- Email: [email protected]
Subconjunctival bevacizumab for iris neovascularisation – Authors' reply
Correspondence
that the maximum concentration of bevacizumab achieved in the iris and ciliary body is much higher when the drug is administered via the intravitreal (109 192·6 ng/g) than the subconjunctival (1418·7 ng/g) route.5 Why the authors chose to use the subconjunctival approach to give bevacizumab is not clear to us. If a subconjunctival approach was deemed preferable because of the presence of dense cataract restricting the view of the fundus, then presumably a smaller molecule such as ranibizumab would have had better ocular penetration. In animal studies, investigators detected high concentrations of both intravitreal and subconjunctival bevacizumab in the plasma. 5 The patient described in Rao and colleagues’ study had total occlusion of the right carotid artery and history of transient ischaemic attacks and could be at an increased risk of thromboembolic events after treatment with subconjuntival bevacizumab. Although subconjunctival bevacizumab might be useful as an interim treatment for rubeosis or neovascular glaucoma, most cases would need more definitive treatment such as retinal photocoagulation or glaucoma surgery. As described by Rao and co workers, the effect of subconjunctival bevacizumab was transient and three injections had to be given in the course of 6 months to sustain the beneficial effect. A more definitive option would be to consider glaucoma drainage devices or transcleral cyclophotocoagulation (if visual prognosis is deemed to be poor) once the intraocular pressure comes under control to avoid the systemic risks of repeated bevacizumab injections. We declare no competing interests.
*Vivien C Yip, Leonard W Yip, Augustinus Laude [email protected] National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 308433, Singapore (VCY, LWY, AL)
450
1
2
3
4
5
Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–80. Chalam KV, Gupta SK, Grover S, Brar VS, Agarwal S. Intracameral avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 2008; 18: 255–62. Zaki AA. Farid SF. Subconjunctival bevacizumab for corneal neovascularisation. Acta Ophthalmol 2010; 88: 868–71. Rao RC, Choudhry N, Apte RS. Regression of iris neovascularisation secondary to diabetic retinopathy with subconjunctival anti-VEGF therapy. Lancet Diabetes Endocrinol 2014; 2: 182. Hiroyuki N, Fumio S, Noriyuki K et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 2009; 50: 4807–13.
Authors’ reply Yip and colleagues1 discuss the use of subconjunctival bevacizumab for iris neovascularisation in our patient with diabetic retinopathy and ocular ischaemic syndrome. The patient’s complete clinical history, some of which could not be included because of space restrictions, informed our decision-making process. The patient had posterior segment silicone oilfill after previous multiple diabetic tractional retinal detachment vitrectomy surgeries. Cataract and silicone oil-fill precluded intravitreal antivascular endothelial growth factor treatment, pan retinal photocoagulation, and pars plana placement of a glaucoma drainage device. The smaller molecular weight of ranibizumab versus bevacizumab might suggest that subconjunctival ranibizumab has better intraocular penetration. However, no report has described the comparative kinetics of intraocular penetration of these agents from the subconjunctival space in animal models or patients. Unexpectedly, despite its smaller size, ranibizumab was not as effective as bevacizumab in inducing corneal neovascularisation regression in rabbits. 1 Although the iris and ciliary body concentration of subconjunctival bevacizumab is
100 times less than intravitreal treatment, our case and another report of three cases showed regression of iris neovascularisation with subconjunctival bevacizumab treatment. 2 By contrast with the positive treatment response in these four patients, no report, to our knowledge, has described subconjunctival delivery of ranibizumab for iris neovascularisation—although we would predict ranibizumab to have a similar response. In the USA, ranibizumab is 40 times more expensive than bevacizumab. 3 Even if the patient had health insurance—which she did not—off-label use of subconjunctival ranibizumab for iris neovascularisation would need substantial out-of-pocket expense (roughly US$2000 per ranibizumab injection vs $50 for bevacizumab). The patient had previously tolerated many injections of intravitreal bevacizumab in her other eye as treatment for diabetic macular oedema without experiencing ocular or systemic complications. Injection of intracameral bevacizumab was considered, but the risk of hyphaema in view of florid iris neovascularisation was thought to be too high. The patient elected to proceed with subconjunctival bevacizumab treatment after discussion of the ocular and systemic risks of subjconjunctival and intracameral antivascular endothelial growth factor treatment, risk:benefit ratio of transcleral cyclophotocoagulation, cost of bevacizumab versus ranibizumab, and treatment history of the other eye. After being followed up for 6 months, investigators recorded partial regression of iris neovascularisation; the patient had no known ocular or system complications secondary to subconjunctival bevacizumab. Should the patient agree to consent, or if neovascular glaucoma became refractory to subconjunctival bevacizumab, we have not excluded future
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
Correspondence
transcleral cyclophotocoagulation. Such treatment is associated with significant rates of hypotony and vision loss, and—less commonly— phthisis bulbi.4, 5 The source had no role in the content of the report, but RCR is required to acknowledge the following grant NEI K12EY022299. We declare no competing interests.
