nested Case–Control Study

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

An Erratum to this article was published on 22 August 2014

Abstract

Background

Intravenous administration of vascular endothelial growth factor (VEGF)-inhibiting drugs is associated with adverse gastrointestinal (GI) events. Clinical trials of VEGF inhibitors used for the treatment of retinal diseases have suggested higher risks of adverse GI events among patients treated with bevacizumab. However, population-based studies have been lacking.

Objective

Our objective was to assess risks for GI adverse events associated with intravitreal injections of VEGF-inhibiting drugs.

Methods

We conducted a population-based, nested case–control study of 114,427 older adults in Ontario, Canada, with retinal disease identified between 1 November 2005 and 30 April 2011. Of these, 3,582 cases were admitted to hospital or assessed in an emergency department for GI adverse events. Controls were matched to cases on the basis of age, sex, and outcome history.

Results

Patients experiencing adverse events were equally as likely as matched controls to have been exposed to bevacizumab or ranibizumab. Adjusted odds ratios for bevacizumab were 1.05 (95 % confidence interval [CI] 0.69–1.61) for upper GI ulceration, 1.29 (95 % CI 0.86–1.96) for diverticular disease, 1.49 (95 % CI 0.84–2.63) for pancreatitis, 0.82 (95 % CI 0.53–1.29) for cholelithiasis, and 1.45 (95 % CI 0.67–3.12) for cholecystitis. For ranibizumab they were 1.25 (95 % CI 0.88–1.77) for upper GI ulceration, 1.12 (95 % CI 0.83–1.52) for diverticular disease, 0.85 (95 % CI 0.51–1.40) for pancreatitis, 0.77 (95 % CI 0.53–1.11) for cholelithiasis, and 0.83 (95 % CI 0.44–1.56) for cholecystitis. Results were similar when the analysis was restricted to patients only exposed to a single type of VEGF inhibitor.

Conclusions

In this population-based study, intravitreal injections of bevacizumab and ranibizumab were not associated with increased risks of adverse GI events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, et al. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration—a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115:1837–46.

    Article  PubMed  Google Scholar 

  2. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432–44.

    Article  CAS  PubMed  Google Scholar 

  3. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–31.

    Article  CAS  PubMed  Google Scholar 

  4. CATT Research Group, Martin D, Maguire M, Ying G, Grunwald J, Fine S, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897–908.

    Article  CAS  PubMed  Google Scholar 

  5. Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102.e1–1112.e1.

    Google Scholar 

  6. Elman MJ, Bressler NM, Qin H, Beck RW, 3rd Ferris FL, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609–14.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Kamba T, McDonald D. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Tuñón J, Ruiz-Moreno JM, Martín-Ventura JL, Blanco-Colio LM, Lorenzo O, Egido J. Cardiovascular risk and antiangiogenic therapy for age-related macular degeneration. Surv Ophthalmol. 2009;54:339–48.

    Article  PubMed  Google Scholar 

  9. Snider KL, Maitland ML. Cardiovascular toxicities: clues to optimal administration of vascular endothelial growth factor signaling pathway inhibitors. Targeted Oncol. 2009;4:67–76.

    Article  Google Scholar 

  10. Csaky K, Do DV. Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol. 2009;148:647–56.

    Article  CAS  PubMed  Google Scholar 

  11. Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–9.

    Article  PubMed  Google Scholar 

  12. Choueiri TK, Mayer EL, Je Y, Rosenberg JE, Nguyen PL, Azzi GR, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol. 2011;29:632–8.

    Article  CAS  PubMed  Google Scholar 

  13. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277.

    Article  CAS  PubMed  Google Scholar 

  14. Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38.

    Article  CAS  PubMed  Google Scholar 

  15. Taugourdeau-Raymond S, Rouby F, Default A, Jean-Pastor MJ, French Network of Pharmacovigilance C. Bevacizumab-induced serious side-effects: a review of the french pharmacovigilance database. Eur J Clin Pharmacol. 2012;68:1103–7.

    Article  CAS  PubMed  Google Scholar 

  16. Fuloria J. Safety profiles of current antiangiogenic therapies for metastatic colorectal cancer. Onco Targets Ther. 2012;5:133–42.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  CAS  PubMed  Google Scholar 

  18. CATT Research Group, Martin DF, Maguire MG, Fine SL, Ying G, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388–98.

