Skip to main content
SpringerLink
Log in

Analyse kardiovaskulärer Erkrankungen nach der Upload-Phase mit intravitrealem Ranibizumab oder Bevacizumab bei Patienten mit exsudativer altersbedingter Makuladegeneration

Analysis of cardiovascular diseases after the upload phase with intravitreal ranibizumab and bevacizumab in patients with exudative age-related macular degeneration

  • Originalien
  • Published:
Der Ophthalmologe Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Nach wie vor wird das Risiko systemischer, insbesondere kardiovaskulärer Risiken durch die intravitreale Therapie mittels VEGF („vascular endothelial growth factor“)-Inhibitoren diskutiert.

Patienten und Methoden

Bei 111 Patienten der Universitätsmedizin Göttingen mit exsudativer altersbedingter Makuladegeneration (AMD) unter IVOM (intravitreale okuläre Medikamentengabe)-Therapie mittels Bevacizumab und Ranibizumab wurden die kardiovaskulären Risikofaktoren und Erkrankungen vor Beginn der Therapie dokumentiert und über den Zeitraum der Upload-Phase mithilfe von Fragebögen das Auftreten von kardiovaskulären Ereignissen prospektiv erhoben.

Ergebnisse

Bei 5 von 111 Patienten trat eine Angina pectoris auf, und bei 6 Patienten musste die Blutdruckmedikation erhöht werden. Es ergab sich kein Unterschied zwischen Bevacizumab und Ranibizumab. Ein bereits kardiovaskulär vorerkrankter Patient erlitt während der Upload-Phase einen Schlaganfall, es konnten keine thrombembolischen Ereignisse bei den anderen Patienten beobachtet werden.

Schlussfolgerungen

Bei geringer Fallzahl, aber prospektiver Erhebung konnte während der Upload-Phase mit den VEGF-Inhibitoren Ranibizumab und Bevacizumab unter Berücksichtigung der Altersgruppe und der Vorerkrankungen kein erhöhtes Risiko für kardiovaskuläre Ereignisse nachgewiesen werden.

Abstract

Background

The intravitreal administration of vascular endothelial growth factor (VEGF) inhibitors is the gold standard in the treatment of exudative age-related macular degeneration (AMD) but the possible risks of systemic, particularly cardiovascular side effects are still discussed.

Patients and methods

We prospectively followed 111 patients at the University Hospital in Göttingen with exudative AMD and intravitreal ocular treatment with bevacizumab and ranibizumab during the upload phase of 3 months using a questionnaire for documentation of possible cardiovascular events.

Results

In 5 out of 111 patients angina pectoris was observed and in 6 patients the antihypertensive medication had to be increased. No differences were found between bevacizumab and ranibizumab. A patient with pre-existing cardiovascular diseases suffered a stroke in the upload phase but no thromboembolic events were observed in the other patients.

Conclusion

In this small but prospective clinical study no increased risk for cardiovascular events during the upload phase of the VEGF inhibitors ranibizumab and bevacizumab could be detected when taking the age and pre-existing cardiovascular diseases into consideration.

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

Literatur

  1. Andersen JT, Pehrson R, Tolmachev V, Daba MB, Abrahmsén L, Ekblad C (2011) Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain. J Biol Chem 286(7):5234–5241

    Article  CAS  PubMed  Google Scholar 

  2. AVASTIN (bevacizumab) solution for intravenous infusion prescribing information. http://www.gene.com/download/pdf/avastin_prescribing.pdf. Zugegriffen: März 2014

  3. Avery R, Castellarin A, Steinle N, Dhoot D, Pieramici D, See R, Couvillion S, Nasir M, Rabena M, Le K, Maia M, Visich J (2014) Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 98:1636–1641

    Article  PubMed  PubMed Central  Google Scholar 

  4. Berg K, Pedersen T, Sandvik L, Bragadóttir R (2015) Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to lucas treat-and-extend protocol. Ophthalmology 122:146–152

    Article  PubMed  Google Scholar 

  5. Biagi C, Conti V, Montanaro N, Melis M, Buccellato E, Donati M, Covezzoli A, Amato R, Pazzi L, Venegoni M, Vaccheri A, Motola D (2014) Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions. Eur J Clin Pharmacol 70:1505–1512

    Article  CAS  PubMed  Google Scholar 

  6. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG (2009) A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 116:1731–1739

    Article  PubMed  Google Scholar 

  7. Bressler NM, Bressler SB, West SK, Fine SL, Taylor HR (1989) The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 107(6):847–852

    Article  CAS  PubMed  Google Scholar 

  8. Choueiri TK, Mayer EL, Je Y, Rosenberg JE, Nguyen PL, Azzi GR, Bellmunt J, Burstein HJ, Schutz FAB (2011) Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 29:632–638