*Rajesh C Rao, Netan Choudhry, Rajendra S Apte [email protected] W K Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA (RCR); Herzig Eye Institute, Toronto, ON, Canada (NC); Washington University School of Medicine, St Louis, MO, USA (RSA) 1
2
3
4
5
Akar EE, Oner V, Kucukerdonmez C, Aydin Akova Y. Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model. Int J Ophthalmol 2013; 6: 136–40. Ryoo NK, Lee EJ, Kim TW. Regression of iris neovascularization after subconjunctival injection of bevacizumab. Korean J Ophthalmol 2013; 27: 299–303. Steinbrook R. The price of sight: ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006; 355: 1409–12. Nabili S, Kirkness CM. Trans-scleral diode laser cyclophoto-coagulation in the treatment of diabetic neovascular glaucoma. Eye (Lond) 2004; 18: 352–56. Pokroy R, Greenwald Y, Pollack A, et al. Visual loss after transscleral diode laser cyclophotocoagulation for primary open-angle and neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2008; 39: 22–29.
Should a pilot on insulin really fly? In their Comment, Simons and colleagues1 proposed that European aeromedical regulations for insulinrequiring diabetic pilots should be changed. They use the example of the few insulin-treated pilots flying in Canada to show low risk in aviation. The changes proposed by the authors are not medically justified, not ethically and practically admissible, and could jeopardise flight safety. Investigators have established the incidence of mild hypoglycaemia and severe hypoglycaemia in real life in insulin-treated people with diabetes.2 Hypoglycaemia leads to cognitive impairment, behavioural changes,
and psychomotor abnormalities. 3 Studies of people with diabetes driving cars can be used to show that a blood glucose lower than 3·1 mmol/L (hypoglycaemia) is dangerous for flight safety;1 however, the decrease in performance begins before signs of neuroglycopenia, might not be detected by the individual with diabetes, and can last a long time after the end of symptoms.4 The modified UK civil aviation protocol requires a HbA1C of 6·5–8·0% for pilots,1 which is, in our view, not acceptable. Epidemiological data show that a high HbA1C is not associated with a low risk of hypoglycaemia in people with type 2 diabetes.5 In addition, for ethical reasons, health must be given top priority and professional pilots should have HbA1C lower than 7%, as recommended to reduce their risk of long-term complications. Of note, the original UK protocol includes a warning to make pilots fully aware of this risk. The protocol allows only one severe hypoglycaemia episode in the previous 5 years (with no restriction on frequent mild hypoglycaemias);1 however, because of this long grounding period, we question which motivated pilot would declare such episodes? The protocol also states that to maintain blood glucose of 5–15 mmol/L during flights, eligible pilots must regularly control their glycaemia in the cockpit, monitoring glucose intake and enacting a rapid landing as necessary. 1 In case of flight-operational priority, they should ingest carbohydrates to avoid a possible hypoglycaemia.1 Copilots must check glucometer values, which causes issues with medical confidentiality and responsibility in case of a crash. If passengers were questioned and protocols really applied, then would they agree to this arrangement and accept that their flight could be delayed, cancelled, or rerouted because of the high or low blood sugar of their pilot?