    Article  PubMed Central  PubMed  Google Scholar 

  19. IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119:1399–411.

    Article  PubMed  Google Scholar 

  20. Cohen D. Roche and Novartis colluded over wet AMD drugs, says Italian regulator. BMJ. 2014;348:g2006.

    Article  PubMed  Google Scholar 

  21. Liew G, Mitchell P. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2007;356:747–8.

    Article  CAS  PubMed  Google Scholar 

  22. Vandenbroucke JP, Psaty BM. Benefits and risks of drug treatments. JAMA. 2008;300:2417–9.

    Article  CAS  PubMed  Google Scholar 

  23. Curtis LH, Hammill BG, Schulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128:1273–9.

    Article  PubMed  Google Scholar 

  24. Campbell RJ, Bell CM, Paterson JM, Bronskill SE, Moineddin R, Whitehead M, et al. Stroke rates after introduction of vascular endothelial growth factor inhibitors for macular degeneration: a time series analysis. Ophthalmology. 2012;119:1604–8.

    Article  PubMed  Google Scholar 

  25. Campbell RJ, Gill SS, Bronskill SE, Paterson JM, Whitehead M, Bell CM. Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study. BMJ. 2012;345:e4203.

    Article  PubMed Central  PubMed  Google Scholar 

  26. French DD, Margo CE. Age-related macular degeneration, anti-vascular endothelial growth factor agents, and short-term mortality: a postmarketing medication safety and surveillance study. Retina. 2011;31:1036–42.

    Article  CAS  PubMed  Google Scholar 

  27. Campbell RJ, Bell CM, Campbell Ed, Gill SS. Systemic effects of intravitreal vascular endothelial growth factor inhibitors. Curr Opin Ophthalmol. 2013;24:197–204.

    Article  PubMed  Google Scholar 

  28. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335:806–8.

    Article  Google Scholar 

  29. Williams JI, Young W. A summary of studies on the quality of health care administration databases in Canada. In: Goel V, Williams JI, Anderson GM, Blackstien-Hirsch P, Fooks C, Naylor CD, eds. Patterns of Health Care in Ontario. The ICES Practice Atlas. 2nd ed. Ottawa: Canadian Medical Association; 1996. pp. 339–345. http://www.ices.on.ca/~/media/Files/Atlases-Reports/1996/Patterns-of-health-care-in-Ontario-2nd-edition/Full%20report.ashx. Accessed 8 May 2014.

  30. Juurlink DN, Preyra C, Croxford R, Chong A, Austin P, Tu J, et al. Canadian Institute for Health Information Discharge Abstract Database: a validation study. ICES Investigative Report. Toronto: Institute for Clinical Evaluative Sciences; 2006. http://www.ices.on.ca/~/media/Files/Atlases-Reports/2006/CIHI-DAD-a-validation-study/Full%20report.ashx. Accessed 8 May 2014.

  31. Gruneir A, Bell CM, Bronskill SE, Schull M, Anderson GM, Rochon PA. Frequency and pattern of emergency department visits by long-term care residents—a population-based study. J Am Geriatr Soc. 2010;58:510–7.

    Article  PubMed  Google Scholar 

  32. Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SLT, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009;169:867.

    Article  PubMed  Google Scholar 

  33. Hux JE, Ivis F, Flintoft V, Bica A. Diabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care. 2002;25:512–6.

    Article  PubMed  Google Scholar 

  34. Cattaruzzi C, Troncon MG, Agostinis L, Garcia Rodriguez LA. Positive predictive value of ICD-9th codes for upper gastrointestinal bleeding and perforation in the Sistema Informativo Sanitario Regionale Database. J Clin Epidemiol. 1999;52:499–502.

    Article  CAS  PubMed  Google Scholar 

  35. Raiford DS, Perez Gutthann S, Garcia Rodriguez LA. Positive predictive value of ICD-9 codes in the identification of cases of complicated peptic ulcer disease in the Saskatchewan Hospital Automated Database. Epidemiology. 1996;7:101–4.

    Article  CAS  PubMed  Google Scholar 

  36. Moores K, Gilchrist B, Carnahan R, Abrams T. A systematic review of validated methods for identifying pancreatitis using administrative data. Pharmacoepidemiol Drug Saf. 2012;21:194–202.

    Article  PubMed  Google Scholar 

  37. Urbach DR, Stukel TA. Rate of elective cholecystectomy and the incidence of severe gallstone disease. CMAJ. 2005;172:1015–9.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ. Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol. 2001;154:854–64.