    Article  CAS  PubMed  Google Scholar 

  9. Dafer RM, Schneck M, Friberg TR, Jay WM (2007) Intravitreal ranibizumab and bevacizumab: a review of risk. Semin Ophthalmol 22(3):201–204

    Article  PubMed  Google Scholar 

  10. Duan Y, Mo J, Klein R, Scott IU, Lin HM, Caulfield J, Patel M, Liao D (2007) Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans. Ophthalmology 114:732–737

    Article  PubMed  Google Scholar 

  11. Evans JR (2001) Risk factors for age-related macular degeneration. Prog Retin Eye Res 20:227–253

    Article  CAS  PubMed  Google Scholar 

  12. Ferrara N (2001) Role of vascular endothelial growth factorin regulation of physiological angionesis. Am J Physiol Cell Physiol 280:C1358–C1366

    CAS  PubMed  Google Scholar 

  13. Fung AE, Rosenfeld PJ, Reichel E (2006) The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 90(11):1344–1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu CC, Ho JD, Lin HC (2010) Neovascular age-related macular degeneration and the risk of stroke: a 5-year population-based follow-up study. Stroke 41(4):613–617

    Article  PubMed  Google Scholar 

  15. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colon cancer. N Engl J Med 350(23):2335–2342

    Article  CAS  PubMed  Google Scholar 

  16. Kernt M, Neubauer AS, Kampik A (2007) Intravitreal bevacizumab (Avastin®) is safe in terms of intraocular and blood pressure. Acta Ophthalmol Scand 85:119–120

    Article  CAS  PubMed  Google Scholar 

  17. Kernt M, Welge-Lüssen U, Yu A, Neubauer AS, Kampik A (2007) Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells. Ophthalmologe 104(11):965–971

    Article  CAS  PubMed  Google Scholar 

  18. Kim JH, Kim JH, Lee YM, Ahn EM, Kim KW, Yu YS (2009) Decursin inhibits retinal neovascularization via suppression of VEGFR-2 activation. Mol Vis 15:1868–1875

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Klein BE, Klein R, Linton KL (1992) Prevalence of age-related lens maculopathy: the Beaver Dam Eye Study. Ophthalmology 99:933–943

    Article  CAS  PubMed  Google Scholar 

  20. Klein R, Klein B, Franke T (1993) The relationship of cardiovascular disease and its risk factors to age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 100(3):406–414

    Article  CAS  PubMed  Google Scholar 

  21. Klein R, Klein B, Tomany S, Cruickshanks K (2003) The association of cardiovascular disease with the long-term incidence of age-related maculopathy. Ophthalmology 110:1273–1280, 636–643

    Article  PubMed  Google Scholar 

  22. Klein R, Klein B, Tomany S, Cruickshanks K (2003) Association of emphysema, gout and inflammatory markers with long-term incidence of age-related maculopathy. Arch Ophthalmol 121:674–678

    Article  PubMed  Google Scholar 

  23. Klein R, Klein B, Tomany S, Wong T (2004) The relation of microvascular characteristics to age-related eye disease: the Beaver Dam Eye Study. Am J Ophthalmol 137:435–444

    Article  PubMed  Google Scholar 

  24. Klein R, Klein B, Knudtson M, Meuer S, Swift M, Gangnon R (2007) Fifteen-Year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 114:253–262

    Article  PubMed  Google Scholar 

  25. Krebs I, Schmetterer L, Boltz A, Told R, Vécsei-Marlovits V, Egger S, Schönherr U, Haas A, Ansari-Shahrezaei S, Binder S, for the MANTA Research Group (2013) A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol 97:266–271

    Article  PubMed  Google Scholar 

  26. Michels S, Rosenfeld PJ (2005) Treatment of neovascular age-related macular degeneration with Ranibizumab/Lucentis®. Klin Monatsbl Augenheilkd 222:480–484

    Article  CAS  PubMed  Google Scholar 

  27. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS (2005) Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 112(6):1035–1047

    Article  PubMed  Google Scholar 

  28. Mitchell RA (1993) Prevalence of age related macular degeneration in persons aged 50 years and over resident in Australia. J Epidemiol Community Health 47(1):42–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Moshfeghi AA, Rosenfeld PJ, Puliafito CA, Michels S, Marcus EN, Lenchus JD, Venkatraman AS (2006) Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 113:2002.e1–e12

    Article  Google Scholar 

  30. Novák J, Novák M, Kruzliak P (2014) Vascular endothelial growth factor inhibitor-induced hypertension: from pathophysiology to prevention and treatment based on long-acting nitric oxide donors. Am J Hypertens 27(1):3–13