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
In this proposed protocol, experts of aviation medicine will check all glycaemia values during and between flights to look for out-of-limits concentration values.1 And yet, we know that the constraints and lifestyle of airline pilots favour hypoglycaemic episodes. As a key principle of aviation medicine, the duties of a pilot should not worsen a pilot’s condition. Finally, in our view, experts of aviation medicine should agree that some medical situations cannot justify a determination to declare a pilot fit to fly. One argument to accept pilots taking insulin in cockpits could be that accidents fortunately do not result from a sudden incapacitation of only the pilot, but from combinations with other circumstances (no copilot on board, tricky stages of flight, etc). But if we accept this notion, in the future, will pilots with any disorder with the potential to jeopardise flight safety be able to fly because there is a specific protocol to manage in-flight complications? We declare that we have no competing interests.
*O Manen, V Martel, R Germa, JF Paris, E Perrier [email protected] French Main Military Aeromedical Centre, Clamart, France (OM, VM, EP); Aeromedical Licensing Authority, Paris, France (RG); and Aeromedical Centre of Roissy, Roissy, France (JFP) 1
2
3
4
5
Simons R, Koopman H, Osinga M. Would you fly with a pilot on insulin? Lancet Diabetes Endocrinol 2013; published online Dec 9. http://dx.doi.org/10.1016/ S2213-8587(13)70197-9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50: 1140–47. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013; 36: 1384–95. Evans ML, Pernet A, Lomas J, Jones J, Amiel SA. Delay in onset awareness of acute hypoglycemia and of restoration of cognitive performance during recovery. Diabetes Care 2000; 23: 893–97. Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ 2010; 340: b5444.
Published Online March 26, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70056-7 For the original policy from the UK Civil Aviation Authority see http://www.caa.co.uk/ docs/2499/20140127DiabetesCertificationGuidanceJan2014v3. pdf
451
that the maximum concentration of bevacizumab achieved in the iris and ciliary body is much higher when the drug is administered via the intravitreal (109 192·6 ng/g) than the subconjunctival (1418·7 ng/g) route.5 Why the authors chose to use the subconjunctival approach to give bevacizumab is not clear to us. If a subconjunctival approach was deemed preferable because of the presence of dense cataract restricting the view of the fundus, then presumably a smaller molecule such as ranibizumab would have had better ocular penetration. In animal studies, investigators detected high concentrations of both intravitreal and subconjunctival bevacizumab in the plasma. 5 The patient described in Rao and colleagues’ study had total occlusion of the right carotid artery and history of transient ischaemic attacks and could be at an increased risk of thromboembolic events after treatment with subconjuntival bevacizumab. Although subconjunctival bevacizumab might be useful as an interim treatment for rubeosis or neovascular glaucoma, most cases would need more definitive treatment such as retinal photocoagulation or glaucoma surgery. As described by Rao and co workers, the effect of subconjunctival bevacizumab was transient and three injections had to be given in the course of 6 months to sustain the beneficial effect. A more definitive option would be to consider glaucoma drainage devices or transcleral cyclophotocoagulation (if visual prognosis is deemed to be poor) once the intraocular pressure comes under control to avoid the systemic risks of repeated bevacizumab injections. We declare no competing interests.
*Vivien C Yip, Leonard W Yip, Augustinus Laude [email protected] National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 308433, Singapore (VCY, LWY, AL)
450
1
2
3
4
5
Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–80. Chalam KV, Gupta SK, Grover S, Brar VS, Agarwal S. Intracameral avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 2008; 18: 255–62. Zaki AA. Farid SF. Subconjunctival bevacizumab for corneal neovascularisation. Acta Ophthalmol 2010; 88: 868–71. Rao RC, Choudhry N, Apte RS. Regression of iris neovascularisation secondary to diabetic retinopathy with subconjunctival anti-VEGF therapy. Lancet Diabetes Endocrinol 2014; 2: 182. Hiroyuki N, Fumio S, Noriyuki K et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 2009; 50: 4807–13.