    Article  CAS  PubMed  Google Scholar 

  39. Bell CM, Hatch WV, Fischer HD, Cernat G, Paterson JM, Gruneir A, et al. Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA. 2009;301:1991.

    Article  CAS  PubMed  Google Scholar 

  40. Breslow N, Day N. Fitting models to continuous data. 82nd ed. France: IARC Scientific Publications; 1987. p. 178–229.

    Google Scholar 

  41. Suissa S. Novel approaches to pharmacoepidemiology study design and statistical analysis. England: Wiley; 2005. p. 811–29.

    Google Scholar 

  42. Breslow N, Lubin J, Marek P, Langholz B. Multiplicative models and cohort analysis. J Am Stat Assoc. 1983;78:1–12.

    Article  Google Scholar 

  43. Essebag V, Platt RW, Abrahamowicz M, Pilote L. Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure. BMC Med Res Methodol. 2005;5:5.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Liddell F, McDonald J, Thomas D. Methods of cohort analysis: appraisal by application to asbestos mining. J R Stat Soc Ser A. 1977;140:469–91.

    Article  Google Scholar 

  45. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–107.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Drazen JM, Curfman GD, Baden LR, Morrissey S. Compounding errors. N Engl J Med. 2012;367:2436–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Contributors

All authors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. RJC drafted the manuscript and approved the final version to be published. SSG, SEB, JMP, MW, EdeLPC, and CMB critically revised the manuscript for important intellectual content. RJC, MW, SEB, SSG, and CMB conducted the statistical analysis. RJC and SSG obtained funding. RJC supervised the study and is the guarantor.

Funding

This study was funded by the Canadian Institutes of Health Research (CIHR) and the Ontario Ministry of Health and Long-Term Care (MOHLTC). The work was also supported by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute funded by the Ontario MOHLTC. RJC is supported by a Clinician Scientist Award from the Southeastern Ontario Academic Medical Organization, which receives funding from the MOHLTC, and holds research grants from the CIHR and the MOHLTC for related work. SSG and SEB are supported by CIHR New Investigator Awards from the Institute of Aging. CMB is supported by a CIHR and Canadian Patient Safety Institute chair in Patient Safety and Continuity of Care.

Data Access and Responsibility

Dr. RJ Campbell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of Interest

RJ Campbell, CM Bell, SE Bronskill, JM Paterson, M Whitehead, EdeL Campbell, and SS Gill have no conflicts of interest.

Role of the Sponsors

The sponsors of this study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit for publication. The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.

Ethical Approval

The study protocol was approved by the Research Ethics Board at Queen’s University, Kingston, Ontario, Canada (file No. 6004374).

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Queen’s University, Kingston, ON, Canada

    Robert J. Campbell & Erica de L. Campbell

  2. Department of Ophthalmology, Hotel Dieu and Kingston General Hospitals, 166 Brock Street, Kingston, ON, K7L 5G2, Canada

    Robert J. Campbell & Erica de L. Campbell

  3. Institute for Clinical Evaluative Sciences (ICES-Central), G1 06, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada

    Robert J. Campbell, Chaim M. Bell, Susan E. Bronskill, J. Michael Paterson, Marlo Whitehead & Sudeep S. Gill

  4. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Chaim M. Bell

  5. Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada

    Chaim M. Bell, Susan E. Bronskill & J. Michael Paterson

  6. Division of Geriatric Medicine, Queen’s University, Kingston, ON, Canada

    Sudeep S. Gill

  7. Division of Geriatric Medicine, St. Mary’s of the Lake Hospital, 340 Union St, Kingston, ON, K7L 5A2, Canada

    Sudeep S. Gill

  8. Institute for Clinical Evaluative Sciences (ICES@Queen’s), Abramsky Hall, Queen’s University, 21 Arch St, Kingston, ON, K7L 3N6, Canada

    Marlo Whitehead

  9. Department of Family Medicine, McMaster University, Hamilton, ON, Canada

    J. Michael Paterson

  10. Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada

    Chaim M. Bell

  11. Department of Medicine, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Chaim M. Bell

Authors
  1. Robert J. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chaim M. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan E. Bronskill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Michael Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marlo Whitehead
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erica de L. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sudeep S. Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert J. Campbell.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campbell, R.J., Bell, C.M., Bronskill, S.E. et al. Adverse Gastrointestinal Events with Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors: Nested Case–Control Study. Drug Saf 37, 723–733 (2014). https://doi.org/10.1007/s40264-014-0211-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-014-0211-6

Keywords

Search

Navigation