    Article  PubMed  Google Scholar 

  31. Ranpura V, Hapani S, Chuang J, Wu S (2010) Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 49(3):287–297

    Article  CAS  PubMed  Google Scholar 

  32. Ratner M (2004) Genentech discloses safety concers over Bevacizumab. Nat Biotechnol 22:1198

    Article  CAS  PubMed  Google Scholar 

  33. Rosenfeld PJ, Rich RM, Lalwani GA (2006) Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am 19(3):361–372

    PubMed  Google Scholar 

  34. Schmid K, Bachmann L, Fäs L, Kessels A, Job O, Thiel M (2014) Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 99:141–146

    Article  PubMed  Google Scholar 

  35. Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK, Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK (2011) Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol 22(6):1404–1412

    Article  CAS  PubMed  Google Scholar 

  36. Solé-Auró A, Michaud PC, Hurd M, Crimmins E (2015) Disease incidence and mortality among older Americans and Europeans. Demography 52(2):593–611. doi:10.1007/s13524-015-0372-7

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sun C, Klein R, Wong TY (2009) Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. Ophthalmology 116(10):1913–1919

    Article  PubMed  Google Scholar 

  38. Ternant D, Paintaud G (2005) Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther 5(Suppl 1):S37–S47

    Article  CAS  PubMed  Google Scholar 

  39. The CATT Research Group (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364(20):1897–1908

    Article  PubMed Central  Google Scholar 

  40. The IVAN Study Investigators (2012) Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration. Ophthalmology 119:1399–1141

    Article  Google Scholar 

  41. Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD (2004) Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Stud. Arch Ophthalmol 122:750–757

    Article  PubMed  Google Scholar 

  42. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT (1995) The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 102(2):205–210

    Article  CAS  PubMed  Google Scholar 

  43. Vingerling JR, Klaver CC, Hofman A, de Jong PT (1995) Epidemiology of age-related maculopathy. Epidemiol Rev 17:347–360

    CAS  PubMed  Google Scholar 

  44. Wang J, Rochtchina E, Lee A, Chia E, Smith W, Cumming R, Mitchell P (2007) Ten-Year incidence and progression of age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology 114:92–98

    Article  PubMed  Google Scholar 

  45. Wong LJ, Desai RU, Jain A, Feliciano D, Moshfeghi DM, Sanislo SR, Blumenkranz MS (2008) Surveillance for potential adverse events associated with the use of intravitreal bevacizumab for retinal and choroidal vascular disease. Retina 28(8):1151–1158

    Article  PubMed  Google Scholar 

  46. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zachary I, Mathur A, Yla-Herttuala S, Martin J (2000) Vascular protection: a novel nonangiogenic cardiovascular role for vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 20(6):1512–1520

    Article  CAS  PubMed  Google Scholar 

  48. Zehetner C, Bechrakis NE, Stattin M, Kirchmair R, Ulmer H, Kralinger MT, Kieselbach GF (2015) Systemic counterregulatory response of placental growth factor levels to intravitreal aflibercept therapy. Invest Ophthalmol Vis Sci 56(5):3279–3286

    Article  CAS  PubMed  Google Scholar 

  49. Zerbib J, Delcourt C, Puche N, Querques G, Cohen SY, Sahel J, Korobelnik JF, Le Goff M, Souied EH (2014) Risk factors for exudative age-related macular degeneration in a large French case-control study. Graefes Arch Clin Exp Ophthalmol 252:899–907

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Augenheilkunde, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Deutschland

    C. Fischer, K. Schäfer & H. Hoerauf

  2. Immundiagnostik AG, Bensheim, Deutschland

    T. Dschietzig

  3. Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité – Universitätsmedizin Berlin, Campus Mitte, Berlin, Deutschland

    T. Dschietzig

Authors
  1. C. Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Dschietzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Hoerauf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Fischer.

Ethics declarations

Interessenkonflikt

H. Hoerauf – Berater- bzw. Gutachtertätigkeit, bezahlte Mitarbeit: Novartis, Bayer, Alcon, Allergan; Beratung, Honorare, Reisekosten: Novartis, Allergan, Alcon, Heidelberg Engineering; Unterstützung von Forschungsprojekten und klinischen Studien, finanzielle Zuwendung: Novartis, Bayer, Heidelberg Engineering, Allergan, Alcon. T. Dschietzig – Beratung Honorare, Reisekosten: Novartis. C. Fischer und K. Schäfer geben an, dass kein Interessenkonflikt besteht.

Alle im vorliegenden Manuskript beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen beteiligten Patienten liegt eine Einverständniserklärung vor.

Additional information

C. Fischer und K. Schäfer arbeiteten gleichwertig an der vorliegenden Arbeit.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fischer, C., Schäfer, K., Dschietzig, T. et al. Analyse kardiovaskulärer Erkrankungen nach der Upload-Phase mit intravitrealem Ranibizumab oder Bevacizumab bei Patienten mit exsudativer altersbedingter Makuladegeneration. Ophthalmologe 113, 589–595 (2016). https://doi.org/10.1007/s00347-015-0214-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00347-015-0214-4

Schlüsselwörter

Keywords

Search

Navigation