Authors’ reply Yip and colleagues1 discuss the use of subconjunctival bevacizumab for iris neovascularisation in our patient with diabetic retinopathy and ocular ischaemic syndrome. The patient’s complete clinical history, some of which could not be included because of space restrictions, informed our decision-making process. The patient had posterior segment silicone oilfill after previous multiple diabetic tractional retinal detachment vitrectomy surgeries. Cataract and silicone oil-fill precluded intravitreal antivascular endothelial growth factor treatment, pan retinal photocoagulation, and pars plana placement of a glaucoma drainage device. The smaller molecular weight of ranibizumab versus bevacizumab might suggest that subconjunctival ranibizumab has better intraocular penetration. However, no report has described the comparative kinetics of intraocular penetration of these agents from the subconjunctival space in animal models or patients. Unexpectedly, despite its smaller size, ranibizumab was not as effective as bevacizumab in inducing corneal neovascularisation regression in rabbits. 1 Although the iris and ciliary body concentration of subconjunctival bevacizumab is
100 times less than intravitreal treatment, our case and another report of three cases showed regression of iris neovascularisation with subconjunctival bevacizumab treatment. 2 By contrast with the positive treatment response in these four patients, no report, to our knowledge, has described subconjunctival delivery of ranibizumab for iris neovascularisation—although we would predict ranibizumab to have a similar response. In the USA, ranibizumab is 40 times more expensive than bevacizumab. 3 Even if the patient had health insurance—which she did not—off-label use of subconjunctival ranibizumab for iris neovascularisation would need substantial out-of-pocket expense (roughly US$2000 per ranibizumab injection vs $50 for bevacizumab). The patient had previously tolerated many injections of intravitreal bevacizumab in her other eye as treatment for diabetic macular oedema without experiencing ocular or systemic complications. Injection of intracameral bevacizumab was considered, but the risk of hyphaema in view of florid iris neovascularisation was thought to be too high. The patient elected to proceed with subconjunctival bevacizumab treatment after discussion of the ocular and systemic risks of subjconjunctival and intracameral antivascular endothelial growth factor treatment, risk:benefit ratio of transcleral cyclophotocoagulation, cost of bevacizumab versus ranibizumab, and treatment history of the other eye. After being followed up for 6 months, investigators recorded partial regression of iris neovascularisation; the patient had no known ocular or system complications secondary to subconjunctival bevacizumab. Should the patient agree to consent, or if neovascular glaucoma became refractory to subconjunctival bevacizumab, we have not excluded future
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
Correspondence
transcleral cyclophotocoagulation. Such treatment is associated with significant rates of hypotony and vision loss, and—less commonly— phthisis bulbi.4, 5 The source had no role in the content of the report, but RCR is required to acknowledge the following grant NEI K12EY022299. We declare no competing interests.
*Rajesh C Rao, Netan Choudhry, Rajendra S Apte [email protected] W K Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA (RCR); Herzig Eye Institute, Toronto, ON, Canada (NC); Washington University School of Medicine, St Louis, MO, USA (RSA) 1
2
3
4
5
Akar EE, Oner V, Kucukerdonmez C, Aydin Akova Y. Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model. Int J Ophthalmol 2013; 6: 136–40. Ryoo NK, Lee EJ, Kim TW. Regression of iris neovascularization after subconjunctival injection of bevacizumab. Korean J Ophthalmol 2013; 27: 299–303. Steinbrook R. The price of sight: ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006; 355: 1409–12. Nabili S, Kirkness CM. Trans-scleral diode laser cyclophoto-coagulation in the treatment of diabetic neovascular glaucoma. Eye (Lond) 2004; 18: 352–56. Pokroy R, Greenwald Y, Pollack A, et al. Visual loss after transscleral diode laser cyclophotocoagulation for primary open-angle and neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2008; 39: 22–29.
Should a pilot on insulin really fly? In their Comment, Simons and colleagues1 proposed that European aeromedical regulations for insulinrequiring diabetic pilots should be changed. They use the example of the few insulin-treated pilots flying in Canada to show low risk in aviation. The changes proposed by the authors are not medically justified, not ethically and practically admissible, and could jeopardise flight safety. Investigators have established the incidence of mild hypoglycaemia and severe hypoglycaemia in real life in insulin-treated people with diabetes.2 Hypoglycaemia leads to cognitive impairment, behavioural changes,
and psychomotor abnormalities. 3 Studies of people with diabetes driving cars can be used to show that a blood glucose lower than 3·1 mmol/L (hypoglycaemia) is dangerous for flight safety;1 however, the decrease in performance begins before signs of neuroglycopenia, might not be detected by the individual with diabetes, and can last a long time after the end of symptoms.4 The modified UK civil aviation protocol requires a HbA1C of 6·5–8·0% for pilots,1 which is, in our view, not acceptable. Epidemiological data show that a high HbA1C is not associated with a low risk of hypoglycaemia in people with type 2 diabetes.5 In addition, for ethical reasons, health must be given top priority and professional pilots should have HbA1C lower than 7%, as recommended to reduce their risk of long-term complications. Of note, the original UK protocol includes a warning to make pilots fully aware of this risk. The protocol allows only one severe hypoglycaemia episode in the previous 5 years (with no restriction on frequent mild hypoglycaemias);1 however, because of this long grounding period, we question which motivated pilot would declare such episodes? The protocol also states that to maintain blood glucose of 5–15 mmol/L during flights, eligible pilots must regularly control their glycaemia in the cockpit, monitoring glucose intake and enacting a rapid landing as necessary. 1 In case of flight-operational priority, they should ingest carbohydrates to avoid a possible hypoglycaemia.1 Copilots must check glucometer values, which causes issues with medical confidentiality and responsibility in case of a crash. If passengers were questioned and protocols really applied, then would they agree to this arrangement and accept that their flight could be delayed, cancelled, or rerouted because of the high or low blood sugar of their pilot?
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
In this proposed protocol, experts of aviation medicine will check all glycaemia values during and between flights to look for out-of-limits concentration values.1 And yet, we know that the constraints and lifestyle of airline pilots favour hypoglycaemic episodes. As a key principle of aviation medicine, the duties of a pilot should not worsen a pilot’s condition. Finally, in our view, experts of aviation medicine should agree that some medical situations cannot justify a determination to declare a pilot fit to fly. One argument to accept pilots taking insulin in cockpits could be that accidents fortunately do not result from a sudden incapacitation of only the pilot, but from combinations with other circumstances (no copilot on board, tricky stages of flight, etc). But if we accept this notion, in the future, will pilots with any disorder with the potential to jeopardise flight safety be able to fly because there is a specific protocol to manage in-flight complications? We declare that we have no competing interests.
*O Manen, V Martel, R Germa, JF Paris, E Perrier [email protected] French Main Military Aeromedical Centre, Clamart, France (OM, VM, EP); Aeromedical Licensing Authority, Paris, France (RG); and Aeromedical Centre of Roissy, Roissy, France (JFP) 1
2
3
4
5
Simons R, Koopman H, Osinga M. Would you fly with a pilot on insulin? Lancet Diabetes Endocrinol 2013; published online Dec 9. http://dx.doi.org/10.1016/ S2213-8587(13)70197-9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50: 1140–47. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013; 36: 1384–95. Evans ML, Pernet A, Lomas J, Jones J, Amiel SA. Delay in onset awareness of acute hypoglycemia and of restoration of cognitive performance during recovery. Diabetes Care 2000; 23: 893–97. Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ 2010; 340: b5444.
Published Online March 26, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70056-7 For the original policy from the UK Civil Aviation Authority see http://www.caa.co.uk/ docs/2499/20140127DiabetesCertificationGuidanceJan2014v3. pdf
451